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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.

  • Frykberg, Robert G1
  • Franks, Peter J2
  • Edmonds, Michael3
  • Brantley, Jonathan N4
  • Téot, Luc5
  • Wild, Thomas6
  • Garoufalis, Matthew G7
  • Lee, Aliza M8
  • Thompson, Janette A9
  • Reach, Gérard10
  • Dove, Cyaandi R11
  • Lachgar, Karim12
  • Grotemeyer, Dirk13
  • Renton, Sophie C
  • 1 Diabetic Foot Consultants, Midwestern University, Glendale, AZ [email protected]
  • 2 Centre for Research and Implementation of Clinical Practice, London, U.K.
  • 3 King's College Hospital, London, U.K.
  • 4 McGuire Veterans Affairs Medical Center, Richmond, VA.
  • 5 Montpellier University Hospital, Montpellier, France. , (France)
  • 6 Medical Center Dessau, Brandenburg Medical School Theodor Fontane, Dessau, Germany. , (Germany)
  • 7 Edward Hines Jr. VA Hospital, Chicago, IL.
  • 8 Salem Veterans Affairs Medical Center, Salem, VA.
  • 9 Washington DC Veterans Affairs Medical Center, Washington, DC.
  • 10 Hôpital Avicenne and Paris 13 University, Bobigny, France. , (France)
  • 11 Advanced Foot & Ankle Center, Las Vegas, NV.
  • 12 Hôpital Simone Veil, Eaubonne, Paris, France. , (France)
  • 13 Hôpitaux Robert Schuman - Hôpital Kirchberg, Luxembourg City, Luxembourg. , (Luxembourg)
Published Article
Diabetes care
Publication Date
Mar 01, 2020
DOI: 10.2337/dc19-0476
PMID: 31619393


Topical 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. Patients with diabetes and chronic DFUs were randomized (double-blind) to either active TWO2 therapy or sham control therapy-both 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. At 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 = 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 = 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 = 0.004. At 12 months postenrollment, 56% of active arm ulcers were closed compared with 27% of the sham arm ulcers (P = 0.013). This 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. © 2019 by the American Diabetes Association.

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