Key Points
Question
Does esmolol hydrochloride gel improve wound healing in diabetic foot ulcers at greater rates than the standard of care?
Findings
In this randomized clinical trial that included 176 patients with diabetic foot ulcers, topical application of esmolol with the standard of care demonstrated a significant proportion of ulcer closure compared with standard of care alone. In addition, benefits were shown in patients with factors that impede the healing of diabetic foot ulcers.
Meaning
The findings of this randomized clinical trial indicate that topical esmolol may be an appropriate addition to the standard of care for treating diabetic foot ulcers.
Abstract
Importance
Preclinical and phase 1/2 studies with esmolol hydrochloride suggest its potential role in treatment of diabetic foot ulcers (DFUs).
Objective
To study the efficacy of topical esmolol for healing of uninfected DFUs.
Design, Setting, and Participants
A randomized, double-blind, multicenter, phase 3 clinical trial was conducted from December 26, 2018, to August 19, 2020, at 27 referral centers across India. Participants included adults with DFUs.
Interventions
Participants were randomized after a run-in phase (1 week) to receive esmolol, 14%, gel with standard of care (SoC), SoC only, or vehicle with SoC (3:3:1 proportion) for 12 weeks (treatment phase) and followed up subsequently until week 24.
Main Outcomes and Measures
The primary outcome was the proportion of wound closure within the 12-week treatment phase in the esmolol with SoC and SoC only groups. Analysis was conducted using an intention-to-treat safety evaluable population, full analysis set or efficacy-evaluable population, and per-protocol population comparing the esmolol plus SoC and SoC only treatment groups.
Results
In the study, 176 participants (122 men [69.3%]; mean [SD] age, 56.4 [9.0] years; mean [SD] hemoglobin A1c level, 8.6% [1.6%]) with DFUs classified as University of Texas Diabetic Wound Classification system grade IA and IC (mean [SD] ulcer area, 4.7 [2.9] cm2) were randomized to the 3 groups. A total of 140 participants were analyzed for efficacy. The proportion of participants in the esmolol with SoC group who achieved target ulcer closure within 12 weeks was 41 of 68 (60.3%) compared with 30 of 72 (41.7%) participants in the SoC only group (odds ratio [OR], 2.13; 95% CI, 1.08-4.17; P = .03). A total of 120 participants completed the end of study visit which were analyzed. Target ulcer closure by the end of the study (week 24) was achieved in 44 of 57 (77.2%) participants in the esmolol with SoC group and 35 of 63 (55.6%) participants in the SoC only group (OR, 2.71; 95% CI, 1.22-5.99; P = .01). The median time for ulcer closure was 85 days for the esmolol with SoC group and was not estimable for SoC only group. Significant benefits of Esmolol with SoC were seen in patients with factors that impede the healing of DFU. Treatment-emergent adverse events were noted in 18.8% of the participants, but most (87.3%) of these events were not attributable to the study drug.
Conclusions and Relevance
In this multicenter, randomized, double-blind clinical trial, the addition of esmolol to SoC was shown to significantly improve the healing of DFUs. With these results, topical esmolol may be an appropriate addition to SoC for treating DFUs.
Trial Registration
ClinicalTrials.gov Identifier: NCT03998436; Clinical Trial Registry, India CRI Number: CTRI/2018/11/016295
This randomized clinical trial evaluates the use of topical esmolol hydrochloride combined with standard of care treatment vs standard care alone in patients with diabetic foot ulcers.
Introduction
Diabetic foot ulcers (DFUs) are common severe complications of diabetes that substantially contribute to morbidity and mortality. The prevalence of DFUs is reported to be 1.3% to 12% in various countries,1,2,3,4 and 15% to 25% of patients with diabetes are likely to develop foot ulcers during their lifetime.5 Foot complications including DFUs substantially contribute to diabetes-related mortality apart from cardiovascular complications.6,7 Patients with DFUs have high mortality7 with 5-year mortality (46%) higher than that associated with many cancers.8 Furthermore, the cost of DFU treatment in India is approximately US $650 to $3250; if the DFU becomes infected, each episode costs $1000.9
Even with the best of therapy, only 30% of wounds associated with diabetes heal despite several advanced treatment modalities, including advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative pressure wound therapy.10,11,12,13 Ulcer recurrence is a common problem with DFUs, with a rate of 40% to 70%.14 Thus, there is a need for the development of new treatment options for DFUs to improve wound healing.
Esmolol hydrochloride is a small-molecule drug in gel formulation administered topically that endeavors to retrigger the intrinsic wound-healing mechanisms. Esmolol as a systemic drug is a β1-selective adrenergic receptor-blocking agent with a short duration of action (elimination half-life, approximately 9 minutes) with no intrinsic sympathomimetic or membrane-stabilizing activity at the approved therapeutic dosages.15 Preclinical work with esmolol noted its pleiotropic actions including inhibition of advanced glycosylation end products generation; promotion of migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue; and increased hydroxyproline content in wound tissue.16 The phase 1/2 clinical study of topical esmolol, 14%, gel suggested safe and effective ulcer area reduction (86.6% area closure vs 80.7%), volume (99.4% vs 84.6%), and earlier wound closure (49.5 vs 53.5 days) compared with the vehicle when added to the standard of care.17 Hence, we evaluated the efficacy and safety of topical esmolol gel, 14%, in a phase 3 study for wound closure in people with DFUs.
Methods
Study Design
The phase 3, randomized, double-blind, vehicle (placebo)-controlled, parallel-group multicenter clinical trial was conducted at 27 tertiary care centers across India from December 26, 2018, to August 19, 2020. The trial protocol (Supplement 1) was approved by the individual institutes’ ethics committees, and the study was conducted according to the Declaration of Helsinki18 and follows the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized clinical trials (Figure 1). All participants provided written informed consent; compensation was provided for their travel expenses.
Figure 1. Enrollment and Flow Chart of the Study Participants.
SoC indicates standard of care.
Participants
Eligible participants aged between 18 and 75 years with type 1 or type 2 diabetes and noninfected full-thickness DFUs of grade IA and IC (University of Texas Diabetic Wound Classification system19) were included in the study. The target ulcers were uninfected, had an area between 2 and 15 cm2 (postdebridement), and had been open for at least 6 weeks at the time of the screening visit. The target ulcers that showed area reduction of more than 30% from the screening visit to the baseline visit were excluded from the study (Supplement 1).
Randomization and Blinding
This was a double-blind trial wherein the investigator, participant, and study nurse coordinator were blinded to the randomization. The blinded investigator was responsible for all wound assessments including the closure of the target ulcer. The participants were assigned a unique randomization number using an interactive web-based randomization system.
A total of 176 participants were enrolled and randomized in a 3:3:1 ratio into 1 of 3 groups. Group 1 comprised treatment with esmolol, 14%, gel plus SoC; group 2, SoC only; and group 3, vehicle plus SoC.
The treatment was administered twice daily in all groups. Total duration of a participant in the study was 25 weeks spread over 3 phases in the following sequence (eFigure in Supplement 2): (1) screening phase of 1 week (7-10 days) starting from the screening visit to baseline visit, (2) treatment phase of a maximum of 12 weeks (84 ± 3 days) starting with the baseline visit, and (3) follow-up phase of 12 weeks (84 ± 5 days). The follow-up phase included a closure confirmation period of 4 weeks (28 ± 3 days) and observation period of 8 weeks (56 ± 5 days).
Participants visited the investigational site once a week during the 12-week treatment phase for wound measurement and completion of study-related assessments and procedures. In the follow-up phase, the participants visited the investigational site at weeks 14, 16, 20, and 24.
Treatment Administration
The amount of the investigational product (esmolol, 14%) or vehicle gel applied varied depending on the area and depth of the target ulcer and a uniform layer of gel was applied. Typically, 0.6 cm of gel was applied from a 15-g tube for every square centimeter of ulcer area. Details of the SoC used in the study, including offloading, are provided in the eMethods in Supplement 2.
Procedures
All study sites used a uniform mobile app (Woundly; WoundlyClinical) for target ulcer area measurement.20 All eligible participants received SoC during the screening period (7 days) before randomization. At the end of the screening period (baseline visit at day 1), participants who were found eligible (with ulcer reduction <30% during the screening period) were randomly assigned to receive 1 of the 3 treatments.
If the ulcer was judged by the blinded evaluator as completely closed, the esmolol or vehicle treatment was discontinued (only SoC allowed). The target ulcer was then tracked for 2 consecutive visits 2 weeks apart to confirm the closure of the target ulcer (primary end point).
Outcomes
The primary and secondary efficacy analysis was performed for all participants in a full analysis set (FAS) (efficacy-evaluable population) and per-protocol population comparing the esmolol plus SoC and SoC only treatment groups. The primary outcome was the proportion of participants achieving target ulcer closure during the 12-week treatment phase (assessed by the blinded investigator). The secondary outcomes included the proportion of participants achieving target ulcer closure by the end of the study (24 weeks), as well as the time to target ulcer closure during the 12-week treatment phase (assessed by the blinded investigator).
Target ulcer closure was defined as 100% reepithelialization without drainage or dressing requirement, confirmed on 2 consecutive site visits (2 weeks apart) from the first observation of closure. Data on follow-up assessments after wound closure and safety evaluation are provided in the eMethods in Supplement 2.
Efficacy variables were further assessed for subgroups stratified by the location of the ulcer (plantar vs nonplantar) and ulcer size (<5 vs ≥5 cm2). Furthermore, efficacy was assessed post hoc on the basis of baseline characteristics that are known to affect the healing of DFUs, such as less than 50% area reduction in the initial 4 weeks of treatment and body mass index greater than 25 (calculated as weight in kilograms divided by height in meters squared), earlier duration of ulcers (ulcer age), low hemoglobin level (<11 g/dL [to convert to grams per liter, multiply by 10]), hemoglobin levels below and above the reference range for males (<13 g/dL or >17 g/dL) and females (<12 g/dL or >15 g/dL), high hemoglobin A1c level (>8% [to convert to proportion of total hemoglobin, multiply by 0.01]), low estimated glomerular filtration rate (<90 mL/min), and low ankle brachial index (<0.9).
Sample Size
The sample size was calculated based on the results of a phase 1/2 study that demonstrated 60% ulcer closures with esmolol, 14%, gel with SoC compared with 39% with SoC alone based on historical data.17 With a 1:1 randomization ratio in the 2 efficacy groups, 176 participants were required to be enrolled as the FAS population for achieving 80% power with a 2-sided α value of 5% nominal significance. In addition to these 2 groups, a third group receiving vehicle with SoC treatment was included for safety assessment, using intention-to-treat analysis (safety evaluable population), in a proportion of 3:3:1, leading to a total FAS population of 206 participants. With assumption of 20% dropouts, 244 participants were to be enrolled in the study.
Statistical Analysis
All analyses were performed using SAS software, version 9.4 (SAS Institute Inc). The intention-to-treat population included all participants who were randomized and had received at least 1 dose of the study treatment. The FAS population included all participants who were randomized and had at least 6 weekly assessments for target ulcer closure or had the target ulcer closed earlier than 6 weeks. The efficacy analysis was also done on the FAS and per-protocol populations.
The χ2 test or Fisher exact test and, where relevant, analysis of variance, were used for estimating P values (significance level <.05), and the estimated effect size is given as an odds ratio (OR) with 95% CI obtained from methods reported by Bland and Altman21 for primary and secondary end point analysis. Logistic regression analysis was used, considering target ulcer closed (yes vs no) as a dependent variable and treatment group, ulcer type (plantar or nonplantar), and baseline ulcer size as continuous covariates, and the Wald 95% CI was calculated for individual independent variables in regression analysis. For the secondary end point, Kaplan-Meier analysis was used to depict the median time (days) to target ulcer closure for the 2 treatment groups.
Results
A total of 251 individuals were screened and 176 patients were randomized into the 3 groups of the study (122 men [69.3%]; 54 women [30.7%]; mean [SD] age, 56.4 [9.0] years). Of randomized participants, 163 were in the FAS population and 137 completed the study (Figure 1). The demographic characteristics of the participants and baseline characteristics of the target ulcers for the intention-to-treat population are provided in Table 1. The mean (SD) target ulcer area was 4.7 (2.9) cm2 and ulcer age was 49.8 (86.92) weeks. The treatment adherence rate at all study visits was mean (SD), 98.8% (8.22%), with a median of 100%.
Table 1. Participant Demographic and Baseline Ulcer Characteristics.
| Characteristic | Treatment group | P value | |||
|---|---|---|---|---|---|
| Esmolol with SoC (n = 76) | SoC only (n = 76) | Vehicle with SoC (n = 24) | Overall (N = 176) | ||
| Age, mean (SD), y | 56.5 (8.96) | 56.1 (9.36) | 57.3 (8.01) | 56.4 (8.97) | .86a |
| Sex, No. (%)b | |||||
| Male | 55 (72.37) | 52 (68.42) | 15 (62.50) | 122 (69.32) | .64c |
| Female | 21 (27.63) | 24 (31.58) | 9 (37.50) | 54 (30.68) | |
| Height, mean (SD), cm | 166.4 (9.43) | 165.3 (8.91) | 164.6 (9.44) | 165.7 (9.18) | .62a |
| Weight, mean (SD), kg | 74.1 (12.91) | 70.8 (13.20) | 70.3 (11.55) | 72.1 (12.91) | .21a |
| BMI, mean (SD) | 26.7 (4.05) | 25.9 (4.30) | 25.9 (3.39) | 26.2 (4.08) | .38a |
| Occupation requirement, No. (%)b | .24c | ||||
| Standing | 1 (1.32) | 1 (1.32) | 0 | 2 (1.14) | |
| Walking | 0 | 1 (1.32) | 0 | 1 (0.57) | |
| Standing and walking | 34 (44.7) | 19 (25.0) | 6 (25.0) | 59 (33.5) | |
| Sitting | 18 (23.7) | 18 (23.7) | 8 (33.3) | 44 (25.00) | |
| Driving | 2 (2.64) | 0 | 1 (4.2) | 3 (1.70) | |
| Housework | 15 (19.7) | 24 (31.6) | 7 (29.2) | 46 (26.1) | |
| Other | 6 (7.9) | 13 (17.1) | 2 (8.3) | 21 (11.9) | |
| Target ulcer leg, No. (%)b | |||||
| Right | 37 (48.7) | 44 (57.9) | 14 (58.3) | 95 (54.0) | .47c |
| Left | 39 (51.3) | 32 (42.1) | 10 (41.7) | 81 (46.0) | |
| Target ulcer location, No. (%)b | |||||
| Plantar toe | 12 (15.8) | 12 (15.8) | 4 (16.7) | 28 (15.9) | .48c |
| Plantar metatarsus or sole | 28 (36.8) | 30 (39.5) | 10 (41.7) | 68 (38.6) | |
| Plantar midfoot or heel | 8 (10.5) | 11 (14.5) | 5 (20.8) | 24 (13.6) | |
| Nonplantar dorsal | 9 (11.8) | 17 (22.4) | 4 (16.7) | 30 (17.0) | |
| Nonplantar medial | 6 (7.9) | 3 (3.9) | 1 (4.2) | 10 (5.7) | |
| Nonplantar lateral | 13 (17.1) | 3 (3.9) | 0 | 16 (9.1) | |
| Target ulcer area, cm2 | |||||
| Mean (SD) | 4.59 (2.77) | 4.75 (2.9) | 5.02 (3.54) | 4.73 (2.94) | .81a |
| Median (range) | 3.70 (1.62-13.47) | 3.48 (1.84-13.96) | 3.49 (2.05-13.17) | 3.56 (1.62-13.96) | |
| Target ulcer age, wk | |||||
| Mean (SD) | 50.6 (76.35) | 51.8 (103.33) | 41.1 (59.68) | 49.8 (86.92) | .87a |
| Median (range) | 24.0 (7.0-500.0) | 18.0 (6.0-818.0) | 22.0 (6.0-296.0) | 21.0 (6.0-818.0) | |
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); SoC, standard of care.
P values were calculated using analysis of variance model.
Percentages were calculated using respective column header count as denominator.
P values were calculated using the χ2 test or Fisher exact test.
For the primary end point overall, 140 participants in the 2 treatment groups were assessed. The proportion of participants who achieved target ulcer closure within 12 weeks was statistically significant, with 41 of 68 (60.3%) participants achieving target ulcer closure in the esmolol with SoC group and 30 of 72 (41.7%) participants in SoC only group (18.6 percentage point difference; OR, 2.13; 95% CI, 1.08-4.17; P = .03).
The secondary end point of the proportion of target ulcer closure by the end of the study (week 24) was assessed for 120 participants with 44 of 57 participants (77.2%) achieving target ulcer closure in the esmolol with SoC group and 35 of 63 participants (55.6%) in SoC only group (21.6 percentage point difference; OR, 2.71; 95% CI, 1.22-5.99; P = .01). When all participants in the FAS group were considered for secondary end point analysis, the last observation carried forward method was used. At the end of the study, 47 of 68 ulcers (69.1%) were closed in the esmolol with SoC group, whereas 36 of 72 ulcers (50.0%) were closed in the SoC only group (19.12 percentage point difference; OR, 2.24; 95% CI, 1.12-4.47; P = .02).
The median Kaplan-Meier time to complete wound closure was 85 days for the esmolol with SoC group indicating that at least 50% of the participants would achieve complete wound closure in approximately 12 weeks of treatment. However, median time to target ulcer closure in the SoC only group was undeterminable because ulcers in only 30 patients (41.7%) healed during the treatment period of 12 weeks.
Subgroup Analysis
The subgroup analysis showed that esmolol with SoC performed better than SoC only irrespective of ulcer size (<5 vs ≥5 cm2) or location (plantar vs nonplantar) (Figure 2). The detailed post hoc analysis is reported in the eMethods and eTable 1 in Supplement 2. The esmolol with SoC group showed significantly more closure of ulcers in people with weight greater than 80 kg (OR, 4.04; 95% CI, 1.07-15.27; P = .04) and body mass index greater than 25 (OR, 2.72; 95% CI, 1.08-6.79; P = .03) compared with the SoC only group.
Figure 2. Proportion of Wound Closure in Subgroups According to Ulcer Location and Size.
A, Closure in plantar (esmolol with standard of care [SoC], n = 46; SoC only, n = 51) vs nonplantar (esmolol with SoC, n = 22; SoC only, n = 21) ulcers. B, Closure by ulcer size in ulcers smaller than 5 cm2 (esmolol with SoC, n = 47; SoC only, n = 46) vs 5 cm2 or larger (esmolol with SoC, n = 21; SoC only, n = 26).
Multivariate Logistic Regression Analysis
The odds of wound closure in the esmolol with SoC group was 2.066 (95% CI, 1.034-4.130; P = .04) when covariates of location (plantar vs nonplantar) and the size of the ulcer were considered. In addition to treatment effect, baseline ulcer size was significantly different in the multivariate analysis (OR, 0.998; 95% CI, 0.997-1.000; P = .01) (Table 2).
Table 2. Summary of Multivariate Logistic Regression Analysis of Participants Achieving Target Ulcer Closure Within 12 Weeksa.
| Parameter | β Estimate (SE) | P value | Odds ratio estimate (Wald 95% CI) |
|---|---|---|---|
| Treatment group | |||
| SoC only | 1 [Reference] | .04 | 1 [Reference] |
| Esmolol with SoC | 0.723 (0.353) | 2.066 (1.034-4.130) | |
| Ulcer type | |||
| Plantar | 1 [Reference] | .28 | 1 [Reference] |
| Nonplantar | 0.462 (0.428) | 1.587 (0.686-3.672) | |
| Baseline ulcer size | −0.002 (0.001) | .01 | 0.998 (0.997-1.000) |
Abbreviations: SE, standard error; SoC, standard of care.
Logistic regression analysis was performed considering target ulcer closed (yes/no) as a dependent variable and treatment group, ulcer type (plantar or nonplantar), and baseline ulcer size as continuous covariates.
Follow-up Phase and Effect of Treatment
Of 62 participants who did not achieve wound closure by the end of treatment, 25 participants were from the esmolol with SoC group and 37 were from the SoC only group. The percentage of ulcer area reduction from the end of treatment to the end of the study for the esmolol with SoC group was 60.7% compared with a negligible reduction of 2.7% in the SoC only group (P = .02). The mean reduction in ulcer area from the end of treatment to the end of the study from baseline in the esmolol with SoC group was 23.32%, whereas an increase in ulcer area (reduction from end of treatment to end of study, −7.54%; P = .05) was observed in the SoC only group. For the vehicle with SoC group, only 10 of 23 participants (43.5%) achieved target ulcer closure at week 12 (end of treatment), with most (n = 14) participants not achieving target ulcer closure even at week 24 (end of study). The proportion of patients with closure of the ulcer within the 12-week treatment phase in the vehicle with SoC group was similar to that in the SoC only group. The esmolol with SoC group had 16.8% more ulcer closures in the 12-week treatment period compared with the vehicle with SoC group. The vehicle with SoC group also showed a reduction in ulcer area during the treatment phase, but the ulcer area expanded by 18.1% between the end of treatment to the end of the study in the vehicle with SoC group compared with a 60.7% reduction in the esmolol with SoC arm (P = .14).
Two ulcers reopened in the esmolol with SoC group and 1 ulcer reopened in the SoC only group during the follow-up phase after achieving the primary end point. Two ulcers in the esmolol with SoC group reopened within 4 weeks (at visit 16) after the first observation of closure; hence, they were considered as open, not meeting the primary end point.
Safety Analysis
Among the intention-to-treat population (n = 176), 33 participants (18.8%) reported 63 treatment-emergent adverse events. Twelve of these events were reported as serious in 7 participants; however, none of the serious adverse events were considered as drug related by the investigators. Most treatment-emergent adverse events (55 [87.3%]) had no association with the study drug. Detailed data on treatment-emergent and serious adverse events are provided in eTable 2 in Supplement 2.
Discussion
To our knowledge, this is the first randomized, double-blind clinical trial to establish the efficacy as well as the safety of the novel topical gel, esmolol, for healing of noninfected DFUs. In this study, we found that significantly more participants with a DFU greater than 2 cm2 treated with esmolol achieved wound closure within a 12-week treatment period than those who received SoC only treatment. The rate of DFU closure within 24 weeks was significantly higher in the esmolol with SoC group compared with the SoC only group.
Despite substantial advances in wound management, including the advent of wound dressing material, over the past few years, the healing rates of DFUs ranged from 24.2% to 59.3% at 12 weeks and slightly better if followed up for a longer duration.22 An increased weight and body mass index are known to exert pressure on plantar ulcers and are key factors delaying wound healing.23 The esmolol with SoC group showed significantly greater wound closure in people with characteristics that impair wound healing, including those with peripheral arterial disease, anemia, and nephropathy compared with SoC alone.24,25
The percentage of reduction of DFUs during the screening period is believed to capture healing trends for foot ulcers. Diabetic foot ulcers that do not heal by at least 15% in the screening period (7-10 days) with SoC only are considered to be nonhealing as opposed to ulcers that show closure greater than 15%, which is considered to represent a healing trajectory.26,27 In the present study, the proportion of ulcers that closed during esmolol with SoC treatment was significantly higher than SoC only treatment in a subgroup of participants with less than 15% reduction during screening. Also, DFUs that show greater than 50% ulcer area reduction at week 4 are more likely to achieve wound closure by week 12, serving as a robust predictor of complete healing compared with a less than 10% chance of closing in those with less than 50% area reduction in the first 4 weeks of treatment.28 We observed that the proportion of ulcer closure was approximately 5-fold (39.3% vs 8.3%) with esmolol with SoC treatment compared with SoC only for the ulcers that did not achieve 50% closure by week 4. There was a 58% greater ulcer area reduction during the period from EOT until study end with esmolol compared with SoC, suggesting the legacy effect, unlike in the vehicle with SoC group, which showed a reduction in ulcer area only during the treatment phase, but the ulcer area expanded by 18.1% during EOT to EOS.
The better results with esmolol with SoC in this study, especially in patients with characteristics associated with poor wound healing, are a major advantage in wound healing in settings outside studies. In preclinical studies, esmolol was shown to inhibit aldose reductase, formation of sorbitol in red blood cells, and advanced glycosylation end product generation, which might decrease cellular damage by reducing oxidative stress in wound tissues.16,29 Esmolol inhibits Casp3, upregulates Bcl-2, and activates ERK1/2 mitogen-activated protein kinase, thereby facilitating wound repair.30,31 Poor nitric oxide generation in diabetes hampers the migration of fibroblasts and generation of the extracellular matrix. The in vivo study of esmolol in rats with diabetes demonstrated induction of nitric oxide in wound tissues16 to facilitate fibroblast migration and angiogenesis32 along with reduction of cytokines.33
Strengths and Limitations
One strength of the present trial is that it followed international guidelines for the design and reporting of studies for wound healing.34 The target ulcer closure was defined in line with recommendations of the US Food and Drug Administration as 100% reepithelialization without drainage or dressing requirement to be confirmed by 2 consecutive site visits 2 weeks apart from the first observation of closure. The randomization with stratification of participants according to ulcer location and size ensured uniform distribution of participants in each group. The risks of allocation, treatment, and assessment bias were avoided by the blinding of investigators, participants, and the nurse coordinator. The SoC was uniform, including footwear for offloading. Treatment adherence was high during the treatment phase because of monitored study nurse visits (ensured by mobile-based app NurseAssist).
The trial has limitations, including that the targeted population proposed as per study assumption could not be recruited due to the COVID-19 pandemic. The required FAS population for 80% power was 176 participants in efficacy-evaluable arms, but 140 participants of 176 completed the study, which was 80% of required participants that was considered appropriate by the study steering committee during evaluation. However, despite the lower population, the study achieved its primary end point. A larger population with a continued trend of ulcer closure would have resulted in better power for the study. The objective assessment for adherence to offloading was not planned in the study, although the nurses ensured offloading during their daily treatment visits.
Conclusions
In this randomized clinical trial, esmolol with SoC treatment improved the rate of wound closure during 12 weeks in participants with neuropathic and neuroischemic DFUs in comparison with SoC only. The use of esmolol in the treatment of DFUs in addition to SoC may be an important addition to the endeavor of healing DFUs.
Trial Protocol and Statistical Analysis Plan
eMethods. Detailed Methods
eFigure. Schema for the Study
eTable 1. Target Ulcer Closure Within 12 Weeks Considering Various Subgroups Based on Baseline Parameters of Factors Associated With Wound Healing
eTable 2. Distribution of AEs and SAEs Across Different Groups in ITT Population
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol and Statistical Analysis Plan
eMethods. Detailed Methods
eFigure. Schema for the Study
eTable 1. Target Ulcer Closure Within 12 Weeks Considering Various Subgroups Based on Baseline Parameters of Factors Associated With Wound Healing
eTable 2. Distribution of AEs and SAEs Across Different Groups in ITT Population
Data Sharing Statement
