Background
Progress of prediabetes
Prevention and treatment of prediabetes with TCM
Individualized treatment based on syndrome differentiation
Herbal medicine formula and acupuncture acupoint prescription
Methods/design
Objectives
Research type
Screening of participants
Groups
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Treatment group: acupuncture and herbal medicine intervention combined with lifestyle intervention
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Control group: lifestyle intervention only
Interventions
Arrangement for intervention
Lifestyle intervention
Acupuncture intervention
Herbal medicine intervention
Randomization
Allocation concealment
Blinding
Sample size
Patient identification and enrollment
Source of participants
Diagnostic criteria (according to the ADA criteria for a diagnosis of prediabetes in 2016 [40, 41])
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IFG: FPG of 5.6 mmol/L (100 mg/dL) to 6.9 mmol/L (125 mg/dL)
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Impaired glucose tolerance (IGT): 2-hPG after a 75-g oral glucose tolerance test (OGTT) of 7.8 mmol/L (140 mg/dL) to 11.0 mmol/L (199 mg/dL)
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HbA1c of 5.7−6.4%
Inclusion criteria
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Fulfill the prediabetes diagnostic criteria
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Be aged 18–50 years old
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Completed and submitted an ICF
Exclusion criteria
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History of diabetes (except gestational diabetes)
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Cardiovascular and cerebrovascular events (cerebrovascular accident in past 6 months, history of myocardial infarction or heart failure; severe organic heart disease; aneurysm of a main artery or dissecting aneurysm; specific angina; type II degree atrioventricular block; sick sinus syndrome)
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Impairment of hepatic or renal function: abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) or creatinine (Cr)
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Endocrine disease, such as hyperthyroidism, autoallergic disease, cancer or other serious or potentially fatal illness
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Pregnancy, preparation for pregnancy or active lactation in women
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Patients with mental illness or those who are uncooperative
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Participation in other clinical trial within the last 2 weeks
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Refusal to provide consent for the study
Rejection criteria
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Did not receive acupuncture treatment or take herbal medicines according to the protocol
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Incomplete data
Suspension criteria
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Poor compliance
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Serious adverse events (SAEs) or complications or unique physiological changes
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Reluctance to continue the trial
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Withdrawal for various reasons such as failure to follow-up or death
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Incomplete information that would influence the trial
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Large error in protocol or significant deviation in implementation
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Decision to terminate the trial by national law, the Ministry of Science and Technology or other authority
Dropout criteria
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Experience SAEs that should stop intervention immediately
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Refuse to receive any kind of intervention or ask for suspension
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Failure to follow-up before all data of primary outcomes have been taken
Follow-up
Data collection points
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Screening period: 1 week before the intervention
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Intervention period: 24 weeks; once a week for 24 weeks
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Follow-up period: 48 weeks after the intervention
Outcome measures
Endpoint events
Primary outcomes
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Fasting plasma glucose (FPG): fasting is defined as no caloric intake for at least 8 h
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2-h plasma glucose (2-hPG) level after 75-g oral glucose tolerance test (OGTT): the test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water
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Glycosylated hemoglobin (HbA1c)
Secondary outcomes
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Middle shear rates of whole-blood viscosity (30/S)
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Low shear rates of whole-blood viscosity (10/S)
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Low shear rates of whole-blood viscosity (1/S)
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Plasma viscosity
Safety indices
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Alanine aminotransferase (ALT) levels
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Aspartate aminotransferase (AST) levels
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Blood urea nitrogen (BUN) levels
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Creatinine (Cr) levels
Additional indicators
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Body Mass Index (BMI): BMI = weight (kg)/square of height (m2). The weight and height of participants will be measured by the same equipment in the Medical Examination Centre of the Fifth Affiliated Hospital of Guangzhou Medical University
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Incidence of type-2 diabetes mellitus
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Reversion rates of FBG, 2-hPG after 75-g OGTT, and HbA1c after 48 weeks of follow-up;
Adverse event monitoring
Reporting of adverse events
Documentation of adverse events
Relationship between adverse event and study treatments
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Whether the suspected adverse reaction appears after treatment administration
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Whether the suspected adverse reaction belongs to the known adverse reactions of the investigated drug
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Whether the suspected adverse reaction disappeared or was mitigated after discontinuation of treatment
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Whether the same reaction occurred again after resuming the investigated drug
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Whether the suspected adverse reaction cannot be explained by the participant’s diseases or consumption of the combination of drugs
Relationship between adverse events and changes in symptoms
Criteria for the evaluation of safety
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Safe without any significant changes in hepatic or renal function
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Relatively safe with less than 20% changes in hepatic and renal function
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Termination of the interventions due to more than 20% changes in hepatic and renal function
Statistical analysis plan
Analysis parameters
Analysis of datasets
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Full analysis set (FAS): according to the intention-to-treat (ITT) principle of analysis, participants will be rejected using the smallest reasonable method. The last observation carried forward (LOCF) method will be used for missing data
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Per-protocol set (PPS): PPS should be used in participants who meet the following characteristics: meet the inclusion criteria; receive an incorrect randomization; are between 80 and 120% compliant; have completed observations; have a time of primary outcome measurement within the accepted window
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Safety set (SS): all documented information on safety will be assessed according to the laboratory test results
Statistical analysis method
Document conservation and summary
Trial management
Data management
Management of acupuncture treatment
Management of herbal medicine
Management of protocols
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Change in protocol: all changes in protocol will be documented, and any modifications of the protocol, including informed consent, must obtain the approval of the Ethics Committee
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Case Report Form (CRF) tracking: all signed ICFs must be submitted before the participants are included. Any questions or comments about CRFs must be submitted directly to the PI
Researcher’s responsibility
Quality control
Quality control of the laboratory
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The GCP office of the Fifth Affiliated Hospital of Guangzhou Medical University has established a uniform standard operating procedures (SOPs) and quality control procedure
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Interventions will be conducted by trained researchers in the hospital, and the hospital can provide suitable medical equipment and emergency facilities
Request for researchers
Measures for compliance of participants
Monitoring and inspection
Bias control
Informed Consent Form (ICF)
Security
Discussion
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For demonstrating the precise hypoglycaemic effects of TCM, objective laboratory examinations including FPG, 2-hPG level after OGTT, and HbA1c will provide the primary outcomes
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For individual treatment, the changes in participants’ symptoms will be recorded carefully according to four diagnostic methods of TCM including inspection, listening and smelling, inquiry, and pulse-taking and palpation, and will be considered as the basis for adjusting the components and doses of the formula, rather than AEs
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For authenticity, we will use RRMS (http://www.medresman.org/login.aspx) to manage the trial data. The changes in participants’ symptoms will be timely entered into RRMS before their next coming and can be checked publicly by a shared password