What has TWO2 taught us about the treatment of chronic diabetic foot ulcers?

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TWO2
Figure 1: The TWO2 study device demonstrating the disposable, inflatable topical oxygen extremity chamber

In a win for proponents of topical oxygen therapy, co-principal investigator of the TWO2 study—a multinational, multicentre, randomised, double-blinded, placebo-controlled trial to evaluate the efficacy of cyclical topical wound oxygen therapy in the treatment of chronic diabetic foot ulcers—Robert Frykberg here outlines how the data from this investigation support the use of adjunctive cyclical pressurised TWO2 therapy healing these wounds. Indeed, the triallists found TWO2 therapy to be superior to optimal standard of care alone, leading to their conclusion of confidence in the treatment.

Oxygen therapies for chronic non-healing wounds have been of interest for many years. While most clinicians are familiar with hyperbaric oxygen therapy (HBOT), topical oxygen therapies (TOT) have been used intermittently for over 50 years. Proponents of HBOT insist that oxygen must be delivered systemically under pressure for there to be any positive effect on tissue regeneration at the wound site. Despite this assumption, the recent clinical trials that attempted to support the superiority of HBOT in healing chronic diabetic foot ulcers (DFU) have all fallen short of their goal.1, 2 Despite study design weaknesses, many initial enrolled patients dropped out of the studies due to adverse events or dissatisfaction with the demands of the therapy that requires many daily visits to a dedicated hyperbaric unit. Topical oxygen therapy, conversely, is a home based therapy that applies oxygen directly to the surface of the wound.

One type of TOT modality—continuous diffusion of oxygen, CDO—delivers a low continuous flow of oxygen through a small catheter that diffuses oxygen over the wound under proprietary dressings.3 The other type of TOT delivers nearly pure oxygen into a disposable extremity chamber that fits onto the affected foot and leg (see Figure 1).4 Specific wound dressings are not required other than that they must be oxygen permeable (or removed during treatment). Uniquely, this device (TWO2) adds cyclical pressurisation to the constant flow of oxygen that allows for reduction of oedema as well as better oxygen diffusion into the wound. Both types of devices have been used clinically with positive outcomes for both DFU as well as venous leg ulcers (VLU).5

We recently reported the results of a very robust randomised trial using the TWO2 device to heal chronic DFUs.6 In this study, patients with diabetes and chronic DFUs were randomised (double blind) to either active TWO2 therapy or sham control therapy, in addition to optimal standard of care. A gradual sequential design was used (n=220) with predetermined interim analyses and stopping rules when 73 and 146 patients had completed the 12-week treatment phase. The primary outcome was the percentage of ulcers in each group achieving 100% healing at 12 weeks.

Our results were quite significant and mandated that we stop enrolment at the first analysis point of 73 completed patients. We found the active TWO2 treated patients to have significantly more healed DFUs, with a closure rate of 41.7% compared with 13.5%. This difference in outcome produced an odds ratio (OR) of 4.57 (97.8% confidence interval [CI] 1.19–17.57; p=0.010). After adjustment for University of Texas Classification (UTC) ulcer grade the odds ratio (97.8% CI) increased to 6.00 (1.44–24.93; p=0.004). Cox proportional hazards modelling, also after adjusting for UTC grade, demonstrated more than 4.5 times the likelihood to heal DFUs over 12 weeks compared to the sham arm with a hazard ratio (HR) of 4.66 (97.8% CI 1.36–15.98; p=0.004). We also evaluated this group at 12 months post enrollment wherein 56% of active arm ulcers were closed compared to 27% of the sham arm ulcers (p=0.013).

TWO2
Robert Frykberg

This sham-controlled, double blind randomised controlled trial confirmed earlier clinical studies4 and demonstrated that, at both 12 weeks and 12 months, adjunctive cyclical pressurised TWO2 therapy was superior in healing chronic DFUs compared to optimal standard of care alone. With this very high quality level-one study, we now have the evidence to confidently support the use of TWO2 therapy for treating chronic DFUs. In concert with prior animal studies7 that demonstrated definite tissue signals to promote wound healing, we corroborated the fact that topically-applied oxygen can indeed lead to improved healing of chronic foot ulcers.  Similar results using TWO2 were obtained when treating chronic VLUs as well.5 As always, however, the success of this adjunctive therapy is predicated upon excellent concurrent wound care including regular debridement and effective offloading.

Robert Frykberg is a diabetic foot and wound care specialist at DM Prevent, Phoenix, USA, and is co-principal investigator of the TWO2 study.

References

  1. Fedorko L, Bowen JM, Jones W, Oreopoulos G, Goeree R, Hopkins RB, et al. Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial. Diabetes Care. 2016 Mar;39(3):392–9.
  2. Santema KTB, Stoekenbroek RM, Koelemay MJW, Reekers JA, van Dortmont LMC, Oomen A, et al. Hyperbaric Oxygen Therapy in the Treatment of Ischemic Lower- Extremity Ulcers in Patients With Diabetes: Results of the DAMO2CLES Multicenter Randomized Clinical Trial. Diabetes Care. 2018 Jan;41(1):112–19.
  3. Niederauer MQ, Michalek JE, Armstrong DG. A Prospective, Randomized, Double-Blind Multicenter Study Comparing Continuous Diffusion of Oxygen Therapy to Sham Therapy in the Treatment of Diabetic Foot Ulcers. J Diabetes Sci Technol. 2017 Sep;11(5):883–91.
  4. Blackman E, Moore C, Hyatt J, Railton R, Frye C. Topical wound oxygen therapy in the treatment of severe diabetic foot ulcers: a prospective controlled study. Ostomy Wound Manage. 2010 Jun;56(6):24–31.
  5. Tawfick WA, Sultan S. Technical and clinical outcome of topical wound oxygen in comparison to conventional compression dressings in the management of refractory nonhealing venous ulcers. Vasc Endovascular Surg. 2013 Jan;47(1):30–7.
  6. Frykberg RG, Franks PJ, Edmonds M, Brantley JN, Teot L, Wild T, et al. A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study. Diabetes Care. 2020 Mar;43(3):616–24.
  7. Fries RB, Wallace WA, Roy S, Kuppusamy P, Bergdall V, Gordillo GM, et al. Dermal excisional wound healing in pigs following treatment with topically applied pure oxygen. Mutat Res. 2005 Nov 11;579(1-2):172–81.

 

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