This study will investigate the efficacy and safety of QSHY as a treatment for Hyperlipidemia diagnosed with Phlegm-blood Stasis Syndrome. This is a randomized, double-blind, placebo-controlled trial. The flow diagram of this trial is shown in Figure. 1. This study will be conducted in Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine.
The visit in this trial are designed as 5-time points during 24 weeks of intervention: Baseline, 6 weeks ± 5 days after enrolment, 12 weeks ± 5 days after enrolment, 18 weeks ± 5 days after enrolment, 24 weeks ± 5 days after enrolment. At each visit time point, participants will have tests according to the study schedule, and data of vital signs will be recorded. The detailed flow path information is shown in Figure.2.
According to the previous results from a single center clinical observation, after treated with QSHY decoction, the fasting serum TC level decreased by 23.84% compared with baseline, and the fasting serum TC level in the control group decreased by 12.71% compared with baseline. It is expected that the decrease of fasting LDL-C level in the QSHY granule group will increase by 15% compared with placebo. Assuming a = 0.05, β = 0.2, nT: nC = 1:1, ẟ=0, πC = 0.155, πT = 0.305, according to the formula of the optimal sample size, 94 samples in each group will be obtained. Considering the leakage rate of 10%, there will be at least 105 cases in each group.
①For patients who meet the diagnostic criteria of Chinese and Western medicine for hyperlipidemia. The diagnostic criteria for hyperlipidemia refer to the Chinese Guidelines for the Prevention and Treatment of Dyslipidemia in Adults (2016 Revised Edition)(39). TCM diagnosis, syndrome differentiation criteria, and their basis refer to the TCM diagnosis and treatment criteria for dyslipidemia formulated by the heart disease branch of the Chinese society of TCM(40).
②Aged over 18 years;
③Participates without ASCVD, 3.4mmol/L < LDL-C < 4.9mmol/L; ASCVD patients, 2.6mmol/L < LDL-C < 4.9mmol/L;
④Patients with fasting TG < 5.7 mmol/L;
⑤BMI < 35 kg/m2;
⑥Willing and able to follow the scheduled visit plan, diet and exercise instructions, laboratory tests and other procedures.
⑦Patients who signed informed consent.
①The patients who used other lipid-lowering drugs 4 weeks before enrollment;
②Patients with uncontrolled endocrine or metabolic diseases that may interfere with blood lipids levels;
③Patients taking oral corticosteroids;
④Patients with a history of alcohol or narcotic drug abuse within 1 year before screening;
⑤Patients with high or very high risk of arteriosclerotic cardiovascular disease;
⑥Patients with congestive heart failure, unstable angina, MI, stroke, coronary artery bypass surgery or angioplasty, or unstable/serious peripheral artery disease in the past 6 months;
⑦Patients who have undergone gastrointestinal surgery in the past year or who have taken weight-loss drugs in the past 3 months and have lost more than 10% of their body weight;
⑧Pregnant or lactating female patients;
⑨Patients with serious primary diseases or other major diseases such as malignant tumors.
Randomization and concealment
Randomization and allocation
The consecutive random sequence of 2 groups will be provided by the clinical medicine center with SAS Version 9.1 statistical software. Eligible participants will be randomly allocated into the QSHY group or the palcebo group in a 1:1 ratio. Random sequence will be sealed in opaque envelopes and locked in the independent clinical medicine center. The allocation concealment will be maintained until the all data of each participant in each visit had been uploaded and locked.
Blind editing and blind bottom preservation: All patients and researchers will be blinded to the treatment assignments until the trial is completed. Personnel unrelated to this clinical trial completes the preparation of drug blinding and emergency letters. Duplicate blinding is adopted in this study. All the data will be uploaded into the electronic database in double copies, and the final statistical plan is confirmed by question answering, verification, and blind review, the database will be locked. After that, the first unblinding will be carried out and the results of the undefined group information corresponding to random number for necessary statistical analysis can be obtained. After the analysis, the main researcher will perform the second unblinding with the identification of two groups. All the unblinding processes will be recorded. In case of emergency, the reason, time, and place of blindness breaking will be recorded, and the cases will be treated as missing cases.
The investigators will be experienced physicians familiar with the trial process. A printed standardized protocol and an informed consent form will be presented during the investigation. The enrolment will be performed after the investigators fully introduce the detailed trial process, probable benefits and potential risks to eligible participant. The investigators will fulfill the case report form (CRF) with participants data after the participants have signed informed consent form. All data collected from participants including personal information will be kept confidential in this trial.
Participants can withdraw at any time and will be recorded the reason for withdrawal. The investigation with the curative effect after medication and the relationship with the trial will be recorded in detail as the evaluation index at the time of termination. The original data of all withdrew and terminated cases should be kept and recorded for further analysis. If adverse events occur, the researchers should judge its relationship with the trial, and take necessary measures to ensure the safety and rights of participates. The severe adverse event should be timely report to the drug regulatory department.
Included participants in the treatment group will receive QSHY granule, while QSHY simulated granule as placebo will be applied in the control group. Both groups of participants will receive regular health education, including diet control, exercise, and behavior modification. ①diet adjustment: diets with low sugar, low fat and high vitamin will be recommended, of which the fat content is less than 30%, protein content accounts for 15%-18%, and carbohydrate accounts for 52%-55% of the daily total energy; ②Strengthen physical exercise: moderate metabolic equivalent exercise will be recommended for more than 30 minutes each time, 4 times a week; ③Adjust emotion and keep a good mood.
The QSHY are compound preparations of 5 Chinese herbs, Artemisiae scopariae herba(Yin Chen), Polygoni cuspinati rhizome et radix(Hu Zhang), Curcumae longae rhizome(Jiang Huang), Gardeniae fructus (Zhi Zi), and Herba hyperici japonici(Tian Jihuang), packaged in consecutively numbered drug containers. The number was distributed according to the randomized number. The placebo will have a identically packaged appearance, weight, and taste compared to the QSHY granule. Both QSHY granule and placebos will be produced by Jiangyin Tianjiang Pharm Co. Ltd (approval number AH20160363), Jiangsu, China. Participants will be advised to take one pack after-meal, twice a day. The drugs are stored in the clinical trial base certified by Good Clinical Practice(GCP) and are managed and distributed in an independent clinical medicine center. The number of drugs received, taken, and returned by the patients will be recorded in detail by the research doctors at each visit. During the experimental period, Non-pharmacologic care is permitted but other TCM herbs and Western medication for lipid-lowering or fatty liver treatment will be prohibited.
Participants will be provided the information of the treatment orally and an informed consent form. Participants will be advised not to take concomitant medications or change the dose and frequency of drugs autonomously. To facilitate completion, participants are suggested to contact the arranged physicians for any questions raised about this trial. The drugs left over will be returned and the related medication compliance will be calculated. Any combination of medications will be recorded in detail. Participants will be recommended to visit the outpatient clinic regularly for post-trial care.
The primary outcome in this study is the percentage change of LDL-C from baseline to week 12. The secondary outcomes are the changes in fasting serum TC, TG, HDL-C, non-HDL-C, apolipoprotein (Apo) A-I, ApoA-II, ApoB and fasting blood glucose at 12-week assessment and 24-week assessment, the change in the ratio of TC/HDL-C at 12-week assessment and 24-week assessment. All mentioned serum biochemical markers will be measured at baseline, 12-week and 24-week after randomization. The measurement of life quality will be assessed by Medical Outcomes Study item short-form health survey (SF-36) questionnaire. The changes in the syndrome of TCM for participants will be measured using four TCM diagnostic methods and the Scores of TCM syndrome Scale. Other outcomes are blood pressure, heart rate, body mass index (BMI), and waist-to-hip ratio (WHR).
Safety indexes are blood and urine routine examination, results of serum liver function test including AST, ALT, alkaline phosphatase (ALP), and serum renal function test including creatinine (CR) uric acid (UA), and blood urea nitrogen (BUN). Adverse events that occurred in the trial period will be monitored at each visit. All collected adverse events and their degree will be recorded with followed medical intervention in the CRF.
The clinical trial protocol was jointly agreed upon by the main researcher and the sponsor, and has been approved by the IRB of Shuguang Hospital affiliated with Shanghai University of TCM before implementation(Ethics approval number: 2019-780-135-01). If the protocol is revised in the process of clinical trial implementation, it needs reapproval from the ethics committee.
Data management will be applied by an electronic data capture system (EDC). Two data administrators will input and proofread the data independently. Divergences raised about the CRF and data proofread will be generated as a concentrator data ready queue (DRQ). Data administrators will send the DRQ to the researchers through the clinical supervisor. The researchers deal with the DRQ and return it as soon as possible. The data administrators will confirm the modification and enter the new data according to the responses of the researchers, and issue DRQ again if necessary. After reviewing and confirming the correctness of the database, the main researchers, applicants, and statistical analysts will lock the data. The locked data file will not be changed. Any problems found after data locking will be corrected. The demographic and clinical information of participants will be kept by doctors confidentiality. The results of this trial will be submitted for publication in peer-reviewed journals and can be disseminated through conference presentations.
The statistical analysis will be performed by an independent statistician. After the trial protocol is determined, the statistician is responsible for formulating the detailed statistical analysis plan in consultation with the principal investigator. Statistical analysis will be conducted using SAS Version 9.1 statistical software. Full analysis set (41) including participants who met the inclusion and exclusion criteria and receiving at least one evaluation at least once after randomization will be statistically analyzed. Per-protocol set (PPS) including participants who had good compliance (80% − 120% of the trial drugs were used), did not take prohibited drugs during the trial, and completed the CRF will be statistically analyzed. Safety analysis will be conducted based on a safety analysis set including participants who have received at least one intervention and safety evaluation. Continuous variables are presented as mean ± standard deviation (42) or median with quartile range, according to the distribution. An independent t-test or the Mann-Whitney U test will be conducted to compare the differences between groups. Dichotomous variables will be presented as frequency and percentage and analyzed with the chi-square test or Fisher's exact test. Subgroup analyses will be performed based on groups with high heterogeneity if necessary.