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A topical cream that helps regulate macrophage activity was effective in treating diabetic foot ulcers, a clinical trial reported.

In 236 patients with foot ulcers treated for 16 weeks, the proportion who had complete healing of the ulcer was significantly higher in the group randomized to receive the topical cream (60.7%) versus a comparator group treated with absorbent dressing (35.1%; OR 2.84, 95% CI 1.66-4.84, P<0.001), said Shun-Cheng Chang, MD, of the Taipei Medical University in Taiwan, and colleagues.

As shown in the team's study online in , the results were similar when the researchers analyzed subgroups of patients with notable risk factors, including those with a glycated hemoglobin level of 9% or higher (47% complete healing in the treatment group vs 22% in the comparator group, P=0.04), those with ulcers bigger than 5 cm² (55% vs 22%, P<0.009), and those with an ulcer duration of at least 6 months (33% vs 11%, P=0.04).

"Topical application of ON101 with gauze immediately after debridement demonstrated significant healing efficacy compared with an absorbent dressing in all patients, including those with DFU [diabetic foot ulcer]-related risk factors," the researchers wrote. "To our knowledge, this study is the first international phase III randomized clinical trial of an investigational drug able to regulate M1/M2 macrophage activities in patients with DFUs."

Chang and co-authors explained that the ON101 cream contains two active ingredients shown to regulate macrophage activity and balance:

• The first, PA-F4, is derived from an extract of , which attenuates proinflammatory M1 macrophages by suppressing the NLRP3-mediated inflammasome pathway and the production of inflammatory cytokines such as interleukin 1β and interleukin 6

• The second ingredient, S1, is derived from an extract of , which activates pro-regenerative M2 macrophages by increasing collagen synthesis and stimulating fibroblast proliferation as well as the migration of keratinocytes

The researchers noted that ON101 had demonstrated wound healing in a mouse model of diabetes, and in a clinical pharmacokinetic study of 12 patients with diabetic foot ulcers, ON101 applied twice daily resulted in limited systemic exposure and no obvious accumulation in the body, which would tend to limit adverse events.

Treatment-emergent adverse events in the new study occurred in 5.7% of the treatment group and 4.4% of the comparator group (P=0.77); serious toxicities, however, occurred only in one patient in the comparator group, the researchers said.

The open-label, phase III, evaluator-blinded trial included patients with debrided diabetic foot ulcers of 1-25 cm² that had been present for at least 4 weeks and with Wagner grade 1 or 2. The majority of patients were men (74%), mean age was 57, and mean glycated hemoglobin level was 8.1%.

Trial participants were randomized 1:1 to twice-daily applications of ON101 or an absorbent dressing changed once a day for 16 weeks, with an additional 12 weeks of follow-up. The primary outcome was complete ulcer healing, defined as complete re-epithelialization observed at two consecutive visits during the treatment period.

Chang and co-authors explained that approximately 80% of lower limb amputations in patients with diabetes are preceded by chronic foot ulcers, resulting in a heavy burden of medical care and expenditure. Current treatments focus primarily on local wound care including debridement, off-loading, infection control, and maintaining a moist environment with dressings.

Adjunctive therapies such as growth factors, tissue engineering products, hyperbaric oxygen, and negative pressure wound therapies are generally used only if the ulcer worsens. Treatments such as tissue repair or anti-inflammatory agents are not well supported by clinical evidence or are not recommended for routine care by the International Working Group on the Diabetic Foot.

Furthermore, diabetic foot ulcers tend to be pathologically complex because patients often have multiple risk factors such as poor adherence to treatment, vascular conditions, poor glycemic control, smoking, and kidney dysfunction. "These factors impose a significant clinical need for novel and effective interventions to tackle this life-debilitating and life-threatening disease," Chang and co-authors said.

Study limitations, the team said, included the open-label design (the intervention was not masked to the patients or clinical investigators, although evaluation of the ulcers was blinded), and the lack of a 2-week run-in period, which would have identified participants who were rapid healers.

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