Study Design and Patient Recruitment
A randomized, double-blind, active comparator-controlled, multi-center trial was conducted at seven medical centers in Shanghai, China. Patients were recruited and enrolled at the seven medical centers if they met the following eligibility criteria: (1) eczema patients who were diagnosed with Western medicine criteria (noncontagious inflammation of the skin, characterized chiefly by redness, itching, and an outbreak of lesions that may discharge serous matter and become encrusted and scaly) (20); (2) patients with standard syndrome of blood heat wind hyperactivity in TCM diagnosis (21); (3) aged 18–65 years old, any sex or ethnicity; (4) volunteered to participate in the clinical trial with informed consent, and could cooperate with the visit schedule; (5) lesion area of approximately 5%–30% of body surface area (BSA), and an Investigator Global Assessment scale of 1–3 points; (6) lesions mainly located in the trunk and limbs; and (7) women who were human chorionic gonadotrophin (HCG) negative.
This study was approved by the Internal Review Board at the Yueyang Hospital of Integrated Chinese and Western Medicine (Approval No. 2015-015). All patients provided written informed consent prior to enrollment.
The target sample size for this study was based on assumptions and clinical experience from a previous study. According to the literature, the percentages of treatment effectiveness in the WM, TCM, and TCM+WM treatment groups were 63.33%, 83.33%, and 86.67%, respectively. In this study, we set the effectiveness percentage as the primary treatment effect outcome, and we assumed the following: an inspection level (α) of 0.05 and test power of 0.8 for two-sided tests, at least 94 patients required for each group, considering a 10% rate of loss to follow up, and 114 patients observed in each group, with 342 patients total between the three groups.
Randomization and Blinding
A centralized randomization system was used. Subjects were registered once they met the inclusion criteria. Basic information on the primary enrolled subjects, including date of birth, sex, ethnicity, full and abbreviated names, and predetermined prognostic factors was recorded. The subject IDs were generated after registration. Subjects were then assigned to a treatment group based on a predetermined randomized design by logging onto the randomized center website. A random coding table was established by statisticians and sealed for preservation in the Yueyang Hospital of Integrated Traditional Chinese and Western Medicine. Statisticians were blinded to the group allocation. Each subject received a medication pack containing 8 weeks of medication for all three groups, but with different medicine allocation; subjects in the TCM group took QZLX granules and a loratadine placebo orally, subjects in the WM group took placebo QZLX granules and loratadine tablets orally, and subjects in the TCM+WM treatment group took QZLX granules and loratadine tablets orally. Each pack and all medicines within it contained a label with a number on it. An emergency letter containing the patient's medication number and group was prepared for each subject for emergency unblinding. The corresponding letters were sent to the centers with the corresponding numbered drugs. A specially assigned person was responsible for testing the experimental indicators, while the statistician was responsible for data collection and statistical analysis.
The intervention was divided into three stages: introduction, treatment, and follow-up.
Stage 1: Introduction
External drugs, including mometasone furoate cream (trade name: Erosone; Shanghai Schering-Plough Pharmaceutical Co., LTD., Shanghai, China), mopifloxacin ointment (trade name: Baiduan; Sino-us Tianjin Skincare Pharmaceutical Co., LTD., Tianjin, China), 3% boric acid solution, and zinc oxide were used. First-generation cephalosporin preparation was the first-choice systemic antibiotic. If a patient was allergic to cephalosporin preparations or was using cephalosporin over 7 days for disease improvement, they received clindamycin orally.
Stage 2: Treatment
The subjects were divided into three groups: TCM treatment group, WM treatment group, and TCM+WM treatment group. Subjects in the TCM group took QZLX granules and a loratadine placebo orally; subjects in the WM group took placebo QZLX granules and loratadine tablets orally, and those in the TCM+WM treatment group took QZLX granules and loratadine tablets orally.
Stage 3: Follow-up
In this stage, all the above-mentioned medications were discontinued, except for moisturizers.
The second stage of treatment lasted for 8 weeks, during which the safety indexes were observed before and after treatment. During the second stage, efficacy indexes were observed at weeks 0, 2, 4, 6, and 8. The efficacy and safety of the treatment were analyzed at the end of the second stage. Complications and adverse reactions were monitored during treatment. Follow-up was performed at 2, 4, 6, and 8 weeks to assess the clinical response and rash. If eczema relapse occurred, follow-up was completed.
Outcomes and Adverse Events
The primary outcome measures were the EASI score and pruritus level (22). The secondary outcome measure was the DLQI score.
Any unexpected responses that were considered possibly or definitely related to the study treatments were reported. In the case of serious adverse events, experimental treatment was stopped immediately, and appropriate treatment was provided. The types and frequencies of adverse events were reported for each group.
We applied SAS software (version 9.4; SAS Institute, Armonk, NY, USA) for data analysis. In this study, our primary analysis was a per-protocol (PP) analysis, which included 270 patients with eczema who completed the treatment and follow-up. We describe the data as means ± standard deviations (SD) for quantitative variables with normal distribution, and as median and interquartile range (IQR) for quantitative variables with a skewed distribution. We also described the data using frequency counts and proportions (rate) for qualitative variables. Student’s t-test and Mann-Whitney U tests were applied to examine the difference between quantitative variables with normal or skewed distribution, respectively, and the chi-square test was used to examine the differences between qualitative variables. Repeated measures ANOVA was applied to evaluate the efficacy of treatment, time, and the interaction between treatment and time. In this study, a two-tailed p-value ≤ 0.05 (two-tailed) was considered statistically significant.