Humbert 2013.

Study characteristics
Methods	Research design: RCT, parallel, multicentre, comparative, randomised, double‐blind clinical trial Care setting: participants' home and care facilities (29 centres participated in the study: 18 centres in France, 3 in Morocco, and 8 in Poland) Country of origin: France, Morocco, and Poland Publication source:International Wound Journal Year of publication: 2013 Duration of follow‐up: 60 days or until complete healing Sources of funding: Laboratoires Genévrier, with the support of local contract research organisations in France, Morocco, and Poland Unit of randomisation: participant Unit of analysis: participant Inclusion criteria: male or female inpatients or outpatients; aged 18 years or over; diagnosis of leg ulcers of venous or mixed arterial/venous origin present for > 2 months and < 4 years; wound with surface area of the selected target ulcer comprised between 5 and 40 cm2; without necrotic tissue; documented past history of deep venous thrombosis of the lower limbs and/or clinical evidence of post‐thrombotic syndrome with chronic oedema and lipodermatosclerosis and/or available data of an arterial‐venous Doppler examination performed within the previous 6 months and showing post‐phlebitic sequels (residual thrombosis), and/or a superficial or profound reflux on the venous system; with no local HA treatment within the 3 months before inclusion; with albuminaemia ≥ 25 g/L; with ankle/brachial Doppler systolic pressure index ≥ 0.8; with an adapted compression treatment which was worn all during the study; covered by a health insurance system; women of childbearing age had to use a reliable contraceptive method for at least 3 months before and during the study Exclusion criteria: pregnant or breastfeeding women or women planning to be pregnant in the course of the study; with an ulcer of non‐vascular origin (phagedenic pyodermatitis); with clinical evidence of significant arterial insufficiency (claudication, pain at decubitus); with an ulcer due to a general cause (haematological cause); with any type of diabetes; suffering from hepatic disorders (ALAT/ASAT ≥ 2.5 ULN); suffering from renal disorders (creatinine clearance < 30 mL/min); with known allergy to local anaesthetics such as to Xylocaıne, Lidocaıne or Prilocaıne; with a clinical suspicion of general infection (erysipelas, phlegmon); presence of at least 1 of the following symptoms, reminiscent of the local and/or general infection: peri‐ulcerous inflammation, odorous and purulent flow, adenopathy, lymphangitis, fever, unexpected healing interruption; presence of a recent venous thrombosis (< 3 months); known allergy to 1 of the components of the investigational medical devices; under treatments delaying the healing process: systemic corticosteroids, cytostatic drugs, immunosuppressive agents; participation in any type of clinical investigation concurrently or within the 2 months preceding the inclusion visit
Participants	Number of participants: 89 participants were included in the analysis (ITT population), instead of the 140 participants previously calculated (group 1: 45 participants; group 2: 44 participants). In addition, 72 participants were defined as per‐protocol population (group 1: 38 participants; group 2: 34 participants). Characteristics of the examined groups: the study was conducted with inpatients or outpatients with 1 or several leg ulcers of venous or mixed arterial/venous origin Female gender: group 1: 44.4% (n = 20); group 2: 54.5% (n = 20) Age: group 1: 59.4 ± 2.5; group 2: 64.1 ± 2.7
Interventions	Details of the intervention Group 1: 0.05% HA impregnated cotton gauze pad (ialuset gauze pad manufactured by Laboratoires Genévrier, Sophia‐Antipolis, France) Group 2: neutral vehicle (same formulation as ialuset gauze pad but without HA) Dressing procedure: the ulcer was cleaned with physiological serum, and the assigned dressing was then applied by a nurse at the participant’s home (for outpatients), or in various care facilities (for inpatients) except during evaluation visits when the dressing was applied by the investigator. The gauze pad was applied to the wound, covered with sterile gauze, and then covered with an appropriate bandage. Co‐interventions: surgical wound excision procedures were authorised if necessary with or without previous local anaesthesia. Systemic antibiotics could be used in case of clinically relevant infection. Systemic analgesics were authorised, provided they were interrupted at least 10 hours before each visit to allow a proper evaluation of wound‐related pain. The use of high‐dosage systemic corticosteroids, cytostatic and immunosuppressive drugs, and local use of proteolytic enzymes for wound debridement were not permitted during the study. Duration of treatment: 60 days or until complete healing
Outcomes	Primary outcomes of the review: complete wound healing (45 days); time to complete wound healing; adverse effect Secondary outcomes: percentage of wound size reduction (after 45 days of treatment); pain was assessed according to VAS
Notes	Losses to follow‐up: 28 participants did not compete the study (n = 18 in group 1; n = 10 in group 2)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomisation list was prepared by Data Management & Statistics Unit of IBSA Institut Biochimique SA, Switzerland using a validated software from SAS Institute Inc., Cary, NC in accordance with international standards"
Allocation concealment (selection bias)	Unclear risk	Allocation method was properly described but there was no mention of concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Authors state it is a double‐blinded study, however, there is no description of the method for blinding.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Two independent readers, equally blind to treatment, measured the wound size based on the drawings on sterile tracing papers, in a centralised fashion and using a digital planimetrics system, Visitrak"
Incomplete outcome data (attrition bias) All outcomes	High risk	Sample size calculation resulted in 140 volunteers. An interim analysis was intended to be performed upon 80 subjects completing the study, however, authors reported that 28 individuals did not complete the study from 89 originally included in the ITT population (10 individuals did not meet inclusion criteria); therefore, less than 80. Authors reported that the study was then stopped based on the significance difference observed for the primary performance parameter (area reduction after 45 days of treatment) in this interim analysis.
Selective reporting (reporting bias)	Low risk	All proposed outcomes described in methods section are presented and properly analysed.
Other bias	Low risk	Participants were not significantly different between the 2 arms as regards gender, age and body mass index, frequency of medical and/or surgical background, localization and duration of target ulcer, proportion of fibrinous or granulation tissue. Only 1 ulcer was assessed per volunteer. Project management and monitoring of the study was carried out by the sponsor, Laboratoiries Genevrier, with the support of local contract research organisations in France, Morocco and Poland.