The study is a randomized, controlled intervention trial examining the effects of the CMNT diet in T2D patients. It will be conducted at the Jinheyuan Outpatient Department and the Department of Shizi Mountain primary care in the local community. The trial is designed according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 checklist. After recruitment, participants’ general information on diet, physical activity, and type and dosage of medications will be obtained. After written informed consent, the participants will be screened further for eligibility. Individuals likely to be ineligible or unsuitable to approach because of comorbidity or other practical or medical obstacles to participation will be removed from the investigation. Each participant will receive a unique identifier upon study entry. This identifier will be used for all data documentation to ensure the participant’s confidentiality.
Randomization sequence of participants will be done by a statistician not involved in the trial using SAS software, version 9.4 (SAS Institute). Then, participants will be randomized at a ratio of 1:1 to the CMNT group or control group. Participants in the intervention group will receive the CMNT diet, whereas the other participants will receive the usual diet for 90 days. To evaluate participants’ compliance, five 24-h dietary recalls will be taken throughout the intervention. All measurements, including anthropometric and biochemical assessments, will be examined at baseline and at the end of the trial. The coordinating centre holds trained physician for conducting study visits and taking informed consent, a study nurse for coordinating study visits and obtaining data during study visits. Any modification to the current study protocol will be submitted to the institutional review board, all trial participants and the trial investigators.
Patient recruitment strategies include specific study calls on the diabetes website and the holding of lectures for patients in specialized diabetes practices. When potentially eligible subjects are interested in participation, physicians will fully explain and discuss the study. The diagram (Figure 1) shows the participant flow through the trial.
Seventy T2D patients will be randomly allocated to receive the CMNT diet or to continue their usual diet as a control for 90 days.
Participants who meet all the following criteria can be included in this trial:
- Patients with a diagnosis of T2D
- Patients with age > 18 years and < 75 years
- Patients with T2D who meet the diagnostic criteria for diabetes issued by the World Health Organization in 1999
- Patients taking T2D medications
- Patients with a body mass index between 18 and 35 kg/m2
- Patients who are willing and able to accurately use a home glucose metre for the self-monitoring of blood glucose
- T2D patients who have an urgent desire to fully understand the CMNT theory to improve their physical conditions
- Patients who can understand and follow the trial procedures and voluntarily participate in the trial
- Patients who provide informed consent
Patients who meet any of the following criteria will not be allowed to participate in this trial:
- Type 1 diabetes or secondary diabetes due to pancreatic injury (such as Cushing's syndrome or acromegaly)
- Having used other drugs that may affect blood glucose metabolism in the last two months, including systemic glucocorticoids (except inhaled or topical), growth hormones, etc.
- Having used antihypertensive drugs or blood lipid regulating drugs used, but with the dose before screening not reaching a stable state
A history or condition of any of the following heart problems within the last 6 months:
- Decompensated cardiac insufficiency (NYHA grade III or IV)
- Unstable angina pectoris, myocardial infarction, coronary artery bypass grafting or stent implantation history
- Uncontrolled or severe arrhythmias (such as long QT syndrome, etc.) that have been evaluated by the investigator as inappropriate to participate in this clinical trial
- Haemorrhagic stroke or ischaemic stroke in the last 6 months rendering the individual ineligible to participate in this clinical trial as assessed by the investigator
- Presence of cerebral thrombosis, cerebral vascular blockage, cerebral haemangioma, mini-stroke, cerebral haemorrhage, cerebral stroke, cerebral infarction, cerebral infarction, hydrocephalus, brain tumour (malignant) and other diseases
- History of carotid artery stent implantation
- Urinary system with nephrotic syndrome, uraemia, polycystic kidney, kidney transplantation, lateral kidney removal/congenital single kidney, renal atrophy, renal tumour
- Digestive system with liver ascites, liver cirrhosis, liver flukes, severe hepatitis, varicose gastric fundus
- Nervous system with cerebellar atrophy, demyelination, cerebral palsy, Parkinson's disease, mania, schizophrenia
- Pulmonary embolism and pulmonary heart disease in the respiratory system
- Circulatory system with arterial rupture
- Immune system with Bezier's disease or eruption of lupus erythaematosus
- Presence of chondrosarcoma, liposarcoma, brucellosis, leukaemia
- History of malignancy within the last 5 years or current assessment for potential malignancy
- Proliferative retinopathy or macular disease accompanied by instability or requiring treatment in the last 6 months
- A history of diabetic ketoacidosis and hyperosmolar nonketotic coma in the last 6 months
- Present history of arteriosclerosis obliterans of the lower limbs
- Severe infection or trauma within the last month
- History of ≥ 2 episodes of severe hypoglycaemia in recent years
- Presence of a clinically significant urinary/reproductive infection, history of complex urinary tract infection, or history of recurrent urinary tract infections in the last 6 months.
- Uncontrolled hypertension with systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure at screening/baseline of 100 mmHg or higher; systolic blood pressure ≤90 mmHg and/or diastolic blood pressure ≤60 mmHg
- Current presentation of thyroid dysfunction that is not steadily controlled
- A history of other serious endocrine diseases, such as multiple endocrine neoplasms
- A history of diabetic ketoacidosis and hyperosmolar nonketotic coma in the last 6 months
- A history of severe liver and kidney disease
- Suspected or confirmed history of alcohol or drug abuse
- Blood donation or blood loss ≥ 400 mL within the last 3 months
- Serious mental illness or language impairment; unwillingness or inability to fully understand and cooperate with the study
- Pregnancy and breastfeeding
- Known alcohol and drug abuse
- Other conditions that the investigator considers inappropriate for participation in this study
Written consent is obtained from participants after a full explanation, an information leaflet is offered, and time is allowed for consideration. The participants have the right to refuse or continue to participate in this study without giving reasons. The chief investigator ensures that participant confidentiality is respected and local data protection requirements are met.
The retention of patients is promoted by close and frequent contact with their nutritional counsellor and physician via telephone, email and study visits. In case of relevant issues, visits outside the study schedule are offered. Discontinuation study criteria include withdrawal of consent, subsequent occurrence of an exclusion criterion (e.g., change toward uncontrolled hypertension), lack of compliance and medical reasons for stopping the intervention.
Food records measure compliance with the intervention. For the CMNT group, there are regular additional meetings during each of the periods. These meetings have to be attended, enabling physicians and nutritional counsellors to evaluate compliance.
During the 90-day experiment, participants will be randomized to the CMNT group or control group. The CMNT group will receive the CMNT diet for 5 consecutive days followed by 10 days of the usual diet, while the control group will receive only the usual diet for 15 days. The use of antidiabetic medications will be continued during the study. Multivitamin and mineral supplementation will be administered throughout the intervention. TCM nutritional intervention food contains a variety of oats, mulberry leaves, Poria cocos, Siraitia grosvenorii and other MFH natural raw materials or extracts (The ingredients of the CMNT diet are listed in Table 2). Both groups follow-up for 180 days.
The physician will educate each participant on the fundamentals of each dietary intervention and provide food lists. The physician will also be easily assessable to each participant for guidance and/or advice throughout the study. Ultimately, these measures should assist with participant compliance. Participants physical activity of CMNT group and control group follow the treatment guidelines for type 2 diabetes. The questionnaire also asks for information on the duration, type, and intensity of any exercise.
The process and rate of any medication reduction will be judged clinically and will depend on glycaemic control. There are clear specific recommendations for each of these medications and other classes of agents. During the intervention, the adjustment of anti-diabetic agents follows the following principles:
1. When participants achieved FBG (fasting blood glucose) or PBG (postprandial blood glucose) ≤5 mmol/L, the physician will reduce the usage of antidiabetic medications.
2. If FBG ≤5 mmol/L, priority should be given to reduce medium, long-acting and ultra long-acting hypoglycemic agents; If PBG ≤5 mmol/L, it will reduce the short-acting and ultra short-acting hypoglycemic agents of corresponding meals.
3. If the action duration of the agents is same or similar, the agents reduced according to the priority: insulin>insulin secretagogues agent>non-insulin secretagogues agent.
4. The recommendation of specific dosage reduction is provided by physician.
There are no major risks for patients participating in this study. We do not expect serious adverse events due to our dietary interventions. The materials or extracts in the CMNT diet are all foods in China, thus, the safety risk is under control. Patients will be asked regarding the tolerability of the interventions, and any adverse events will be recorded. Physicians will be asked to inform the research team about serious adverse events (SAEs) and adverse events (AEs). Participants will be asked at every visit about SAEs and AEs, which will be recorded at study visits and during telephone contacts with the research team.
The trial is conducted in compliance with Good Clinical Practice principles (with which all investigators are confirmed to be familiar) and the applicable regulatory requirements. The study is subject to inspection and audit by the National Health and Family Planning Commission, Adherence to Good Clinical Practice in Research.
The endpoint will be assessed by an experienced evaluator who is blinded to both clinical data and allocation. All outcomes will be measured at baseline and at the end of the dietary intervention.
To evaluate the remission effect of the CMNT diet, our primary outcome is the diabetes remission which is defined as a glycated haemoglobin (HbA1c) level of less than 7% (<53 mmol/mol) after at least 6 months off all antidiabetic medications.
Anthropological measures, biochemical assessments and questionnaires will be evaluated.
- Glycosylated haemoglobin (HbA1c)
- Fasting blood glucose (FBG), postprandial blood glucose (PBG)
- Systolic and diastolic blood pressure
- Total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol
- Measure of quality of life from EQ-5D-5 L
During each dietary intervention, in addition to daily dietary recall, fasting blood glucose and postprandial blood glucose will be assessed.
Anthropometry, that is, height (to the nearest centimetre) and body mass (to the nearest 100 g), will be measured using a stadiometer and electronic scale, respectively. Participants will be measured without shoes and while wearing light clothing. The questionnaires employed in the project have been validated or used previously in similar settings. The EQ-5D-5 L is a validated quality of life questionnaire that measures the effects of disease and health status on perceived quality of life. It describes 5 health-related quality of life dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), all of which can take one of 3 or 5 responses depending on the level of severity[26-27].
Blood sampling and collection
After an overnight fast (minimum of 10 h), a 10-ml venous blood sample will be drawn by venous puncture from the brachial vein of the participant for the assessment of biomarkers of metabolic health. These biomarkers include HbA1c, triglycerides, LDL, HDL and total cholesterol.
The CMNT is a diet intervention, so it is difficult to achieve double blindness. The control group only continues to maintain their usual diet and exercise habits. In the dietary intervention study, it is not possible for participants or all study personnel to be blinded to the group assignment. The study will be assessor-blinded, as the nurses who will perform the data collection (e.g., anthropometrics, doses of medications and blood pressure) and the technicians conducting laboratory work will be blinded to the intervention assignment.
Data collection and management
The Electronic Data Capture (EDC) system will be used for data management, including data entry, query, coding, security, and storage. Data will be gathered in source documents and then transferred onto paper case report forms. The data will be locally collected and transferred to the EDC system. The data will be coded and anonymised and then stored in an encrypted folder in a password protected computer. To improve the accuracy of data entry, entries will be verified for the proper format and expected range, as well as double-checked. Overall data quality will be assured by independent monitoring throughout the study.
Analysis Statistical methods
Data analysis will be performed using IBM SPSS Statistics (version 23, IBM Corporation, NY, USA). Two-tailed statistical significance will be accepted at P < 0.05. Continuous variables will be compared between the two groups by the independent sample t test, whereas the chi-square test will be used to compare categorical variables. Normally distributed continuous variables will be reported as the mean±SD. For binary outcomes, presentation of both absolute and relative effect sizes. The estimated effect size will be reported its precision such as 95% confidence interval. Multiple imputation will be used for missing data. We will adjust our final results for potential confounding factors using multivariable regression modelling.
The primary outcome is the diabetes remission. Assuming a one-sided type I error of 5% and a power of 80%. According to primary care-led weight management for remission of type 2 diabetes (DiRECT), calculations assumed diabetes remission in 22% of participants in the intervention group (the effect size deemed potentially important, a priori) compared with an estimated 5% in the control group. Accounting for an approximate 15% dropout, a total of 72 participants were recruited. the sample size was calculated using the following formula:
An interim analysis for futility and efficacy is planned at the midpoint of the trial. At this point the sample size may also be re-assessed.
The study results will be disseminated by peer reviewed scientific journals, internal reports, conference presentations and publication on websites. No identifiable personal data will be published. All anthropometric and personal clinical data will be expressed as the mean/median and spread of the population in the study. All participants will be informed of the results at the conclusion of the study, and details of any publications that arise from the study will be disseminated to participants. We will comply with the official eligibility guidelines for authorship for all publications and do not intend to use professional writers.
Throughout the study, an independent monitoring manager monitors study documents. Four nutritional scientists/dietitians are responsible for the implementation of nutritional interventions and have frequent personal contact with study physicians. Study team and principle investigators meet every month to supervise, review and discuss study progress and all study related issues. A safety report will be submitted to the Medical Research Ethics Committee every year.