Latent Autoimmune Diabetes in Adults (LADA)
Conditions
Keywords
LADA, Adult-Onset Autoimmune Diabetes, DPP-4 inhibitor, Beta-cell Function, Randomized Controlled Trial, C-peptide, Vitamin D3, Cofrogliptin
Brief summary
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.
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.
Interventions
DRUGCofrogliptin
5 mg/tablet, oral; 2 tablets (10 mg) once every 2 weeks. Administered from randomization through Week 52.
DRUGVitamin D3
400 IU/capsule, oral; 5 capsules (2000 IU) once daily. Administered from randomization through Week 52.
DRUGMetformin
Background therapy. Oral; typical daily dose 1.5 g, adjustable from 1.0 to 1.7 g/day per investigator judgment.
DRUGInsulin
Background therapy, as needed. Subcutaneous; individualized daily dose per investigator judgment.
Sponsors
Second Xiangya Hospital of Central South University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A single-center, randomized, open-label, controlled, parallel-group study with a 1:1 allocation ratio.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour Mixed-Meal Tolerance Test (MMTT) C-peptide Area Under the Curve (AUC) | Baseline, Week 52 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glutamic Acid Decarboxylase Autoantibody (GADA) Titers | Baseline, Week 52 | 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. |
| Change From Baseline in Insulinoma-Associated Antigen-2 Autoantibody (IA-2A) Titers | Baseline, Week 52 | 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. |
| Change From Baseline in Zinc Transporter 8 Autoantibody (ZnT8A) Titers | Baseline, Week 52 | 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. |
| Change From Baseline in Body Weight | Baseline, Week 12, Week 26, Week 38, Week 52 | 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. |
| Change From Baseline in Body Mass Index (BMI) | Baseline, Week 12, Week 26, Week 38, Week 52 | 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. |
| Change From Baseline in 2-hour MMTT C-peptide AUC at Weeks 12, 26, and 38 | Baseline, Week 12, Week 26, Week 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. |
| Change From Baseline in Fasting C-peptide (FCP) | Baseline, Week 12, Week 26, Week 38, Week 52 | 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. |
| Change From Baseline in 60-Minute Post-Meal C-peptide | Baseline, Week 12, Week 26, Week 38, Week 52 | 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. |
| Change From Baseline in 120-Minute Post-Meal C-peptide | Baseline, Week 12, Week 26, Week 38, Week 52 | 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. |
| Change From Baseline in Glycated Hemoglobin (HbA1c) | Baseline, Week 26, Week 52 | 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. |
| Proportion of Participants Achieving HbA1c < 7.0% | Week 12, Week 26, Week 38, Week 52 | 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. |
| Change From Baseline in Mean Daily Insulin Dose | Baseline, Week 12, Week 26, Week 38, Week 52 | 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. |
| Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | Baseline, Week 12, Week 26, Week 38, Week 52 | 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. |
| Change From Baseline in Homeostatic Model Assessment of β-cell function (HOMA-β) | Baseline, Week 12, Week 26, Week 38, Week 52 | 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. |
Countries
China
Contacts
CONTACTZhiguang Zhou, MD,PhD
CONTACTChuqing Cao, PhD
PRINCIPAL_INVESTIGATORZhiguang Zhou, MD,PhD
The Second Xiangya Hospital, Central South University
Outcome results
None listed