A prospective, randomized, controlled, crossover study comparing three multilayered foam dressings for the management of chronic wounds

This was a prospective, randomized, controlled clinical trial (RCT) using a 2 × 2 crossover (repeated measures) design to evaluate the efficacy and safety of three multilayer foam dressings in the management of chronic, exuding wounds in the outpatient setting. Subjects presenting with a VLU or DFU were assessed according to study inclusion and exclusion criteria and eligible subjects were asked to provide written informed consent. The study was conducted at three outpatient clinical centers in the USA (Newark, NJ [1]; San Francisco, CA [2]; and Pittsburgh, PA (one of the centers of the Serena Group [6]) ) between May and October 2019. The clinical protocol was approved by an independent ethics committee and the investigation was performed in accordance with the ethical principles outlined in the Declaration of Helsinki and applicable regulatory requirements.

When designing the study, the principal investigator thought that the best way to study the wound dressings would be to use a repeated measures design for two main reasons: the similarity in the devices and; the ability to compare the dressings in treating the same wound. There are benefits and disadvantages to using a repeated measures (crossover) design. In repeated measures designs, the subjects are their own controls because the model assesses how a subject responds to all of the treatments. By including the subject block in the analysis, it is possible to control for factors that cause variability between subjects. The result is that only the variability within subjects is included in the error term, which usually results in a smaller error term and a more powerful analysis. Benefits include more statistical power, fewer subjects, quicker and less costly than the traditional parallel design, and the ability to assess an effect over time. The biggest drawbacks are known as order effects, and they are caused by exposing the subjects to multiple treatments. Order effects are related to the order that treatments are given but not due to the treatment itself. In wound care (for example), effects and scores can improve over time due to the progress of healing. Order effects can interfere with the ability of the analysis to correctly estimate the effect of the treatment itself. Randomization allows time between treatments and counterbalances the order of treatments among others. The other disadvantage (unlikely with wound dressings) is carry-over effect. These are caused by an effect caused by the first treatment that lingers after the crossover occurs.

The study recruited adults (18–85 years of age) with VLUs and DFUs, and adequate circulation for healing. To rule out moderate-to-severe peripheral artery disease (PAD) in the study population, all subjects had ankle-brachial index (ABI) determined by Doppler. Although the Society for Vascular Surgery refers to an ABI of ≤0.9 as the threshold for the diagnosis of peripheral artery disease (PAD) [15], subjects with ABI ≥0.7 were considered suitable for inclusion in the trial, thus enabling ‘real world’ patients with mild PAD to be included in the study population. Although ABI measurement is a relatively simple and effective tool for PAD diagnosis, its sensitivity among diabetic patients is low. This low sensitivity is attributed to arterial wall calcification and atherosclerotic changes that give rise to high (1.4 and above) ABI values [16]. Thus, if the measured ABI was >1.0, then a toe pressure had to be obtained. Only those subjects with toe pressure >70 mmHg or toe-brachial index in the range 0.5–0.75 were considered for inclusion. Subjects with ABI <0.7 were excluded.

Basic care for the VLU subjects was standardized multilayer compression. All participants with DFUs received off-loading (non-removable offloading boot with insole, customized to the subject's weight and wound size by the investigator). All participants visited the clinic on a twice-weekly basis over a 4-week period.

Individuals were excluded from the study if they: had a pressure ulcer (as defined by international guidelines issued by the European Pressure Ulcer Advisory Panel, the National Pressure Injury Advisory Panel and the Pan Pacific Pressure Injury Alliance [17]) or local wound infection (based on clinical signs and symptoms) or evidence of PAD (ABI <0.7); had been diagnosed with a malignancy (other than cutaneous basal cell carcinoma) or were currently receiving or had received radiotherapy or chemotherapy within 3 months of randomization; had received growth factor therapy (e.g., autologous platelet-rich plasma gel) within 2 weeks prior to screening; were pregnant or lactating during the study period; had been enrolled or participated in another investigational device, drug or biological trial within 30 days prior to study baseline; had a history of alcohol or drug abuse, known allergy/hypersensitivity to any of the components of the dressings or for any reason at the investigator's discretion.

The three wound dressings under evaluation were: Mepilex^® Border Flex (Mölnlycke Health Care, Gothenburg, Sweden) [MxBF], Allevyn Life (Smith & Nephew Inc, MA, USA; AL), and Optifoam^® Gentle EX (Medline Industries Inc, IL, USA; OGEX). All three dressings are considered ‘bordered dressings’ with a wound contact (pad) foam surrounded by an adhesive border. The selection of the dressing size was based on the wound surface area (WSA): equal to or less than 60% of the dimensions of the wound contact pad (Table 1).

Participants were allocated to four treatment groups by computer randomization (Pharma Consulting Group, Uppsala, Sweden) as shown in Table 2. Wound debridement was allowed at the investigator's discretion prior to enrolment; however, additional debridement during the study was not permitted. Wound dressings were applied on Day 1 (Week 1) and the subjects were seen twice-weekly throughout the treatment period. Assessments of wound and surrounding skin characteristics, as well as all other evaluations, took place once-weekly at dressing change. The scheduled dressing change was on Day 7 of each treatment week (e.g., Visit Days 7, 14, 21 and 28), unless a dressing change became necessary due to strikethrough, loss of adherence or subject discomfort or pain. In total, subjects attended the wound care center for up to eight visits during treatment. At each visit, evaluations were performed to assess the condition of the wound dressing, wound status, presence of infection, wound pain and subject comfort. Any medication which was considered necessary for the subject's safety and well-being could be used, however topical medications were prohibited.

Wound dressing wear time and durability were determined by investigator's judgement and photographic assessment of dressing strikethrough (i.e. inability of dressings to stay sealed over wounds, causing leakage of exudate). Exudate absorption and dispersion on the wound contact foam pad were determined clinically and by photo-digital planimetry. The outer and inner facings of the dressings were examined for exudate absorption and strikethrough. WSA was measured serially using photo-digital planimetric software (PictZar Pro (Version 7.6.1), Biovisual Technologies, NJ, USA) [18]. Dressing comfort and subject-reported outcomes were captured at the end of weeks 2 and 4. Health-Related Quality-of-Life (HRQoL) SF-12 [19] was captured at the initial visit and then bi-weekly.

Subjective clinical wound assessments, undertaken by the investigators in line with normal clinical practice, consisted of: type of wound drainage (serous, sanguineous, serosanguineous, purulent); exudate amount (none, scant/minimal, moderate, heavy); exudate absorption (very poor, poor, good, very good, not applicable); exudate dispersion (over 1–25% of pad, 26–50%, 51–75%, 76–100%); wound granulation (none, trace islands of granulation tissue, <25% of wound base covered with granulation tissue, 25–49%, 50–74%, 7%–99%, 100%); nonviable tissue (eschar, fibrin slough, both; none, <25%, 25–49%, 50–74%, 75–100%); wound size and wound healing (%). Condition of the surrounding skin was assessed by signs of inflammation (erythema, oedema, induration), skin irritation at the dressing site, skin rash, skin erosion, stasis dermatitis, vesicular erosion (blistering) and degree of skin maceration (none, slight, moderate or severe).

Signs and symptoms of infection were determined clinically by the investigator and included: increased pain and tenderness, increased warmth, sudden increase in ulcer size, presence or absence of localized erythema, foul smelling exudate and easy bleeding of the wound.

Local wound pain was evaluated using the Baker-Wong (Faces) Scale [20], before and after each dressing change defined as: local wound and skin pain prior to removal, pain at removal, local wound or skin pain immediately after dressing removal, preprocedural or intraprocedural pain medication given at dressing removal (concomitant medication).

Dressing comfort and conformability, as evaluated by subjects, were judged by comfort during wear, overall impression of dressing, dressing bulkiness (lack of), friction, discrete appearance, stay-on-ability, dressing stick to ‘hairy skin’ (lack of) and durability during showering (all ranked as very poor, poor, good, very good, not applicable). Investigator-reported dressing outcomes were assessed by ease of handling, ability to remain intact, ease of application, ability to be repositioned, conformability, ability to stay in place and ease of removal (all ranked as very poor, poor, good, very good). Additionally, it was recorded whether the dressing caused skin stripping, left material behind at dressing change, adhered to the wound bed, led to wound re-injury or skin trauma upon removal, absorbed exudate even under compression and whether it caused trauma to wound edges. A printed questionnaire was used to capture these subjective assessments.

Viedoc (Viedoc Technologies, Uppsala, Sweden), a web-based electronic case report form (eCRF) system, was used to capture data. The eCRF system complied with FDA Title 21 CFR part 11 (ER/ES) requirements and training in its use was given to personnel at the investigational sites before or at study initiation, together with training on other aspects of the study protocol (e.g., the application of the test dressings).

The primary end point was wound dressing durability (dressing wear time), defined as the interval of time (in days) to dressing strikethrough (loss of edge seal/adherence, leaks, dislodgement) and need for dressing change. Dressings were evaluated as ‘Unchanged’ (looks the same as when applied), ‘Partly Saturated’ (<50% saturated with exudate but remaining intact), ‘Mostly Saturated’ (>50% saturated with exudate) and ‘Strikethrough.’ Strikethrough was defined as the inability of the dressing to stay sealed over the wound, causing leakage of wound exudate. Strikethrough could be the result of complete saturation, loss of edge seal/adherence, dislodgement and/or a defect in the dressing.

Secondary end points were: investigator-judged dressing performance, clinical wound characteristics (wound healing status, condition of surrounding skin, signs of infection and local pain levels), adverse events (AE), device related adverse events (ADE) associated with the dressings and subject-centered outcomes between the treatment groups.

The plan was to enroll approximately 40 subjects (1:1, DFU to VLU) in order to provide sufficient statistical power for the primary end point. The anticipated mean difference in number of days to strikethrough between Period 1–Period 2 between the two groups MxBF and active control was assumed to be twice the difference in the effect MxBF minus active control. It was estimated (assumed) that the standard deviation (SD) for the difference in time to strikethrough would be 0.65 days, between Period 2 and Period 1, both in the group starting with MxBF and in the group starting with active control. In order to find a difference of 0.5 days between the number of days to strikethrough between MxBF and active control, with a power of 80%, a total of 16 evaluable subjects per crossover study would be needed.

The full analysis set (FAS) included all participants with at least one measurement of follow up; the per protocol (PP) population included all subjects who fulfilled all inclusion/exclusion criteria, who completed the 2 × 2 weeks study and who were not described as protocol violators; the safety population included all enrolled individuals who had applied at least one of the study dressings.

The primary efficacy variable, mean number of days to strikethrough, and all of the other efficacy variables follow a non-normal distribution. Therefore, non-parametric tests were used. It was assumed that wound status would be improved during the second period of the crossover, implying that the statistical analysis should adjust for period effect in the crossover study.

For the primary efficacy variable, all other continuous outcome variables, all ordered categorical variables and all dichotomous variables, the adjustment for period effect would be performed in the following way: for all individuals, the difference in the efficacy variable between Period 2 and Period 1 in the crossover would be calculated. These differences would then be compared between subjects who began with Mepilex Border Flex in Period 1 and subjects who started with active control in Period 1, with an optimal two-sided two-sample test. Continuous variables were described with mean, SD, median, minimum, and maximum and categorical variables by number and percentages. For continuous variables, the differences would be analyzed with Fisher's nonparametric permutation tests between the two groups and for ordered categorical variables and dichotomous variables the differences, number and percentages improved, not changed and worsened, would be analyzed with Mantel-Haenszel Exact Chi-square test.

The main statistical analysis was performed on the FAS, with an additional statistical analysis performed on the PP population. The primary end point analysis consisted of a two-sided sign test on both the FAS and PP populations at a significance level of 0.05 on each of the treatment arms. All analyses were performed using SAS^® v9.4 (NC, USA) or later.

Forty-one subjects were enrolled in the study, of whom 20 were randomized to MxBF versus AL and 21 to MxBF versus OGEX (Figure 1). Among these subjects, 31 completed the study. Across all treatment arms, ten subjects left the study prematurely – one was withdrawn immediately after randomization due to ineligibility, two were withdrawn because of adverse events, six were withdrawn because their wound had healed before their Day 28 visit and one subject was lost to follow-up (Figure 1). The FAS consisted of 38 subjects (VLU, n = 17; DFU, n = 21) and the PP population of 24 subjects. The baseline demographic features of the subjects were similar across studies; more men than women took part in the study (Table 3).

Wound characteristics at baseline are presented in Table 4. Thirty-six percent had a >6 week history of not healing and 37% had wounds that were older than 1 year. The majority of the wounds (68.4%) were unresponsive to previous treatments and had moderate exudate. The type of wound exudate was described as serosanguineous in 84% of the wounds. Nearly 95% of the wounds studied were fully covered with granulation tissue.

As the PP population was relatively small and a statistical analysis revealed similar findings to that undertaken on the FAS population, only data from the FAS analysis are reported here.

Among the safety population (n = 40), there were no serious AEs or ADEs. Two AEs were reported (both local wound infections) that were not associated to a treatment regimen. Both subjects were discontinued from the study and treated with appropriate antibiotic therapy until resolution. One device deficiency was reported in the AL group (dressing became wet while the subject was showering) but this did not affect safety.