Hantangping-a traditional Chinese medicine compound versus metformin for treating early type 2 diabetes mellitus:study protocol for a non-inferiority randomized controlled trial

Background: Hantangping is a traditional Chinese medicine compound, founded by Professor Saimei Li of the First Aliated Hospital of Guangzhou University of Chinese Medicine, and has been used to treat type 2 diabetes mellitus for more than 10 years. Clinical practice has shown that for early stage type 2 diabetes patients with acceptable islet secretion function, Hantangping can reduce blood glucose and improve islet function while correcting lipid metabolism disorders, preventing diabetes complications, and reducing adverse reactions..However, there is currently a lack of randomized controlled clinical trials that can conrm the ecacy of Hantangping in the treatment of early type 2 diabetes. We designed this study to objectively evaluate the effectiveness and safety of Hantangping in the treatment of early type 2 diabetes. Methods/Design: A randomized, open, parallel controlled and non-inferiority clinical trial was designed. Participants were randomly divided into Hantangping group(experimental group) and metformin group(positive control group) at a ratio of 1:1, and were intervened with Chinese medicine Hantangping and Western medicine metformin respectively.The participants will receive 12 weeks of drug intervention and 8 weeks of follow-up.The primary outcome measure is glycosylated hemoglobin a1c. The secondary outcome measures are fasting blood glucose(cid:0) index of β-cell function in Homeostasis Model Assessment,and index of Insulin resistance in Homeostasis Model Assessment, etc. Discussion:This study can provide scientic and rigorous evidence-based medical evidence for the effectiveness and safety of Hantangping in the treatment of early type 2 diabetes, and may also provide new ideas and methods for the treatment of type 2 diabetes.

Participants were randomly divided into Hantangping group(experimental group) and metformin group(positive control group) at a ratio of 1:1, and were intervened with Chinese medicine Hantangping and Western medicine metformin respectively.The participants will receive 12 weeks of drug intervention and 8 weeks of follow-up.The primary outcome measure is glycosylated hemoglobin a1c. The secondary outcome measures are fasting blood glucose index of β-cell function in Homeostasis Model Assessment,and index of Insulin resistance in Homeostasis Model Assessment, etc.
Discussion:This study can provide scienti c and rigorous evidence-based medical evidence for the effectiveness and safety of Hantangping in the treatment of early type 2 diabetes, and may also provide new ideas and methods for the treatment of type 2 diabetes.

Background
With the development of economy and society, the prevalence rate of pre-diabetes and diabetes is rising all over the world. Epidemiological survey showed that the prevalence of diabetes in Chinese adults in 2013 was as high as 10.9% [1] , and most of them were type 2 diabetes (T2DM), with a prevalence of 10.4% [2] . Although there are many treatment options for diabetes, the current control of T2DM is still not optimistic. A recent study showed that only half of the patients undergoing treatment had their blood glucose level adequately controlled [3] .
T2DM is a metabolic disease characterized by hyperglycemia. Insulin resistance and insu cient insulin secretion caused by β-cell dysfunction are the two core pathogenesis of T2DM. In traditional Chinese medicine (TCM), T2DM usually presents different TCM syndromes at different stages, and its treatment varies accordingly. Professor Saimei Li, who works at the First A liated Hospital of Guangzhou University of Chinese Medicine, advocated that in TCM T2DM should be treated by stages and syndromes. She believes that in the early stages of T2DM, most patients have adequate pancreatic islet secretion function, and the hyperglycemia is clinically manifested as Yang syndrome and heat syndrome of TCM. She founded the Chinese medicine compound Han Tang Ping to treat T2DM (patients' islet secretion function is acceptable).Clinical reports show that Hantangping has a signi cant effect on the treatment of early T2DM. With independent treatment of Hantangping, the patient's hyperglycemia and dyslipidemia may return to normal, and the islet function is signi cantly improved [4] . At present, both international and Chinese diagnosis and treatment guidelines of diabetes recommend metformin as the rst-line medication for the treatment of T2DM and the basic medication in the drug combination.
Metformin, recognized as the rst choice and basic antidiabetic drug for T2DM, has reliable short-term and long-term hypoglycemic e cacy. Since some original trials, follow-up and short-term studies (usually 3-6 months) using metformin have demonstrated mean glycosylated hemoglobin a1c (HbA1c) reductions on the order of 1% (10.9 mmol/mol) to 1.5% (16.4 mmol/mol). [5,6,7] . Therefore, in this study, metformin is used as a positive control drug to carry out a randomized controlled clinical trial to objectively evaluate the clinical e cacy of Chinese herbal compound Hantangping.

Study design
This study adopts a randomized, open, parallel controlled trial design. The participants are randomly divided into Hantangping group and metformin group at a ratio of 1:1. Well-trained researchers must introduce the trial to the participants, give them information sheets and consent forms. All participants must sign a written informed consent form before enrolment. The study's ow chart is shown in Fig. 1. Symptoms: Polyphagia or easy to hunger, Dry mouth or drink more or bitter taste or ozostomia, Dry throat or pharyngalgia, Oral ulcer or acne or swelling and aching of gum, Insomnia or irritability, Flushed face or erubescence, Yellow urine, Dry stool or sticky stool; Conditions of tongue and pulse: Red or dull-red tongue, Yellow coating on tongue, Rapid or full or slippery pulse; It can be diagnosed with two symptoms or one symptom plus one tongue pulse.
Inclusion criteria 1. Participant is between 18 and 60 years of age; 2. Participant met the diagnostic criteria for diabetes issued by the World Health Organization in 1999 and the classi cation criteria for T2DM in the classi cation criteria for the etiology of diabetes issued by the American Diabetes Association in 1997; 3. Participant meets the criteria of TCM syndrome diagnosis of excess-heat syndrome in middle burner; 4. Participant had not received any hypoglycemic treatment and had poor blood glucose control after 3 months of diet and exercise treatment, or had short-term hypoglycemic treatment (< 1 month) and stopped more than 3 Months; 5. Participant's pancreatic islet secretion function is acceptable, and the insulin releasing test shows that the peak insulin/ original insulin ≥ 3 (Ip/ Io ≥ 3), or the insulin release time is normal or delayed; .

Interventions
All participants must receive basic diabetes treatment, including diet therapy and exercise therapy, while undergoing experimental intervention. The participants will be asked to record their daily diet and exercise in the form (Additional le 2). Every week after the intervention, the researchers will contact the participants by phone and ask about the implementation of diet and exercise therapy, medication consumption, blood glucose self-test level, adverse events, which will be recorded in the case report form (CRF).
(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, ushes 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 con dentiality) .
(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.

Blinding
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: 1. Conduct uni ed 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; 2. Concomitant medication should be minimized during the intervention process, and the researchers should be informed if it must be used.
3. The concealment of the random allocation plan adopts the envelope random method to select participants; 4. Researchers and supervisors involved in recording results, e cacy evaluation, data management, and statistical analysis remain blind during the trial.

Outcome measures
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 re ect 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.

Safety assessments
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 A liated 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[(µ 1−α + µ 1−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 (µ 1−α and µ 1−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 nal 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.

Con dentiality
All study-related information will be stored at the study site securely. All participants' information will be stored in a locked le cabinet in a restricted-access area. All reports, data and forms will be identi ed by a coded identi cation (ID) number. All records containing the participant' s name or other personal identi ers will be stored separately from the study records identi ed 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.

Dissemination
We plan to report the results of the trials in appropriate journals and exchange them at academic conferences. Our nal report will follow the Consolidated Standards of Reporting Trials (CONSORT) guidelines.

Statistical analysis
The statistical analysis of this study will be carried out by statisticians from Guangzhou University of Chinese Medicine. They will use statistical analysis software packages SPSS 23.0 and SAS 9.1. P < .05 is considered statistically signi cant. Full analysis set (FAS) will analyze with intention-to-treat (ITT), and per-protocol set (PPS) will be statistically analyzed by per-protocol(PP). Demographic and other baseline characteristics will be analyzed using FAS. The e cacy and safety analysis will use PPS. Normally distributed data is represented by the mean ± standard deviation, and non-normally distributed data is represented by the median and interquartile range. Comparisons between measurements from the two groups will be performed using the independent sample T-test, and intra-group differences will be tested with paired T-test. Differences between the count data sets will be assessed with chi-square test. Multiple imputation will be adopted to handle missing data statistically. An exploratory subgroup analysis will be conducted to explore clues for further research when necessary.

Discussion
Currently, there are many clinical trials evaluating the e cacy of TCM in the treatment of T2DM. Compared with modern medicine, TCM has many advantages in the treatment of T2DM, such as overall regulation, co-regulation of blood glucose and blood lipids, and improvement of patients' quality of life. HbA1c, 2hPG and BMI of the Jiangtang Xiaozhi capsule group were signi cantly reduced. Compared with the pioglitazone tablet group, the difference was not statistically signi cant [9] .However, there are few studies evaluating the e cacy of TCM in enhancing pancreas islet function in the published randomized controlled trials.
A number of studies have shown that a variety of TCMs can signi cantly reduce blood glucose levels independently. Such as golden thread, prepared rehmannia root, ginseng, kudzuvine root, rhubarb root and rhizome, etc. can lower blood glucose level and improve clinical outcomes, and may also lower HbA1c levels [10] .The composition of Hantangping contains these Chinese medicines. In terms of TCM theory, the TCM compound Hantangping was established on the basis of the therapeutic idea of "lowering blood glucose not far from cold, strengthening body depending on nourishing spleen and kidney, and qi and blood preferring smooth circulation". It is based on the principle of "both lowering blood glucose and strengthening the body", taking into account the therapies of clearing internal heat, opening stagnation, tonifying de ciency,invigorating pulse-beat, and dissipating dampness, so as to achieve the effects of strengthening the body, lowering blood glucose and regulating blood lipids, reducing insulin resistance and preventing diabetes complications.
This study has limitations. The sample size of this study is small, so the credibility of the results is limited. In order to provide more stable and consistent results, our later clinical trials will expand the sample size on this basis for further veri cation.
TCM has accumulated rich experience in diagnosis and treatment In long-term clinical practice. But it is a subjective assessment and is considered to be low-quality evidence-based medical evidence. Therefore, it is important to conduct well-designed clinical studies to provide high-quality evidence-based medicine. Therefore, it is important to conduct well-designed clinical studies to provide high-quality evidence-based medicine.Based on the sound theory of TCM and rigorous trial design, the completion of this study will provide the necessary foundation for future large-scale multi-center clinical trials. Study ow chart. The ow chart of enrolment, allocation, intervention, and analysis. Schedule of enrollment and assessments.

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