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

Abstract

OBJECTIVETopical oxygen has been used for the treatment of chronic wounds for more than 50 years. Its effectiveness remains disputed due to the limited number of robust high-quality investigations. The aim of this study was to assess the efficacy of multimodality cyclical pressure Topical Wound Oxygen (TWO2) home care therapy in healing refractory diabetic foot ulcers (DFUs) that had failed to heal with standard of care (SOC) alone. RESEARCH DESIGN AND METHODSPatients with diabetes and chronic DFUs were randomized (double-blind) to either active TWO2 therapy or sham control therapydboth in addition to optimal SOC. The primary outcome was the percentage of ulcers in each group achieving 100% healing at 12 weeks. A group sequential design was used for the study with three predetermined analyses and hard stopping rules once 73, 146, and ultimately 220 patients completed the 12-week treatment phase. RESULTSAt the first analysis point, the active TWO2 arm was found to be superior to the sham arm, 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% CI 1.19, 17.57), P 5 0.010. After adjustment for University of Texas Classification (UTC) ulcer grade, the OR increased to 6.00 (97.8% CI 1.44, 24.93), P 5 0.004. Cox proportional hazards modeling, also after adjustment for UTC grade, demonstrated >4.5 times the likelihood to heal DFUs over 12 weeks compared with the sham arm with a hazard ratio of 4.66 (97.8% CI 1.36, 15.98), P 5 0.004. At 12 months postenrollment, 56% of active arm ulcers were closed compared with 27% of the sham arm ulcers (P 5 0.013). CONCLUSIONSThis sham-controlled, double-blind randomized controlled trial demonstrates that, at both 12 weeks and 12 months, adjunctive cyclical pressurized TWO2 therapy was superior in healing chronic DFUs compared with optimal SOC alone.Clinical trial reg. no. NCT02326337, clinicaltrials .gov. This article contains Supplementary Data online at https://care.diabetesjournals.org/lookup/suppl/

Editorial and Mini-Review: Topical Oxygen Therapy for Diabetic Foot Ulcerations - Avenue Towards New Hope?

“…The same group also reported similar results with continuously diffused topical oxygen therapy in a smaller study along with the intriguing observation that the efficacy of TOT was greater in more chronic and larger wounds [19]. More recently, Frykberg et al have reported that topical wound oxygen therapy applied with pressure varied cyclically was superior (p = 0.007) to sham therapy and standard care in achieving complete wound closure, thereby increasing the likelihood of DFU healing at 12 weeks by up to 4-fold [20].…”

“…In conclusion, TOT appears promising in terms of improving healing rates of DFUs [18][19][20]. Ease of use is a further advantage.…”

“…By contrast, 3 studies have yielded positive results [18][19][20]. Niederauer et al reported an almost two-fold higher rate (p < 0.033) of complete DFU closure at 12 weeks in 146 subjects [18].…”

Number Eight in the Service of Diabetic Foot Ulcer Healing

“…In this issue of Diabetes Care, Frykberg et al (1) further enhance the armamentarium of diabetic foot ulcer (DFU) treatment by publishing the outcome of a double-blinded, randomized, placebocontrolled study evaluating the effect of cyclical topical wound oxygen therapy.…”

“…With the significant differences in methods, devices, distribution pressures, amount of delivered oxygen, and oxygen delivery cycles, it might be difficult to evaluate TOT as an entity until a more uniform definition is set. In this issue of Diabetes Care, Frykberg et al (1) report the outcome of a randomized, double-blinded, placebo-controlled study evaluating the efficacy of a multimodality cyclical pressure Topical Wound Oxygen therapy (TWO2, HyperBox, AOTI Ltd., Galway, Ireland).…”