Protective Effects of Saxagliptin (And Vitamin D3) on β Cell Function in Adult-onset Latent Autoimmune Diabetes

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate whether saxagliptin or (and vitamin D3) with metformin (and insulin) therapy can better protect islet β cell function than metformin(and insulin) .

Detailed Description
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LADA is actually a form of type 1 diabetes, which is caused by autoimmune damage of islet β cells and triggered by environmental factors based on genetic susceptibility. LADA shows some characteristics of type 2 diabetes at its onset, which develops slowly and latent, and easily be misdiagnosed as type 2 diabetes due to slowly β cell function deterioration. This is a multi-center, open- label, 1:1:1 randomized controlled trial to investigate the protective effects of saxagliptin and vitamin D3 in LADA patients. The study comprises the 0-6weeks of screening period and the 104-week intervention period. After obtaining the informed consent，the screening will find out the eligible patients according to the inclusion/exclusion criteria, then the patients will be randomized to the 104-week intervention period. Subjects will be randomized into one of the three groups(arms) through central dynamic randomization: metformin (and insulin), metformin(and insulin) +saxagliptin, metformin(and insulin) +saxagliptin+vitamin D3. Our previous randomized- controlled pilot study showed that dipeptidyl peptidase 4 (DPP-4) inhibitors could significantly improve islet β-cell function in patients with LADA. The main purpose of this study: To evaluate whether saxagliptin (and vitamin D3) with metformin (and insulin) therapy can better protect islet β cell function than metformin (and insulin).

Official Title
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A Randomized Controlled, Open-label, Multi-center Study With 104-week Saxagliptin or (and) Vitamin D3 Assessing Protective Effects on Beta Cell Function in Latent Autoimmune Diabetes in Adults (LADA) Treated With Metformin (and Insulin)

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Saxagliptin
* Drug: Vitamin D3
* Drug: Insulin
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Volunteer to participate in the study with informed consent; The LADA patients to be included in this study are defined as: (1) Meet the 1999 WHO Diagnostic Criteria for Diabetes Mellitus; (2) Age at diagnosis of DM ≧ 18 years old; (3) Glutamic acid decarboxylase antibody (GADA) positive; (4) Serum fasting C-peptide ≥ 100 pmol/L or 2-hour postprandial C-peptide≥ 200 pmol/L; 3. Age between 18-70 years old; 4. Diabetes duration <4 year; 5. Outpatient or inpatient. Exclusion Criteria: Pregnancy, breastfeeding or planned pregnancy within two years; Gestational diabetes mellitus or other specific types of diabetes; Allergic to saxagliptin, vitamin D3 and their excipient; Treatment with any anti-diabetic medication other than insulin in the last 8 weeks prior to randomization; Use of systemic corticosteroids therapy (oral, intravenous) continuously for more than 7 days over the past 6 months; Treatment with cytochrome P450 3A4/5 (CYP450 3A4/5) inhibitor; Alanine aminotransferase (ALT) or aspartate transaminase(AST) more than 3 times of the normal upper limit, total bilirubin (TBIL) more than 2 times of the normal upper limit; Creatinine levels ≧ 1.5 mg/dL(132μmol/L) for males and ≧ 1.4 mg/dL (123μmol/L) for females or creatinine clearance ≦ 50 mL/min; History of malignant tumors; History of mental disorders; History of alcohol abuse or illegal drug abuse; Serious systemic disease which the investigators think would not be suitable for the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin (and insulin) + saxagliptin<br>Patients who have diagnosed LADA are assigned to receive Saxagliptin tablets 5mg/d and Metformin 1.5g/d (and insulin at individual dose) for 104-week. | Drug: Saxagliptin<br>* Take saxagliptin tablet 5mg p.o. qd. for 104 weeks after randomization.<br>* Other names: Dipeptidyl peptidase 4 (DPP-4) inhibitor;Drug: Insulin<br>* For optimal control of patients' glucose, researchers can initiate insulin therapy at any time in this trial, choose any brands of insulin after discussion with the patient.<br>* Other names: Recombinant Human Insulin, Insulin analogue.;Drug: Metformin<br>* Take Metformin tablet 1.5g p.o. per day for 104 weeks (adjust the dose between 1-1.7g per day according to subject's specific situation) before or after randomization.<br>* Other names: Metformin Hydrochloride tablet;|
| Experimental: Metformin(insulin)+saxagliptin +vitamin D3<br>Patients who have diagnosed LADA are assigned to receive Saxagliptin tablets 5 mg/d, vitamin D drop 2000IU/d, Metformin 1.5g/d (and insulin at individual dose) for 104-week. | Drug: Saxagliptin<br>* Take saxagliptin tablet 5mg p.o. qd. for 104 weeks after randomization.<br>* Other names: Dipeptidyl peptidase 4 (DPP-4) inhibitor;Drug: Vitamin D3<br>* Take vitamin D drops 2000 IU p.o. qd. for 104 weeks after randomization.<br>* Other names: Cholecalciferol;Drug: Insulin<br>* For optimal control of patients' glucose, researchers can initiate insulin therapy at any time in this trial, choose any brands of insulin after discussion with the patient.<br>* Other names: Recombinant Human Insulin, Insulin analogue.;Drug: Metformin<br>* Take Metformin tablet 1.5g p.o. per day for 104 weeks (adjust the dose between 1-1.7g per day according to subject's specific situation) before or after randomization.<br>* Other names: Metformin Hydrochloride tablet;|
| Active Comparator: Metformin (and insulin)<br>Patients who have diagnosed LADA are assigned to receive Metformin 1.5g/d(and insulin at individual dose) for 104-week. | Drug: Insulin<br>* For optimal control of patients' glucose, researchers can initiate insulin therapy at any time in this trial, choose any brands of insulin after discussion with the patient.<br>* Other names: Recombinant Human Insulin, Insulin analogue.;Drug: Metformin<br>* Take Metformin tablet 1.5g p.o. per day for 104 weeks (adjust the dose between 1-1.7g per day according to subject's specific situation) before or after randomization.<br>* Other names: Metformin Hydrochloride tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute changes from baseline in Fasting C-peptide levels at week 104. | To evaluate the efficacy of saxagliptin plus metformin (and insulin) on beta cell function in LADA patients compared with metformin (and insulin) treatment. By measure absolute changes from baseline in Fasting C-peptide levels at week 104. To evaluate the efficacy of saxagliptin (add on vitamin D) plus metformin (and insulin) on beta cell function in LADA patients compared with metformin (and insulin) treatment.By measure absolute changes from baseline in Fasting C-peptide levels at week 104. | From baseline to 104 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute changes from baseline in fasting C-peptide levels and at week 26, 52 and 78. | To evaluate the efficacy of saxagliptin (add on vitamin D) plus metformin (and insulin) on indicators of beta cell function compared with LADA patients treated with metformin (and insulin). By measure absolute changes from baseline in fasting C-peptide levels and at week 26, 52 and 78. | From baseline to 26, 52, 78 week | 
| Absolute changes from baseline in C peptide at 60-min and 120-min (AUC) during a mixed-meal tolerance test and at week 26, 52, 78 and 104. | To evaluate the efficacy of saxagliptin (add on vitamin D) plus metformin (and insulin) on indicators of beta cell function compared with LADA patients treated with metformin (and insulin). By measure absolute changes from baseline in C peptide at 60-min and 120-min (AUC) during a mixed-meal tolerance test and at week 26, 52, 78 and 104. | From baseline to 26, 52, 78, 104 week | 
| The proportion of subjects with increased (decreased, unchanged) fasting or post-stimulus C peptide level compared with baseline after 104 weeks of treatment. | To evaluate the efficacy of saxagliptin (add on vitamin D) plus metformin (and insulin) on indicators of beta cell function compared with LADA patients treated with metformin (and insulin). By measure the proportion of subjects with increased (decreased, unchanged) fasting or post-stimulus C peptide level compared with baseline after 104 weeks of treatment. | From baseline to 104 week | 
| The increased percentage of C peptide pre-and post mixed-meal tolerance test (Delta C peptide) after 104 weeks of treatment. | To evaluate the efficacy of saxagliptin (add on vitamin D) plus metformin (and insulin) on indicators of beta cell function compared with LADA patients treated with metformin (and insulin). By measure the increased percentage of C peptide pre-and post mixed-meal tolerance test (Delta C peptide) after 104 weeks of treatment | From baseline to 104 week | 
| Changes of HbA1c levels from baseline and at week 26, 52, 78 and 104. | To evaluate the efficacy of saxagliptin (add on vitamin D) plus metformin (and insulin) on glycemic control compared with LADA patients treated with metformin (and insulin). By measure Changes of HbA1c levels from baseline and at week 26, 52, 78 and 104. | 26, 52, 78, 104 week | 
| The proportion of subjects responding to glucose therapy (i.e. HbA1c<7%) after 104 weeks of treatment. | To evaluate the efficacy of saxagliptin (add on vitamin D) plus metformin (and insulin) on glycemic control compared with LADA patients treated with metformin (and insulin). By measure the proportion of subjects responding to glucose therapy (i.e. HbA1c<7%) after 104 weeks of treatment. | 104 week | 
| Changes of average daily insulin dose (U/kg/d) from baseline and at week 26, 52, 78 and 104 | To evaluate the efficacy of saxagliptin (add on vitamin D) plus metformin (and insulin) on glycemic control /insulin-sparing compared with LADA patients treated with metformin (and insulin). By measure Changes of average daily insulin dose (U/kg/d) from baseline and at week 26, 52, 78 and 104. | From baseline to 26, 52, 78, 104 week | 
| Changes of GADA titers from baseline and at week 52 and 104. | To evaluate the efficacy of saxagliptin (add on vitamin D) plus metformin (and insulin) on glycemic control /insulin-sparing/changes of autoantibody titer compared with LADA patients treated with metformin (and insulin). By measure changes of GADA titers from baseline and at week 52 and 104. | From baseline to 52, 104 week | 
| Absolute changes of body weight and BMI level from baseline and at week 26, 52, 78 and 104. | To evaluate the efficacy of saxagliptin (add on vitamin D) plus metformin (and insulin) on body weight/BMI level compared with LADA patients treated with metformin (and insulin). By measure Changes of BMI from baseline and at week 26, 52, 78 and 104. | From baseline to 26, 52, 78, 104 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LADA, saxagliptin, vitamin D3, C-Peptide