Twice-daily esmolol hydrochloride gel (Galnobax, NovaLead) appears to significantly improve closure of diabetic foot ulcers, particularly in patients with risk factors for impeded wound healing, say Indian researchers.
Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the US Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.
As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.
The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.
The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m2 and in those who weighed more than 80 kg (176 lb).
"The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers," write Ashu Rastogi, MD, DM, Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.
Rastogi first presented the findings at the European Association for the Study of Diabetes 2022 Annual Meeting. As reported by Medscape Medical News, the results were well received, with one clinician describing them as "astounding."
However, Andrew Boulton, MD, PhD, told Medscape Medical News that although the final published data are "interesting," they "need further confirmation" because "there are one or two unusual features" about the study. Boulton is a professor of medicine, Division of Diabetes, Endocrinology & Gastroenterology, at the University of Manchester, UK.
He highlighted that the study was of "basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy."
In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Boulton explained is "very unusual and would therefore include some atypical and not truly diabetic 'foot' ulcers."
And Frances Game, MBBCh, Department of Diabetes and Endocrinology, University Hospitals of Derby and Burton NHS Foundation Trust, Derby, UK, added that there are questions about the study methodology.
She told Medscape Medical News that although it is a "fascinating study," the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. "How were they blinded [to treatment]?" she wondered.
The "biggest problem" with the study, however, is that the primary outcome was reported as a per protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.
"That kind of makes [esmolol gel] look better than it is because they've taken out the ones who got worse," Game noted. She concluded, however, that the findings, although not conclusive, do warrant further study of esmolol gel.
The authors note that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.
Moreover, "even with the best therapy," such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.
Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.
The current phase 3 randomized controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.
Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups:
Esmolol 14% gel plus standard of care
Standard of care only
Vehicle plus standard of care
The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.
Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.
In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm2 and the average ulcer duration was 49.8 weeks.
The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.
Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group, with an odds ratio (OR) of 2.13 (P = .03).
The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.
In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone, with an OR of 1.72 (P = .01).
Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg, versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 kg/m2 (OR, 2.72; P = .03).
Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious.
"However, none of the serious adverse events were considered as drug-related by the investigators," conclude the researchers.
The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Rastogi has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.
JAMA Netw Open. 2023;6:e2311509. Full text
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