Effects of Cofrogliptin on Beta-Cell Function in LADA Patients

Key Effects of Cofrogliptin on Beta-cell Function in Adults With Latent Autoimmune Diabetes (LADA): A Single-Center, Randomized, Controlled Trial - KOLA Study

This single-center, randomized, open-label, controlled study aims to evaluate the effect of cofrogliptin on pancreatic β-cell function in adults with latent autoimmune diabetes in adults (LADA). Following a screening period of up to 6 weeks, 84 eligible participants will be randomized in a 1:1 ratio via a sealed-envelope method, stratified by baseline GADA titer (≥0.3 vs <0.3). Participants will be assigned to one of two treatment arms: (1) metformin (with or without insulin) plus vitamin D3, or (2) metformin (with or without insulin) plus vitamin D3 and cofrogliptin. Cofrogliptin will be administered orally at a dose of 10 mg once every 2 weeks, and vitamin D3 at 2000 IU once daily, for a total treatment duration of 52 weeks. Study visits are planned at baseline and at Weeks 12, 26, 38, and 52, during which mixed-meal tolerance tests (MMTT) and other protocol-specified assessments will be conducted.

Study Overview

• Status: Not yet recruiting
• Conditions: Latent Autoimmune Diabetes in Adults (LADA)
• Intervention / Treatment: Drug: Cofrogliptin; Drug: Vitamin D3; Drug: Metformin; Drug: Insulin

Detailed Description

Latent autoimmune diabetes in adults (LADA) is a form of autoimmune diabetes characterized by the progressive destruction of pancreatic beta cells. Preclinical and clinical evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors and vitamin D possess immunomodulatory effects that may help preserve residual beta-cell function. Cofrogliptin is a novel, ultra-long-acting DPP-4 inhibitor.

This study will enroll patients with LADA who will first enter a screening period. Eligible participants will be randomized (1:1) into two parallel arms on Day 1. The experimental group will receive cofrogliptin and vitamin D3 in addition to their background therapy. The active comparator group will receive vitamin D3 plus background therapy. Background therapy includes metformin, with insulin permitted and adjusted per investigator's judgment. Follow-up clinic visits are scheduled at Weeks 12, 26, 38, and 52. Efficacy will be assessed through MMTT-derived C-peptide and glucose measurements, as well as other glycemic indices. Safety will be monitored through the recording of adverse events, laboratory tests, and vital signs throughout the 52-week treatment period.

• Study Type: Interventional
• Enrollment (Estimated): 84
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Zhiguang Zhou, MD,PhD; Phone Number: +8673185292154; Email: zhouzhiguang@csu.edu.cn
• Study Contact Backup: Name: Chuqing Cao, PhD; Email: csuccq@163.com

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410000
      • The Second Xiangya Hospital, Central South University
      • Contact: Zhiguang Zhou, MD,PhD; Phone Number: +8673185292154; Email: zhouzhiguang@csu.edu.cn
      • Contact: Chuqing Cao, PhD; Email: csuccq@163.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 1. Voluntarily signed informed consent.
• 2. Age 18 to 70 years, inclusive.
• 3. Diagnosed with LADA, defined as meeting all of the following:
• (1) Meets 1999 WHO criteria for diabetes mellitus.
• (2) Age at diagnosis of diabetes ≥ 18 years.
• (3) Positive for at least one islet autoantibody (GADA, IA-2A, or ZnT8A).
• (4) Did not require continuous insulin therapy for at least 6 months after diagnosis.
• 4. Stimulated C-peptide ≥ 200 pmol/L.
• 5. Glycated Hemoglobin (HbA1c) ≤ 9.0%.
• 6. For women of childbearing potential, must agree to use a highly effective method of contraception throughout the study.

Exclusion Criteria:

• 1. Pregnant, breastfeeding, or planning to become pregnant during the study.
• 2. Gestational diabetes or other specific types of diabetes.
• 3. Known hypersensitivity to Cogliptin, Vitamin D3, or their excipients.
• 4. Use of DPP-4 inhibitors, GLP-1 receptor agonists, or thiazolidinediones (TZDs) within 8 weeks prior to randomization.
• 5. Hypercalcemia (serum calcium above the upper limit of the normal range).
• 6. Systemic corticosteroid therapy (oral or IV) for more than 7 consecutive days within 6 months prior to screening.
• 7. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN), or total bilirubin > 2 times ULN.
• 8. Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m².
• 9. History of acute diabetic complications such as diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state.
• 10. History of pancreatitis or pancreatic surgery.
• 11. New York Heart Association (NYHA) class III or IV congestive heart failure, or known left ventricular ejection fraction (LVEF) < 40%.
• 12. History of malignancy.
• 13. Severe psychiatric illness.
• 14. History of alcohol or illicit drug dependence.
• 15. Any other severe systemic disease that the investigator deems unsuitable for enrollment.

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 + Vitamin D3 + Background Therapy; Participants will receive Cofrogliptin (10 mg orally every 2 weeks) and Vitamin D3 (2000 IU orally once daily), in addition to background therapy consisting of metformin (with or without insulin), over a period of 52 weeks.	Drug: Cofrogliptin; 5 mg/tablet, oral; 2 tablets (10 mg) once every 2 weeks. Administered from randomization through Week 52.; Drug: Vitamin D3; 400 IU/capsule, oral; 5 capsules (2000 IU) once daily. Administered from randomization through Week 52.; Drug: Metformin; Background therapy. Oral; typical daily dose 1.5 g, adjustable from 1.0 to 1.7 g/day per investigator judgment.; Drug: Insulin; Background therapy, as needed. Subcutaneous; individualized daily dose per investigator judgment.
Active Comparator: Vitamin D3 + Background Therapy; Participants will receive Vitamin D3 (2000 IU orally once daily), in addition to background therapy consisting of metformin (with or without insulin), for a total duration of 52 weeks.	Drug: Vitamin D3; 400 IU/capsule, oral; 5 capsules (2000 IU) once daily. Administered from randomization through Week 52.; Drug: Metformin; Background therapy. Oral; typical daily dose 1.5 g, adjustable from 1.0 to 1.7 g/day per investigator judgment.; Drug: Insulin; Background therapy, as needed. Subcutaneous; individualized daily dose per investigator judgment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 2-hour Mixed-Meal Tolerance Test (MMTT) C-peptide Area Under the Curve (AUC)	Change from baseline in the area under the curve from 0 to 120 minutes (AUC0-120) for serum C-peptide during a mixed-meal tolerance test (MMTT), calculated using the trapezoidal rule from C-peptide measured at 0, 60, and 120 minutes.	Baseline, Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 2-hour MMTT C-peptide AUC at Weeks 12, 26, and 38	The 2-hour Mixed-Meal Tolerance Test (MMTT) C-peptide Area Under the Curve (AUC) will be calculated using the trapezoidal rule from C-peptide levels measured at 0, 60, and 120 minutes during the MMTT. Change from baseline is defined as the post-baseline value minus the baseline value. This outcome assesses the overall C-peptide response to a standardized meal stimulus.	Baseline, Week 12, Week 26, Week 38
Change From Baseline in Fasting C-peptide (FCP)	Fasting C-peptide (FCP) is measured from a blood sample taken after an overnight fast of at least 8 hours. It reflects the basal insulin secretion capacity of pancreatic β-cells.	Baseline, Week 12, Week 26, Week 38, Week 52
Change From Baseline in 60-Minute Post-Meal C-peptide	Serum C-peptide will be measured at 60 minutes during the mixed-meal tolerance test (MMTT). Change from baseline is defined as the post-baseline 60-minute C-peptide value minus the baseline 60-minute C-peptide value. This measurement assesses the early dynamic response of pancreatic β-cells to a meal stimulus.	Baseline, Week 12, Week 26, Week 38, Week 52
Change From Baseline in 120-Minute Post-Meal C-peptide	Serum C-peptide will be measured at 120 minutes during the mixed-meal tolerance test (MMTT). Change from baseline is defined as the post-baseline 120-minute C-peptide value minus the baseline 120-minute C-peptide value. This measurement assesses the late dynamic response of pancreatic β-cells to a meal stimulus.	Baseline, Week 12, Week 26, Week 38, Week 52
Change From Baseline in Glycated Hemoglobin (HbA1c)	HbA1c provides an indication of the average blood glucose levels over the preceding 2-3 months. This outcome measures the long-term glycemic control in participants.	Baseline, Week 26, Week 52
Proportion of Participants Achieving HbA1c < 7.0%	The percentage of participants in each group who achieve a target HbA1c level of less than 7.0% (53 mmol/mol), which is a standard therapeutic goal for glycemic control in adults with diabetes.	Week 12, Week 26, Week 38, Week 52
Change From Baseline in Mean Daily Insulin Dose	The change from baseline in the mean daily insulindose will be calculated as units per kilogram per day (u/kg/day), based on data recorded in participant diaries. This outcome is designed to evaluate the effect of the intervention on the requirement for exogenous insulin.	Baseline, Week 12, Week 26, Week 38, Week 52
Change From Baseline in Homeostatic Model Assessment of β-cell function (HOMA-β)	HOMA-β is calculated using fasting glucose and fasting C-peptide levels. It provides an estimate of basal pancreatic β-cell function. Change from baseline is defined as the post-baseline value minus the baseline value.	Baseline, Week 12, Week 26, Week 38, Week 52
Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)	HOMA-IR is calculated using fasting glucose and fasting C-peptide levels. It provides an estimate of insulin resistance. Change from baseline is defined as the post-baseline value minus the baseline value.	Baseline, Week 12, Week 26, Week 38, Week 52
Change From Baseline in Glutamic Acid Decarboxylase Autoantibody (GADA) Titers	GADA is a marker of the autoimmune process in LADA. Change from baseline is defined as the Week 52 value minus the baseline value. Changes in its titers may reflect modulation of the autoimmune response.	Baseline, Week 52
Change From Baseline in Insulinoma-Associated Antigen-2 Autoantibody (IA-2A) Titers	IA-2A is a marker of the autoimmune process in LADA. Changes in its titers may reflect modulation of the autoimmune response. Change from baseline is defined as the Week 52 value minus the baseline value.	Baseline, Week 52
Change From Baseline in Zinc Transporter 8 Autoantibody (ZnT8A) Titers	ZnT8A is a marker of the autoimmune process in LADA. Changes in its titers may reflect modulation of the autoimmune response. Change from baseline is defined as the Week 52 value minus the baseline value.	Baseline, Week 52
Change From Baseline in Body Weight	Body weight will be measured in kilograms (kg) at scheduled visits. Change from baseline is defined as the post-baseline value minus the baseline value.	Baseline, Week 12, Week 26, Week 38, Week 52
Change From Baseline in Body Mass Index (BMI)	Body Mass Index (BMI) will be calculated as weight in kilograms divided by the square of height in meters (kg/m²) to assess changes in body composition. Change from baseline is defined as the post-baseline value minus the baseline value.	Baseline, Week 12, Week 26, Week 38, Week 52

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)	Safety will be evaluated by recording the number of participants who experience treatment-emergent adverse events and serious adverse events throughout the study, including events of special interest such as severe hypoglycemia and potential hypercalcemia.	Throughout the study (52 weeks)
Number of participants with Clinically Significant Abnormal Vital Signs, Laboratory Tests, or ECG Findings	Safety will be monitored by assessing the number (and proportion) of participants who experience clinically significant changes from baseline in vital signs (systolic and diastolic blood pressure, heart rate, body temperature), clinical laboratory parameters (hematology, clinical chemistry, and urinalysis), or 12-lead electrocardiogram (ECG) findings. Clinically significant changes will be evaluated by the investigator. Each participant will be counted once if any qualifying abnormality occurs.	At scheduled visits through Week 52

Collaborators and Investigators

• Sponsor: Second Xiangya Hospital of Central South University
• Investigators: Principal Investigator: Zhiguang Zhou, MD,PhD, The Second Xiangya Hospital, Central South University

Study record dates

Study Major Dates

• Study Start (Estimated): May 15, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: February 9, 2026
• First Submitted That Met QC Criteria: March 9, 2026
• First Posted (Actual): March 10, 2026

Study Record Updates

• Last Update Posted (Actual): May 8, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Vitamin D3; Beta-cell Function; C-peptide; LADA; DPP-4 inhibitor; Adult-Onset Autoimmune Diabetes; Cofrogliptin
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Nutritional and Metabolic Diseases; Latent Autoimmune Diabetes in Adults; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Organic Chemicals; Lipids; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Biguanides; Guanidines; Amidines; Insulins; Pancreatic Hormones; Proinsulin; Cholestenes; Cholestanes; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Metformin; Insulin; Cholecalciferol
• Other Study ID Numbers: KOLA Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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