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, placebo-controlled study evaluating the effect of cyclical topical wound oxygen therapy.

The importance of oxygen in human physiology is not least marked by the 2019 Nobel Prize in Physiology awarded to William Kaelin Jr., Sir Peter Ratcliffe, and Gregg Semenza for their pioneering research into how human cells respond to changing oxygen levels. It is well established that chronic DFUs are not infrequently characterized by hypoxia, and in the microenvironment of these ulcers there exists a substantial imbalance between the supply of oxygen and the high energy demand of the healing (2). Treatment modalities such as hyperbaric oxygen therapy (HBOT) and topical oxygen therapies (TOT) have both been shown to increase vascular endothelial growth factor production and subsequently promote neovascularization (3–6). HBOT has been used in clinical practice as an adjunct to standard therapy for many years, although the outcomes of randomized controlled trials (RCT) are inconclusive (3,7–10). However, there is marked heterogeneity in the patient and ulcer inclusion criteria among these studies, and the latest high-quality RCT, showing a numerical difference in major amputations between HBOT and control groups, unfortunately recruited too few participants to reach statistical power (10). There are lessons from these trials also to be learned in the field of TOT (Fig. 1). As for HBOT, TOT is based on a fairly robust ground of preclinical evidence, predominately from animal models, showing an increase over time in transcutaneous oxygen pressure levels, increased concentrations of vascular endothelial growth factor, improved angiogenesis, improved tissue remodeling, and faster ulcer closure as compared with control subjects, usually treated with air (4,5,11–14). Although some earlier clinical studies have shown promising results, the outcomes of two recently published RCTs, with low risk of bias, are conflicting (15,16). In both trials, healing at 12 weeks in people with grade IA ulcers according to the University of Texas classification of DFUs (UTC) were evaluated. Whereas Niederauer et al. (16) showed a significantly higher healing rate (32.4% vs. 16.7%) comparing TOT (TransCu O2 System) with a sham device (placebo), Driver et al. (15) could not show any differences in healing rates at 12 weeks between groups given transdermal continuous oxygen delivery or placebo as an adjunct to moist wound therapy (15,16). In these studies, 146 and 122 patients were randomized, respectively.

In this context, the prospect was good for the well-designed, double-blinded, multicenter, multinational, placebo-controlled RCT including people with UTC grade I and II by Frykberg et al. (1), aiming for 220 randomized participants, to straighten out the question mark for the place of TOT in the armamentarium of DFU treatment. However, an interim analysis according to the protocol suggesting end of recruitment after only 73 randomized participants because of a statistically significant result in favor of the intervention—41.7% vs. 13.5% healing rate at 12 weeks (P = 0.007)—might at the end of the day cast a shadow over the impressive outcome of this trial.

One plausible failing of the otherwise well-balanced study protocol is the lack of stratification before randomization. The importance of stratification is greater the smaller the study population is, and indeed and unfortunately, important differences were present between groups in baseline characteristics, such as ulcer depth, previous history of lower extremity amputation, and C-reactive protein levels (P = 0.05). The numerical differences in ulcer location between groups might also have had an impact on the outcome, not least as the total numbers of healed ulcers were low, 15 and 5. A subsequent publication including these data would clarify these issues. Some other crucial data are also yet to be reported. The protocol accepted inclusion of postamputation ulcers older than 30 days. The higher number of UTC grade II ulcers (38.9% vs. 16.2%) and more participants with a history of previous amputation (47.2% vs. 21.6%) in the intervention group might either suggest a population with a more severe prognosis or a higher presence of postamputation ulcers in the intervention group.

One of the major strengths of this study is its straightforward inclusion and exclusion criteria allowing a general and representative study population with nonischemic UTC grade I or II ulcers with <30% wound size reduction during a 2-week run-in period. Therefore, it is concerning that only 136 patients were considered for participation over a time frame of 3 years in 17 study centers. Of these participants, 34 (25%) were excluded due to a wound size reduction of ≥30% during the run-in period. When all is said and done, these statistics indicate an annual randomization rate of 1.4 study participants per site. Interestingly, Lavery et al. (17), based on the data from the TOT RCT by Niederauer et al. (16), have shown that when frequent debridement was applied, the relative usefulness of TOT increased. The importance of debridement per se has long since been appreciated, and differences between sites and countries might affect study outcomes (18).

As discussed by Frykberg et al. (1), the 12- and 52-week healing rates in the placebo arm were rather low, 13.5% and 27%, respectively. Although the 12-week healing rate was comparable to the positive TOT RCT reported by Niederauer et al. (17%), it was lower than in the negative TOT RCT reported by Driver et al. (49%) (15,16). The 1-year healing rate was comparable to that of the placebo group in an HBOT RCT in which 73% of the ulcers were classified as Wagner grade 3 or more, 49% of the participants had a history of previous vascular disease, and 29% had an arterial toe blood pressure ≤35 mmHg (9). However, irrespective of the reasons for the low healing rate in the placebo group, the study highlights an implication for a general ethical discussion about statistical power when designing DFU studies.

The present design is fully applicable to present standards, and yet it is worth considering that the rationale for the predetermined study ending at 73 participants (a P value of <0.022) would have fallen if the outcome had been different in two of the cases. In the current study, several of the concerns raised might have been resolved by a larger study population. Although these data are interesting, they need to be confirmed by another RCT with appropriate design and numbers of patients recruited.

This fine RCT by Frykberg et al. has shed light upon the plausible usefulness of TOT in the armamentarium of diabetic foot ulcer treatment: it has provided a little blue in the sky.