Mikosinski 2021a.

Study characteristics
Methods	Research design: RCT, parallel, prospective, multicentre, multinational, randomised, double‐blind, clinical study conducted between 13 June 2017 and 31 December 2018 Care setting: 14 centres, 2 in France and 12 in Poland Country of origin: France and Poland Publication source:Wounds Year of publication: 2021 Duration of follow‐up: 23 weeks or until complete healing Sources of funding: IBSA Institut Biochimique S.A Unit of randomisation: participant Unit of analysis: participant Inclusion criteria: adult males and females older than 18 years were eligible for the study if they experienced 1 or more chronic leg ulcers of venous or mixed (venous and arterial, with a predominant venous component) origin of more than 2 months and less than 4 years’ duration. In participants presenting with more than 1 ulcer, the investigator selected a target ulcer. Exclusion criteria: patients with an ulcer of non‐vascular origin or related to a general cause, evidence of dominant significant arterial insufficiency and/or ABPI that was not between 0.8 and 1.2, diabetes mellitus, hepatic or renal failure, clinical suspicion of wound infection, an ulcer with exposed tendon or bone or due to malignancy, recent history of venous thrombosis, and/or ongoing treatment with drugs known to adversely affect the healing process were excluded
Participants	Number of participants: 189 patients were screened, 169 were randomised, and 168 (82 in the HA gauze pad group and 86 in the neutral gauze pad group) were eventually enrolled in the study and received at least 1 application of the IMD (safety analysis set). Of these, 164 (83 in the HA gauze pad group and 81 in the neutral gauze pad group) were included in the full analysis set (all people in the safety analysis set who received 1 or more postbaseline efficacy assessment). Female gender: HA gauze pad group: 54.9% (n = 45); neutral gauze pad group: 57% (n = 49) Age: HA gauze pad group: 72.6 ± 13.80 (n = 82); neutral gauze pad group: 67.20 ± 12.48 (n = 86)
Interventions	Details of the intervention Group 1: the HA‐containing gauze pad was a 10 cm x 10 cm, sterile, ready‐to‐use, fixed‐dose dressing for topical use, impregnated with 0.05% sodium hyaluronate Group 2: the neutral comparator contained the same ingredients except for HA and had identical visual and physical characteristics to the test product Dressing procedure: study treatments were used in conjunction with standard local therapy that specified cleansing the target ulcer with sterile saline before each application, with or without the use of surgical debridement or local anaesthesia as necessary. In the event of clinical evidence of infection (confirmed on swabbing), therapy with systemic antibiotics was considered, but the use of topical antimicrobials and antiseptics was prohibited. After wound cleansing, the HA gauze pad or neutral comparator was applied directly to the target ulcer once daily by the study nurse or authorised study personnel either at the participant’s home or at the clinic. During the study visits, the gauze pad was applied by the investigator (or designee). The gauze pads were placed onto the entire cavity of the target ulcer, and the wound area was then covered with a sterile dressing and finally completed by appropriate pressure bandaging. Wound debridement, dressing, and compression were only applied by personnel with knowledge and experience in the assessment and management of patients with leg ulcers. Co‐interventions: standard care (i.e. ulcer cleansing, debridement/anaesthesia as necessary, and optimised compression) Duration of treatment: 20 weeks, or until complete healing
Outcomes	Primary outcomes of the review: ulcer healing as evaluated by the central assessor blinded to the product used and confirmed 3 weeks after the end of treatment Secondary outcomes: the percentage of completely healed target ulcers as assessed by the investigator and at all other scheduled study visits as assessed by the blinded central assessor. Endpoints also included target ulcer residual area relative to baseline, calculated as percentage relative to the ulcer area at the time of randomisation, the condition of the peri‐ulcerous skin, the total amount of analgesics used, the percentage of participants presenting with infection after application of the first IMD confirmed by swabbing of the target ulcer, patient adherence to treatment, time to achieve complete healing as centrally assessed, and pain intensity as measured by VAS.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomization list was prepared by the Data Management and Statistics Department of the sponsor according to standard operating procedures, using validated software (SAS Institute Inc)."
Allocation concealment (selection bias)	Low risk	Quote: "The study was conducted in double‐blind fashion, with treatment allocation hidden to the participants, investigator, sponsor, contract research organization team, and the central assessor, located separately from any of the study sites. Strict procedures were adopted to maintain the blind throughout the study."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Strict procedures were adopted to maintain the blind throughout the study."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All personnel involved in the trial were blinded to the treatment, and the HA gauze pads and neutral gauze pads, packaging, and labelling were indistinguishable from one another. In addition, the clinical assessment of the primary efficacy variable (target ulcer healing) was centrally and independently performed by an experienced, blinded assessor judging clinical results on standardised photography of the target ulcer.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Overall, 144 patients (71 in the HA gauze pad group; 73 in the neutral gauze pad group) completed the study; 25 discontinued treatment (13 in the HA group; 12 in the neutral gauze pad group). Of those, 18 withdrew (9 in each group) for personal reasons—3 in the HA group (2 for AEs and 1 for other reasons) and 2 in the neutral gauze pad group due to lack of efficacy. One person in each group was lost to follow‐up. Among the 5 participants who had more than 1 major protocol deviation (3 in the HA group; 2 in the neutral gauze pad group), the most common reason was violation of exclusion criteria."
Selective reporting (reporting bias)	Low risk	Outcomes in methods section were described in results section.
Other bias	Low risk	The study was sponsored and funded by IBSA Institut Biochimique S.A. The project was managed and monitored by the contract research organisation CROMSOURCE through its local organisations in Poland and France. Participants and target ulcer were similar between groups.