Value of Glycated Albumin in Intervention of Glycemic Control in Patients With Type 2 Diabetes: A Multicenter, Randomized Controlled Clinical Study
Phase: NA
Conditions: Type 2 Diabetes Mellitus
Sponsor: Asahi Kasei Therapeutics Corporation

Value of Glycated Albumin in Intervention of Glycemic Control in Patients with Type 2 Diabetes: A Multicenter, Randomized 
Controlled Clinical Study                                        Study Protocol   Ver 2.0；20211228 
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Study Protocol 
 
 
 
Title: Value of Glycated Albumin in Intervention of 
Glycemic Control in Patients with Type 2 Diabetes: A 
Multicenter, Randomized Controlled Clinical Study   
 
 
 
 
 
NCT No.:    NCT05227677 
VERSION:    2.0 
DATE:      December 28, 2021 

Value of Glycated Albumin in Intervention of Glycemic Control in Patients with Type 2 Diabetes: A Multicenter, Randomized 
Controlled Clinical Study                                        Study Protocol   Ver 2.0；20211228 
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1. Research Background and Rationale for the Study 
 
With the aging population and changes in lifestyle in China, diabetes has 
evolved from a rare disease to a widespread epidemic. The prevalence of 
diabetes surged from 0.67% in 1980 to 11.2% in 2017 [1]. As research into the 
disease has deepened, treatment options for diabetes have expanded 
significantly. However, previous studies have shown that only 35% of patients 
treated with oral antidiabetic drugs (OADs) alone and 26% of those treated with 
OADs combined with insulin achieved the target glycated hemoglobin A1c 
(HbA1c) level of <7% [2]. Inappropriate treatment choices may be a major 
factor contributing to poor glycemic control. Therefore, identifying clinical 
biomarkers to adjust and evaluate treatment efficacy is a crucial step in 
personalized diabetes management. 
 
Currently, HbA1c and self-monitoring of blood glucose (SMBG) are commonly 
used clinical indicators for adjusting glycemic control. HbA1c is recommended 
by both international and domestic guidelines as the gold standard for assessing 
glycemic control [3–5]. Although HbA1c reflects the average blood glucose 
level over the past 2–3 months and serves as a reliable indicator of diabetes 
control, it is susceptible to interference from age, abnormal hemoglobin, and 
certain conditions such as hemolytic anemia and normal pregnancy, which 
accelerate red blood cell turnover and affect HbA1c measurements. For patients 
undergoing treatment adjustments or newly diagnosed with diabetes, HbA1c 
cannot promptly reflect recent changes in glycemic control. While SMBG 
provides real-time glucose readings, a recent randomized controlled trial 
published in JAMA showed that SMBG does not improve glycemic control in 
non-insulin-treated type 2 diabetes patients [6].  
 
In recent years, glycated albumin (GA) has emerged as a promising biomarker 
for glycemic control and treatment adjustment in diabetes [7–10]. Studies have 
shown that GA has a half-life of 17–19 days, allowing it to reflect the average 
blood glucose level over the past 2–3 weeks and recent changes in glucose levels, 
without being affected by age, gender, diet, medications, or glucose 
fluctuations—thus addressing the limitations of HbA1c [11]. Recent short-term 
studies have found that changes in GA can predict changes in HbA1c levels three 
months later in newly diagnosed type 2 diabetes patients and those undergoing 
treatment adjustments [8]. Furthermore, preliminary results from a pilot study 
conducted for this research showed that patients whose treatment was adjusted 
based on GA had an HbA1c target achievement rate (<7%) of 76.9% after three 
months of follow-up, compared to 46.2% in the control group. Similarly, the 
achievement rate for HbA1c <6.5% was 30.8% in the GA-adjusted group versus 
23.1% in the control group. Therefore, our research hypothesis is that adjusting 

Value of Glycated Albumin in Intervention of Glycemic Control in Patients with Type 2 Diabetes: A Multicenter, Randomized 
Controlled Clinical Study                                        Study Protocol   Ver 2.0；20211228 
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treatment based on GA results is more beneficial for improving patients’ average 
blood glucose levels (HbA1c). 
 
 
2. Research Objective 
 
To validate the hypothesis that "adjusting treatment regimens based on glycated 
albumin (GA) test results is more effective in helping patients achieve target 
average blood glucose levels (HbA1c)." 
 
 
3. Research Methods and Design 
 
3.1 Study Population, Inclusion Criteria, Exclusion Criteria, and 
Withdrawal Criteria 
 3.1.1 Study Population:  
  A total of 200 newly diagnosed type 2 diabetes patients will be enrolled based 
on the 1999 WHO diagnostic criteria. 
 
 3.1.2 Inclusion Criteria: 
  3.1.2.1 Patients voluntarily signed informed consent forms; 
  3.1.2.2 Age between 20 and 70 years; 
  3.1.2.3 Newly diagnosed type 2 diabetes patients with a disease duration of 
less than 1 year and no use of antidiabetic medications in the past 3 months; 
HbA1c ≥7.5% and <10.5%; 
 
 3.1.3 Exclusion criteria: 
  3.1.3.1 Presence of proliferative retinopathy or macular degeneration requiring 
treatment, painful diabetic neuropathy, diabetic foot, diabetic 
ketoacidosis, or hyperglycemic hyperosmolar state within the past 3 
months; 
  3.1.3.2 History or presence of the following conditions within the past 6 
months: 
    1) Decompensated heart failure (NYHA class III or IV); 
    2) Myocardial infarction, coronary artery bypass grafting, or coronary 
artery stent implantation;     3) Uncontrolled severe arrhythmia, and 
deemed unsuitable for participation in this clinical trial by the 
investigator; 
    4) Hemorrhagic stroke or ischemic stroke, and deemed unsuitable for   
participation in this clinical trial by the investigator;  
  3.1.3.3 Laboratory test results meet any of the following criteria: 
    1) Alanine transaminase (ALT) or aspartate transaminase (AST) > 3 times 
the upper limit of normal; 

Value of Glycated Albumin in Intervention of Glycemic Control in Patients with Type 2 Diabetes: A Multicenter, Randomized 
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    2) Total bilirubin > 2 times the upper limit of normal; 
    3) Hemoglobin < 100 g/L; 
    4) Total protein < 60 g/L; 
    5) Albumin < 30 g/L; 
    6) Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m²; 
  3.1.3.4 Any condition that may cause red blood cell instability and affect 
HbA1c testing, such as thalassemia or hemolytic anemia;  
  3.1.3.5 Currently has uncontrolled thyroid dysfunction; 
  3.1.3.6 Has received systemic steroid therapy within the past month 
(excluding inhaled or topical use); 
  3.1.3.7 Pregnant or lactating women; 
  3.1.3.8 Two or more episodes of severe hypoglycemia within the past year 
prior to screening; 
  3.1.3.9 Patients whom the investigator deems require initiation of sulfonylurea, 
glinide, insulin, or insulin analog therapy; 
  3.3.3.10 Patients currently receiving calcium hydroxybutyrate treatment or 
with a condition requiring calcium hydroxybutyrate treatment, and who the 
investigator believes may require additional calcium hydroxybutyrate 
treatment in the near future.  
  3.1.3.11 The investigator deems the subject unsuitable for observation. 
 
 3.1.4 Withdrawal criteria: 
  3.1.4.1 Withdrawal decided by the investigator 
  The investigator may decide to withdraw a subject from the study under the  
following circumstances: 
   1) Safety concerns arise, and the investigator believes that continuing the  
study may compromise the subject's safety; 
 
2) Serious complications or adverse events occur during the study, 
rendering the subject unsuitable for continued participation; 
 3) Poor compliance by the subject or severe non-adherence to study 
procedures, which may affect safety or efficacy evaluation; 
  3.1.4.2 Subject withdrawal 
 Subjects may withdraw from the study at any time. Subjects may freely  
terminate study participation at any time without affecting further treatment. 
Study completion or termination should be documented in the CRF, along 
with all reasons for termination. Possible reasons for subject withdrawal 
from the study include: 
    1) Withdrawal of informed consent by the participant; 
    2) Loss to follow-up (at least three documented attempts to contact the 
participant must have been made prior to loss to follow-up); 
 3) Other circumstances leading to withdrawal from the study (e.g., change 
of residence rendering continued medication and follow-up impossible). 
 

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3.2 Study Population Grouping 
Participants will be randomly assigned into two groups: the intervention group 
(Group A) and the control group (Group B), with 100 participants in each group. 
Randomization will be conducted using SAS software version 9.4 or higher, 
employing a block randomization method to generate a reproducible 
randomization table. Randomization will be implemented via sealed envelopes, 
assigning eligible participants to either Group A or Group B in a 1:1 ratio. 
 
 After randomization, physicians will prescribe antidiabetic medications 
according to standard clinical practice. The use of sulfonylureas, meglitinides, 
insulin, or insulin analogs is prohibited in this study due to the risk of 
hypoglycemia. 
 
During the first month of follow-up, GA levels will be measured in Group A. 
Based on the principle of “GA normalization,” physicians will adjust the 
treatment regimen accordingly (details in section 3.3.4.2). Blood samples will 
also be collected during the second and third months of follow-up for GA 
measurement, but these results will not be used to adjust treatment; they are 
solely for statistical analysis. 
 
In Group B, blood samples will be collected at the same time points (1st, 2nd, 
and 3rd months) for GA measurement, but these results will also not be used for 
treatment adjustments and will be used only for statistical analysis. 
 
3.3 Research steps and follow-up plan 
The research steps and follow-up plan are shown in Figure 1 and Table 1.  
 
                                                             Achievement rate 
                                                                      of A1C 7% or less 
 
 
Figure 1. Research process diagram 

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Table 1 Research flowchart  
 
Screening 
visits 
Baseline# 
Follow-up 
Measurement  
of GA  
Frozen sample 
Visit number 
1 
2 
3A 
3B 
4 
5 
visit time 
Days  
-7 to 0 
Day 0 
4 weeks 
(baseline:  
28 ± 3 days) 
4 weeks 
(follow-up 
visit 3A + 5 
days) * 
8 weeks 
(baseline 
56 ± 3 
days) 
12 weeks 
(baseline 
84 ± 3 
days) 
Follow-up 
visit 
completed 
informed consent 
X 
 
 
 
 
 
 
Demographic 
information 
(name, 
gender, ethnicity, date 
of birth) 
X 
 
 
 
 
 
 
Medical history a 
X 
 
 
 
 
 
 
Physical examination 
b 
X 
 
Xh 
Xg 
X 
X 
 
Collect samples and perform the following laboratory tests： 
Blood glucose-related tests 
c 
Xi 
 
 
 
 
X 
 
Complete blood count d 
Xi 
 
 
 
 
X 
 
Liver and kidney function 
e 
Xi 
 
 
 
 
X 
 
lipids f 
Xi 
 
 
 
 
X 
 
Blood or urine pregnancy 
test  
Xi 
 
 
 
 
 
 
Blood 
sample 
collection 
(for 
GA 
measurement) 
X 
 
Xh 
 
X 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 

Value of Glycated Albumin in Intervention of Glycemic Control in Patients with Type 2 Diabetes: A Multicenter, Randomized 
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criteria 
Confirm eligibility for 
enrollment 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Treatment plan 
 
X 
 
 
 
 
 
Distribution of subject 
diaries 
 
X 
Xh 
Xg 
X 
 
 
Check 
and 
collect 
participants' report 
 
 
Xh 
Xg 
X 
X 
 
GA measurement 
 
 
Xg 
 
 
X 
 
Adjust treatment plan 
 
 
Xh 
Xg 
X 
 
 
Recording medication 
treatment 
X 
X 
Xh 
Xg 
X 
X 
 
 Record and review 
(since the previous 
visit) (S) AE 
 
X 
Xh 
Xg 
X 
X 
 
study termination 
 
 
 
 
 
X 
 
Determination of GA 
in frozen samples 
 
 
 
 
 
 
X 
Notes: 
#If screening and baseline are conducted on the same day, all duplicate steps need only be performed 
once 
*It is best to conduct the visit within 3 days after the 3A visit, with a maximum of 5 days 
a. Medical history includes information such as disease course and treatment methods 
b. Physical examination includes: height, weight, waist circumference, blood pressure, pulse (screening 
period); weight, waist circumference, blood pressure, pulse (follow-up period) 
c. Blood glucose-related tests include: fasting blood glucose, HbA1c, fasting C-peptide, fasting insulin 
d. Complete blood count: red blood cells (RBC), white blood cells (WBC), platelets (PLT), 
hemoglobin (HGB) 
e. Liver and kidney function: total bilirubin (Tbil), alanine transaminase (ALT), aspartate transaminase 
(AST), total protein (TP), albumin, blood urea nitrogen (BUN) or urea (Urea), serum creatinine (Cr), 
uric acid (UA) 
f. Lipid profile: Total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C), 
high-density lipoprotein (HDL-C) 
g. Only for Group A participants 
h. Only for Group B participants 
i. If the patient has laboratory test results within the past 7 days, historical results may be used, and 
repeat testing is not required. 

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3.3.1 Visit 1 - Screening Period (Days -7 to 0) 
 3.3.1.1 Voluntarily sign an informed consent form; 
 3.3.1.2 Obtain demographic information (name, gender, ethnicity, date of birth); 
 3.3.1.3 Obtain relevant medical history information (disease course, treatment 
methods); 
 3.3.1.4 
Physical 
examination 
(measurements: 
height, 
weight, 
waist 
circumference, blood  pressure, pulse rate); 
 3.3.1.5 Collect samples and perform relevant tests: Blood glucose-related tests: 
fasting blood glucose, HbA1c, fasting C-peptide, fasting insulin; 
Complete blood count: red blood cells (RBC), white blood cells (WBC), 
platelets (PLT), hemoglobin (HGB);Liver and kidney function: total 
bilirubin 
(Tbil), 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), total protein (TP), albumin, blood urea nitrogen 
(BUN) or urea, serum creatinine (Cr), uric acid (UA);Lipid profile: total 
cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C), 
high-density lipoprotein (HDL-C); Pregnancy test (blood or urine) for 
women of childbearing age. If the patient has laboratory test results 
within the past 7 days, historical results may be used, and repeat testing 
is not required. If any results are incomplete or certain indicators exceed 
7 days, additional testing must be conducted during the screening period. 
 3.3.1.6 Blood draw and cryopreservation (to be measured at study completion 
for GA determination); 
 3.3.1.7 Initial review of inclusion/exclusion criteria.  
 
3.3.2 Visit 2 - Baseline (Day 0) 
If screening and baseline are conducted on the same day, all duplicate steps need 
only be completed once. 
 3.3.2.1 Record and check: any AEs and SAEs, concomitant medications since 
the last visit[X4] (Record all concomitant medications, with particular 
attention to systemic corticosteroids, calcium hydroxybenzoate, and 
whether hypoglycemic medications were used during the period) 
 3.3.2.2 Further review of inclusion/exclusion criteria 
 3.3.2.3 Randomize patients into groups. Divide into Group A (intervention 
group) and Group B (control group). 
 3.3.2.4 Develop a diabetes treatment plan for patients according to the 
“Chinese Guidelines for the Prevention and Treatment of Type 2 
Diabetes (2020 Edition)” [13]. Due to the risk of hypoglycemia, 
sulfonylureas, glinides, insulin, and insulin analogues are prohibited in 
this study. 
 3.3.2.5 Hypoglycemia: Investigators should instruct participants to complete a 
participant diary and monitor blood glucose levels as frequently as 
possible using a blood glucose meter when hypoglycemia occurs. If 

Value of Glycated Albumin in Intervention of Glycemic Control in Patients with Type 2 Diabetes: A Multicenter, Randomized 
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hypoglycemic 
symptoms 
do 
not 
improve 
after 
carbohydrate 
supplementation, participants should seek medical attention at a hospital. 
If hypoglycemic symptoms are suspected, investigators should diagnose 
the condition and record it in the CRF. Investigators should classify 
events according to the following categories: 
 1) Severe hypoglycemia: An event requiring assistance from another 
person to administer carbohydrates, glucagon, or other resuscitation 
measures. 
     2) Documented symptomatic hypoglycemia: During the event, typical 
symptoms of hypoglycemia are present with measured blood glucose 
levels ≤70 mg/dL (3.9 mmol/L). 
     3) Asymptomatic hypoglycemia: An event without typical symptoms of 
hypoglycemia, but with a measured blood glucose concentration ≤70 
mg/dL (3.9 mmol/L). 
     4) Possible symptomatic hypoglycemia: During the event, hypoglycemia 
symptoms were present without blood glucose measurement, but it is 
suspected that they may have been caused by a blood glucose 
concentration ≤70 mg/dL (3.9 mmol/L). 
     5) Relative hypoglycemia: Following the event, the diabetic patient reports 
any typical symptoms of hypoglycemia and symptoms consistent with 
hypoglycemia, but measured blood glucose concentration is > 70 mg/dL 
(3.9 mmol/L).  
       Researchers will collect the following items and record them in the      
CRF: Symptoms of hypoglycemia; duration (start and end date and 
time); severity grading (Grade 1 hypoglycemia: blood glucose < 3.9 
mmol/L and ≥ 3.0 mmol/L; Grade 2 hypoglycemia: blood glucose < 3.0 
mmol/L; Grade 3 hypoglycemia: severe event requiring assistance from 
others for treatment, accompanied by altered consciousness and/or 
physical changes, but without specific blood glucose thresholds); 
Measures taken (self-feeding, assistance required to eat, assistance 
required to go to the hospital for intravenous glucose infusion; other); 
Outcome; Blood glucose level measured by a blood glucose meter (at 
the time of hypoglycemia); Time of blood glucose measurement by a 
blood glucose meter (at the time of hypoglycemia);  
 
 
3.3.3 Visit 3A - Follow-up Period (Baseline ± 3 days) 
 3.3.3.1 Patients in Group B undergo a physical examination (measurements: 
weight, waist circumference, blood pressure, pulse rate); blood samples 
are collected and frozen for storage (to be used for GA measurement at the 
end of the study); all data are recorded (medication changes, occurrence of 
hypoglycemia, other safety events).The study physician determines 
whether patients require medication adjustments based on clinical 

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guidelines (refer to Figure 2). 
 3.3.3.2 Patients in Group A undergo blood collection and GA measurement. 
 
3.3.4 Visit 3B - Follow-up Period (Visit 3A + 5 days) 
*Preferably within 3 days after Visit 3A, with a maximum of 5 days.  
 3.3.4.1 Patients in Group B will not participate in this follow-up visit. 
 3.3.4.2 Patients in Group A will undergo a physical examination 
(measurements: weight, waist circumference, blood pressure, pulse rate). 
The GA results for Group A patients will be communicated to the study 
physician and the patients. The study physician will adjust the medication 
based on the GA results. 
Drug adjustments follow the “GA normalization” principle: if GA > 16%, 
the study physician increases the type of oral medication based on the 
2020 Chinese Diabetes Prevention and Control Guidelines (Figure 2). 
Due to the risk of hypoglycemia, sulfonylureas, glinides, insulin, or 
insulin analogues are prohibited in this study. If GA ≤ 16%, no drug 
adjustments are made. However, if a patient reports hypoglycemia within 
the past month, the cause of hypoglycemia must be identified first and 
appropriate 
management 
provided. 
Since 
this 
study 
excludes 
sulfonylureas, glinides, insulin, or insulin analogues, the theoretical risk 
of hypoglycemia is extremely low. If unexplained hypoglycemia occurs, 
the investigator may consider reducing the dose of oral hypoglycemic 
agents as appropriate. 
 3.3.4.3 Record all data (medication status, occurrence of hypoglycemia, and 
other adverse events). 
 
 
3.3.5 Visit 4 – Follow-up period (baseline ±3 days) 
 3.3.5.1 Physical examination (measurements: weight, waist circumference, 
blood pressure, pulse rate); 
 3.3.5.2 Blood samples collected and frozen for storage in both Group A and 
Group B (to be measured for GA at the end of the study); 
 3.3.5.3 Record all data (medication changes, occurrence of hypoglycemia, other 
safety events). 
 3.3.5.4 The study physician conducting this visit should generally not adjust 
medications. However, adjustments may be made if the patient reports 
adverse events related to medication. Since this study excludes 
sulfonylureas, glinides, insulin, and insulin analogues, the theoretical risk 
of hypoglycemia is extremely low. If the patient reports hypoglycemia 
within the past month, the cause must first be identified and appropriate 
management provided. If unexplained hypoglycemia occurs, the 
investigator may consider reducing the dose of oral hypoglycemic agents 
as appropriate.  

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3.3.6 Visit 5 - Follow-up period (baseline: 84 ± 3 days) 
 3.3.6.1 Physical examination (measurements: weight, waist circumference, 
blood pressure, pulse rate); 
 3.3.6.2 Collect samples and perform relevant tests: fasting blood glucose, 
HbA1c, fasting C-peptide, fasting insulin, glycated albumin (GA); 
Complete blood count: red blood cells (RBC), white blood cells (WBC), 
platelets (PLT), hemoglobin (HGB);Liver and kidney function: total 
bilirubin (Tbil), alanine transaminase (ALT), aspartate transaminase (AST), 
total protein (TP), albumin, blood urea nitrogen (BUN) or urea (Urea), 
serum creatinine (Cr), uric acid (UA);Lipid profile: Total cholesterol (TC), 
triglycerides (TG), low-density lipoprotein (LDL-C), high-density 
lipoprotein (HDL-C); 
 3.3.6.3 Determine that the subject has completed the entire trial. 
 3.3.7 Each center measures GA frozen samples.  
 
3.4 outcome measures  
 3.4.1 Primary endpoint:  
      Proportion of participants achieving HbA1c < 7% at Visit 5 (Week 12 ± 3 
days from baseline). 
 
 3.4.2 Secondary endpoints: 
  3.4.2.1 Proportion of participants achieving HbA1c < 6.5% at Visit 5. 
  3.4.2.2 Change in HbA1c levels from baseline to Visit 5. 
  3.4.2.3 Incidence and frequency of hypoglycemia 
  3.4.2.4 Changes in pancreatic β-cell function (HOMA- = 20 × FINS / (FPG – 
3.5)); 
  3.4.2.5 Changes in insulin resistance levels (HOMA-IR = FINS × FPG/22.5); 
  3.4.2.6 Changes in body weight, waist circumference, and BMI; 
 
3.5 Sample size 
100 cases each in the intervention group and the control group. Sample size 
calculation method: 
In our previous single-center pilot study (n=40) targeting this research, the 
results showed that patients whose treatment regimens were adjusted based on 
GA achieved an HbA1c target rate (<7%) of 76.9% at 3-month follow-up, 
compared with 46.2% in the control group (p=0.226).Statistical significance was 
set at P < 0.05, with a statistical power of 0.8 and a 30% difference between the 
experimental and control groups as the calculation basis. Considering the 
follow-up completion rate of the pre-experimental patients (72.5%) and other 
factors such as a multi-center study, the target sample size for this study was 
determined to be 100 cases each for the intervention and control groups.  
 

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3.6 Expected overall duration of the clinical trial  
Considering the time required for clinical trial sites to complete all subject 
enrollment, follow-up, and sample testing, it is estimated that the study will take 
18 months from the first subject enrollment to database lock. If the 
implementation time exceeds the expected duration, the protocol will not be 
amended.  
 
 
4. Preliminary Research Basis 
In recent years, glycated albumin (GA) has gained increasing attention as an 
important biological marker for diabetes. The measurement of GA is not affected 
by albumin concentration, blood glucose levels, bilirubin levels, or lactose. 
Long-term frozen samples (e.g., the DCCT study, with samples frozen for up to 
23 years) remain unaffected by these factors. Additionally, the clinical reference 
range for GA has been established [7-10]. In the latest edition of the “Chinese 
Clinical Application Guidelines for Blood Glucose Monitoring (2015 Edition),” 
glycated albumin (GA) is also proposed as a sensitive indicator of blood glucose 
changes [12]. Recently, a short-term study conducted by our laboratory found 
that changes in GA could predict changes in HbA1c levels three months later in 
newly diagnosed type 2 diabetes patients and type 2 diabetes patients undergoing 
treatment adjustments. This is the first study to report that GA can predict drug 
efficacy [8]. Additionally, in a preliminary small-scale pilot study conducted by 
our team for this research, patients whose treatment regimens were adjusted 
based on GA achieved an HbA1c target rate (<7%) of 76.9% after three months 
of follow-up, compared to 46.2% in the control group; Similarly, in the 
GA-adjusted treatment group, the HbA1c achievement rate (<6.5%) was 30.8%, 
while the control group was 23.1%. 
 
 
5. Statistical Analysis 
 
5.1 Analysis Population: 
Randomized Population: All subjects who were randomly assigned to a treatment 
group constitute the randomized population. 
Full Analysis Set (FAS): Subjects who were randomly assigned, met the study 
inclusion criteria, and had baseline measurements for the primary efficacy 
endpoint. The FAS analysis follows the intention-to-treat (ITT) principle. 
Per-Protocol Set (PPS): Participants in the FAS who demonstrated good 
compliance and had no important protocol deviations that affected the primary 
efficacy assessment (specific criteria will be confirmed during data verification). 
Safety Set (SS): All participants with at least one safety assessment are included 
in the safety analysis. 

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Efficacy analysis is based on the FAS and PPS, while safety analysis is based on 
the SS. 
 
5.2 Statistical software used in this study: 
Statistical analysis was performed using SAS version 9.4 or higher.  
 
5.3 Baseline and Demographic Characteristics 
Demographic data and other baseline characteristics between treatment groups 
will be described according to group. Quantitative indicators will be statistically 
described based on data distribution characteristics, including mean, standard 
deviation, median, quartiles, minimum value, and maximum value. Count data 
will be statistically described using various frequencies and composition ratios. 
 
5.4 Adherence Analysis 
Statistical descriptions of medication adherence records for each visit during the 
entire treatment period will be provided.  
 
5.5 Analysis of Primary Endpoint Measures 
 - Proportion of participants with HbA1c < 7% at Visit 5 (Week 12 ± 3 days). 
 - The number and percentage of participants achieving HbA1c < 7% and the 
95% confidence interval (CI) will be calculated. 
 - The difference in proportions between groups (intervention – control) and its 
95% CI will be computed. 
 - Chi-square test or Fisher’s exact test will be used for between-group 
comparisons. 
 - Sensitivity analysis: The Cochran-Mantel-Haenszel (CMH) test will be used 
to adjust for center effects. 
 
5.6 Analysis of Secondary Endpoints 
Secondary endpoints includes: 
 - Proportion with HbA1c < 6.5% at Visit 5 
 - Change in HbA1c from baseline 
 - Incidence and frequency of hypoglycemia 
 - Change in β-cell function (HOMA- = 20 × FINS / (FPG – 3.5)) 
 - Change in insulin resistance (HOMA-IR = FINS × FPG / 22.5) 
 - Changes in weight, waist circumference, and BMI 
 - Categorical variables: Chi-square or Fisher’s exact test 
 - Continuous variables: t-test or Wilcoxon rank-sum test 
 
5.7 Safety analysis 
Safety analysis was conducted using the safety analysis set (SS) as the primary 
analysis set. Adverse events (AEs) and serious adverse events (SAEs) occurring 
during treatment were summarized and analyzed by treatment group based on 

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their incidence rates and severity, and classified according to major system 
organs and medical terminology. Other safety data, including laboratory test 
results, were analyzed and compared with the screening period using descriptive 
methods.  
 
 
6. Case allocation among study centers 
This trial uses a competitive enrollment method, and the case allocation plan for 
each study center is each center will recruit 10 subjects in the control group and 
10 subjects in the intervention group, for a total of 100 subjects in the control 
group and 100 subjects in the intervention group.  
 
 
7. Subject Protection (if applicable) 
This clinical trial will be conducted in accordance with the Declaration of 
Helsinki (2008 revised edition) and relevant Chinese laws and regulations 
governing clinical trials. Prior to the commencement of the trial, approval must 
be obtained from the Ethics Committee, and the trial may only be conducted 
after such approval has been granted. Any modifications to the trial protocol 
must be approved by the Ethics Committee prior to implementation. 
Prior to the start of the trial, an informed consent form must be provided to each 
participant, and they must be instructed to read it carefully. The study physician 
is responsible for explaining the contents of the informed consent form in detail 
and addressing any questions the participant may have. The participant must be 
fully informed about the purpose of the trial, the treatment regimen, laboratory 
tests, potential risks, and their rights and benefits. Participants must also be 
informed that they may choose alternative treatment options and withdraw from 
the trial at any time without facing any adverse consequences. Each patient must 
voluntarily sign the informed consent form before entering the trial. The study 
physician must ensure that all informed consent forms are properly stored in the 
study records. The privacy of participants must be protected, and information 
related to their participation in the trial must not be disclosed without 
authorization. If necessary, the drug regulatory authorities, ethics committee, or 
sponsor may review the records of participants in the trial in accordance with 
applicable regulations. 
 
 
8. Research Management 
8.1 Requirements for Investigators to Enter Data 
Investigators must ensure that all data is entered into the case report form 
truthfully, accurately, completely, timely, and in compliance with applicable laws 
and regulations. 

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 8.1.1 For all patients who have signed the informed consent form and been 
screened eligible for the trial, investigators must carefully and thoroughly 
record all observed information in the case report form, ensuring no items 
are left blank or omitted. 
8.1.2 All data in the case report form must be verified against the original 
medical records of the subject to ensure accuracy. 
 8.1.3 The case report form serves as the original data. Any corrections must be 
made by striking through the original text, adding notes in the margin, and 
signing and dating the correction by the researcher. 
 8.1.4 Original laboratory test results (or copies of original laboratory test 
results) must be affixed to the designated section for laboratory test results 
in the study medical records. 
 8.1.5 Data that is significantly higher or lower than expected or outside the 
clinically acceptable range must be verified or rechecked, and the 
researcher must provide necessary explanations.  
 
8.2 Database Establishment and Data Entry/Storage 
 8.2.1 Database Establishment: Data programmers will construct the database 
interface based on CRF or eCRF documentation and perform logical 
validation programming in accordance with the DVP. 
 8.2.2 Data Entry: CRCs or investigators will be responsible for data entry 
according to the eCRF completion guidelines. 
 8.2.3 Data Review: CRAs will perform SDV on the data and send any 
inconsistent data to the clinical team for resolution. 
 8.2.4 The EDC system has both system-generated and manual query modes. 
When abnormal data is entered, the EDC system will issue real-time alerts 
to prompt the data entry personnel to verify the data. Data managers will 
conduct manual reviews of the data and raise queries for any issues 
identified. 
 8.2.5 The clinical research implementation unit shall ensure the traceability of 
clinical data and retain all original data in its entirety. All original 
documents, data processing records, and related materials shall be retained 
by the participating hospitals for a period of 10 years following the 
completion of the clinical study.  
 
8.3 Specimen Collection, Storage Facilities, and Laboratory Premises 
The specimen collection, storage facilities, and laboratory premises for this trial 
are located at each center. 
 
9 Requirements for Reporting Adverse Events 
9.1 Definition of Adverse Events 
 (1) Adverse Event (AE): An unfavorable medical event occurring during the 
clinical trial, regardless of whether it is related to the trial. 

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 (2) Serious Adverse Event (SAE): An adverse event that results in death or a 
serious deterioration in health, including fatal diseases or injuries, permanent 
defects in bodily structure or function, hospitalization or prolongation of 
hospitalization, medical or surgical intervention to prevent permanent defects 
in bodily structure or function; fetal distress, fetal death, or congenital 
anomalies, or congenital defects. 
Note: The following situations do not constitute SAEs: 
  a) Hospitalization that was already planned prior to screening and did not 
result in a serious deterioration in health; 
  b) Expected, non-worsening fluctuations in pre-existing or detected abnormal 
conditions or diseases at the time of screening; 
  c) Hospitalization or prolonged hospitalization during the clinical study period 
as specified in the protocol (if applicable).  
 
9.2 Reporting Procedures 
 (1) In the event of any adverse event, investigators shall promptly report and 
file a report with the principal investigator, the clinical trial institution, the 
ethics committee, and the sponsor. 
 (2) In the event of a serious adverse event during a clinical trial, investigators 
shall immediately take appropriate therapeutic measures for the subject, 
simultaneously submit a written report to the medical device clinical trial 
management department of the clinical trial institution to which they belong, 
and notify the sponsor in writing through such department. The medical 
device clinical trial management department shall report the incident in 
writing to the relevant ethics committee and the food and drug supervision 
department and health and family planning authority of the province, 
autonomous region, or municipality where the clinical trial institution is 
located within 24 hours. In the event of a death, the clinical trial institution 
and the investigator shall provide the ethics committee and the sponsor with 
all necessary information. 
 (3) For serious adverse events and device defects that may lead to serious 
adverse events, the sponsor shall report to the food and drug supervision and 
administration department and the health and family planning authority at the 
same level within 5 working days of becoming aware of the event, and shall 
notify other clinical trial institutions and investigators participating in the trial, 
and the medical device clinical trial management department shall promptly 
notify the ethics committee of the clinical trial institution. 
 
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