Franck David 1 Jean-Louis Wurtz 2 Nicolas Breton 3 Olivier Bisch 4 Philippe Gazeu 5 Jean-Charles Kerihuel 6 Odile Guibon 7

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1 Received: 27 July 2017 Revised: 6 October 2017 Accepted: 11 October 2017 DOI: /iwj ORIGINAL ARTICLE A randomised, controlled, non-inferiority trial comparing the performance of a soft silicone-coated wound contact layer (Mepitel One) with a lipidocolloid wound contact layer (UrgoTul) in the treatment of acute wounds Franck David 1 Jean-Louis Wurtz 2 Nicolas Breton 3 Olivier Bisch 4 Philippe Gazeu 5 Jean-Charles Kerihuel 6 Odile Guibon 7 1 Verzy, France 2 ResearchLink France, Mundolsheim, France 3 ResearchLink France, Béziers, France 4 ResearchLink France, Bischheim, France 5 Mauguio, France 6 Vertical, Paris, France 7 Medical Affairs Department, Mölnlycke Health Care, Wasquehal, France Correspondence F. David, MD, General Practitioner, 18 rue Arthur Lallement, Verzy, France. dr.fdavid.verzy@wanadoo.fr Wound contact layer (WCL) dressings are intended to protect tissue during the healing process. A randomised controlled trial was undertaken to compare 2 such dressings. Outpatients with acute wounds were randomly allocated to treatment with either a soft silicone-coated WCL (intervention group, n = 59) or a lipidocolloid-impregnated WCL (control group, n = 62). At the first dressing removal (day 3), 89.8% of patients in the intervention group experienced nonpainful dressing removal (defined as a pain rating <30 mm on a 100 mm visual analogue scale), compared with 73.6% of patients in the control group (P =.017) (per protocol population). At day 21, wounds were considered as healed in 66.1% of patients in the intervention group compared with 43.5% in the control group (P =.012) (intention-to-treat population). Both dressings were well tolerated and rated highly in terms of in-use characteristics, although the soft silicone-coated WCL was rated significantly higher than the lipidocolloid-impregnated WCL in terms of its ability to remain in place (P=.016). The results indicate that the soft silicone-coated WCL is suitable for the management of acute wounds as it can minimise dressing-associated pain and support healing. KEYWORDS acute wound, burn, randomised controlled trial, traumatic wound, wound dressing-associated pain 1 INTRODUCTION Wound contact layers (WCLs) are primary dressings that are widely used in the management of non-complicated acute wounds or chronic wounds at the proliferative stage of the healing process. While numerous types of WCL dressings are available, they all share a common basic structure composed of a thin non- or low-adherent layer impregnated with various compounds. The main purpose of WCLs is to protect granulation tissue growth and reepithelialisation from external stresses in order to promote a smooth healing process. 1 WCL dressings are also expected to limit periwound skin damage and, while not designed to absorb and retain moderate to strong exudation, it was designed to favour drainage of excessive wound fluids towards secondary absorbent dressings. 2 In addition, WCL dressing changes should be atraumatic to viable tissue and as painless as possible. 3 This latter aspect was the main deficiency of the first available WCL dressings, which were generally composed of a simple nylon or polyester layer impregnated with petrolatum or paraffin. 4 If these dressings were left in place for Int Wound J. 2018;15: wileyonlinelibrary.com/journal/iwj 2017 Medicalhelplines.com Inc and John Wiley & Sons Ltd 159

2 160 DAVID ET AL. extended periods (eg, more than 3-4 days), the compound impregnating the dressings had a tendency to be absorbed by the secondary dressing and, to a lesser extent, by the wound bed itself. Consequently, these early WCL dressings were prone to drying out, ultimately increasing the risk of dressing adherence to the wound and surrounding skin. Dressing removal was therefore potentially very painful and had the propensity to cause injury to viable underlying tissue. Another adverse event (AE) of these dressings was the potential for growth of granulation tissue into the large pores of their mesh-like structure, thereby further increasing the risk of tissue damage on dressing removal. Two technological advancements have contributed to improvements in the performance of this class of wound dressing. The first approach involves the use of a mixture of carboxymethylcellulose (CMC) particles combined with lipidic particles. This mixture, when applied on the wound bed, forms a gel that facilitates atraumatic removal and enhances fluid management. 5,6 This technology is commercially available in the form of the UrgoTul dressing, supplied by Urgo Medical. The second approach is based on the concept of covering a polyester or nylon mesh with a very thin micro-perforated layer of silicone, a gentle pressure-sensitive adhesive. Silicone is biocompatible, and as it is a solid, there is no risk of it being absorbed into secondary dressings while its micro-perforations help to drain excessive wound fluids away from the wound bed. In addition, as a result of the gentle but secure adhesive properties of silicone, dressings coated with this compound will remain firmly in place but can still be easily removed without damaging the wound bed or the peri-wound skin, thus minimising pain to the patient The very first, and still most widely used, silicone WCL dressing is Mepitel, supplied by Molnlycke Health Care. Now, since it has been introduced on the market, Mepitel One, a new version of Mepitel, is also used. Mepitel One is coated with silicone on just one side (ie, the one that comes into contact with the wound). Due to the lack of controlled trials comparing WCLs, WCL dressing selection is primarily based on empirical evidence and personal experiences. 13 For this reason, a randomised controlled trial (RCT) was undertaken to verify that, at worst, the Mepitel One WCL dressing is not inferior, in terms of both pain induced by dressing removal and healing rate, to the lipidocolloid-impregnated WCL dressing in the management of acute wounds typically seen in usual daily practice. 2 MATERIALS AND METHODS This 2-arm, parallel-group RCT of outpatients with acute wounds was conducted from September 2014 to November 2015 by 22 French general practitioners (GPs). Key Messages wound contact layer (WCL) dressings are primarily used to protect granulation and reepithelialisaton from external stresses, thereby facilitating the healing process while minimising wound trauma and pain the aim of this randomised, controlled, non-inferiority trial was to compare the performance of 2 WCLs (a soft silicone-coated WCL and a lipidocolloid-impregnated WCL) in terms of pain experienced during dressing change, wound closure, in-use dressing characteristics, and safety when used in the management of non-infected acute wounds (3 days or less after injury) significantly more patients in the soft silicone-coated WCL group experienced non-painful dressing removal (defined as a pain rating <30 mm on a 100 mm visual analogue scale) at the first dressing removal (day 3) than in the lipidocolloidimpregnated WCL group; this was confirmed with statistical analyses in the PP and intention-to-treat (ITT) populations in the ITT population, wounds were considered healed in significantly more patients in the soft silicone-coated WCL group compared with the lipidocolloid-impregnated WCL group at day 21 local tolerability was good in both groups, and in-use dressing characteristics evaluated by the patients were similar between groups; The soft silicone-coated WCL significantly outperformed the lipidocolloid-impregnated WCL in terms of the ability of the dressing to remain in place 2.1 Patients eligibility criteria Patient eligibility criteria for this study were similar to those used in the RCTs that have previously established the efficacy of Mepitel and UrgoTul, the reference treatment in the present non-inferiority trial. 4,17,18 Adult patients, aged 18 years, were eligible if they presented with an acute wound of traumatic origin (dermabrasion, skin tears, other) or a benign thermal burn (superficial burn without factors that can affect the severity outcome, such as age >60, impairment of vital or functional location or associated lesion, and involving less than 10% of total body surface) requiring the use of dressings. Wound size had to be between 3 and 240 cm 2 and be covered by a maximum of 2 investigational products. Patients had to be seen at the latest 3 days after injury. Exclusion criteria were surgical wounds; infected, moderately to highly exuding, and haemorrhagic wounds; diagnosed underlying disease (eg, diabetic neuropathy, cerebrovascular accident), which as judged by the investigator could have interfered with the pain assessment; and known hypersensitivity to any of the components of the investigational products. 2.2 Study design Patients meeting the selection criteria were asked to participate, and after providing written consent, they were allocated by centralised randomisation to either the

3 DAVID ET AL. 161 investigational dressing (Mepitel One) or the control dressing (UrgoTul) for a period of 21 days. At the inclusion visit (V1), main demographic characteristics and relevant medical history were collected by the investigator and recorded in an electronic case report form. The origin and nature of the wound were reported along with the time elapsed between injury and visit. Any previous local treatments were noted, including the consumption of analgesics. Using a furnished camera, standardised photography of the wound was taken before performing any wound care except for cleansing with normal saline. The first application of the investigational dressing was performed by the investigator according to the instructions for use supplied with the assigned WCL. A secondary dressing and fixation were used if required as judged by the clinician. Hypoallergenic dressing, sterile gauze, or absorbent compress were the recommended secondary dressings, whereas recommended fixations were tubular net, silicone film dressing (such as Mepitel Film, Mölnlycke Health Care, Gothenburg, Sweden), tubular bandage (such as Tubifast 2-way Stretch, Mölnlycke Health Care), or bandage. At the end of the first dressing application, pain experienced by the patient was assessed using a 100 mm visual analogue scale (VAS), the beginning of which (ie, 0 ) represented no pain and the end (ie, 100 ) represented the most severe pain possible. The patient was further instructed not to remove the applied WCL dressing before day 3, the date of the first follow-up visit (V2). If appropriate, a window of 1 extra day was allowed for V2. At that visit, the investigator performed the first dressing removal according to a standardised procedure in order to avoid bias in relation to this evaluator-related process. This was performed after any secondary dressing had been removed by taking one corner of the WCL and gently and regularly stripping it out. In the case of dried dressings or if the WCL had stuck to the wound, use of normal saline was recommended. Immediately after dressing removal, the patient was asked to quantify induced pain by using the 100 mm VAS. Wound bed and peri-wound skin were clinically assessed and carefully inspected to detect, in particular, any bleeding, maceration, or tissue growth through the dressing mesh. Possible local and serious AEs were screened by open questions. If required, the wound was rinsed with normal saline, and photographs were taken. A new WCL, the same as allocated by randomisation, was then applied to the wound. At the end of this visit, the investigator provided his/her opinion about dressing performance. In addition, the patients were given a sufficient quantity of dressings to cover the investigational period and a diary that was used to record any dressing changes undertaken by the patients, family members, or health professionals. Between V2 and day 21 (visit 3, V3), additional dressing changes were performed as often as necessary, according to the instructions for use leaflet supplied with the investigational product. The use of analgesics was allowed during the course of the study if judged necessary by the investigator. The nature, frequency, and time of use of analgesics were carefully recorded. At the final visit (day 21, 2 days), the wound was again inspected, and closure or otherwise was reported. Final photography was undertaken, and any emergent AE was noted by questioning the patient and by reviewing his or her local care diary. Finally, patients provided their overall opinion about dressing performance, particularly in terms of comfort during wear, ability to remain in place, and ease of handling/application and removal. 2.3 Investigational products The investigational dressing Mepitel One (Mölnlycke Health Care) is a sterile, low-adherent dressing, which consists of a Safetac WCL on one side and a transparent, flexible, thin, and perforated polyurethane film on the other. Safetac is a soft silicone adhesive technology. Mepitel One is not absorbent. The open perforated structure allows exudate to pass vertically into a secondary absorbent dressing pad, which must be changed as required by the conditions of the wound and the amount of exudate in order to prevent maceration. Only size cm, lot number , was used during the study. The control dressing UrgoTul (Urgo Medical, France) is a sterile non-occlusive, non-adhesive, lipidocolloid contact layer. It is made of a polyester mesh impregnated with hydrocolloid particles (CMC), paraffin oil petroleum jelly, and carrier polymers. Only size cm, lot number 66874, was used during the study. 2.4 Main study outcomes Considering the risk of pain induced by dressing removal, the primary study objective was to demonstrate the noninferiority of using Mepitel One compared with UrgoTul in the management of acute wounds. If non-inferiority was demonstrated, then the intention was to test for superiority. Pain severity is a commonly used outcome measure in the clinical evaluation of WCLs. 4,14 21 In the present study, the main outcome was the frequency and percentage of patients experiencing a pain level <30 mm on a 100 mm VAS at day 3 (V2) immediately after the first allocated dressing had been removed. This pain parameter was selected based on previous research that demonstrates a likelihood of patients recording moderate or severe pain on a 4-point categorical pain scale scoring above 30 mm on a 100 mm VAS. 22 Secondary objectives were to compare the 2 treatment groups in terms of the percentage of wound closure at day 21 post-inclusion, dressing technical performances, and the nature of emergent local AEs. This study was an open-label RCT. Investigators opinion about wound evolution was centrally and blindly controlled by measuring wound area reduction using digital

4 162 DAVID ET AL. tracing (PictZar software, Elmwood Park, NJ) based on wound photography. Furthermore, all pictures were assessed by 2 independent and experienced clinicians who were unaware of the dressing allocation to rule out possible bias related to a priori investigators opinion. Complete closure evaluated at day 21 (2 days) was defined as 100% reepithelialisation of the wound (based on the investigators evaluation and a blind assessment from wound photographs), which no longer required protection with a dressing. 2.5 Randomisation and blinding Centralised randomisation was carried out using a web-based system (Viedoc, Pharma Consulting Group, Uppsala, Sweden). A 1:1 allocation was applied and stratified according to wound type (traumatic wound or burn). Dressing assignment was immediately provided to the investigator. 2.6 Statistical analyses Statistical analyses were conducted by 2 institutions, independent from the study sponsor (Vertical, Paris, France; Statistiska Konsultgruppen, Gothenburg, Sweden). Analyses were performed using SAS software (version 9.2; SAS Institute, North Carolina) and SPSS 18.0 software (IBM Inc., USA). The safety population consisted of all patients who were allocated to treatment and had at least one investigational or control dressing applied. Frequencies were provided per dressing group, and overall descriptions of the type of event were recorded: AE, serious adverse event (SAE), adverse device effect (ADE), device deficiency, and serious adverse device effect. Any local and general AEs occurring and those already present but worsening during the course of the investigation were to be described in the Safety population. All randomised patients with at least 1 exposure to either an investigational or control dressing were included in the intention-to-treat (ITT) population. Patients were analysed in the treatment groups to which they were randomly assigned to avoid bias in the treatment comparisons. The population of completers consisted of all enrolled patients who satisfied the entry criteria of the investigation and who completed all visits, including the last visit (even if the visit was not completed within the given time window). The per protocol (PP) population consisted of all enrolled patients who satisfied the entry criteria of the investigation, who had an assessment of main criteria at day 3 (or in the window day allowed), and who completed the assessments and treatment without major violations of the protocol and within the given time window. For a WCL appropriately adapted to the management of acute wounds, it was expected that around 95% of patients would not report clinically relevant pain (defined as pain severity 30 mm on a 100 mm VAS) at dressing removal. This was based on previous research that demonstrated success in reducing pain during dressing changes after switching from adherent to non-adherent dressings 4 Furthermore, based on experts recommendations, a difference greater than 10% when comparing Mepitel One with UrgoTul should be regarded as sufficiently large to consider that any possible advantages of Mepitel One WCL dressing cannot counterbalance excessive dressing-induced pain at removal. Non-inferiority margin was based on experts recommendations. As recommended in various guidelines, the main analysis of non-inferiority was conducted on the PP population and had to be confirmed when applied to the ITT population. Calculations of confidence intervals used the exact method as described by Miettinene and Nurminen. 23 Furthermore, it was stated in the study protocol that if the lower limit did not cross to null value, superiority could be concluded. According to the nature of the variables, secondary end points were analysed with either a Student s t test or a χ 2 test and were primarily conducted on the ITT population and confirmed on the PP or other populations, with a 95% bilateral confidence interval. Indeed, for assessments of complete closure in order to confirm and reinforce results obtained in the ITT population, a robustness analysis was performed on the population of FIGURE 1 Non-inferiority analysis

5 DAVID ET AL. 163 completers. To exclude possible bias related to a priori investigators opinions, a blind assessment of wound healing was performed by 2 independent evaluators who were unaware of the allocated dressing. 2.7 Sample size From the statistical assumptions, 59 patients per group were required to confirm that the 97.5% unilateral lower limit of the Mepitel One UrgoTul difference would not cross the 10% non-inferiority margin, with a study power of 80%. Thus, considering an attrition rate equal to 10%, 66 patients were expected for each group (ie, 132 patients) to obtain the required power. 2.8 Ethics This RCT, sponsored by Mölnlycke Health Care (Sweden), was initiated in France in accordance with the ethical principles that have originated from the Declaration of Helsinki and applicable French regulatory requirements. This study obtained the authorisation from the French Agency for the Safety of Health products (ANSM) under reference number 2014-A and was approved by a French Ethics Committee (CPP Sud Ouest III, France) before enrolment of any patient into the investigation. 3 RESULTS In total, 123 patients were enrolled by 22 investigators during the period between September 1, 2014 and November 27, 2015; 60 and 63 patients were randomly allocated to the Mepitel One and UrgoTul groups, respectively. Eleven patients (3 in the Mepitel One group and 8 in the UrgoTul group) did not complete the investigation as per protocol (the main reasons for study premature arrests are given in Table 1). Overall, 121 patients were included in the ITT population: 59 in the Mepitel One group and 62 in the UrgoTul group. In the PP population, 102 patients were included in the analysis: 49 in the Mepitel One group and 53 in the UrgoTul group) (Figure 1). 3.1 Patient and wound characteristics at baseline Main patient and wound characteristics are presented in Table 2. Mean population age was 64.8 and 59.8 years in the Mepitel One and UrgoTul groups, respectively. Out of the 121 patients included in the ITT population, 31 patients (52.5%) were female in the Mepitel One group, and 28 patients (45.2%) were female in the UrgoTul group. At the inclusion visit (V1), it was recorded that 32 (54.2%) of wounds in the Mepitel One group had been previously treated, and 33 (53.2%) of wounds in the Urgo- Tul group had been previously treated. Previous dressings had been used in the management of 28 (87.5%) and 27 (81.8%) of wounds in the Mepitel One and UrgoTul groups, respectively. In the Mepitel One group, 7 patients (11.9%) were taking analgesics relating to the wound; 5 (8.1%) patients were taking analgesics relating to the wound in the UrgoTul group. In both groups, the majority of the wounds were of traumatic origin (84.7% in the Mepitel One group; 80.6% in the UrgoTul group). The upper and lower limbs were the main anatomical locations of the wounds in both groups. Median wound areas assessed by the investigators were 8.0 and 9.0 cm 2 in the Mepitel One and UrgoTul groups, respectively, with a large range (from 3.0 to cm 2 in the Mepitel One group; from 3.0 to cm 2 in the Urgo- Tul group). In terms of wound area measurements, there were 3 extreme outliers at baseline in the UrgoTul group. Consequently, post-hoc analysis was performed excluding these 3 values. The median wound areas without extreme outliers were 8.0 cm 2 in the UrgoTul group (from 3.0 to 72.0 cm 2 ), confirming that there is no significant difference between groups relating to this parameter in both analyses. Finally, median wound areas assessed by PictZar software also confirmed that there is no significant difference between groups. Mean (SD) pain reported by patients on the VAS after the primary dressing application was 22.2 (22.4) mm and 20.5 (22.4) mm in Mepitel One and UrgoTul groups, respectively. The 2 groups were well balanced at baseline, and no statistically significant difference was detected for any of the parameters measured. 3.2 Main study outcome Overall, mean (SD) VAS pain severity during the primary dressing removal at day 3 was 9.76 (12.46) mm and 14.8 (20.2) mm in the Mepitel One and UrgoTul groups, respectively (PP population). For the PP population, at day 3 postinclusion, 44 out of 49 patients (89.8%) did not experience pain severity 30 mm on the VAS immediately after the first primary dressing removal in the Mepitel One group. Comparatively, in the UrgoTul group, 39 of 53 patients (73.6%) did not experience pain severity 30 mm immediately after the first primary dressing removal. The difference between the 2 groups was +16.2% in favour of Mepitel One, with a +1.1% lower limit of the unilateral 97.5% confidence interval. As this limit does not cross the null value, superiority can be concluded (unilateral one-sided P =.017, Figure 2). An additional analysis was performed by using a bilateral 2-sided test with a 95% confidence interval, and statistical significance was again confirmed (P =.043). Overall, mean (SD) VAS pain severity during the primary dressing removal at day 3 was 8.85 (11.85) mm and 13.4 (19.4) mm in the Mepitel One and UrgoTul groups, respectively (ITT population). Robustness analysis was conducted on the ITT population. For these patients, the first

6 164 DAVID ET AL. TABLE 1 Study populations and reasons for discontinuation Mepitel One (n = 60) UrgoTul (n = 63) Total (n = 123) Study populations Safety population 60 (100.0%) 63 (100.0%) 123 (100.0%) Intent-to-treat population 59 (98.3%) 62 (98.4%) 121 (98.4%) Completers a 57 (95.0%) 55 (87.3%) 112 (91.1%) Per protocol population 49 (81.7%) 53 (84.1%) 102 (82.9%) Patients not completing study follow up 3 (5.0%) 8 (12.7%) 11 (8.9%) Main reasons Inclusion/exclusion criteria b 0 (0.0%) 1 (12.5%) 1 (9.1%) Serious adverse event 1 (33.3%) 4 (50.0%) 5 (45.5%) Consent withdrawn b 1 (33.3%) 0 (0.0%) 1 (9.1%) Other c 1 (33.3%) 3 (37.5%) 4 (36.4%) Abbreviation: ITT, intention-to-treat. Patients seen at D21 final visit. Not included in ITT population. Lost to follow up. dressing removal took place between days 2 and 5 after inclusion. Accordingly, the percentage of patients not experiencing pain severity 30 mm on the VAS at dressing removal was 91.5% in the Mepitel One group (54 out of 59) compared with 75.8% in the UrgoTul group (47 out of 62). The difference was +15.7% in favour of Mepitel One, with a 97.5% confidence interval lower limit of +2.6%. Therefore, superiority was confirmed (unilateral 1-sided P =.01). Statistical significance was confirmed using a bilateral 2- sided test with a 95% confidence interval, P = Secondary study outcomes Percentage of wound healed at day 21 In the ITT population, the wounds were considered completely healed (100% reepithelialisation) by the last visit (day 21, 2 days) in 39 out of 59 patients (66.1%) in the Mepitel One group and in 27 out of 62 (43.5%) in the Urgo- Tul group. The difference was +22.6% in favour of Mepitel One, with a 95% bilateral confidence interval of +4.8%/ +38.9% (P =.012; Figure 3). Enrollment Assessed for eligibility (n=123) Excluded (n=0) Not meeting inclusion criteria (n=0) Declined to participate (n= 0) Other reasons (n=0) Randomised (n=123) Allocated to Mepitel One (n=60) Received allocated intervention (n=60) Did not receive allocated intervention (give reasons) (n=0) Allocated to UrgoTul (n=63) Received allocated intervention (n=63) Did not receive allocated intervention (give reasons) (n=0) Analysis Intention-to-treat (n=59) Excluded from analysis (consent withdrawn) (n=1) Intention-to-treat (n=62) Excluded from analysis (deviation inclusion/exclusion criteria) (n=1) Per Protocol (n=49) Excluded from analysis (Day 3 not done as per protocol) (n=10) Completers (n=57) Excluded from analysis (LFUP (1) ; SAE (1) (n=2) Per Protocol (n=53) Excluded from analysis (Day 3 not done as per protocol) (n=9) Completers (n=55) Excluded from analysis (Discontinued intervention/sae (4); LFUP (3) (n=7) FIGURE 2 Study flow diagram

7 DAVID ET AL. 165 TABLE 2 Demography and wound characteristics at inclusion (V1) Demography Age mean (SD) median (ranges) Mepitel One (n = 59) UrgoTul (n = 62) P value 64.8 (21.2) 68.0 (18.0; 94.0) Male/female 28/ %/52.5% Previous local treatments 59.8 (23.0) 62.0 (18.0; 95.0) 34/ %/45.2% Wound previously treated 32 (54.2%) 33 (53.2%) Previous dressing(s) 28 (87.5%) 27 (81.8%) Analgesics taken after injury 7 (11.9%) 5 (8.1%) Type of wound Traumatic wound 50 (84.7%) 50 (80.6%).63 Benign burn 9 (15.3%) 12 (19.4%) Type of traumatic wound Dermabrasion 23 (46.0%) 29 (58.0%).24 Skin tears 25 (50.0%) 17 (34.0%) Other 2 (4.0%) 4 (8.0%) Location of target wound Head/neck 1 (1.7%) 2 (3.2%).61 Thorax/abdomen 2 (3.4%) 6 (9.7%) Lower limb 22 (37.3%) 26 (41.9%) Foot 3 (5.1%) 3 (4.8%) Hands 7 (11.9) 10 (16.1%) Upper limb 22 (37.3%) 14 (22.6%) Other 2 (3.4%) 1 (1.6%) Wound area cm 2a 13.3 (19.0) 8.0 (3.0; 135.0) Pain after first dressing application (mm) 22.2 (22.4) 19.5 (0.0; 77.0) Results presented as mean (SD), median (range) for scale variables, and as frequency (%) for nominal variables. a Length and width of wound measured by the investigator (28.0) 9.0 (3.0; 143.0) 20.5 (22.4) 12.0 (0.0; 80.0) In addition to the investigators evaluations and to rule out a possible impact of bias related to a priori investigators opinion, a blind assessment of wound healing was performed by 2 independent evaluators who were unaware of the dressing allocation. They evaluated wound evolution based on digital wound photographs and scored the evolution according to a predefined 7-point scale. The analyses were conducted on 106 patients out of 121 (56 patients of the Mepitel One group and 57 patients of the UrgoTul group) with at least 1 evaluation performed by 1 of the 2 independent evaluators. No statistically significant difference was observed between the wound evolution scores measured by the investigators and the measurements made by the blind assessors. To confirm the results obtained in the ITT population, an additional sensitivity analysis was conducted in the completers population. This population consisted of 57 and 55 patients who completed the 3-week study follow up in the Mepitel One and UrgoTul groups, respectively. The percentage of wounds completely healed was still in favour of the Mepitel One group (68.4% vs 49.2%; P =.038; Figure 3). Finally, to confirm the robustness of the above results, post hoc analyses were conducted in the ITT and PP populations, excluding the extreme outliers in the UrgoTul group. The results obtained were in the same trend as those reported earlier (ITT; P =.052; PP, P =.024) Assessment of wound and peri-wound condition At days 3 and 21, non-healed wounds were inspected by the investigators to monitor wound bed aspect and wound condition in terms of any bleeding and/or maceration and to detect any granulation tissue in-growth into the dressing. At day 3, mild or moderate bleeding was recorded in 30.5% of wounds in the Mepitel One group and 34.4% of wounds in the UrgoTul group, decreasing to 22.2% (mild bleeding) and 14.8% (mild bleeding) at day 21, respectively. At day 3, 15.3% of wounds in the Mepitel One group were recorded as mildly or moderately macerated, compared with 27.5% of wounds in the UrgoTul group; at day 21, 22.2% of wounds were considered mildly macerated in the Mepitel

8 166 DAVID ET AL. 70% 66.1% p= % p= % 50% 43.5% 49.2% 40% 30% 20% 10% 0% MepitelOne n=59 ITTpopulation Urgotul n=62 MepitelOne n=57 Completer s Urgotul n=55 FIGURE 3 day 21 Percentage of wounds healed at One group, compared with 14.8% of wounds in the UrgoTul group. No statistically significant differences were found between the 2 groups in terms of bleeding or maceration at day 3 or day 21 (Table 3). In terms of tissue in-growth into the dressing, this was noted in 36.2% of wounds (mild or moderate) in the Mepitel One group and 31.6% of wounds (mild or moderate) in the UrgoTul group at day 3 and in 22.2% of wounds (mild or moderate) at day 21 for both groups (no statistically significant difference between groups at day 3 or day 21) (Table 3). In terms of peri-wound skin condition, at baseline, 78% of patients in the Mepitel One group had healthy periwound skin, compared with 83.9% of those in the UrgoTul group; at day 21, this increased to 91.2% and 85.7% in the Mepitel One group and the UrgoTul group, respectively. However, no statistically significant difference was found (Table 3) Assessment of dressing performance by investigators and patients At visit 2 (day 3), the investigators were invited to evaluate dressing performance. Ten parameters were assessed and scored from very poor to very good ; very good scores were significantly in favour of the Mepitel One dressing for all parameters (ITT population) (P <.0001). However, when very good and good scores were combined, no statistically significant difference was detected. Investigators were also asked whether the dressing adhered to the wound; investigators answered no in 87.7% and 77.4% of cases for the Mepitel One and UrgoTul groups, respectively (no statistically significant difference between groups, P =.21). At the study end (visit 3, day 21), patients were invited to evaluate dressing performance. Eleven parameters were assessed and scored from very poor to very good. Although very good scores were significantly in favour of TABLE 3 Aspects of wound bed and peri-wound skin (ITT population) Mepitel One UrgoTul Both groups combined P value Wound bed aspect Day 3 No bleeding detected 41/59 (69.5%) 38/58 (65.5%) 79/117 (67.5%).565 No maceration detected 50/59 (84.7%) 42/58 (72.4%) 92/117 (78.6%).082 No tissue growth through dressing mesh 37/58 (63.8%) 39/57 (68.4%) 76/115 (66.1%).563 Day 21 No bleeding detected 14/18 (77.8%) 23/27 (85.2%) 37/45 (82.2%).465 No maceration detected 14/18 (77.8%) 23/27 (85.2%) 37/45 (82.2%).465 No tissue growth through dressing mesh 14/18 (77.8%) 21/27 (77.8%) 35/45 (77.8%).999 No peri-wound skin problems (healthy intact peri-wound skin) Day 0 46/59 (78.0%) 52/62 (83.9%) 98/121 (80.9%).369 Day 3 47/59 (79.7%) 48/62 (77.4%) 95/121 (78.5%).669 Day 21 52/57 (91.2%) 48/56 (85.7%) 100/113 (88.5%).272 Abbreviation: ITT, intention-to-treat.

9 DAVID ET AL. 167 the Mepitel One dressing for all parameters (P.0001), no difference was detected between groups when good / very good scores were combined, except for the assessments of ability of dressing to remain in place (P =.016, Table 4) Dressing changes Over the 21 days of study follow up, the mean (SD) number of dressings used was 5.51 (2.36) and 5.21 (2.81) in the Mepitel One and UrgoTul groups, respectively (P =.37). Maximal numbers of dressings used were, respectively, 11 and 16 in the Mepitel One and UrgoTul groups AEs and safety aspects In total, 6 AEs occurred in the Mepitel One group, and 7 AEs occurred in the UrgoTul group. In terms of SAEs during the study, 1 SAE was reported in the Mepitel One group and 4 in UrgoTul group. These SAEs were judged as being unlikely to be related to the investigational products. A single local ADE deemed to be related to the applied dressing was reported. This took the form of a slight and transitory peri-wound skin rash in a patient allocated to the Mepitel One group. The dressing was replaced with a nonsilicone-coated one, and the cutaneous problem resolved promptly within a few days. No further investigations were performed to confirm a possible local allergic reaction. 4 DISCUSSION This RCT, conducted in usual care settings by a group of GPs, is the first to compare a WCL dressing coated with a micro-perforated soft silicone layer (Mepitel One) to a WCL dressing type impregnated with a lipidocolloid mixture (UrgoTul). Both studied WCL dressings are largely used to manage uncomplicated and slightly exudating acute wounds as well as chronic wounds at the proliferative stage of healing. 5,6,8,10,24 The primary objective of this trial was to confirm that Mepitel One is, at worst, not inferior to UrgoTul in terms of pain induced by dressing removal in order to conclude that both dressing types can be considered therapeutically equivalent. However, based on the PP population, significantly fewer patients experienced pain severity 30 mm on VAS at first dressing removal with Mepitel One compared with UrgoTul. For non-inferiority studies, a recommendation is made to conduct the main analysis on the PP population as this is the most conservative approach to evaluate therapeutic equivalence. 25 Furthermore, this superiority of Mepitel One was confirmed when analysing results based on the ITT population, including all patients with a pain severity evaluation and those that were not strictly performed on day 3. This 30 mm pain threshold is recognised as a means of identifying the minimal level above which perceived pain should be regarded as clinically relevant (moderate pain on a verbal scale). 22,26 28 Such a difference in favour of a silicone-coated WCL dressing has previously been observed in studies involving post-surgical wounds and benign burns in children. 15,20 In these studies, control groups were treated with petrolatumimpregnated WCL dressings, whose performances might be inferior to that of lipidocolloid WCL dressings. Nevertheless, numerous experimental studies conducted in healthy volunteers support low induced pain and skin irritation when removing silicone-coated dressings, 12,29,30 a conclusion reinforced by the results of the present study. In addition to being statistically significant, the lower levels of pain severity at dressing change associated with Mepitel One have clinical and economic implications. Pain can contribute to considerable levels of discomfort and anxiety, which, in turn, can negatively impact patient quality of life. 31 Furthermore, heightened pain requires additional health care intervention and resource use which, in turn, escalates treatment costs. 32 Patients treated with dressings that are associated with minimal pain on removal will generally require less analgesia than those treated with ones that are associated with higher pain severity and thus will help to drive down associated costs. 33 TABLE 4 Overall dressing performances according to patients opinion ( good / very good scores combined) Mepitel One UrgoTul N % N % P value Ease of handling 53/ % 52/ %.999 Ability to maintain its integrity 52/ % 51/ %.999 Ease of application 53/ % 52/ %.999 Repositioned during application 52/ % 48/ %.165 Conformability 53/ % 47/ %.096 Ability of dressings to stay in place 52/ % 44/ %.016 Transparency 50/ % 44/ %.367 Comfort during wear 53/ % 52/ %.210 Transfer wound fluid to secondary dressing 50/ % 48/ %.367 Ease/speed of removal 53/ % 50/ %.210 Overall impression 53/ % 51/ %.368

10 168 DAVID ET AL. More surprising are the results in terms of complete wound closure at day 21 in the present trial. Such a significant difference in favour of a silicone-coated WCL dressing has not yet been published, except in some previously reported studies, which compared this type of WCL to silver sulfadiazine in the treatment of benign burns. 14,34 It could be hypothesised that a lower pain level at dressing change reflects a lower injury risk for the wound bed and the periwound skin. Furthermore, pain is known to cause psychological stress, which may delay healing, 35 thereby increasing the risk of chronicity. As prolonged healing can impact patient quality of life and health care expenditure, the use of atraumatic dressings that minimise pain and anxiety appears justified. 36 However, slight (yet statistically not significant) differences at baseline between groups may also have had an impact on the findings. For instance, upper limbs were more often involved in the Mepitel One group. In addition, while median wound size at inclusion was similar between groups, there were 3 unexpected extreme outliers in the UrgoTul group. It appears advisable to confirm this difference in closure rate by conducting another controlled trial before definitively claiming a true superiority on this parameter of importance. Finally, in terms of in-use dressing characteristics, both dressings appeared to be similar, although the capacity to remain in place was better for Mepitel One. Local dressing tolerability was good in both groups. The main study limitation was, as for all trials comparing wound dressings, its open-label design. However, to control for this potential source of bias, centrally and independent blind assessments of some study outcomes (wound area tracings and photographs) were performed and did not detect any systematic, more favourable attitude of investigators towards one of the studied medical devices. 5 CONCLUSION In conclusion, this randomised and prospective controlled study suggests that Mepitel One, a silicone-coated primary WCL dressing, is suitable for the management of acute wounds and presents clinically relevant characteristics, including the ability to effectively minimise dressingassociated pain and support healing in these wounds. ACKNOWLEDGEMENTS The study was sponsored (Gothenburg, Sweden). AUTHOR CONTRIBUTIONS by Mölnlycke Health Care All the authors participated in the study implementation. Investigators who contributed to the study (ONLY study group): N Abenhaim (Strasbourg, France), C Bortolotti (Oignies, France), P Bouche (Grenay, France), M Bur (Herrlisheim, France), R Castera (Bassussary, France), B Courtot (Carbon Blanc, France), M Cunin (La Madeleine, France), S Delabroye (La Forêt sur Sèvres, France), P Hasselmann (Villey St Etienne, France), JP Jacquet (St Jean d Arvey, France), S Le Mouël (Hinx, France), P Leprince (Tours, France), C Lousqui (Strasbourg, France), P Mercier (Tours, France), A Solanilla (Lesparre, France), D Taminau (Rosiers d Egletons, France), and C Vanbelle (Aix-Les- Bains, France). REFERENCES 1. Rippon M, Davies P, White R. Taking the trauma out of wound care: the importance of undisturbed healing. J Wound Care. 2012;21(8): Fowler A. Atraumatic dressings for non-complex burns. Pract Nurs. 2006;17(4): Edwards J, Mason S. Hand burn management: minimising pain and trauma at dressing change. 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