Mikosinski 2021b.

Study characteristics
Methods	Research design: RCT, parallel‐group, prospective, multicentre, randomised, double‐blind, clinical study conducted between 13 June 2017 and 17 April 2019 Care setting: 20 centres in Poland Country of origin: 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 18 years or older were eligible for inclusion in the study if the following criteria were met: 1 or more chronic leg ulcers of venous (varicose or post‐thrombotic) or mixed (venous and arterial) origin with a predominance of venous origin, with a duration of at least 2 months but less than 4 years; the target ulcer area was at least 5 cm2 but no more than 40 cm2, with less than 50% of necrotic tissue; an arteriovenous Doppler examination showing superficial or profound venous reflux and/or a well‐documented history of deep venous thrombosis and/or clinical evidence of post‐thrombotic syndrome with chronic oedema and lipodermatosclerosis Exclusion criteria: the presence of a non‐vascular ulcer or a general cause (e.g. haematologic cause), ankle‐brachial index less than 0.8 or higher than 1.2 and/or dominant significant arterial insufficiency, diabetes mellitus of any type, hepatic or renal failure, presence of wound infection, an ulcer with exposed tendon or bone or due to malignancy, a recent history of venous thrombosis, and ongoing treatment with drugs known to adversely affect the healing process
Participants	Number of participants: a total of 199 European participants were screened, and 168 (85 in the HA cream group and 83 in the neutral cream group) were eventually enrolled in the study and received at least 1 application of the IMD (safety analysis set). Of these participants, 164 were included in the full analysis set (all participants in the safety analysis set who had at least 1 postbaseline efficacy assessment), with 83 in the HA cream group and 81 in the neutral cream group. A total of 144 participants (HA cream group, 70; neutral cream group, 74) completed the study. Female gender: HA cream group: 61.2% (n = 52); neutral cream group: 60.2% (n = 50) Age: HA cream group: 68.9 ± 12.95 (n = 85); neutral cream group: 70.0 ± 12.17 (n = 83)
Interventions	Details of the intervention Group 1: the active treatment (HA cream) contained HA 0.2% intended for topical use and was supplied for the study in 100‐gram tubes Group 2: the neutral comparator cream contained the same ingredients, with the exception of HA, and had visual and physical characteristics identical to those of the active cream Dressing procedure: after wound cleansing, the HA cream or neutral comparator cream was applied directly to the target ulcer once daily by the study nurse or authorised study personnel at either the participant's home or clinic. Following application of the cream, the wound area was covered with a sterile gauze dressing and an appropriate long‐stretch graduated elastic bandage with stirrup (BIFLEX 16+ PRACTIC bandage), which was provided to all sites; this regimen was applied to all participants according to the standard of care. 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: the primary efficacy endpoint was ulcer healing, defined as 100% re‐epithelialisation of the wound area at 20 weeks or at any earlier visit if healing occurred before week 20, as evaluated by the central blinded assessor and confirmed 3 weeks after initial healing achievement Secondary outcomes: secondary efficacy endpoints included the percentage of completely healed target ulcers as assessed by the investigator, and at all other scheduled study visits as assessed by the central blinded assessor; target ulcer area relative to baseline at each study visit; condition of the peri‐ulcerous skin; total amount of analgesics used; rate of infection of the target ulcer; adherence to treatment; time to achieve complete healing as centrally assessed; and pain intensity as self‐assessed by the participant on a VAS at each study visit
Notes	Dropouts: a total of 144 participants (HA cream group, 70; neutral cream group, 74) completed the study. 26 participants (HA cream group, n = 17; neutral cream group, n = 9) discontinued treatment. Of those, 14 participants (HA cream group, n = 9; neutral cream group, n = 5) withdrew from the study for personal reasons. 3 participants (HA cream group, n = 2; neutral cream group, n = 1) withdrew due to adverse events and 3 (HA cream group, n = 1; neutral cream group, n = 2) due to serious adverse events. 3 participants in the HA cream group withdrew because of a protocol violation (n = 1) or were lost to follow‐up (n = 2), and 3 participants (HA cream group, n = 2; neutral cream group, n = 1) withdrew for other reasons. 1 participant in each group was lost to follow‐up. A total of 5 participants (HA cream group, n = 4; neutral cream group, n = 1) had at least 1 major protocol deviation, most commonly for prohibited concomitant medication.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomization list was prepared using validated software (SAS Institute Inc) by the Data Management and Statistics Department of the sponsor and stored in electronic form in a secure directory to ensure confidentiality in full respect of standard operating procedures."
Allocation concealment (selection bias)	Low risk	Quote: "The study was double‐blind; treatment allocation was kept hidden to the subject, investigator, sponsor, contract research organization team, and central assessor. Strict procedures were followed throughout the study to maintain blinding."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The active treatment (HA cream) contained HA 0.2% intended for topical use and was supplied for the study in 100‐g tubes. The neutral comparator cream contained the same ingredients, with the exception of HA, and had visual and physical characteristics identical to those of the active cream. All personnel involved in the trial were blinded to the treatment, and the presentation, packaging, and labeling of the HA cream and neutral comparator cream were fully indistinguishable."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "To minimize bias, the test and comparator treatments were randomly allocated using a standard central randomization system, and access to the randomization code information was strictly regulated and monitored, and the clinical assessment of the primary efficacy variable was centrally and independently performed by an experienced, blinded assessor judging clinical results via standardized photography of the target ulcer. All personnel involved in the trial were blinded to the treatment, and the presentation, packaging, and labeling of the HA cream and neutral comparator cream were fully indistinguishable."
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "A total of 144 subjects (HA cream group, 70; neutral cream group, 74) completed the study. Twenty‐six subjects (HA cream group, n = 17; neutral cream group, n =9) discontinued treatment. Of those, 14 subjects (HA cream group, n = 9; neutral cream group, n = 5) withdrew from the study for personal reasons. Three subjects (HA cream group, n = 2; neutral cream group, n = 1) withdrew for AEs and 3 (HA cream group, n = 1; neutral cream group, n = 2) for SAEs. Three subjects in the HA cream group withdrew because of a protocol violation (n =1) or were lost to follow‐up (n = 2), and 3 subjects (HA cream group, n = 2; neutral cream group, n = 1) withdrew for other reasons. One subject in each group was lost to follow‐up. A total of 5 subjects (HA cream group, n = 4; neutral cream group, n = 1) had at least 1 major protocol deviation, most commonly for prohibited concomitant medication." Comment: the sum for the number of participants in the description does not match the number of dropout reported.
Selective reporting (reporting bias)	Low risk	Comments: all outcomes described in the methods section were described in the results section.
Other bias	Low risk	Participants and target ulcer were similar between groups. The study was sponsored and funded by IBSA Institut Biochimique S.A.