Following their publication in the American Diabetes Association (ADA) journal Diabetes Care, results of a double-blinded, randomised controlled trial have been announced, showing that at both 12 weeks and 12 months, adjunctive cyclical pressurised topical oxygen wound therapy (TWO2) was superior in healing chronic diabetic foot ulcers (DFUs) compared to standard of care alone. The multi-centre study was conducted across multiple nations and enrolled a total of 220 patients.
Although topical oxygen has been an option for the treatment of chronic wounds (including DFUs) for over 50 years, questions have been asked about the efficacy of the technique, especially due to the lack of high-quality clinical trials that have confirmed its potential for improving wound healing trajectories and patient outcomes.
Speaking about the benefits of TWO2 and the results of this trial, at the Desert Foot Conference (4–7 December 2019, Phoenix, USA), principal investigator Cyaandi Dove (Las Vegas, USA) commented: “There is a much higher level of patient acceptance for topical oxygen, as people are more likely to choose a small device they can use in their home than a chamber which they have to travel to on a regular basis. It is also much cheaper and completely safe, though it must be said that there is not a lot of research in this area, hence the need for further investigations.
“Something that is good about this therapy as well is that it allows for no-contact compression, which is very valuable for patients who have venous leg ulcers. Last, but not least, this device also provides a humid environment for the wound and it has been well-documented that wounds heal better in these conditions.”
The study, titled “A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study,” was led by Dove’s fellow principal investigator Robert Frykberg (University of Arizona College of Medicine, Phoenix, USA), and aimed to assess whether or not TWO2 home care therapy would be successful in healing refractory DFUs that had failed to heal with standard treatment alone.
As part of the trial, patients with diabetes and chronic DFUs were randomised to either an active TWO2 group or sham control therapy, with both cohorts also receiving “optimal standard of care”. On this point, Dove emphasised that this trial implemented the gold standard procedure for offloading, which was consistent across all patients.
“This is not always the case and, typically, you will have several options that is left to the discretion of individual investigators at different sites,” she argued, before adding that “the device was not only validated, but also found to be equivalent to a total-contact cast”.
The presenter also underlined that, as a principal investigator, she had no idea what kind of treatment the patients were receiving, whether that be topical oxygen or a sham device. “This is because there was a separate team who went with patients to their homes and set up the device; also the real devices and sham devices looked the same to patients,” according to Dove.
In terms of a primary outcome, the key endpoint of the trial was the percentage of ulcers in each group that achieved 100% healing at 12 weeks. In addition, 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.
Upon arrival at the first analysis point (12 weeks), 41.7% of those who underwent TWO2 treatment completely healed, compared to 13.5% in the sham arm (OR: 0.99, 97.8% CI 1.44, 24.93 [p=0.010]). Taking into account ulcer severity, it was further demonstrated that DFUs were six times more likely to completely heal within 12 weeks than standard care alone. Furthermore, ulcers were six-times more likely to remain healed after 12 months after being treated with TWO2 therapy.
Moreover, Cox proportional hazards modelling (also after adjustment for ulcer severity) found that the likelihood of TWO2 healing DFUs, compared with the sham arm, was over four times higher (97.8% CI 1.36, 15.98 [p=0.004]). At the second analysis point of 12 months following enrolment, 56% of TWO2 arm ulcers were closed compared with 27% of the sham arm ulcers (p=0.013).
Concluding her presentation, Dove summarised: “This is one of the most important studies that has been done focusing on TWO2 for diabetic foot ulcers, and because the standard of care was so good (e.g. offloading), it was only the recalcitrant wounds that were actually studied, while no blinding biases were possible because the blinding protocol was so rigid. When looking at a robust trial like this, it is clear that at 12 weeks, you are going to have significantly superior wound healing with the support of topical oxygen.
“We also know that even if some diabetic foot ulcers were not healed in the active treatment arm, they were most likely on the trajectory to healing. Lastly, I know that in terms of the homecare therapy, my patients were very happy with it, and even those these people were not in the study, patients in a real-world scenario they are going to pick the easiest option for them.”
Frykberg also commented on the success of the trial: “The investigators could not be prouder to have participated in this groundbreaking study that emphatically demonstrates, utilising one of the most robust protocols ever developed for the wound care space, that cyclical pressurized TWO2 therapy should be considered a front-line adjunctive treatment option for DFUs that have failed to heal with standard care alone.
“The ease of use and homecare application of this approach are additional benefits that aid both patient compliance and offer enormous cost saving potential,” argued Frykberg, “when compared to existing facility based Full Body Hyperbaric Oxygen (HBO) and other adjunctive treatment options.”