ABSTRACT
Diabetic foot ulcers (DFUs) are a devastating complication of diabetes that markedly affects quality of life and generates significant socioeconomic and healthcare burdens. When DFUs fail to respond to standard of care (SOC), advanced therapies including Cellular, Acellular and Matrix‐like Products (CAMPs) are often employed. A novel composite CAMP comprising ovine forestomach matrix and high molecular weight hyaluronic acid, termed ‘OFM‐HA’ has been developed for the treatment of chronic wounds and evaluated in a prospective multi‐centre controlled trial. For this trial, 143 subjects were randomized to receive OFM‐HA plus SOC or SOC alone for the treatment of chronic full thickness wounds of the foot in people with diabetes meeting prespecified eligibility criteria. The primary endpoint was the proportion of wounds healed by 12 weeks. Secondary endpoints included healing time, percentage area reduction, adverse events and changes in pain and quality of life. For the modified intent‐to‐treat population, 46% (31/68) of the OFM‐HA plus SOC group healed by 12 weeks compared to 24% (17/72) in the SOC alone group (p = 0.008). Kaplan–Meier analysis favoured OFM‐HA plus SOC over 12 weeks (log‐rank p = 0.023). No unexpected safety‐related occurrences were observed. OFM‐HA plus SOC increased 12‐week closure in this selected population. Interpretation is limited by post‐randomization exclusions, differential withdrawal and an adjusted comparison close to the significance threshold (p = 0.045).
Keywords: chronic wound, diabetic foot ulcer, hyaluronic acid, ovine forestomach matrix, randomized controlled trial
Key Points
Ovine forestomach matrix with high molecular weight Hyaluronic acid heals more diabetic foot wounds versus standard of care alone.
High molecular weight Hyaluronic acid has unique biological properties for the treatment of diabetic wounds.
Kaplan Meyer survival curves favor OFM‐HA with SOC versus SOC alone in time to healing diabetic foot wounds.
1. Introduction
Diabetic foot ulcers (DFUs) are a devastating complication of diabetes that markedly affects quality of life and generates significant socioeconomic and healthcare burdens throughout the world. Globally, 18.6 million people are affected by a DFU each year, translating to an estimated $USD2.5 trillion in international burden by 2030 [1, 2]. Approximately 34% of people with diabetes develop a DFU during their lifetime [3]. DFUs are notoriously difficult to treat due to neuropathy, poor vascular perfusion, impaired fibroblast and keratinocyte function, disrupted moisture balance, chronic inflammation and elevated tissue protease concentrations [4, 5]. Because of these challenges, DFUs are prone to infection, presenting a significant risk for lower limb amputation [1]. Between 50% and 60% of DFUs become infected and 80% of lower limb amputations among diabetics result from a DFU [1]. The 5‐year mortality rate for patients with a DFU is 30%, but exceeds 70% when a major amputation (above the ankle) is performed [1]. Remarkably, when compared to cancer, the 5‐year mortality rate following a major amputation is second only to lung cancer at 80% [6, 7]. Furthermore, an increase in all‐cause mortality and resource utilization has been reported for DFUs [1, 8], as well as significant disparities between racial and socioeconomic groups [9].
Current DFU standard of care (SOC) involves off‐loading, debridement, infection management and revascularization when indicated [10]. However, when DFUs fail to respond to SOC, advanced therapies including Cellular, Acellular and Matrix‐like Products (CAMPs, formerly, ‘skin substitutes’) are often employed [11, 12]. CAMPs are intended to promote the repair and regeneration of injured tissue by supporting favourable cellular communication and matrix production in the wound environment [13]. Clinical and economic benefits have been reported for selected CAMPs and populations [14, 15]; these findings do not establish cost‐effectiveness or limb preservation for the present OFM‐HA regimen. A recent meta‐analysis including 29 randomized controlled trials (RCTs) and 2255 patients demonstrated that DFUs managed with CAMPs plus SOC were three times more likely to achieve 100% wound closure than those treated with SOC alone [16].
Ovine forestomach matrix (OFM) is a decellularized extracellular matrix (ECM) bioscaffold technology that has been utilized for the treatment of acute and chronic wounds, and surgical reconstruction. OFM serves as a bioscaffold for cell repopulation and the synthesis of new tissue ECM [17]. In addition to providing structural cues for regeneration, OFM contains many naturally occurring ECM components and has been shown to inhibit excessive matrix metalloprotease (MMP) activity [18], promote angiogenesis and signal cell proliferation, migration and differentiation [17, 19, 20]. As such, OFM‐based devices have been widely studied for the treatment of DFUs, with a good performance and safety profile [21, 22, 23, 24, 25, 26, 27, 28, 29]. More recently, a layered composite of OFM and high molecular weight hyaluronic acid (HMWHA), termed here‐in ‘OFM‐HA’, has been developed [30]. HMWHA was selected as a component of the composite CAMP given its unique biological properties that make this naturally occurring polymer especially suited for the treatment of chronic wounds, and especially DFUs [31, 32, 33]. Pre‐clinical studies have demonstrated that the addition of HMWHA to OFM significantly improves cellular migration, proliferation and moisture retention in OFM‐HA devices [30].
While available data surrounding OFM‐HA is limited, this device has been shown to support chronic wound healing, including DFUs, with no adverse events (AEs) or recurrences [34, 35, 36]. The largest case series to date reported the successful use of OFM‐HA to treat chronic lower extremity wounds in a complicated elderly patient population with several complicating comorbidities. The authors reported successful healing of these challenging lesions, with most defects (90%) achieving 50% reduction in wound area by 4 weeks, 60% incidence of closure at 12‐weeks, and a median time to healing of 9 weeks, following a median of 4 product applications of OFM‐HA [36].
To expand the current literature, we report a multi‐centre, RCT comparing the effectiveness of OFM‐HA plus SOC versus SOC alone in the treatment of non‐healing DFUs.
2. Materials and Methods
2.1. General
This study was designed as a prospective, multi‐centre, parallel‐group, RCT based on a study design that has been extensively validated for assessing comparative effectiveness of CAMPs in DFU outcomes [37, 38, 39, 40]. Ethical approval was obtained by WCG IRB (reference number: 20231642; ClinicalTrials.gov: NCT06035536). All patients provided written informed consent for their images and data to be used for research and publication purposes. The study was conducted in accordance with World Medical Association Declaration of Helsinki ethical guidelines.
2.2. Patient Screening
Patient screening (SV1) occurred 14 days before randomization; at this time, written informed consent was obtained and a single DFU per patient was selected as the index ulcer. Eligible index ulcers were chronic full thickness wounds of the foot in people with diabetes, meeting the prespecified perfusion and infection eligibility criteria. The protocol classified eligible wounds as Wagner grade 1 or 2; these original eligibility categories are retained in Table 1. Eligible ulcers had at least 50% of the wound below the malleolus, a surface area of 1–25 cm2 and a duration of 4–52 weeks. If the subjects had more than one DFU, they had to be greater than 2 cm apart and the investigator selected the largest DFU that met the eligibility criteria according to Table 1. During screening, various assessments were documented, including: demographics, medical history, concomitant medications, vital signs, physical examination findings, laboratory diagnostics, pregnancy test results, ulcer history and assessments, pain, peripheral neuropathy (Semmes Weinstein 10‐point monofilament exam), circulation and wound quality of life assessments. As specified in Table 1, perfusion eligibility could be documented within 3 months before SV1 by dorsal transcutaneous oxygen or skin perfusion pressure measurement of 30 mmHg, ABI 0.7–1.3, or, alternatively, arterial Doppler showing biphasic dorsalis pedis and posterior tibial waveforms at the ankle or TBI > 0.6. These were alternative eligibility routes, not jointly required tests, and did not establish the absence of peripheral artery disease. Wound quality of life (W‐QoL) was established with the validated tool that consists of a 17‐item questionnaire with a 5‐level Likert response to each question [41]. Upon examination, the index ulcer was excluded if probed to bone. At SV1 and throughout the study, pain assessments were completed using the numeric pain rating scale (NPRS), used by subjects to indicate a numerical value from 1 to 10 that best represented their pain intensity, with 0 being ‘no pain’ and 10 being ‘the worst possible pain’. The index ulcer was imaged (digital photography) and measured (eKare inSight System, Virginia, USA) at SV1 and throughout the study.
TABLE 1.
Inclusion and exclusion criteria.
| Inclusion criteria | Exclusion criteria |
|---|---|
|
|
Abbreviations: ABI, ankle brachial index; DFU, diabetic foot ulcer; HIV, human immunodeficiency virus; ICF, informed consent form; IRB, institutional review board; SOC, standard of care.; SPP, skin perfusion pressure; SV1, screening visit; TBI, toe brachial index; TCOM, transcutaneous oxygen measurement; TV1, first treatment visit.
At SV1 and over the course of the 2‐week screening and run in period, all subjects received a weekly SOC collagen/alginate dressing (Fibracol, Solventum, Minnesota, USA) following weekly sharp debridement and rigorous cleansing. During the 2‐week screening and run period, patients and their ulcers were assessed for continued eligibility to the inclusion/exclusion criteria. Any participant who failed to meet the inclusion/exclusion criteria at SV1 or during the 2‐week screening and run in period (Table 1) exited the study as a ‘screen fail’.
2.3. Treatment Phase
Following the 2‐week run in period, ulcers were randomized 1:1 at the initial treatment visit (TV1) and received OFM‐HA (Symphony, Aroa Biosurgery Limited, Auckland, New Zealand) plus SOC, or SOC alone. Index ulcers were cleansed and debrided prior to application of the treatment. Secondary dressings included a non‐adherent silicone dressing (Mepitel Soft Silicone Wound Contact Layer, Mölnlycke Health Care US LLC, Indianapolis, IN, USA, or equivalent), padded dressing (4 × 4 cm, 3‐layer gauze pads), soft roll and compressive wrap (Threeflex 3‐Layer Compression System, Medline Industries Inc., Northfield, IL, USA, or equivalent), with appropriate offloading with a removable boot (Foot Defender, Defender Ops, Miami, FL, USA) or total contact casting. Participants were evaluated and treated weekly (±3 days), and at each weekly treatment visit (TV2 through TV13, or as required) participants and their index ulcers were assessed according to SV1, and additionally for any device or non‐device treatment emergent AEs. Participants were seen weekly until the index ulcer was ‘healed’, defined as 100% epithelialization and free of drainage. If the index ulcer was judged ‘healed’, on or before the last treatment visit (TV13), then a healing confirmation visit (HCV) was scheduled for 2 weeks later. Initial closure was assessed by the site investigator and confirmed by a designated blinded assessor, on site or remotely using wound images. An independent validation committee reviewed wound images and validation forms at the end‐of‐study and healing confirmation assessments. This describes endpoint‐assessor blinding; it does not imply that participants or treating clinicians were blinded. Participants who did not achieve a healed status on TV13 exited the study and were managed according to institutional protocols and best practice.
2.4. Statistical Analysis
The primary study endpoint was the proportion of participants that obtained complete closure by TV13. Secondary endpoints included: time to wound closure (at TV13); percentage wound area reduction (PAR%) from TV1 to TV13 as measured weekly with digital planimetry and physical examination; number and type of treatment emergent AEs; changes in pain of the target ulcer (NPRS); and change in quality of life (w‐QoL assessment).
Descriptive statistical methods were used to summarize the data from the study, with hypothesis testing performed for primary and secondary endpoints. Summary statistics include the number of subjects (n), mean, median, standard deviation, minimum and maximum for continuous data and frequencies and percentages for categorical data. All statistical testing was two‐sided and performed using a significance (alpha) level of 0.05. All statistical analyses were conducted using IBM SPSS Statistics (v30).
The populations defined for the analysis included modified intent‐to‐treat (mITT), per protocol (PP) and safety populations, as previously described [40, 42, 43]. Briefly, the mITT population consisted of all randomized participants, excluding: (a) participants who were randomized but were later identified to be screen failures; and (b) participants randomized to one treatment group, but who received the other treatment group in error. The PP population additionally excluded: (a) participants who were withdrawn for any reason (e.g., lost to follow‐up, withdrawn at the investigators' discretion due to protocol adherence); (b) participants withdrawn due to a treatment emergent AE; and (c) participants with major protocol violations. The safety population included all participants who were randomized and received at least one treatment.
In terms of sample size calculations, several scenarios were simulated (15 000 simulations each) using a group sequential design with 2 looks when 60 and 120 subjects, respectively, completed the trial using the O'Brien‐Fleming analog alpha‐spending function for the primary endpoint. The final scenario achieved a 98% power to detect a difference of 0.35 between a treatment group proportion of 0.70 and a control group proportion of 0.35 at the 0.05 significance level (alpha) using a two‐sided Z‐Test (Pooled) (PASW software). Data from a single pilot study of 11 subjects treated with OFM‐HA plus SOC in similar index wounds showed that 64% healed by 12 weeks.
Although a formal interim analysis was conducted when 60 subjects had completed the study, it was later decided to add 20 subjects to the trial (N = 140) based on conditional power for the primary endpoint results with 120 subjects. The number of subjects added [20] did not inflate type 1 error since the conditional power was already above the promising zone [44].
Any missing complete wound healing endpoint data by TV13 was imputed by the analyst for the mITT population by scoring the following situations as not healed: participant died, participant was withdrawn, or participant experienced an amputation on the index foot that obliterated the Index Ulcer. This non‐healing imputation applied to the binary 12‐week closure endpoint; it is distinct from censoring in the time‐to‐event analysis. Other endpoint data was not imputed, with the exception of %PAR, which was set to 100% at the week of initial healing and all subsequent TVs.
Summary statistics for complete wound healing by 12 weeks (TV13) were calculated for each treatment group. Primary endpoint analysis was conducted using Fisher's exact test. A generalized linear model (logit link function) was created to adjust for differences between groups based on available patient and wound‐related variables that could influence wound healing significantly if the Fisher exact tests were statistically significant. The dependent binary variable was whether the wound healed or not by 12 weeks. Generalized linear models with additional variables were built using stepwise addition of variables starting with treatment group; model parsimony was checked using stepwise deletion of all available variables. The covariate‐adjusted analysis was supportive and used data‐driven variable selection; the unadjusted primary endpoint comparison remained the principal efficacy analysis.
Secondary endpoint analysis of time to heal within 12 weeks was conducted using the Kaplan–Meier (KM) approach and the log rank test with treatment as the factor. The %PAR was calculated using the following formula: ((A1 − Ax)/A1) × 100 where A1 is the baseline area (at TV1), and Ax is the area at the specified TV. Analysis was conducted using linear mixed modelling (LMM; repeated measures) with treatment, study visit and treatment‐by‐visit as fixed factors, area at randomization as a covariate, and percentage change as the response. For w‐QoL, the mean change in scores between randomization and EOS visits was calculated for each treatment group and compared using the Mann–Whitney test. VAS pain scores were analysed similarly using a population that had VAS pain score > 0 any time during the study. Type 1 error control used a hierarchical testing procedure, conditional on a statistically significant unadjusted primary endpoint: (1) time to heal; (2) PAR; (3) w‐QoL; (4) pain. Because the PAR hypothesis was not rejected, confirmatory testing did not proceed to w‐QoL or pain; these outcomes are descriptive.
3. Results
A total of 197 subjects were assessed and screened for eligibility in the study (Figure 1), from 10 sites between June 2023 and November 2025. Fifty‐four subjects were initially considered screen fails (27.4%). At randomization, 70 participants were assigned to the OFM‐HA plus SOC treatment group and 73 subjects were assigned to the SOC alone group. Three ulcers were removed to create the mITT population. One ulcer was removed as a screen failure having undergone randomization and treatment but later identified as a screen failure and was also found to have received the wrong randomization treatment. A second ulcer was removed as it received the wrong treatment in error following randomization, and a third ulcer was removed as a screen fail having undergone treatment. The mITT analysis was undertaken using 68 and 72 in the OFM‐HA plus SOC and SOC groups, respectively. Thirty participants in the mITT population withdrew or were withdrawn during the study: 10/68 (14.7%) in the OFM‐HA plus SOC group and 20/72 (27.8%) in the SOC group. In the OFM‐HA plus SOC group, 10 subjects withdrew or were withdrawn from the trial. Four subjects were removed due to AEs, two subjects due to a PI decision, one subject withdrew consent, one subject was withdrawn due to non‐compliance, one subject received a prohibited treatment, and one subject died. In the SOC group, 20 subjects withdrew or were withdrawn from the trial. The majority were due to AEs (n = 11). Five subjects were additionally lost to follow‐up, one subject withdrew consent, one subject was withdrawn due to non‐compliance, one subject was withdrawn due to a PI decision, and one subject died. The PP analysis was undertaken using 57 and 52 in the OFM‐HA plus SOC and SOC alone groups, respectively.
FIGURE 1.
CONSORT diagram. AE, adverse event; I&E, inclusion/exclusion criteria; mITT, modified intent‐to‐treat; OFM‐HA, ovine forestomach matrix‐hyaluronic acid; PP, per‐protocol; SOC, standard of care.
Key subject‐related variables in the mITT population (Table 2) showed that variables were reasonably balanced between treatment groups with the exception of diabetes duration (years), in which the OFM‐HA plus SOC group was significantly higher (OFM‐HA plus SOC: 18.4 years; SOC: 15.2 years, p = 0.048); history of DFU recurrence in which the SOC group was significantly higher (OFM‐HA plus SOC: 52%; SOC: 69%; p = 0.038); and HbA1c at both randomization (OFM‐HA plus SOC: 8.4; SOC: 7.5, p = 0.004) and EOS (OFM‐HA plus SOC: 7.7; SOC: 7.3, p = 0.033) in which the OFM‐HA plus SOC group was consistently and significantly higher. A comparison by treatment group for key subject‐related variables in the PP population (Table 3) showed that variables were reasonably balanced between treatment groups with the exception of significantly higher (prior) minor amputation counts in the OFM‐HA plus SOC group; and HbA1c at EOS in which the OFM‐HA plus SOC group was significantly higher (OFM‐HA plus SOC: 8.5; SOC: 7.7, p = 0.036). A comparison by treatment group for key comorbidities is shown in Supplementary Materials S1 and S2. Documented PAD/PVD was present in 11/68 (16%) OFM‐HA plus SOC participants and 9/72 (13%) SOC participants in the mITT population, despite meeting the perfusion eligibility criteria. A comparison by treatment group for key wound‐related variables in the mITT (Table 4) PP populations (Table 5) showed that variables were well balanced between treatment groups. In the mITT population, Table 4 records offloading for 68/68 and 67/72 participants, respectively; the reported mean percentage of visits with offloading was 88.8% (SD 8.36) versus 87.6% (SD 9.80; p = 0.63). This visit‐level measure does not establish continuous offloading between visits.
TABLE 2.
Subject related variables of the mITT population.
| Variable | OFM‐HA plus SOC | SOC | p |
|---|---|---|---|
| Age (years) | 59.5 (9.87) | 61.0 (10.25) | 0.40 |
| Race | |||
| White | 48 (71) | 58 (81) | 0.38 |
| Black/African American | 5 (7) | 3 (4) | |
| Latino | 15 (22) | 11 (15) | |
| Ethnicity | |||
| Hispanic/Latino | 44 (65) | 35 (49) | 0.062 |
| Sex | |||
| Male | 60 (88) | 54 (75) | 0.052 |
| Female | 8 (12) | 18 (25) | |
| BMI | 29.9 (6.04) | 31.0 (7.21) | 0.49 |
| Tobacco use | |||
| Current | 6 (9) | 9 (12) | |
| Former | 21 (31) | 25 (35) | 0.62 |
| Never used tobacco | 41 (60) | 38 (53) | |
| Diabetes duration (years) a | 18.4 (10.45) | 15.2 (10.21) | 0.048 |
| Subject age when first DFU appeared (years) | 56.4 (9.55) | 56.6 (10.58) | 0.74 |
| Prior DFU count |
2.6 (3.22) Median: 2; IQR: 3 |
3.1 (2.98) Median: 2; IQR: 4 |
0.19 |
| Other concurrent DFUs at screening | |||
| 0 | 58 (85) | 62 (86) | 1.0 |
| 1 | 10 (15) | 10 (14) | |
| History of DFU recurrence | 35 (52) | 50 (69) | 0.038 |
| Major amputation | 5 (7) | 3 (4) | 0.49 |
| Minor amputations | |||
| 0 | 40 (59) | 33 (46) | |
| 1 | 17 (25) | 17 (24) | 0.078 |
| 2 | 6 (9) | 14 (19) | |
| ≥ 3 | 5 (7) | 8 (11) | |
| Major foot deformities b | |||
| Charcot | 3 (4) | 4 (6) | 1.0 |
| Hammertoe | 3 (4) | 2 (3) | 0.67 |
| Equinus | 1 (2) | 0 (0) | 0.49 |
| Hallux valgus | 2 (3) | 0 (0) | 0.23 |
| Creatinine (mg/dL) c | 1.2 (0.43) | 1.2 (0.42) | 0.77 |
| HbA1c | |||
| At randomization | 8.4 (1.76) | 7.5 (1.57) | 0.004 |
| At EOS d | 7.7 (1.71) | 7.3 (2.07) | 0.033 |
|
Blood sugar (mg/dL) Mean (all visits) e |
193 (80.01) | 188 (70.64) | 0.96 |
Note: Figures are counts (percentages) for categorical variables and means (SD) for continuous variables, with medians and IQRs also for non‐normal variables.
Abbreviations: BMI, body mass index; DFU, diabetic foot ulcer; DFU, diabetic foot ulcer; EOS, end of study; HbA1c, haemoglobin A1c; mITT, modified intent‐to‐treat; OFM‐HA, ovine forestomach matrix‐hyaluronic acid; SOC, standard of care.
All subjects had type 2 diabetes.
Each tested separately.
7 values missing in the OFM‐HA plus SOC group and 10 values missing in the SOC group.
14 values missing in the OFM‐HA plus SOC group and 19 values missing in the SOC group.
Starting at day of randomization, excluding any unscheduled visits.
TABLE 3.
Subject related variables of the PP population.
| Variable | OFM‐HA plus SOC | SOC | p |
|---|---|---|---|
| Age (years) | 59.4 (9.78) | 60.2 (11.60) | 0.71 |
| Race | |||
| White | 38 (67) | 42 (81) | 0.22 |
| Black/African American | 4 (7) | 3 (6) | |
| Latino | 15 (26) | 7 (13) | |
| Ethnicity | |||
| Hispanic/Latino | 37 (65) | 25 (48) | 0.085 |
| Sex | |||
| Male | 49 (86) | 42 (81) | 0.61 |
| Female | 8 (14) | 10 (19) | |
| BMI | 29.5 (5.94) | 30.8 (5.58) | 0.26 |
| Tobacco use | |||
| Current | 6 (10) | 7 (13) | |
| Former | 18 (32) | 19 (37) | 0.70 |
| Never used tobacco | 33 (58) | 26 (50) | |
| Diabetes duration (years) a | 18.6 (10.47) | 15.3 (10.28) | 0.11 |
| Subject age when first DFU appeared (years) | 56.4 (9.38) | 55.5 (10.75) | 0.71 |
| Prior DFU count |
2.7 (3.40) Median: 2; IQR: 3 |
3.2 (3.19) Median: 2; IQR: 4 |
0.25 |
| Other concurrent DFUs at screening | |||
| 0 | 50 (88) | 46 (89) | 1.0 |
| 1 | 7 (12) | 6 (11) | |
| History of DFU recurrence | 29 (51) | 34 (65) | 0.17 |
| Major amputation | 5 (9) | 0 (0) | 0.058 |
| Minor amputations | |||
| 0 | 35 (61) | 22 (42) | |
| 1 | 12 (21) | 12 (23) | 0.029 |
| 2 | 5 (9) | 11 (21) | |
| ≥ 3 | 5 (9) | 7 (14) | |
| Major foot deformities b | |||
| Charcot | 2 (4) | 2 (4) | 1.0 |
| Hammertoe | 2 (4) | 2 (4) | 1.0 |
| Equinus | 1 (2) | 0 (0) | 1.0 |
| Hallux valgus | 2 (4) | 0 (0) | 0.50 |
| Creatinine (mg/dL) c | 1.2 (0.45) | 1.2 (0.40) | 0.52 |
| HbA1c | |||
| At randomization | 8.5 (1.75) | 7.7 (1.70) | 0.036 |
| At EOS d | 7.7 (1.76) | 7.4 (2.11) | 0.062 |
|
Blood sugar (mg/dL) Mean (all visits) e |
198 (80.60) | 189 (74.84) | 0.57 |
Note: Figures are counts (percentages) for categorical variables and means (SD) for continuous variables, with medians and IQRs also for non‐normal variables.
Abbreviations: BMI, body mass index; DFU, diabetic foot ulcer; EOS, end of study; HbA1c, haemoglobin A1c; OFM‐HA, ovine forestomach matrix‐hyaluronic acid; PP, per‐protocol; SOC, standard of care.
All subjects had type 2 diabetes.
Each tested separately.
7 values missing in the OFM‐HA plus SOC group and 10 values missing in the SOC group.
14 values missing in the OFM‐HA plus SOC group and 19 values missing in the SOC group.
Starting at day of randomization, excluding any unscheduled visits.
TABLE 4.
Wound related variables for the mITT population.
| Variable | OFM‐HA plus SOC | SOC | p |
|---|---|---|---|
| Wound area (cm2) a |
3.0 (3.41) Median: 2.0; IQR: 1.8 |
4.2 (4.53) Median: 2.2; IQR: 3.2 |
0.078 |
| Wound age (weeks) b |
17.7 (11.32) Median: 16; IQR: 17 |
17.6 (12.61) Median: 14.8; IQR: 19.8 |
0.66 |
| Vertical location | |||
| Plantar | 48 (71) | 47 (65) | 0.59 |
| Dorsal | 20 (29) | 25 (35) | |
| Position | |||
| Medial | 41 (60) | 40 (56) | 0.47 |
| Lateral | 26 (38) | 32 (44) | |
| Central | 1 (2) | 0 (0) | |
| Anatomical location | |||
| Toe | 9 (13) | 11 (15) | |
| Forefoot | 36 (53) | 32 (45) | |
| Midfoot | 12 (18) | 13 (18) | 0.53 |
| Hindfoot | 1 (2) | 6 (8) | |
| Heel | 7 (10) | 6 (8) | |
| Ankle | 3 (4) | 4 (6) | |
| Depth (mm) | 2.4 (5.46) | 1.9 (2.19) | 0.96 |
| Wagner grade | |||
| 1 | 37 (54) | 42 (58) | 0.73 |
| 2 | 31 (46) | 30 (42) | |
| Offloaded | 68 (100) | 67 (93) | 0.059 |
| Offloading type | |||
| CAM boot | 66 (96) | 64 (96) | |
| TCC | 1 (2) | 3 (4) | 0.36 |
| Other | 1 (2) | 0 (0) | |
| Offloading, mean of visits (%) | 88.8 (8.36) | 87.6 (9.80) | 0.63 |
| Number of debridements | 10.0 (4.19) | 9.8 (3.68) | 0.38 |
Note: Figures are counts (percentages) for categorical variables and means (SD) for continuous variables (median [IQR] additionally for non‐normal variables).
Abbreviations: mITT, modified intent‐to‐treat; OFM‐HA, ovine forestomach matrix‐hyaluronic acid; SOC, standard of care.
At randomization.
At screening.
TABLE 5.
Wound related variables for the PP population.
| Variable | OFM‐HA plus SOC | SOC | p |
|---|---|---|---|
| Wound area (cm2) a |
2.8 (2.91) Median: 1.8; IQR: 1.8 |
3.7 (4.18) Median: 2.0; IQR: 2.7 |
0.28 |
| Wound age (weeks) b |
17.1 (11.38) Median: 15.0; IQR: 16.5 |
18.1 (13.25) Median: 15.0; IQR: 19.7 |
1.0 |
| Vertical location | |||
| Plantar | 40 (70) | 38 (73) | 0.83 |
| Dorsal | 17 (30) | 14 (27) | |
| Position | |||
| Medial | 36 (63) | 24 (46) | 0.47 |
| Lateral | 20 (35) | 28 (54) | |
| Central | 1 (2) | 0 (0) | |
| Anatomical location | |||
| Toe | 8 (14) | 7 (13) | |
| Forefoot | 30 (53) | 23 (44) | |
| Midfoot | 10 (17) | 11 (21) | 0.75 |
| Hindfoot | 1 (2) | 4 (8) | |
| Heel | 6 (10) | 5 (10) | |
| Ankle | 2 (4) | 2 (4) | |
| Depth (mm) | 2.4 (5.89) | 1.7 (2.21) | 0.22 |
| Wagner grade | |||
| 1 | 32 (56) | 32 (62) | 0.70 |
| 2 | 25 (44) | 20 (38) | |
| Offloaded | 57 (100) | 49 (94) | 0.11 |
| Offloading type | |||
| CAM boot | 55 (96) | 47 (96) | |
| TCC | 1 (2) | 2 (4) | 0.51 |
| Other | 1 (2) | 0 (0) | |
| Offloading, mean of visits (%) | 88.7 (8.66) | 87.8 (10.21) | 0.73 |
| Number of debridements | 10.4 (4.02) | 10.7 (3.45) | 0.75 |
Note: Figures are counts (percentages) for categorical variables and means (SD) for continuous variables (median [IQR] additionally for non‐normal variables).
Abbreviations: OFM‐HA, ovine forestomach matrix‐hyaluronic acid; PP, per‐protocol; SOC, standard of care.
At randomization.
At screening.
For the mITT population, 46% (31/68) of the OFM‐HA plus SOC group were deemed healed at TV13 compared to 24% (17/72) in the SOC alone group (p = 0.008) (Table 6, Figure 2). The following variables were tested in various combinations within a generalized linear model (binomial distribution and logit link): wound area; ethnicity; sex; diabetes duration; history of DFU recurrence; minor amputation count category; and HbA1c at randomization. The final model, using a hybrid parameter estimation method and robust estimator, included treatment, area at randomization and history of DFU recurrence as significant variables. The estimated marginal means from the model adjusted for area at randomization and history of DFU recurrence were; OFM‐HA plus SOC, 43% healed; SOC, 26% healed; p = 0.045. For the mITT population, the reported Kaplan–Meier mean estimate over the observed study period for the OFM‐HA plus SOC group was 67.4 (95% CI: 61.6–73.2) days versus 75.2 (95% CI: 70.8–79.7) days in the SOC alone group (p = 0.023) (Table 6 and Figure 2). For the PP population, 54% (31/57) of OFM‐HA plus SOC group healed at 12 weeks versus 33% (17/52) in the SOC alone group (p = 0.033). When adjusted for significant variables, namely history of DFU recurrence, the estimated marginal means from the linear regression were OFM‐HA plus SOC; 55% healed; SOC, 35% healed; p = 0.039. A tipping‐point sensitivity analysis varied the assumed binary healing outcomes for the 30 withdrawn participants: 10 from the OFM‐HA plus SOC arm and 20 from the SOC arm (Supplementary Material S3). Statistical significance depended on the assumed outcomes; this analysis does not eliminate potential bias from differential withdrawal. Though not significant, the 6‐ and 12‐week PAR was greater in the OFM‐HA plus SOC group versus SOC group for both the mITT and PP populations (Table 6). Changes in wound QoL and patient‐reported pain between TV1 and EOS are reported descriptively in Table 6 for the mITT and PP populations; no confirmatory between‐group benefit is claimed because the testing hierarchy stopped at PAR. OFM‐HA treated ulcers received a mean of 8.6 ± 3.67 product applications across the mITT population. (Figures 3 and 4).
TABLE 6.
Primary and secondary efficacy outcomes mITT and PP populations.
| Outcome | OFM‐HA plus SOC | SOC alone | p |
|---|---|---|---|
| mITT | |||
| Complete wound closure at 12 weeks | 46% (31/68) | 24% (17/72) | 0.008 |
| Complete wound closure at 12 weeks—adjusted a | 43% | 26% | 0.045 |
| Kaplan–Meier mean estimate (days) |
67.4 (95% CI: 61.6–73.2) |
75.2 (95% CI: 70.8–79.7) |
0.023 |
| PAR% | |||
| 6‐week | 59.7 (SD: 42.24) | 45.7 (SD: 67.50) | Not tested d |
| 12‐week | 62.0 (SD: 103.82) | 45.5 (106.18) | Not tested d |
| Wound QoL Score—difference c | 0.5 (0.84) | 0.2 (0.70) | Not tested e |
| Pain Score—difference c | 1.0 (2.41) | −0.2 (2.03) | Not tested e |
| PP | |||
| Complete wound closure at 12 weeks | 54% (31/57) | 33% (17/52) | 0.033 |
| Complete wound closure at 12 weeks—adjusted b | 55% | 35% | 0.039 |
| Kaplan–Meier mean estimate (days) |
65.4 (95% CI: 58.9–71.9) |
73.2 (95% CI: 67.7–78.7) |
0.041 |
| PAR% | |||
| 6‐week | 61.4 (SD: 42.07) | 54.4 (SD: 61.46) | Not tested d |
| 12‐week | 62.4 (SD: 104.72) | 46.3 (SD: 107.10) | Not tested d |
| Wound QoL Score—difference c | 0.6 (0.89) | 0.4 (0.75) | Not tested e |
| Pain Score—difference c | 1.0 (2.47) | 0.3 (1.80) | Not tested e |
Abbreviations: CI, confidence interval; mITT, modified intent‐to‐treat; OFM‐HA, ovine forestomach matrix‐hyaluronic acid; PAR%, percent area reduction PP, per‐protocol; SD, standard deviation; SOC, standard of care.
Adjusted for; area at randomization and history of DFU recurrence.
Adjusted for history of DFU recurrence.
Difference between baseline and EOS.
Only tested as part of TV2‐13 in a linear mixed model (not statistically significant).
Due to failure to reject PAR hypothesis.
FIGURE 2.
(A) Comparison of the incidence of healing at 12 weeks for the mITT and PP populations. Kaplan–Meier survival curves comparing time to complete wound closure within 12 weeks for subjects in the mITT (B) and PP (C) populations. Shaded areas represent the 95% confidence intervals. MITT ** p = 0.008 PP * p = 0.033.
FIGURE 3.
48‐Year‐old male, right plantar midfoot DFU. (A) TV1, initial presentation (4.7 × 7.1 × 0.3 cm) and day of the first OFM‐HA treatment. (B) TV6, marked wound area reduction and depth resolution. (C) TV12 (11 weeks post‐OFM‐HA treatment start), wound closure achieved after 11 total OFM‐HA applications. (D) HCV, wound epithelialization confirmed. Closure was confirmed at the HCV; longer‐term recurrence was not assessed in this trial.
FIGURE 4.
67‐Year‐old female, left lateral forefoot DFU. (A) TV1, initial presentation (1.8 × 2.3 × 0.3 cm) and day of the first OFM‐HA treatment. (B) TV9, wound area reduction and eradication of depth noted. (C) TV13, (12 weeks post‐OFM‐HA treatment start), wound closure achieved after 12 total OFM‐HA applications. (D) HCV, wound epithelialization confirmed. Closure was confirmed at the HCV; longer‐term recurrence was not assessed in this trial.
There were 119 AEs of which 56 AEs were in the OFM‐HA plus SOC group and 63 AEs in the SOC group. The AE rates over 12 weeks in the safety (also the mITT) population on a per subject basis were 50% for the OFM‐HA plus SOC group and 51% for the SOC group. No unexpected safety‐related occurrences were noted during the study. In terms of index ulcer‐related infections, there were 10 events associated with 9 subjects in the OFM‐HA plus SOC group, a rate of 13% on a per subject basis. Corresponding values for the SOC group were 14 events in 12 subjects for a rate of 17%. Using osteomyelitis or gangrene descriptors as markers of deep wound infection, there was 1 occurrence in the OFM‐HA plus SOC group and 7 occurrences in the SOC group. Serious AEs included two deaths, one with symptoms of atrial fibrillation, and a second subject who developed acute renal failure with oliguria. Categorization of AE severity and relatedness are shown in Table 7. Two severity categories were noticeably different between treatment groups. In the OFM‐HA plus SOC group, moderate was the dominant category (50%) with fewer mild AEs (39%) whereas these categories were reversed for the SOC group (36% and 56%, respectively). Relatedness patterns were reasonably similar for both treatment groups. In the OFM‐HA plus SOC group, the AEs classified as possibly related all involved infection with the exception of one new wound (only 2 out of the 6 infection cases involved non‐index wounds). In the SOC group, all 5 cases involved index ulcer‐related infections.
TABLE 7.
Categorization of AEs by severity and relatedness.
| AE category | OFM‐HA plus SOC | SOC |
|---|---|---|
| Severity | ||
| Mild | 22 (39) | 35 (56) |
| Moderate | 28 (50) | 23 (36) |
| Severe | 4 (7) | 4 (6) |
| Life‐threatening | 1 (2) | 0 (0) |
| Death | 1 (2) | 1 (2) |
| Relatedness | ||
| Not related | 44 (79) | 54 (86) |
| Unlikely (to be related) | 5 (9) | 4 (6) |
| Possibly related | 7 (12) | 5 (8) |
Note: Figures in parentheses represent percentages for each treatment group.
Abbreviations: AE, adverse event; OFM‐HA, ovine forestomach matrix‐hyaluronic acid; SOC, standard of care.
4. Discussion
Ulceration in people with diabetes reflects interacting systemic and local factors. Neuropathy with repetitive loading, footwear injury, trauma and ischemia may initiate or perpetuate a focal wound; fixed structural deformity is not required in every case [1, 45]. Normal wound healing in DFUs is impaired by persistent unresolving inflammation, decreased angiogenesis and dysfunctional cellular migration and proliferation. As such, DFUs commonly do not progress through the normal phases of wound healing to achieve complete re‐epithelialization [45]. In the current study, a composite CAMP containing OFM and HMWHA significantly increased the incidence of wound closure over a 12‐week period compared to SOC alone. The Kaplan–Meier comparison also favoured OFM‐HA plus SOC during the 12‐week observation period.
OFM‐HA is a bioscaffold‐based therapeutic intervention that aims to address the unique cellular deficiencies seen in DFUs, namely, inflammation, elevated tissue proteases, moisture imbalance, impaired angiogenesis and cellular dysfunction. OFM‐HA is a multi‐layered composite bioscaffold composed of minimally processed decellularized OFM and a layer of HMWHA, whereby the multi‐layered device is fabricated without the need for chemical crosslinking or additional additives. Avoidance of chemical crosslinking provides a rationale for reducing crosslinking‐associated host responses [46, 47], while preserving a scaffold architecture compatible with cellular migration and exudate egress [30]; these processes were not measured in this RCT. OFM is predominantly composed of collagens, but additionally includes many naturally occurring proteins that exist in association with tissue ECM and play a role in tissue homeostasis and importantly during the wound healing cascade [17, 48]. While OFM serves a structural role to support cell infiltration and tissue repair, lesser components are also available to participate in cellular processes and advance wound healing. For example, early in vitro and ex vivo studies demonstrated that soluble components of OFM stimulated endothelial cell migration and proliferation as well as angiogenesis [19]. Further studies demonstrated that components of OFM inhibited tissue proteases, including various MMPs (MMP‐1, MMP‐8, MMP‐13, MMP‐2, MMP‐9, MMP‐3 and MMP‐10), as well as neutrophil elastase [18]. More recently, progenitor cell homing has been shown in response to peptides found within OFM [20], potentially further contributing to the anti‐inflammatory properties of this technology.
For OFM‐HA, the addition of HA, and specifically HMWHA (> 1000 kDa), was made due to its known anti‐inflammatory properties, including the suppression of MMPs, amplification of growth factor activity and maintenance of moisture balance [49]. HA is an essential component of tissue ECM, existing as the key polymeric component of the interstitial matrix. During normal tissue homeostasis, HMWHA is predominant. Following tissue injury, HMWHA polymers are rapidly cleaved via reactive oxygen species and hyaluronidases to low molecular weight HA (LMWHA), which in turn drives cytokine release, inflammatory cell recruitment (e.g., macrophages, neutrophils), and stimulates angiogenesis [50, 51].
In the context of chronic wounds, including DFUs, there is a sustained shift towards LMWHA driven by persistent oxidative stress and elevated hyaluronidase activity, resulting in ongoing fragmentation of HMWHA and perpetuation of a pro‐inflammatory microenvironment that impairs normal healing [52, 53]. Given the role of LMWHA in wound chronicity, its accumulation and HA fragmentation profiles have been proposed as a surrogate marker for wound chronicity [53]. Therefore, considering the depletion of HMWHA within the chronic wound environment, and the overabundance of LMWHA, the application of exogenous HMWHA, for example as OFM‐HA, has the potential to overcome the inflammatory burden and progress a stalled wound to normal healing. Several of the anti‐inflammatory effects of HMWHA are mediated through multivalent binding and clustering to the CD44 receptor on leukocytes, which modulates downstream inflammatory signalling [54]. For example, the inhibition of pro‐inflammatory toll‐like receptor signalling, the production of anti‐inflammatory cytokines, as well as the activation of immune cell types like regulatory T cells and natural killer T cells [54]. The HMWHA‐CD44 binding also appears to be central in the downregulation of various MMPs, potentially through the induction of the MKP‐1 pathway [55]. Furthermore, the HMWHA‐CD44 complex has been implicated in the regulation of downstream growth factor signalling, including TGF‐β–mediated pathways [56]. Moist wound healing is a key tenet of modern wound medicine, and in normal tissue HA plays a key role in moisture retention and balance within the interstitial space. HA is extremely hydrophilic and able to sequester ~1000 times its weight in water to form a hydrogel material [30, 57]. As such, the application of exogenous HMWHA, for example in the form of OFM‐HA, may reduce the risk of wound desiccation during the critical processes of tissue repair and regeneration.
To our knowledge, OFM‐HA is the only CAMP that contains unmodified HMWHA. However, various HA formulations have been developed for wound care applications [49], and the effectiveness of HA‐based formulations has been widely studied for the treatment of DFUs. For example, a meta‐analysis of HA‐based devices in DFU treatment included 456 DFUs from seven RCTs, concluded that HA improved the incidence of healing and reduced the time to healing, without an increase in AEs, compared to control dressings [31]. Lee et al. [58] demonstrated that DFUs treated with an HA‐based dressing had a significantly greater healing rate, reduced time to 50% PAR, as well as a significantly faster overall healing velocity, compared to a SOC. Similarly, Uccioli et al. [59] and separately, Caravaggi et al. [60] demonstrated significantly improved healing outcomes using an HA‐based autologous engineered graft compared to SOC dressings, while Abbruzzese et al. [61] showed similar outcomes versus SOC using an HA‐based gel formation. The present results support further evaluation of the composite OFM‐HA device. The trial did not measure MMP activity, angiogenesis, HA fragmentation or CD44 signalling. These mechanisms provide biological rationale, but comparison of the composite with SOC cannot isolate the independent contribution of HA or demonstrate synergy between HA and OFM.
Interpretation also requires attention to infection, nutrition and perfusion. Armstrong DG and Lipsky BA emphasized clinical assessment of infection severity, evaluation for osteomyelitis and appropriately directed treatment [62]. The present infection event counts are descriptive and do not demonstrate an anti‐infective effect of OFM‐HA.
In a separate randomized trial, Armstrong DG and colleagues found no overall improvement in healing with oral arginine, glutamine and beta‐hydroxy‐beta‐methylbutyrate supplementation; post hoc findings suggested potential benefit in participants with lower albumin and/or impaired perfusion [63]. That study supports attention to nutritional and vascular heterogeneity, but does not establish a nutritional treatment effect in the present trial.
The Society for Vascular Surgery WIfI framework described by Mills JL Sr and colleagues considers wound extent, ischemia and foot infection separately [64]. Full thickness describes wound depth; it is not a complete assessment of limb threat. Meeting the present perfusion eligibility criteria did not exclude PAD, consistent with the intersocietal PAD guideline caution that no single test value reliably excludes PAD [65]. WIfI stages cannot be retrospectively assigned from the aggregate data reported here.
Moisture balance remains part of wound care. The 2023 IWGDF wound‐healing guideline recommends against collagen or alginate dressings specifically as interventions to enhance DFU healing, with low‐certainty evidence [66]. This recommendation should not be interpreted as evidence that every use is harmful or that all matrix products are interchangeable. The present comparison concerns the specified OFM‐HA and control regimens.
Strengths include the randomized multi‐centre design, blinded endpoint assessment and an explicit hierarchy for secondary outcomes. Important limitations remain. The analysis excluded three randomized participants and is therefore mITT rather than full ITT. Withdrawal was more frequent in SOC than OFM‐HA plus SOC (27.8% vs. 14.7%), and the supportive adjusted closure comparison was close to the significance threshold (p = 0.045). The results apply to selected chronic full thickness foot wounds meeting the trial criteria, including the protocol‐defined Wagner grade 1 or 2 categories, and should not be generalized to all infected or ischemic wounds. Visit‐level offloading was recorded, but continuous adherence between visits, detailed initiating biomechanics, arm‐level perfusion test distributions, and site‐specific treatment effects are not characterized in this report. These factors limit assessment of treatment fidelity and generalizability. Confirmation of closure approximately 2 weeks later does not establish sustained remission. Longer follow‐up is needed to evaluate recurrence, amputations, mortality and resource use. A separate economic model is planned for publication; this RCT does not establish cost‐effectiveness.
5. Conclusions
In selected chronic full thickness wounds of the foot in people with diabetes meeting the study eligibility criteria, OFM‐HA within the specified care regimen increased 12‐week closure compared with SOC. Interpretation requires consideration of post‐randomization exclusions, differential withdrawal, limited biomechanical characterization and the adjusted result close to the significance threshold. This trial does not determine the independent contribution of HA or establish long‐term recurrence, limb preservation or economic outcomes.
Funding
This study was funded through a research grant from Aroa Biosurgery Limited (Auckland, New Zealand); provided to the Professional Education and Research Institute (PERI).
Ethics Statement
Ethical approval was obtained by WCG IRB (reference number: 20231642; ClinicalTrials.gov: NCT06035536).
Consent
All patients provided written informed consent for their images and data to be used for research and publication purposes. The study was conducted in accordance with the World Medical Association Declaration of Helsinki ethical guidelines.
Conflicts of Interest
David G. Armstrong, DPM, MD, PhD received research funds from PERI to design and administrate the study and also assist with the writing and review of the manuscript. Dennis P. Orgill, MD, PhD received research funds to serve as a plastic surgeon to review study photos and assist with the writing and review of the manuscript. Robert D. Galiano, MD received research funds to serve as a plastic surgeon to review study photos and assist with the writing and review of the manuscript. John C. Lantis, MD received research funds to assist in review of the final data analysis and writing and review of the manuscript. Paul Glat, MD received research funds to serve as a plastic surgeon to review study photos and assist with the design of the protocol. Unfortunately, he succumbed to cancer prior to the study conclusion and drafting of the manuscript. Alexander M. Reyzelman, DPM received research funds as a clinical investigator in the research trial and assisted with the review of the manuscript. Robert J. Snyder, DPM, his university received research funds as a clinical investigator in the research trial and he assisted with review of the manuscript. Marissa J. Carter, PhD received research funds to provide assistance with study design as well as the statistical analysis plan, provide the statistical analysis for this trial and assist with writing of the result section of the manuscript. Charles M. Zelen, DPM is the medical director of the PERI and his company received research funds to administrate the clinical trial and write the paper for publication. There are no other conflicts of interests with any of the authors in relationship to this study, or with regard to Aroa Biosurgery Limited (Auckland, New Zealand); IRB conflicts of interest statements are on file with PERI. Adam L. Isaac declares no conflicts of interest.
Supporting information
Supplementary Material S1: Selected comorbidities noted at first physical examination by treatment group for the mITT population.
Supplementary Material S2: Selected comorbidities noted at first physical examination by treatment group for the PP population.
Supplementary Material S3: Sensitivity analysis heat map.
Acknowledgements
The authors acknowledge staff at the Professional Education and Research Institute (PERI) for support in execution of the study.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material S1: Selected comorbidities noted at first physical examination by treatment group for the mITT population.
Supplementary Material S2: Selected comorbidities noted at first physical examination by treatment group for the PP population.
Supplementary Material S3: Sensitivity analysis heat map.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.