Gethin 2007.

Study characteristics
Methods	Design: 2‐arm, open‐label, multicentre RCT Country: Ireland Setting: hospital and community leg ulcer clinics Sample size calculation: a sample size of 156 participants randomly allocated to 2 equal groups of 78 estimated as having 80% power to detect a minimum difference of 20% at the 5% 2‐sided significance level. Ethical approval: obtained from each centre involved in the trial. Informed consent: obtained
Participants	Total sample: 108 participants recruited from February 2003 to January 2006 Inclusion criteria: having an uninfected venous ulcer, aged > 18 years, able to provide written informed consent, having ≥ 50% of wound bed covered in slough, wound area < 100 cm², ABPI ≥ 0.8 Exclusion criteria: aged < 18 years, unable to provide written informed consent, having an ulcer > 100 cm², ulcer diagnosed as being malignant, having a cavity wound, clinical diagnosis of wound infection, currently taking antibiotics for any reason, currently taking oral immunosuppressants, having poorly controlled diabetes, having previously enrolled into the study, pregnant women or lactating mothers Mean age: overall mean not reported Group 1 (hydrogel dressing): 68.3 years Group 2 (manuka honey dressing): 68.5 years ABPI: results not reported Baseline data collected: gender, age, wound size and duration, ulcer location and history of recurrence Medical information collected: history of deep venous thrombosis, hypertension, trauma or surgery to the affected limb, diabetes, immunosuppression and current medications Ulcer duration Group 1 (hydrogel dressing): 29.9 weeks Group 2 (manuka honey dressing): 39.5 weeks Baseline ulcer surface Group 1 (hydrogel dressing): median: 4.2 cm² Group 2 (manuka honey dressing): median: 5.4 cm² Margolis index 0, 1, 2 Group 1 (hydrogel dressing): 46%, 31%, 22% Group 2 (manuka honey dressing): 33%, 30%, 37% Wounds covered in slough Group 1 (hydrogel dressing): 78% Group 2 (manuka honey dressing): 86% Numbers randomised Group 1 (hydrogel dressing): 54 participants Group 2 (manuka honey dressing): 54 participants Unit of analysis: ulcer Ulcer infection: was reported Comments: the trial authors reported that each participant could only contribute with 1 ulcer (the uppermost ulcer or the largest ulcer was selected if > 1 was present)
Interventions	Group 1: hydrogel dressing (IntraSite Gel, Smith & Nephew Healthcare) at 3 g/20 cm² Group 2: monofloral (manuka) honey dressing (Woundcare 18+) at 5 g/20 cm² Description of compression therapy: all participants were subjected to compression therapy applied weekly Secondary dressing: Allevyn hydrocellular foam (Smith & Nephew Healthcare) Length of treatment: 4 weeks, dressing changes and compression therapy. Quote: "After four weeks received follow up on treatment based on clinical assessment of the wound by the local investigator, which varied from patient to patient." Follow‐up: week 12
Outcomes	Complete wound healing: at 12 weeks Group 1 (hydrogel dressing): 18/54 (33.3%) Group 2 (manuka honey dressing): 24/54 (44.4%) The authors' regression analysis was adjusted for Margolis score: they reported an odds ratio of 3.1 (95% CI 1.15 to 8.35) and a risk ratio of 1.38 (95% CI 1.02 to 1.88) Incidence of wound infection Group 1 (hydrogel dressing): 12/54 Group 2 (manuka honey dressing): 6/54 Change in ulcer size: not reported Time to ulcer healing: not reported Recurrence of ulcer: not reported Health‐related quality of life: not reported Pain: not reported Costs: not reported
Notes	Healing was a secondary outcome. The primary outcome was change in area of slough at 4 weeks. Funding: Research and Education Foundation in Sligo General Hospital, European Wound Management Association and the Health Research Board of Ireland
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "78 pieces of both green and yellow card were counted, checked, and shuffled by a person independent of the trial. The card was then inserted into opaque brown envelopes, counted, sealed, and shuffled by another person independent of the trial. The envelopes were then, sequentially numbered. This process represented generation of an unpredictable allocation sequence. Yellow indicated allocation to the Manuka honey treatment and green allocation to the IntraSite treatment."
Allocation concealment (selection bias)	Low risk	Quote: "Envelopes were given to a person independent of participant enrolment at a remote location. This process ensured allocation concealment. When a person agreed to participate and having met the inclusion criteria and signed the consent form, the recruiting nurse phoned the remote number, gave details of the patient including, name, gender, trial centre, ABPI, percentage of wound covered in slough and ulcer size. The external person then, using the pre‐generated allocation sequence, allocated the trial number for the patient and the treatment allocation."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "The consequence of this for the writers RCT is that patients cannot be blinded to the treatment as the intervention is an orange/brown ointment, while the comparator IntraSite Gel™ is a clear gel, thus the difference between treatments is obvious." Comment: blinding of participants and healthcare providers not done.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "Blinded outcome assessment is not possible for two reasons. As stated, honey leaves an orange staining on the periwound skin (photo 3.1) which would identify which treatment the patient is receiving and secondly, within the main study centre clinic and in community leg ulcer clinics, a person trained in wound management would not be available to assess wounds. Photographs would not be used for blinded outcome assessment, as the ability to achieve high quality photos from each centre for each patient was not possible. Therefore, the trial would be classified as open label." Comment: primary outcome assessors were not blinded. Quote: "However, to add some element of blinding, the laboratory would not be made aware of which treatment the patient was receiving and the statistician would not be aware of the identity of each group." Comment: secondary outcome assessors were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: figure 5.2 shows that no participants were lost to follow‐up, but there were 9/54 withdrawals in the manuka honey group (6 due to infection in the study wound) and 17/54 withdrawals in the hydrogel group (12 due to infection in the study wound). This was relatively small compared with the event rate, so acceptable. Quote: "Data were analysed on an intention to treat (ITT) basis." Comment: ITT analysis had been done, as all the randomised participants were included in the final results.
Selective reporting (reporting bias)	Low risk	Comment: the study protocol was not available, but all trial outcomes described in the methods section of the report were included in the results section.
Other bias	Unclear risk	Quote: "Analysis using independent t‐test determined there was no statistically significant difference between treatment groups for any of the baseline continuous variables such as wound duration, size, patient age, and slough. Chi‐square analysis did not report any statistically significant differences between groups for baseline categorical." Comment: ulcers in the honey group were larger (median ulcer areas: 4.2 cm² with hydrogel dressing vs 5.4 cm² with manuka honey dressing; mean ulcer areas: 9.87 cm² with hydrogel dressing vs 10.52 cm² with manuka honey dressing), present for longer (median durations: 14 weeks with hydrogel dressing vs 18 weeks with manuka honey dressing; mean durations: 29.9 weeks with hydrogel dressing vs 39.4 weeks with manuka honey dressing) and had a greater area covered by slough (78.2% with hydrogel dressing vs 85.5% with manuka honey dressing); however, these factors would affect the likelihood of healing in the honey group. The Margolis index had a higher proportion of score 2 patients in the honey group (22% with hydrogel dressing vs 37% with manuka honey dressing). The study seemed free from other forms of bias. In addition, the randomised treatments were for only 4 weeks and then treatment was given according to clinical assessment; this was not reported, so no information on comparability of treatments.