Chu 2009.

Methods	Within‐participant, randomised controlled trial This study was conducted at a single centre in Taiwan
Participants	67 participants with chronic hand eczema Inclusion criteria of the trial Males or females 20 years of age or older Participants must have chronic hand dermatitis based on clinical diagnosis and at least mild dermatitis of both hands at baseline, as defined by an Investigator Global Assessment score of 2 (mild) to 5 (very severe) Participants must have been informed of study procedures and therapies and must have given their written informed consent Exclusion criteria of the trial Women who are pregnant or who are breast‐feeding Participants who have received systemic corticosteroids (i.e. oral, intravenous, intra‐articular, rectal, intramuscular) within 1 month before first application of study medication Participants who have received phototherapy (e.g. UVB, PUVA) or systemic therapy (e.g. immunosuppressants, cytostatics) known or suspected to have an effect on hand dermatitis within 1 month before first application of study medication Patients who were treated with topical therapy (e.g. tar, topical corticosteroids) known or suspected to have an effect on hand dermatitis within 7 days before first application of study medication Patients who have a diagnosis on the hands of active atopic dermatitis, dyshidrotic eczema, psoriasis, urticaria, active fungal or bacterial infection, or identified allergic contact dermatitis (e.g. poison ivy dermatitis) Patients with hypersensitivity to vitamin B, vitamin C, vitamin E, beta‐carotene Study population Gender: 52 female, 15 male Age: mean age 42.95 years, range 20.5 to 72.6 years
Interventions	Intervention • E‐DO (HK‐03) topical lotion, once daily (evening), for 4 weeks, applied to 1 hand in 67 participants Control intervention • Placebo applied once daily on the contralateral hand for 4 weeks, on 67 contralateral hands Duration 4 weeks
Outcomes	Primary outcome of the trial Observer‐rated therapeutic response rate (clear or almost clear) based on Investigator Global Assessment (IGA) at week 4 (or at time of early discontinuation) Secondary outcomes of the trial Participant‐rated reduction in severity: the proportion of participants with at least 50% improvement (clinically significant response) base on the patient's global assessment (PaGA) at week 4 (or at time of early discontinuation)  Observer‐rated reduction in severity: the percent change in HEAS (Hand Eczema Area and Severity Score) from baseline to post treatment during 4 weeks  Change in pruritus score and pain score from baseline to post treatment during 4 weeks Change in the degree of moisture on the skin's surface, and water evaporation on skin surfaces by transepidermal water loss (TEWL) after 4 weeks Change in quality of life scores (DLQI) from baseline to end of study during 4 weeks  Safety and tolerability of E‐DO including adverse events/serious adverse events reported during 4 weeks
Notes	This study is (not yet) published but was registered on clinicaltrials.gov, and Dr. Chu released the results in personal communication after obtaining consent from HenKan Pharmaceutical The secondary outcomes ‐ reduction in severity, investigator‐rated and participant‐rated ‐ were included but did not provide reproducible data Declarations of interest: not stated, although the study was sponsored by HenKan Pharmaceutical Co. Funding: the study was sponsored by HenKan Pharmaceutical Co., Ltd., and results of this negative study (E‐DO was not statistically significant better than vehicle) were not published, although HenKan Pharmaceuticals did give Dr. Chai‐Yu consent to release the results Sample size rationale: not stated
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The report and the trial register claim a randomised design; however it is unclear how randomisation was done Personal communication did not reveal further information
Allocation concealment (selection bias)	Unclear risk	Not described in the protocol; personal communication did not reveal further details
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "randomized, double‐blind, vehicle controlled..." Comment: double‐blind study in which a placebo vehicle was used
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "randomized, double‐blind, vehicle controlled..." Comment: double‐blind study; unclear how this was done
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "sixty‐three subjects received at least one dose of each investigational product (..) and [having] at least one post‐baseline assessment on both hands were included in the ITT population" Comment: intention‐to‐treat analysis was carried out on all participants who received the study drug. Only 63 of the 67 randomised participants received the study drug (94%)
Selective reporting (reporting bias)	Unclear risk	The trial was registered at clinicaltrials.gov (NCT00556855). We found no major discrepancies between the trial registration and the final study report; however for most of the secondary outcomes (quality of life, TEWL, HEAS, pain score), the report states only that no statistically significant differences were found and does not provide actual numbers
Other bias	Low risk	Baseline comparisons: a baseline comparison with regards to disease severity is provided; however because this trial used a within‐participant design, this is not further applicable Diagnostic certainty: yes The study was completed