Jump-starting Healing in Venous Leg Ulcers

December 2023

Jump-starting Healing in Venous Leg Ulcers: Should Electrical Stimulation be Considered in Synergy with Compression Therapy?

Editorial Summary High-quality evidence to guide treatment selection of chronic wounds remains lacking. The conventional parallel-arm randomized controlled trial (RCT) model for wound healing studies has limitations. Complete wound closure as a primary endpoint necessitates trials with large sample sizes and prolonged follow-up to achieve adequate statistical power. Such trials are logistically difficult to conduct and may fail to detect more modest treatment effects on wound healing kinetics. Novel metrics have been suggested such as percentage area reduction (PAR) over a 4-week period as a surrogate endpoint. The Food and Drug Administration (FDA) now recognizes PAR as a potential primary endpoint for registrational wound healing trials. PAR following a linear trajectory over time, allows more granular detection of changes in wound healing rate. The self-controlled study model leverages within-patient comparisons, thereby removing potential confounding from between-patient differences. A recent two-phase study of 60 patient with VLUs provides a salient example of this trial design. There was an initial 4-week run-in phase with standard compression therapy alone. Patients were then randomized to continue compression alone or add adjunctive neuromuscular electrical stimulation (NMES) for an additional 4 weeks. The addition of NMES significantly increased the PAR rate compared to compression alone in the same patient cohort (p=0.016). Meanwhile, the control group’s healing rate was unchanged between study phases. These findings demonstrate the feasibility of employing PAR and within-patient controls to efficiently discriminate treatment effects with a limited sample size over a 2-month study duration. The design of wound healing trials has been constrained by overreliance on complete wound closure in large cohorts. Metrics like PAR may provide higher quality evidence to improve wound care.

Novel Approaches in Chronic Wound Healing Research

C

hronic wounds, such as venous leg ulcers (VLUs), impose a substantial global disease burden, with costs exceeding $14 billion annually in the United States alone.1 Yet, there is a dearth of high-quality evidence supporting effective treatments.

The conventional randomized controlled trial (RCT) model employed in wound healing research is fraught with significant limitations that impede the efficient assessment of new therapies. Relying on complete wound closure as the primary outcome necessitates protracted, large-scale trials that pose logistical challenges and frequently fail to detect treatment effects.

Consequently, there have been calls to question this conventional wisdom by embracing alternative metrics and study designs better suited to evaluating healing rates over shorter timeframes.

Shortcomings of the Conventional RCT Model

Dr Keith Gordon Harding Welsh Wound Innovation Centre Pontyclun, United Kingdom

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The customary RCT protocol, which compares complete healing between groups, renders wound healing studies particularly arduous.

The extreme heterogeneity of chronic wounds makes it challenging to match intervention and control groups. Furthermore, the binary nature of the complete healing outcome lacks statistical power compared to quantitative metrics. Thus, demonstrating significant differences between groups mandates following large patient cohorts over many months, leading to exorbitant costs, high dropout rates, and delayed results.

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A systematic review in 2016 identified only two interventions with significant evidence from RCTs - compression and pentoxifylline. Out of thousands of wound therapy studies, merely 48 RCTs met the criteria for quality, and only eight yielded stand-alone findings of effectiveness.

This glaring scarcity of high-quality evidence primarily stems from the methodological challenges intrinsic to the conventional RCT design for wound healing.

Firstly, the cohort comparison framework is unable to overcome inter-patient variations in wound chronicity, size, microbiome, comorbidities, adherence, and other confounding factors. Achieving matching intervention and control groups is unattainable given this heterogeneity. Secondly, complete healing is inherently a binary outcome - either achieved or not. Analyzing such binary data using frequency statistics lacks sensitivity compared to quantitative metrics capable of assessing the degree of change. Thirdly, the protracted follow-up required until a sufficient number of wounds achieve complete closure makes maintaining subject engagement and ensuring consistent assessment over months of treatment challenging.

Alternative Metrics and Study Designs In recent years, experts have proposed addressing these issues by embracing alternative primary endpoints and study models.

Continuous Metrics of Healing Rate Instead of focusing on final complete closure,

Jump-starting Healing in Venous Leg Ulcers: Should Electrical Stimulation be Considered in Synergy with Compression Therapy?

“The primary outcome was PAR over each 4 week phase, rather than final complete closure. The addition of NMES significantly increased the PAR healing rate compared to compression alone for the same patients.”

assessing intermediate outcomes related to the healing rate could offer greater statistical power.

Metrics such as wound area, volume, depth, or diameter changes over a fixed period can be analyzed as continuous variables to detect significant differences with fewer subjects and shorter durations. In 2020, the FDA suggested percentage area reduction (PAR) over 4 weeks as a potential primary endpoint for wound trials.

PAR has been shown to follow a consistent linear trajectory during this timeframe, enabling the quantification of changes in the healing rate after introducing an intervention.

Self-Controlled Study Designs Rather than cohort comparisons, self-controlled models eliminate between-patient confounding by conducting within-patient comparisons.

Each subject serves as their control. Variations include split-body comparisons, contralateral controls, or pre-post-treatment assessments of the same wound. The pre-post self-controlled approach compares the initial baseline healing rate over weeks with a subsequent treatment phase healing rate for the same wound. This allows the detection of differential effects of the new treatment while controlling for all stable patient factors. By removing confounders, self-controlled studies can identify significant differences with far fewer subjects and shorter durations.

Feasibility of New Approaches A VLU trial conducted in 2021 illustrated the potential of employing PAR and a pre-post selfcontrolled design to efficiently discern treatment effects. This trial compared compression alone versus the addition of neuromuscular electrical stimulation (NMES) for 60 patients over an 8 week period. The two-phase structure involved a 4 week control run-in period with compression alone to establish a baseline healing trajectory. Subsequently, patients were randomized to either continue with compression

alone or add NMES for another 4 weeks. By comparing each patient’s healing rate between phases, confounding variables were intrinsically controlled.

The primary outcome was PAR over each 4 week phase, rather than final complete closure.

The addition of NMES significantly increased the PAR healing rate compared to compression alone for the same patients. Meanwhile, the control group’s PAR rate remained unchanged between phases. This exemplifies how a smaller number of patients studied over a shorter duration can yield statistically significant results when using PAR and within-patient controls, as opposed to relying solely on complete healing cohorts.

New Approaches to Overcome Conventional RCT Limitations The implementation of alternative metrics and self-controlled designs can help address the principal limitations of the traditional RCT approach to wound healing research.

Overcoming Patient Heterogeneity

and

Wound

Self-controlled studies eliminate confounding by comparing outcomes for the same patient, thereby controlling for individual characteristics that may influence healing, such as age, comorbidities, nutritional status, microbiome, wound location, etc. Comparing the same wound over time also accounts for differences in chronicity, area, depth, tissue type, vascular supply, and other wound factors.

Enhancing Statistical Quantitative Metrics

Power

with

PAR provides a continuous variable metric that is amenable to sensitive parametric statistics.

This enhances the ability to discern differential effects with smaller sample sizes compared to

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Jump-starting Healing in Venous Leg Ulcers: Should Electrical Stimulation be Considered in Synergy with Compression Therapy?

“The wider adoption of these approaches necessitates addressing certain considerations related to blinding, validity, recruitment, and regulatory acceptance.”

binary complete healing outcomes. Assessing the degree of change, rather than solely focusing on whether healing is achieved or not, better reflects clinical reality where any acceleration of healing is considered beneficial.

Improving Logistical Shorter Trials

Feasibility

with

The 4 week PAR endpoint allows for trials as short as 8 weeks, as opposed to the months required for complete closures. Greater feasibility results from quicker enrollment, better subject retention over weeks rather than months, consistent wound assessment over a shorter period, and faster acquisition of results.

Additional Implementation Considerations The wider adoption of these approaches necessitates addressing certain considerations related to blinding, validity, recruitment, and regulatory acceptance. While blinding the intervention assignment may be challenging when patients can discern whether they are receiving electrical stimulation, it is still possible to blind wound assessments using standardized photography and assessors unaware of the treatment phase. Questions remain regarding the external validity and generalizability of results from self-controlled trials with limited patient populations. Nonetheless, patient cohorts should be sufficiently large to empower the detection of clinically meaningful differences in healing rates, and the inclusion of diverse wound chronicities and types would enhance generalizability.

Efficient recruitment and retention are pivotal for feasibility. Stringent inclusion and exclusion criteria may minimize heterogeneity but could hinder recruitment. These criteria could be broadened to some extent, provided they do not significantly affect the magnitude of withinpatient confounding. While self-controlled designs conceptually require perfect protocol

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adherence and subject retention, modern statistical methods allow for intention-to-treat analysis approaches with these designs.

Finally, regulatory acceptance of PAR and selfcontrolled trials would facilitate implementation.

The FDA’s recent draft guidance endorses PAR over 4 weeks as a potential primary endpoint.

Self-controlled methods are also suitable for evaluating medical devices, as long as patients serve as their own controls.

Conclusion In conclusion, designing wound healing studies using PAR over fixed intervals as the primary outcome and analyzing them within a selfcontrolled model offers significant advantages over traditional complete healing RCTs. This approach finally furnishes the methodology necessary to efficiently generate rigorous evidence on interventions to address the substantial unmet needs of chronic wound patients. Given the immense disease burden, advancing wound care necessitates questioning conventional research practices and embracing more innovative and feasible trial designs. The success of recent trials, such as the NMES study, underscores the promise of new metrics and models. Wider adoption would expedite the acquisition of definitive evidence to enhance care and outcomes for the millions suffering from chronic wounds worldwide.

References 1. Rice JB, Desai U, Cummings AK, et al. Burden of venous leg ulcers in the United States. J Med Econom 2014;17(5):347–356.

2. Neumann HAM, Cornu-Thenard A, Junger M, et al. Evidence-based (S3) guidelines for diagnostics and treatment of venous leg ulcers. J Eur Acad Dermatol Venereol 2016;30:1843– 1875.

3. Nelson EA, Adderley U. Venous leg ulcers. BMJ Clin Evid 2016;2016:1902.

4. Godwin M, Ruhland L, Casson I, et al. Pragmatic controlled clinical trials in primary care: The struggle between external and internal validity. BMC Med Res Methodol 2003;3:28; doi: 10.1186/ 1471-2288-3-28 5. Eckert KA, Carter MJ. Assessing the uncertainty of treatment outcomes in a previous systematic review of venous leg ulcer randomized controlled trials: Additional secondary analysis. Wound Repair Regen 2021;29(2):327–334.

6. Robson MC, Hill DP, Woodske ME, et al. Wound healing trajectories as predictors of effectiveness of therapeutic agents. Arch Surg 2000;135:773– 777.

7. Fife CE, Eckert KA, Carter MJ. Publicly reported wound healing rates: The fantasy and the reality. Adv Wound Care (New Rochelle) 2018;7(3):77–94; doi: 10.1089/wound.2017.0743 8. Gelfand JM, Hoffstad O, Margolis DJ. Surrogate endpoints for the treatment of venous leg ulcers. J Invest Dermatol 2002;119(6):1420–1425; doi: 10.1046/j.1523-1747.2002 9. Polansky M, Van Rijswijk L. Utilizing survival analysis techniques in chronic wound healing studies. Wounds 1994;6:150–158.

10. Gault N, Castan˜eda-Sanabria J, De Rycke Y, et al. Self-controlled designs in pharmacoepidemiology involving electronic healthcare databases: A systematic review. BMC

Jump-starting Healing in Venous Leg Ulcers: Should Electrical Stimulation be Considered in Synergy with Compression Therapy?

Med Res Methodol 17: 25(2017); doi: 10.1186/s12874-016-0278-0 11. FDA Wound Healing Clinical Focus Group. Guidance for industry: Chronic cutaneous ulcer and burn wounds-developing products for treatment. Wound Repair Regen 2001;9(4):258–268.

12. Verma KD, Lewis F, Mejia M. Food and Drug Administration perspective: Advancing product development for nonhealing chronic wounds. Wound Repair Regen 2022;30(3):299–302.

13. Driver VR, Gould LJ, Dotson P, et al. Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community. Wound Repair Regen 2017;25(3): 454–465; doi: 10.1111/wrr.12533 14. Driver VR, Gould LJ, Dotson P, et al. Evidence supporting wound care end points relevant to clinical practice and patients’ lives. Part 2. Literature survey. Wound Repair Regen 2019;27(1): 80–89. 15. Bull RH, Staines KL, Collarte AJ, et al. Measuring progress to healing: A challenge and an opportunity. Int Wound J 2022;19(4):734–740.

16. Aleksandrowicz H, Owczarczyk-Saczonek A, Placek W. Venous leg ulcers: Advanced therapies and new technologies.

Biomedicines 2021;9(11): 1569.

17. Bull RH, Clements D, Collarte AJ, et al. The impact of a new intervention for venous leg ulcers: A within-patient controlled trial. Int Wound J 2023 [Epub ahead of print]; doi: 10.1111/iwj .14107 18. Tucker A, Maass A, Bain D, et al. Augmentation of venous, arterial and microvascular blood supply in the leg by isometric neuromuscular stimulation via the peroneal nerve. Int J Angiol 2010;19(1):e31– e37.

19. Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. BMC Med 2010; 8:18; doi: 10.1186/1741-7015-8-18 20. Sully BG, Julious SA, Nicholl J. A reinvestigation of recruitment to randomised, controlled, multicenter trials: A review of trials funded by two UK funding agencies. Trials 2013;14:166.

21. O’Meara S, Cullum N, Nelson EA, et al. Compression for venous leg ulcers. Cochrane Database Syst Rev 2012;11(11):CD000265; doi: 10.1002/14651858.CD000265.pub3 22. Eaglstein WH, Kirsner RS, Robson MC. Food and Drug Administration (FDA) drug approval end points for chronic cutaneous ulcer studies. Wound Repair Regen 2012;20(6):793–796.

23. Maderal AD, Vivas AC, Eaglstein WH, et al. The FDA and designing clinical trials for chronic cutaneous ulcers. Semin Cell Dev Biol 2012;23(9): 993–999.

24. Darwin E, Tomic-Canic M. Healing chronic wounds: Current challenges and potential solutions. Curr Dermatol Rep 2018;7(4):296– 302; doi: 10.1007/s13671-018-0239-4.

25. Va˚gesjo¨ E, Grigoleit P, Fasth A, et al. How can we optimize the development of drugs for wound healing? Expert Opin Drug Discov 2022;17(2): 93–96. 26. Gagne JJ, Fireman B, Ryan PB, et al. Design considerations in an active medical product safety monitoring system. Pharmacoepidemiol Drug Saf 2012;21(Suppl. 1):32–40.

27. Lehr AM, Jacobs WC, Stellato RK, et al. Methodological aspects of a randomized within-patient concurrent controlled design for clinical trials in spine surgery. Clin Trials 2022;19(3):259–266.

28. Birmingham TB, Marriott KA, Leitch KM, et al. Association between knee load and pain: Withinpatient, between-knees, case-control study in patients with knee osteoarthritis. Arthritis Care Res (Hoboken) 2019;71(5):647–650.

29. Melandri D, De Angelis A, Orioli R, et al. Use of a new hemicellulose dressing (Veloderm) for the treatment of splitthickness skin graft donor sites A within-patient controlled study. Burns 2006; 32(8):964–972.

30. Leshem YA, Wong A, McClanahan D, et al. The effects of common over-the-counter moisturizers on skin barrier function: A randomized, observerblind, within-patient, controlled study. Dermatitis 2020;31(5):309–315.

31. Zhang M, Sun J, Zhu M, et al. Within-patient randomised clinical trial exploring the development of microskin implantation in the treatment of pressure ulcers. Int Wound J 2022; doi: 10.1111/ iwj.14051 32. Wan F. Statistical analysis of two arm randomized pre-post designs with one post-treatment measurement. BMC Med Res Methodol 2021;21(1):150.

33. Gibelli G, Negrini M, Bruno AM, et al. Chronic effects of transdermal nitroglycerin in stable 8 BULL ET AL. angina pectoris: A within-patient, placebocontrolled study. Int J Clin Pharmacol Ther Toxicol 1989;27(9):436–441.

34. Martı´nez-Jime´nez EM, Losa-Iglesias ME, Antolı´nGil MS, et al. Flexor digitorum brevis muscle dry needling changes surface and plantar pressures: A pre-post study. Life (Basel) 2021;11(1):48.

35. Jime´nez-Garcı´a JF, Aguilera-Manrique G, ArboledasBello´n J, et al. The effectiveness of advanced practice nurses with respect to complex chronic wounds in the management of venous ulcers. Int J Environ Res Public Health 2019;16(24):5037.

36. Gault N, Castan˜eda-Sanabria J, Guillo S, et al. Underuse of self-controlled designs in pharmacoepidemiology in electronic healthcare databases: A systematic review. Pharmacoepidemiol Drug Saf 2016;25(4):372–377.

37. Dolibog P, Franek A, Taradaj J, et al. A comparative clinical study on five types of compression therapy in patients with venous leg ulcers. Int J Med Sci 2013;11(1):34–43; doi:10.7150/ijms.7548 38. Sealed Envelope Ltd. Power calculator for binary outcome superiority trial. [Online]. 2012. Available from: https://www. sealedenvelope.com/power/ binary-superiority/ [Last accessed: August 21, 2023].

39. Lucas Y, Niri R, Treuillet S, et al. Wound size imaging: Ready for smart assessment and monitoring. Adv Wound Care (New Rochelle) 2021;10(11):641–661.

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