The trial was a randomized, double-blind, positive drug-controlled, multicenter clinical trial with double modeling methods; it was conducted in 18 hospitals in China, and the start and end dates of the trial were March 2015 and November 2017. The Research Institutions Examination Committee approved each participating research center (ClinicalTrials.gov, Registration number: ChiCTR1800016668). Considering the Declaration of Helsinki and the relevant rules and regulations of clinical trial research in China, the experimental scheme was approved by the Institutional Review Board of Affiliate Hospital of Nanjing University of Chinese Medicine and the Sub-Center Ethics Committee. Further, all subjects signed a written informed consent form.
The participating units included the Jiangsu Province Hospital of Chinese Medicine, First Affiliated Hospital of Anliui Medical University, Second Hospital of Shanxi Medical University, Affiliated Hospital of Shanxi College of Traditional Chinese Medicine Changzhi People’s Hospital, Luoyang No.2 Hospital of Traditional Chinese Medicine, General Hospital of Dongfeng Motor Company, The Second Affiliated Hospital of Baotou Medical College, Chongqing Traditional Chinese Medicine Hospital, Second Affiliated Hospital of Shaanxi College of Traditional Chinese Medicine, Taizhou Hospital of Traditional Chinese Medicine, Nanjing Hospital of Traditional Chinese Medicine, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Affiliated Hospital of Inner Mongolia University for Nationalities, Ezhou Central Hospital, Chifeng Municipal Hospital, The Second People’s Hospital of Hunan Province and Affiliated Hospital of Chengdu University of Traditional Chinese Medicine.
Inclusion and exclusion criteria
Inclusion criteria: Patients aged 18 to 65 years, regardless of sex, who had mild to moderate UC in the active stage (Mayo score > 2, mild to moderate Truelove-Witts evaluation), volunteered to participate in this clinical trial and signed the informed consent form were included.
Exclusion criteria: Patients who were in remission or the severe active phase, pregnant, lactating, or had recently given birth; patients with a severe allergic constitution or who were allergic to known components in the enteric-coated HuDi capsules or enteric-coated mesalazine tablets; patients complicated with severe cardiovascular and cerebrovascular diseases or severe primary diseases involving the liver, kidney or hematopoietic system and in whom blood alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were above the normal upper limit and blood creatinine (Cr) was above normal upper limit; patients with UC who had serious complications, such as local stenosis, intestinal obstruction, intestinal perforation, multiple intestinal polyps, toxic megacolon, and rectal cancer; and patients with mental disorders or intellectual disability were excluded.
Randomization and masking
Given the number of seeds according to SAS v9.4 statistical software, a random arrangement of subjects (random coding table) was generated. Personnel unrelated to clinical observation, monitoring and statistical analysis in this clinical trial placed the corresponding drug number in a conspicuous location on the external packaging of the drug according to an established processing code and sent the packed test medicine boxes to the test centers. Secondary blinding was used in this experiment.
The random coding table was established by the data management and statistical units involved in the clinical trial. Two copies were sealed; one was submitted to the applicant, and the other was submitted the lead unit for proper preservation.
Patients who met the inclusion criteria and did not meet the exclusion criteria were randomly divided into three groups: an enteric-coated HuDi capsules group who received enteric-coated HuDi capsules and enteric-coated mesalazine tablet simulators, an enteric-coated mesalazine tablet group who received enteric-coated HuDi capsule simulators and enteric-coated mesalazine tablets and a combined drug group who received enteric-coated HuDi capsules and enteric-coated mesalazine tablets. The enteric-coated HuDi capsules and enteric-coated HuDi capsule simulators were taken 4 capsules at a time, 3 times a day, at 1 h before breakfast, midday and dinner, respectively. The enteric-coated mesalazine tablets and enteric-coated mesalazine tablet simulators were taken 1 g at a time, 3 times a day, in the morning, afternoon, and night, respectively. Before the participants were formally enrolled in the group, a two-week screening period was established, and medicines for UC were discontinued. During the treatment period, spicy food, seafood, milk and other foods that can aggravate the disease were avoided. Moreover, medicines with the same efficacy as the experimental drugs were also forbidden.
Clinical and mucosalmeasurements
The subjects were assessed to establish their Mayo scores and identify symptoms of abdominal pain, diarrhea, or visible mucus or blood in the stool at the time of admission and at 2, 4 and 6 weeks after treatment and were examined by colonoscopy at 0 weeks before treatment (within 6 weeks before admission) and 6 weeks after treatment (within 2 weeks after treatment). Routine blood tests were conducted and liver function (ALT, AST, r-GT, TBil, ALP) and renal function (blood urea nitrogen (BUN), Cr) were examined at 0, 2 and 6 weeks before treatment. Electrocardiogram results were examined before and 6 weeks after treatment. The type, degree and incidence of adverse events were recorded. The primary endpoint was clinical efficacy and remission after 6 weeks of treatment, and the secondary endpoints were endoscopic response, mucosal healing rate, and improvement of chemical parameters (ESR, CRP).
Clinical efficacy criteria: The total Mayo score decreased from baseline by more than 30% or more than 3 points, and the absolute score of the stool subscale decreased by more than 1 point or was 0 or 1 point.
Clinical remission criteria: The total Mayo score was < 2 and no single score was > 1.
Endoscopic response criteria: The Mayo score and endoscopy subscore decreased by at least 1 point relative to baseline.
Standard of mucosal healing: The absolute score of the Mayo endoscopy subscore was 0 or 1.
After the test plan was determined, the statistical professionals were responsible for formulating the statistical analysis plan in consultation with the main researchers. SAS 9.4 statistical software was used for the descriptive statistical analysis. Qualitative indicators are described by frequencies, percentages or composition ratios, and quantitative indicators are described in terms of means and standard deviations or medians, lower quartiles (Q1), upper quartiles (Q3), or minimum and maximum values. Regarding the comparative analysis of two groups, qualitative data were analyzed using chi-square tests, Fisher’s exact tests, Wilcoxon rank sum tests, Cochran-Mantel-Haenszel (CMH) 2 tests, and weighted least squares (WLS) covariance. Quantitative data conforming to a normal distribution were analyzed using the t-test (homogeneity test of variance was conducted among groups, 0.05 was used as the test level, and a t-test considering the Satterthwaite method was used for correction when the variance was uneven). Wilcoxon rank sum tests and general linear model (GLM) covariance were used for non-normally distributed data. The hypothesis test employed the bilateral test and provided the test statistics and corresponding P values. Statistical significance was considered at P < 0.05 and P < 0.01.