70 patients with T2DM who meet the screening criteria will be recruited through recruitment advertisements and introductions from outpatient doctors of endocrinology department from the First Affiliated Hospital of Guangzhou University of Chinese Medicine, China.
TCM syndrome differentiation criteria
In accordance with the Diabetes Professional Committee of China Association of Chinese Medicine, “Diabete Diagnosis and Syndrome Differentiation Reference criteria” of"Diabetes Traditional Chinese Medicine Staging and Efficacy Evaluation criteria(1992)", the Diagnostic criteria for the of excess-heat syndrome in middle burner in diabetes were formulated.
Symptoms:①Polyphagia or easy to hunger, ②Dry mouth or drink more or bitter taste or ozostomia, ③Dry throat or pharyngalgia, ④ Oral ulcer or acne or swelling and aching of gum, ⑤Insomnia or irritability, ⑥Flushed face or erubescence, ⑦Yellow urine, ⑧Dry stool or sticky stool;
Conditions of tongue and pulse: ①Red or dull-red tongue, ②Yellow coating on tongue, ③Rapid or full or slippery pulse;
It can be diagnosed with two symptoms or one symptom plus one tongue pulse.
(1) Hantangping group(exprimental group)
Participants in the Hantangping group will be treated with Chinese medicine compound Hantangping granules (in its composition, red yeast rice and stevia rebaudiana granules have not been produced yet, so the dosage form will still be Chinese herbal decoction pieces). The participants will take Hantangping granules orally, one dose each time, twice a day, half an hour after breakfast and dinner. The Chinese medicine decoction, boiled from 500 ml water decocting red yeast rice and stevia rebaudiana decoction pieces to 250 ml, flushes other Chinese medicine formula granule. A course of treatment requires 12 weeks, and the observation window is a course of treatment. The drug manufacturers are Guangdong Yifang Pharmaceutical Co., Ltd. (Chinese medicine granules) and Guangzhou Zhixin Pharmaceutical Co., Ltd. (Chinese medicine decoction pieces).
The composition of Hantangping includes kudzuvine root, zingiber, zingiber, golden thread, rhubarb root and rhizome, unprocessed rehmannia root, ginseng, red yeast rice, stevia rebaudiana, etc. (Because the TCM compound Hantangping has been patented, its composition and dosage cannot be published temporarily due to confidentiality) .
(2) Metformin group(positive control group)
Participants in the metformin group will receive western medicine metformin hydrochloride tablets (trade name: Glucophage). Participants will orally take metformin hydrochloride tablets after meals, 1 tablet each time, 3 times a day. The observation window is the same as that of the Hantangping Group. The drug manufacturer is Sino-US Shanghai Squibb Pharmaceutical Co., Ltd.
Randomization and allocation
Use SAS 9.4 software for randomization to generate a random number table, and formulate a corresponding drug and case allocation plan (enclosed with an opaque envelope). After informed consent, the participants will be randomly divided into Hantangping group (experimental group) and metformin group (positive control group). The trial doctor will dispense the medications in the order originally arranged. An independent staff (Xiaoli He) who is not involved in observing or evaluating participants has a computer-generated random sequence.
Open design is adopted in this study. Due to the large differences in the appearance and dosage of the drugs between the two groups, the participants could not be kept blind. But in order to control bias as much as possible, some measures have been taken:
Conduct unified training for the staff involved in the research. Two staff members measure or record data at the same time to reduce measurement and record deviation;
Concomitant medication should be minimized during the intervention process, and the researchers should be informed if it must be used.
The concealment of the random allocation plan adopts the envelope random method to select participants;
Researchers and supervisors involved in recording results, efficacy evaluation, data management, and statistical analysis remain blind during the trial.
The schedule for all outcome measures is shown in Fig. 2. All demographic data will be determined prior to treatment, including the date of birth, gender, past medical history, medication history, smoking and drinking history.
The primary outcome is the change in HbA1c from baseline after 12 weeks of treatment.HbA1C is the product of the combination of hemoglobin in red blood cells and glucide in serum, which is formed through a slow, continuous and irreversible glycation reaction. It is an important evaluation indicator for overall blood glucose control, and it can effectively reflect the blood glucose control of diabetic patients in the past 2 to 3 months.
The secondary outcomes included changes of the following indexes from the baseline to the end: fasting blood glucose (FBG), 2-hour post-meal blood glucose (2hPG), index of β-cell function in homeostasis model assessment (HOMA-β), index of insulin resistance in homeostasis model assessment (HOMA-IR), area under the curve of insulin (AUCI), total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), body weight, BMI.
During the trial, all researchers must comply with Good Clinical Practice (GCP) and the protocol of the clinical trial. Specialized medical examiners will be dispatched to perform physical examinations on participants. At each visit of the participant, examiners will observe the patient's systemic response and evaluate the participant's safety indicators, including blood pressure, heart rate, electrocardiogram, blood routine, urine routine, liver function and renal function.
Researchers will record all adverse events during the study, including toxicity and side effects, such as gastrointestinal reactions, medicamentous liver impairment and renal damage, and grade them in detail. When a serious adverse event occurs, should immediately terminate the ongoing trial intervention and provide all necessary treatments. Then researchers will report the adverse event to the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine. Patients who experience adverse reactions during the trial will receive free medical care.
Sample size calculation
The number of participants in this study is calculated based on relevant literature data and statistical principles. According to the unilateral test level α, the allowable probability of the second type of error does not exceed β. Under the condition of T = S, a non-inferiority test The sample size required for each group is: n = 2[(µ1−α + µ1−β)(s/δ)]2
n is the sample size of each group, α is the inspection level, β is the second type of error, 1-β is the power, µ is the standard normal deviation boundary value (µ1−α and µ1−β represent 1-α and 1-β respectively corresponding one-sided boundary value), s is the standard deviation, and δ is the non-inferiority boundary value.
After estimation, the final sample size was determined to be 35 cases in the Hantangping group and 35 cases in the metformin group, with a total of 70 patients..
Data collection and management
A comprehensive data and safety monitoring committee will be established to ensure that the quality of each step in the testing process is as high as possible. As an independent party, the Data Monitoring Committee is responsible for the quality control and safety supervision of this study.
After completing the observation of each participant, the researchers should immediately submit the study record to the designated CRF input personnel. CRF importers are responsible for recording the clinical examination, treatment effect evaluation and follow-up information in the CRF of each patient. And they are responsible for form’s completeness and authenticity. The research record is the original document of the clinical research object and should be kept in the hospital. CRF will be counted and analyzed by the data statisticians of this institution. When the statistician has any questions about the original data, the researchers should answer the questions in time.
All study-related information will be stored at the study site securely. All participants’ information will be stored in a locked file cabinet in a restricted-access area. All reports, data and forms will be identified by a coded identification (ID) number. All records containing the participant’ s name or other personal identifiers will be stored separately from the study records identified by the code number. All local databases will be protected with a password-protected access system. The information will not be released outside of the study without the participant’ s written permission.
We plan to report the results of the trials in appropriate journals and exchange them at academic conferences. Our final report will follow the Consolidated Standards of Reporting Trials (CONSORT) guidelines.