Efficacy and Safety Comparison of Cofrogliptin Add-on Versus Metformin Dose-escalation in Type 2 Diabetes Patients Inadequately Controlled With SGLT-2 Inhibitors Plus Low-Dose Metformin:A Multicenter, Open-Label Trial

The aim of this study is to evaluate the change in glycated hemoglobin (HbA1c) levels of adding cofrogliptin compared to escalation of metformin dose after 24 weeks in type 2 diabetes patients who have failed to achieve adequate glycemic control despite receiving combination therapy with SGLT2i and metformin. Participants will be asked to use either cofrogliptin combined with SGLT2i and metformin or SGLT2i combined with increased dose of metformin.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Metformin dose escalation; Drug: Cofrogliptin+SGLT2i+Metformin

Detailed Description

The primary objective of this study is to evaluate the change in glycated hemoglobin (HbA1c) levels of adding cofrogliptin compared to escalation of metformin dose after 24 weeks in type 2 diabetes patients who have failed to achieve adequate glycemic control despite receiving combination therapy with SGLT2i and metformin.

The secondary objectives of this study are to evaluate the changes in the following parameters (for indicators requiring pre-post comparison, the baseline level during the baseline treatment period is used for comparison):of adding cofrogliptin compared to escalation of metformin dose after 24 weeks in type 2 diabetes patients who have failed to achieve adequate glycemic control despite receiving combination therapy with SGLT2i and metformin:

1. The proportion of subjects with HbA1c < 7.0% and < 6.5% after 24 weeks of treatment.
2. Changes in 2-hour postprandial plasma glucose (2h-PPG) and fasting plasma glucose (FPG) from baseline at 12 and 24 weeks of treatment.
3. Change in HbA1c levels from baseline after 12 weeks of treatment.
4. Changes in body weight, fasting C-peptide, insulin sensitivity, and β-cell function from baseline after 24 weeks of treatment.
5. The proportion of subjects who withdrew due to the need for rescue therapy for hyperglycemia.
6. The safety profile of triple therapy with cofrogliptin.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Wenheng Zeng, Doctor; Phone Number: +86 137 5711 8319; Email: 42590910@qq.com

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Recruiting
      • Second Affiliated Hospital, School of Medicine, Zhejiang University
      • Contact: Wenheng Zeng, Doctor; Phone Number: +86 137 5711 8319; Email: 42590910@qq.com
      • Principal Investigator: Chao Zheng, Doctor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Able to understand and voluntarily sign a written informed consent form.
• Male or female aged 18-74 years (inclusive).
• Meet the diagnostic criteria for type 2 diabetes mellitus (T2DM).
• Have initiated treatment with any one of the SGLT2i monotherapy (dapagliflozin 10mg/d, canagliflozin 100mg/d, empagliflozin 10mg/d, ertugliflozin 5mg/day, or henagliflozin 10mg/day) for at least 8 weeks.
• Have received 500-1000mg/day metformin treatment for at least 8 weeks with a stable, unchanged dose maintained during the screening period.
• HbA1c level within the range of 7.5% to 9.5% inclusive.
• Fasting blood glucose (FBG) level less than 15 mmol/L before randomization.
• Body mass index (BMI) less than or equal to 40 kg/m2 before randomization.
• Urine ketone test negative before randomization.
• Estimated glomerular filtration rate (eGFR) of 60 ml/min/1.73m2 or higher before randomization.
• Agree to maintain the same diet and exercise habits throughout the trial, and be willing and able to correctly use a home blood glucose meter for self-monitoring of blood glucose (SMBG) and keep records.

Exclusion Criteria:

• Type 1 diabetes mellitus.
• Various types of secondary diabetes.
• Pending or having undergone pancreatic or β-cell transplantation.
• History of pancreatitis or pancreatic resection.
• Complicated with diabetic ketoacidosis or hyperosmolar coma.
• Moderate or severe liver insufficiency of any cause, defined as ALT (SGPT), AST (SGOT), or alkaline phosphatase serum levels greater than 3 times the upper limit of normal (ULN) during the screening period.
• Acute coronary syndrome (ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, unstable angina), stroke, or transient ischemic attack (TIA) within the past 3 months.
• Uncontrolled hypertension: systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 90 mmHg.
• Hemoglobin level less than 10 g/l or 100 mg/dl.
• Recurrent genitourinary infections more than twice within the past 3 months.
• History of bariatric surgery or other gastrointestinal surgeries causing chronic malabsorption within the past 2 years.
• Received anti-obesity medication within the past 3 months or any other treatment (e.g., surgery, radical diet plans) that led to unstable body weight at the time of screening.
• History of cancer (except basal cell carcinoma) and/or cancer treatment within the past 5 years.
• Human immunodeficiency virus (HIV) positivity.
• Severe peripheral vascular disease.
• Hematological malignancies or any diseases causing hemolysis or erythrocyte instability (e.g., malaria, babesiosis, hemolytic anemia).
• Coexisting immune system diseases or currently receiving systemic corticosteroid therapy.
• Changes in thyroid hormone dosage within the past 6 weeks, or any other uncontrolled endocrine or metabolic disorders outside of T2DM.
• Alcohol or drug abuse within the past 3 months that may reduce trial compliance, or any chronic illnesses that the investigator believes may lead to reduced trial compliance or reduced use of the study drug.
• Known allergies to components of the study medication or other drugs with similar chemical structures or excipients.
• Pregnant women, women planning to become pregnant during the study, or lactating women. Subjects unwilling to use reliable contraception (including condoms, spermicides, or intrauterine devices) from the time of signing the informed consent form until 28 days after the last administration of the study medication, or women planning to use progesterone-containing contraceptives during this period. Men with fertility plans during the study.
• Participation in any other clinical study within the past 30 days.
• Any other condition deemed unsuitable for participation in this study by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: cofrogliptin add-on group; The cofrogliptin add-on group will continue their existing SGLT2i plus metformin regimen and dosing, with the add-on of cofrogliptin over 24 weeks of triple combined therapy.	Drug: Metformin dose escalation; The metformin dose escalation group will have their metformin dose gradually increased to the target dose.
Active Comparator: Metformin dose escalation group; The metformin dose escalation group will have their metformin dose gradually increased to the target dose	Drug: Cofrogliptin+SGLT2i+Metformin; The cofrogliptin add-on group will continue their existing SGLT2i plus metformin regimen and dosing, with the add-on of cofrogliptin over 24 weeks of triple combined therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the change in glycated hemoglobin (HbA1c) levels	the change in glycated hemoglobin (HbA1c) levels of adding cofrogliptin compared to escalation of metformin dose after 24 weeks in type 2 diabetes patients who have failed to achieve adequate glycemic control despite receiving combination therap	throughout the study, about 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of subjects with HbA1c < 7.0% and < 6.5%	The proportion of subjects with HbA1c < 7.0% and < 6.5% after 24 weeks of treatment.	throughout the study, about 1 year
2h-PPG and FPG	Changes in 2-hour postprandial plasma glucose (2h-PPG) and fasting plasma glucose (FPG) from baseline at 12 and 24 weeks of treatment.	throughout the study, about 1 year
Change in HbA1c levels	Change in HbA1c levels from baseline after 12 weeks of treatment.	throughout the study, about 1 year
Changes in body weight, fasting C-peptide, insulin sensitivity, and β-cell function	Changes in body weight, fasting C-peptide, insulin sensitivity, and β-cell function from baseline after 24 weeks of treatment.	throughout the study, about 1 year
proportion of subjects who withdrew	The proportion of subjects who withdrew due to the need for rescue therapy for hyperglycemia.	throughout the study, about 1 year
The safety profile	The safety profile of triple therapy with cofrogliptin.	throughout the study, about 1 year

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Collaborators: Ningbo Medical Center Lihuili Hospital; Wenzhou Central Hospital; The Second Affiliated Hospital of Dalian Medical University; Hangzhou Traditional Chinese Medicine Hospital
• Investigators: Principal Investigator: Chao Zheng, Doctor, Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Estimated): March 30, 2025
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: March 3, 2025
• First Submitted That Met QC Criteria: March 3, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 3, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: t2dm
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus, Type 2; Diabetes Mellitus; Physiological Effects of Drugs; Hypoglycemic Agents; Metformin
• Other Study ID Numbers: 2024-0986

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: medical data should be analyzed before sharing to avoind misunderstanding

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No