Accepted Article
Dehydrated Amnion/Chorion Membrane and Venous Leg Ulcers1
Jaime E. Dickerson, Jr., PhD1,2 and Herbert B. Slade, MD1,3
1
Smith & Nephew, Inc. Fort Worth, TX 2
Dept. of Immunology and Cell Biology University of North Texas Health Science Center Fort Worth, TX 3
Dept. of Pediatrics University of North Texas Health Science Center Fort Worth, TX
Corresponding Author and for Reprints: JED Smith & Nephew, Inc 3909 Hulen St. Fort Worth, TX 76107 (817) 302-3914 [email protected] running head: EpiFix and Venous Leg Ulcers Key Words: amnion, venous leg ulcer, study design
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/wrr.12257 This article is protected by copyright. All rights reserved.
Accepted Article
To the Editor: Thomas Serena, et al. and the EpiFix VLU Study Group have reported what appear to be very good outcomes achieved in the healing of venous leg ulcers (VLU) when treated with dehydrated human amnion/chorion membrane (dHACM) used in conjunction with standard multi-layer compression.1 New approaches are badly needed as many people suffering with VLU are not healed with standard compression therapy alone. While we agree that the use of an extracellular matrix product derived from placental tissues is certainly of interest several aspects of the study design raise concerns that we feel require the results of this study to be interpreted with caution. We offer the following considerations in the spirit of constructive criticism. Our view is that better trial designs with clear conclusions will allow those suffering with VLU to have the best chance of success with advanced therapeutic options. It is well known that between 30% to 75 % of all VLU will respond to standard compression therapy and heal.2 Those VLU that do not respond become chronic and represent the unmet medical need. A novel therapy, such as dHACM, designed to improve upon standard care (i.e. multi-layer compression bandaging) should be tested in the population it is intended to benefit, namely, chronic ulcers that have failed to respond to compression. One way to accomplish this is to employ a run-in period prior to randomization where the rate of healing is monitored under compression alone. VLU that respond during this period should not be randomized ensuring that only the nonresponsive, chronic ulcers are enrolled.3 In this study there was a requirement for ulcers to have been treated for 2 weeks with compression therapy however, inexplicably, there were no exclusions for rapid healers. To the contrary, ulcers that had been non-healing under one year of compression were excluded from the trial. It is also well known that small ulcers heal more rapidly and successfully than large ulcers. The minimum eligible ulcer size is given as 2 cm2 in the published paper but as 5 cm2 in the clinicaltrials.gov posting (NCT01552447). The median size enrolled was 4.4 cm2 for the dHACM group and 4.1 cm2 for compression thus half of the ulcers across the study were 4 cm 2 or less and relatively easy to heal. Taken together, it would seem that the study population likely included small, rapid-healing ulcers and excluded many of the chronic ulcers that were the aim of the study. Our greatest concern lies in the choice of endpoint. The only valid endpoint recognized by the FDA and other regulatory bodies is ulcer closure defined as 100% reepithelialized, without drainage and not requiring a dressing. Moreover, this closure must be confirmed at two subsequent visits, each at two-week intervals. Instead, the This article is protected by copyright. All rights reserved.
Accepted Article
authors chose the surrogate endpoint of 40% wound closure at 4 weeks. While there is some literature suggesting that this may be a good predictor of ultimate healing at 12 or 24 weeks, the same literature acknowledges that it is only correct about 70% of the time.4,5 Taking this 70% accuracy and applying it to the 62% of ulcers achieving a 40% reduction in area by week 4 (.62 x .7), an estimated 43% would have been closed at 12 weeks. As the authors did not validate this endpoint by following the patients for a full 12 weeks, this seems to be the most reasonable conclusion. The problems with this paper are not limited to the study population and the primary endpoint, but also include patient bias and inaccurate wound area measurements. Ulcer pain was a stated secondary endpoint and was assessed using the visual analog scale (VAS). While this is a standard method, it is inherently subjective and therefore susceptible to patient bias. Patients were not blind to treatment and, as noted in the paper, 3 patients randomized to compression alone withdrew from the study because they were unhappy with the treatment assignment suggesting that patients viewed the control group as an inferior treatment. Ulcer area and not closure was the primary endpoint in this trial, therefore there was a critical need for accurate measurement of the ulcers. While ruler measurements may be adequate for “real world” ulcer management, digital wound measurement devices have become the standard in sponsored clinical trials. It is disappointing that area was assessed as length x width using a ruler. While we agree that dHACM is an interesting treatment that may provide a benefit for healing chronic VLU, this has not been demonstrated with any surety in the current trial. Additional studies with the appropriate patient population and appropriate endpoints are needed.
Jaime E. Dickerson, Jr., PhD and Herbert B. Slade, MD
REFERENCES 1. Serena TE, Carter MJ, Le LT, Sabo MJ, DiMarco DT. A multi-center randomized controlled clinical trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multi-layer compression therapy vs. multi-layer compression therapy alone in the treatment of venous leg ulcers. Wound Repair Regen 2014; doi:10.1111/wrr.12227. 2. O’Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane Database Syst Rev 2009; 1: CD000265.
This article is protected by copyright. All rights reserved.
Accepted Article
3. Kirsner RS, Marston, WA, Snyder RJ, Lee TD, Cargill DI, Slade HB. Spray-applied cell therapy with human allogeneic fi broblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2012;380:977–85. 4. Phillips TJ, Machado F, Trout R, Porter J, Olin J, Falanga V. Prognostic indicators in venous ulcers. J Am Acad Dermatol 2000;43:627-30. 5. Gelfend JM, Hoffstad O, Margolis DJ. Surrogate endpoints for the treatment of venous leg ulcers. J Inves Dermatol 2002;119:1420-5.
ACKNOWLEDGEMENTS JED and HBS are employees of Smith & Nephew, Inc.
This article is protected by copyright. All rights reserved.
Dehydrated Amnion/Chorion Membrane and Venous Leg Ulcers1
Jaime E. Dickerson, Jr., PhD1,2 and Herbert B. Slade, MD1,3
1
Smith & Nephew, Inc. Fort Worth, TX 2
Dept. of Immunology and Cell Biology University of North Texas Health Science Center Fort Worth, TX 3
Dept. of Pediatrics University of North Texas Health Science Center Fort Worth, TX
Corresponding Author and for Reprints: JED Smith & Nephew, Inc 3909 Hulen St. Fort Worth, TX 76107 (817) 302-3914 [email protected] running head: EpiFix and Venous Leg Ulcers Key Words: amnion, venous leg ulcer, study design
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/wrr.12257 This article is protected by copyright. All rights reserved.
Accepted Article
To the Editor: Thomas Serena, et al. and the EpiFix VLU Study Group have reported what appear to be very good outcomes achieved in the healing of venous leg ulcers (VLU) when treated with dehydrated human amnion/chorion membrane (dHACM) used in conjunction with standard multi-layer compression.1 New approaches are badly needed as many people suffering with VLU are not healed with standard compression therapy alone. While we agree that the use of an extracellular matrix product derived from placental tissues is certainly of interest several aspects of the study design raise concerns that we feel require the results of this study to be interpreted with caution. We offer the following considerations in the spirit of constructive criticism. Our view is that better trial designs with clear conclusions will allow those suffering with VLU to have the best chance of success with advanced therapeutic options. It is well known that between 30% to 75 % of all VLU will respond to standard compression therapy and heal.2 Those VLU that do not respond become chronic and represent the unmet medical need. A novel therapy, such as dHACM, designed to improve upon standard care (i.e. multi-layer compression bandaging) should be tested in the population it is intended to benefit, namely, chronic ulcers that have failed to respond to compression. One way to accomplish this is to employ a run-in period prior to randomization where the rate of healing is monitored under compression alone. VLU that respond during this period should not be randomized ensuring that only the nonresponsive, chronic ulcers are enrolled.3 In this study there was a requirement for ulcers to have been treated for 2 weeks with compression therapy however, inexplicably, there were no exclusions for rapid healers. To the contrary, ulcers that had been non-healing under one year of compression were excluded from the trial. It is also well known that small ulcers heal more rapidly and successfully than large ulcers. The minimum eligible ulcer size is given as 2 cm2 in the published paper but as 5 cm2 in the clinicaltrials.gov posting (NCT01552447). The median size enrolled was 4.4 cm2 for the dHACM group and 4.1 cm2 for compression thus half of the ulcers across the study were 4 cm 2 or less and relatively easy to heal. Taken together, it would seem that the study population likely included small, rapid-healing ulcers and excluded many of the chronic ulcers that were the aim of the study. Our greatest concern lies in the choice of endpoint. The only valid endpoint recognized by the FDA and other regulatory bodies is ulcer closure defined as 100% reepithelialized, without drainage and not requiring a dressing. Moreover, this closure must be confirmed at two subsequent visits, each at two-week intervals. Instead, the This article is protected by copyright. All rights reserved.
Accepted Article
authors chose the surrogate endpoint of 40% wound closure at 4 weeks. While there is some literature suggesting that this may be a good predictor of ultimate healing at 12 or 24 weeks, the same literature acknowledges that it is only correct about 70% of the time.4,5 Taking this 70% accuracy and applying it to the 62% of ulcers achieving a 40% reduction in area by week 4 (.62 x .7), an estimated 43% would have been closed at 12 weeks. As the authors did not validate this endpoint by following the patients for a full 12 weeks, this seems to be the most reasonable conclusion. The problems with this paper are not limited to the study population and the primary endpoint, but also include patient bias and inaccurate wound area measurements. Ulcer pain was a stated secondary endpoint and was assessed using the visual analog scale (VAS). While this is a standard method, it is inherently subjective and therefore susceptible to patient bias. Patients were not blind to treatment and, as noted in the paper, 3 patients randomized to compression alone withdrew from the study because they were unhappy with the treatment assignment suggesting that patients viewed the control group as an inferior treatment. Ulcer area and not closure was the primary endpoint in this trial, therefore there was a critical need for accurate measurement of the ulcers. While ruler measurements may be adequate for “real world” ulcer management, digital wound measurement devices have become the standard in sponsored clinical trials. It is disappointing that area was assessed as length x width using a ruler. While we agree that dHACM is an interesting treatment that may provide a benefit for healing chronic VLU, this has not been demonstrated with any surety in the current trial. Additional studies with the appropriate patient population and appropriate endpoints are needed.
Jaime E. Dickerson, Jr., PhD and Herbert B. Slade, MD
REFERENCES 1. Serena TE, Carter MJ, Le LT, Sabo MJ, DiMarco DT. A multi-center randomized controlled clinical trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multi-layer compression therapy vs. multi-layer compression therapy alone in the treatment of venous leg ulcers. Wound Repair Regen 2014; doi:10.1111/wrr.12227. 2. O’Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane Database Syst Rev 2009; 1: CD000265.
This article is protected by copyright. All rights reserved.
Accepted Article
3. Kirsner RS, Marston, WA, Snyder RJ, Lee TD, Cargill DI, Slade HB. Spray-applied cell therapy with human allogeneic fi broblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2012;380:977–85. 4. Phillips TJ, Machado F, Trout R, Porter J, Olin J, Falanga V. Prognostic indicators in venous ulcers. J Am Acad Dermatol 2000;43:627-30. 5. Gelfend JM, Hoffstad O, Margolis DJ. Surrogate endpoints for the treatment of venous leg ulcers. J Inves Dermatol 2002;119:1420-5.
ACKNOWLEDGEMENTS JED and HBS are employees of Smith & Nephew, Inc.
This article is protected by copyright. All rights reserved.
