Study design and participants
This single-center double-blinded non-inferiority randomized controlled trial is expected to last 3 years at the Shanghai Pudong Hospital affiliated to Fudan University in China. Individuals diagnosed with hyperuricemia will be recruited from the outpatient and inpatient departments of Shanghai Pudong Hospitals affiliated to Fudan University, China. Screening for eligibility will be conducted by clinicians not involved in the study. Patients who express willingness to participate and satisfy the inclusion and exclusion criteria listed below will be provided a detailed explanation—written in understandable language—regarding the purpose of the study and the methods that will be followed. All participants will provide their consent in writing.
A total of 72 individuals will be recruited and use the random number table randomly assigned in a 1:2 ratio to one of two treatment groups: a Western medicine group (WG; n = 24) and a Western medicine combine Chinese herbal medicine group (WJNSG; n = 48). Both groups will undergo a 24-week treatment. The protocol follows the Standard Protocol Items for Clinical Trials 2013 (SPIRIT 2013) .
Diagnostic criteria for HUA
Participants are diagnosed with hyperuricemia which is defined as serum uric acid > 420 μmol/L on two repeated measurements (on different days)
Diagnostic criteria for TCM syndrome differentiation
A patient should have at least two primary symptoms and two secondary symptoms, consistent with tongue and pulse examination which is diagnostic of phlegm and blood stasis syndrome.
Hyperuricemia is defined as serum uric acid > 420 μmol/L on two repeated measurements (on different days):
History of cardiovascular disease
Serious respiratory, digestive, hematological, and liver disease; malignancy; infectious disease; mental disorder
History of allergy to TCM
Pregnancy or lactation
Not expected to comply with prescribed medications or to attend regular follow-up
History of participation in another clinical trial in the previous 2 weeks
Refusal to sign the consent form
Participant elimination criteria
Patients will be removed/withdrawn from the study if they meet any of the following criteria:
Patients who are not follow up on time or fail to follow up the protocol
The creatinine level 30% higher than baseline, drug dose change in response to harms
The alanine transaminase (ALT) or aspartate transaminase (AST) level 3 times higher than normal
Patients with serious adverse events, complications, or specific physiological changes, who are not suitable to continue the trial
Patients with insufficient evidence, failing to determine the effectiveness of the trial, request discontinuing
All of the groups will be treated with test drugs or placebo together with basic treatment.
Basic treatment: Avoid strenuous exercise, low purine diet, drink more water, control blood pressure, blood sugar
WG: basic treatment + febuxostat 40 mg once daily; febuxostat (trade name: You litong in Chinese pinyin) is manufactured by Jiangsu Wanbang biochemical medicine group Co., Ltd.
WJNSG: basic treatment + febuxostat 20 mg once daily + Jiangniaosuan formula (200 mL of the decoction) two times a day orally. Constituents of Jiangniaosuan formula are shown in Table 1.
JNSG: basic treatment + febuxostat placebo daily + Jiangniaosuan formula (200-mL decoction) two times a day orally. JNSF are manufactured by Shanghai Kangqiao Chinese Medicine Tablet Co. Febuxostat placebo taste and packaging same as febuxostat, which are manufactured by Jiangsu Wanbang biochemical medicine group Co., Ltd.
The total treatment process will be divided into two stages:
Stage 1: WG patients (n = 24) will receive febuxostat, while the WJNSG (n = 48) patients will receive febuxostat 20 mg plus Jiangniaosuan formula. After 12 weeks of this treatment, patients will enter the second stage of treatment.
Stage 2: WJNSG patients (n = 48) will be randomly divided into two equal subgroups: WJNSG (n = 24) will continue to receive febuxostat 20 mg and Jiangniaosuan formula, while the other subgroup (JNSG) will receive Jiangniaosuan formula and febuxostat placebo. The second stage will last for 12 weeks too.
The study flow chart is shown in Fig. 1.
Hyperuricemia patients in the Department of Integrated Traditional Chinese and Western Medicine and the nephrology department of Shanghai Pudong Hospital could receive detailed details of this study. The doctors, nurses, and careworkers for patients in the ward were informed. They will encourage patients to participate.
During the 24 weeks of treatment, the participants will be asked to visit the clinic every 4 weeks. At each follow-up visit, blood and urine will be examined and the TCM symptom score will be calculated. The whole process will be supervised by 2 different supervisors. Strategies to improve adherence to treatment include series of diet courses on uric acid–lowering and certain transportation subsidies, which will promote retention and completion of follow-up assessments. Other uric acid–lowering treatments during the trial are not allowed.
Participants will be assessed at seven time points: at baseline and at 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, and 24 weeks (Fig. 1).
The primary outcomes of this study will be the serum levels of uric acid.
Secondary outcome measures
Secondary outcomes include TCM symptom improvement, Scr, BUN, eGFR, 24 h UUA, fasting insulin, TG, TC, HDL, and LDL.
CHM is prescribed by TCM physicians according to patients’ symptoms and signs, tongue, manifestations, and pulse condition. The TCM symptom scoring form is designed to assess the internal accumulation of phlegm and blood stasis . These symptoms are scored on an ordinal scale of absent, mild, moderate, and severe. The scoring tool will be completed by the assessing TCM physician, and the patient’s pulse and tongue appearance will be assessed from the TCM perspective. Information collected from the questionnaire will be used to assess the response to JNSG. Each symptom or sign will be given a score (Table 2), and the total score will be recorded. The change of score can calculate an efficacy indicator (EI) for the treatment efficacy.
EI = (Total symptom score at baseline − Total symptom score post−treatment)/Total symptom score at baseline × 100%
The degree of symptom improvement will be divided into four categories: full recovery (EI ≥90%), good recovery (90% > EI ≥ 70%), modest recovery (70% > EI ≥ 30%), and no recovery (EI < 30%).
Both cohorts undergo a 24-week treatment. Case-report forms, prepared prior to study commencement, will be used by the researchers to collect a range of information. Patients who fail to visit the clinic for follow-up will be contacted over the phone (Table 2). Each visit allows a window of 3 days.
① Demographic data: age, sex, nationality, occupation, and so on
② Physical examination: breathing, body temperature, pulse, blood pressure, weight, waist-hip ratio, tongue coating, pulse, and so on
③ General clinical data: history of comorbidity, allergy, family history, and so on
Laboratory index: SUA, 24-h urine uric acid (24hUUA), Scr, BUN, fasting insulin, TG, TC, HDL, and LDL.
Safety indicators: blood routine, urine routine, stool routine, liver and kidney function, and blood electrolyte electrocardiogram
For safety monitoring and assessment, the following biological indicators will be assessed at each follow-up visit: blood routine, liver function (aspartate transaminase, alanine transaminase), renal function (blood urea nitrogen, serum creatinine), stool routine, and electrocardiogram.
Any unexpected symptoms or signs or feelings of discomfort will be recorded as adverse events (AEs). For each adverse event, the duration (starting date, ending date), severity, relationship to the trial, and potential to trigger patient dropout from the study will be recorded. Patients experiencing an adverse event will be monitored until it resolves.
When adverse events are found, the doctor reported to the project leader to assist DSMC in determining the treatment plan according to the patient’s condition, and a follow-up investigation should be carried out for the cases of drug withdrawal due to adverse reactions. All of the interventions should be recorded in detail. In case of serious adverse events, the researcher shall immediately take protective measures for the subjects and report to the sponsor, ethics committee, and DSMC within 24 h. Any adverse reactions are actively treated and followed up until fully improved.
All blood specimens after the test will be collected and stored in a specific −80 °C refrigerator of Pudong Hospital, which is kept by special personnel of the clinical laboratory. The later test can be applied. Until the experiment is complete, sterilization is performed.
Data and safety monitoring
An independent Data Safety and Monitoring Committee (DSMC) includes statisticians, cardiologist, and so on. All relevant investigators will receive a 2-h training before the trial begins. They will monitor the whole trial process. They will join an online organization WeChat group, and they provide day-to-day support and coordinate works smoothly every day. They will meet once every month to monitor the safety of the trial and detect any difficulties or errors. It is independent from the sponsor and competing interests. All of the patients’ data will be stored in a password-protected Excel file. Healthcare inspectors, auditors, monitors, and members of the medical ethical commission might be allowed to access the database and biological specimens as required by the law. All data collected using the case-report forms will be submitted to an online clinical research data capture computer system developed by the research group. Two researchers are in charge of the database data. The data entry adopts a double-person verification system, one-person entry and one-person verification to ensure that the data are correct. Only the two data researchers participate in data recruitment or intervention.
All trial team members join an online research working WeChat group. If there are any plans and notifications to change the study, the final protocol will be announced in the working WeChat group to ensure that everyone receives a notification. All members of the research team, the organizer, the doctors, the nurses, and the data researchers will perform the latest protocol after receiving the eventual modifications of the study. At the same time, the researchers will update the protocol in the clinical trial registry.
Personal information will be protected carefully from the beginning of the recruitment process. The patient’s information will be graded on a notebook from the first day of enrollment. The personal information including name, age, gender, contact family address, and emergency contact person will be kept in a separate notebook. When registered to the computer, each person will anonymously be a number, and the information will be registered to a folder with a password, and the name of the patient will be deleted. At last, we will use the summary data instead of the personal data in order to protect the research’s privacy, even the anonymized individual trial data will not be shared with other researchers.
Sample size calculation
To detect treatment response rates of 93.3% and 63.3%, respectively, in the JNSF group and the control group with a significance level of 5% and power of 80%, we would need to have 30 patients in each group (total 60 patients). Assuming that there might be a 10% loss to follow-up or early withdrawal from the study, we decided to enroll 72 patients, with 24 patients in each group. These assumptions have been based on data of Zheng PD .
The randomization list was generated using a random number table by a statistician using SPSS. A statistician unrelated to this trial will use the random number table assigning the patients. After screening, if the patient agrees to participate in the trial and signs the informed consent form, he/she will receive a random number from the physician. In stage 1, 72 patients will be randomly divided into WG and WJNSG in a ratio of 1:2. In stage 2, after a 4-week treatment, the WJNSG will be randomly divided into WJNSG and JNSG in a ratio of 1:1. The sequence will be sealed in the opaque envelope. Only the statistician who generated the randomization is aware of the group assignments.
This clinical trial will be double-blinded, from stage 1 to stage 2 of the study. Physicians and patients were all blinded for the allocation. Only the statistician knows the allocation.
If an emergency occurs, the study designer will ask an independent physician to unblind the patient. The incident will be recorded and reported to the independent safety monitoring board. When all the data analysis is finished, the results will be released.
Data analysis will be performed by a statistician who does not know the groupings in accordance with the specified statistical plan. The statistician comes from the Experimental Center of Shanghai Pudong Hospital, Shanghai, China. SPSS 22.0 (IBM Corp., Armonk, NY, USA) will be used to analyze the experimental data. Baseline differences between groups, gender, and age will be assessed with the χ2 test or Student’s t-test. Continuous variables will be presented as means ± standard deviations or medians, and differences in such variables will be analyzed using an independent t-test. Comparisons between the groups and within groups will be conducted using analysis of covariance (ANCOVA), with the baseline as the covariate. For efficacy analysis, repeated-measures analysis of variance (ANOVA) will be used to analyze the changes in scores from baseline to the endpoint of treatment. Within each group, differences will be assessed with the paired t-test for normally distributed data and the Wilcoxon signed-rank test for non-normally distributed data. For analysis of the final dataset, missing data will be filled in using the last-observation-carried-forward approach. P < 0.05 will be considered significant. No additional analyses are scheduled.