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

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)

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) .

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Drug: Saxagliptin; Drug: Insulin; Drug: Metformin; Drug: Vitamin D3

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing
    • Peking, Beijing, China, 100044
      • Peking University People's Hospital
    • Peking, Beijing, China, 100730
      • Beijing Hospital of the Ministry of Health
  • Chongqing
    • Chongqing, Chongqing, China, 400042
      • The First Affiliated Hospital of Chongqing Medical University
  • Fujian
    • Quanzhou, Fujian, China, 350005
      • Quanzhou First Hospital, Fujian
  • Fuzhou
    • Fujian, Fuzhou, China, 350005
      • The First Affiliated Hospital of Fujian Medical University
  • Gansu
    • Lanzhou, Gansu, China, 730000
      • Gansu Provincial Hospital
  • Guangdong
    • Dongguan, Guangdong, China, 523059
      • Dongguan People's Hospital
    • Guangzhou, Guangdong, China, 510120
      • The First Affiliated Hospital of Guangzhou Medical University
    • Guangzhou, Guangdong, China, 510080
      • Guangdong General Hospital
    • Guangzhou, Guangdong, China, 510120
      • Guangzhou First People's Hospital
  • Guangxi
    • Nanning, Guangxi, China, 530021
      • The First Affiliated Hospital of Guangxi Medical University
  • Hainan
    • Haikou, Hainan, China, 570311
      • Hainan General Hospital
  • Hebei
    • Tangshan, Hebei, China, 063000
      • Tangshan Gongren Hospital
    • Tangshan, Hebei, China, 063000
      • Tangshan Gongren Hospital063000
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150081
      • Harbin Medical University
  • Henan
    • Luoyang, Henan, China, 471023
      • The First Affiliated Hospital of Henan University of Science And Technology
    • Zhengzhou, Henan, China, 450003
      • Henan Provincial People's Hospital
  • Hunan
    • Changde, Hunan, China, 415003
      • The First People's Hospital of Changde
    • Changsha, Hunan, China, 410011
      • Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University
    • Hengyang, Hunan, China, 421001
      • The First Affiliated Hospital of South China University
    • Hengyang, Hunan, China, 421001
      • The Second Hospital University of South China
    • Huaihua, Hunan, China, 418000
      • The First People's Hospital of Huaihua
    • Yueyang, Hunan, China, 414000
      • The First People's Hospital of Yueyang
  • Inner Mongolia
    • Hohhot, Inner Mongolia, China, 010050
      • The Affiliated Hospital of Inner Mongolia Medical University
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • Jiangsu Province Hospital
    • Yangzhou, Jiangsu, China, 225001
      • The Northern Jiangsu People's Hospital
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • The First Affiliated Hospital of Nanchang University
    • Nanchang, Jiangxi, China, 330008
      • The Third Affiliated Hospital of Nanchang University
  • Jilin
    • Changchun, Jilin, China, 130021
      • Jilin Province People's Hospital
    • Changchun, Jilin, China, 130000
      • The Second Hospital of Jilin University
  • Liaoning
    • Shenyang, Liaoning, China, 110122
      • The First Hospital of China Medical University
  • Shandong
    • Qingdao, Shandong, China, 266000
      • The Affiliated Hospital of Qingdao University
  • Shanghai
    • Shanghai, Shanghai, China, 200031
      • Shanghai Xuhui District Central Hospital
  • Shanxi
    • Changzhi, Shanxi, China, 046000
      • Heping Hospital of Changzhi Medical College
    • Changzhi, Shanxi, China, 140400
      • Affiliated Heji Hospital of Changzhi Medical College
    • Xi'an, Shanxi, China, 710032
      • The First Affiliated Hospital of the Fourth Military Medical University
  • Yunnan
    • Kunming, Yunnan, China, 650032
      • First People's Hospital of Yunnan Province
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310009
      • The Second Affiliated Hospital of Zhejiang University School of Medicine
    • Wenzhou, Zhejiang, China, 325000
      • The Second Affiliated Hospital of Wenzhou Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Volunteer to participate in the study with informed consent;
2. 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:

1. Pregnancy, breastfeeding or planned pregnancy within two years;
2. Gestational diabetes mellitus or other specific types of diabetes;
3. Allergic to saxagliptin, vitamin D3 and their excipient;
4. Treatment with any anti-diabetic medication other than insulin in the last 8 weeks prior to randomization;
5. Use of systemic corticosteroids therapy (oral, intravenous) continuously for more than 7 days over the past 6 months;
6. Treatment with cytochrome P450 3A4/5 (CYP450 3A4/5) inhibitor;
7. 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;
8. 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;
9. History of malignant tumors;
10. History of mental disorders;
11. History of alcohol abuse or illegal drug abuse;
12. Serious systemic disease which the investigators think would not be suitable for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Metformin (and insulin) + saxagliptin; 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; Take saxagliptin tablet 5mg p.o. qd. for 104 weeks after randomization.; Other Names: Onglyza; Dipeptidyl peptidase 4 (DPP-4) inhibitor; Drug: Insulin; 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.; Other Names: Recombinant Human Insulin, Insulin analogue.; Drug: Metformin; 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.; Other Names: Metformin Hydrochloride tablet
EXPERIMENTAL: Metformin(insulin)+saxagliptin +vitamin D3; 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; Take saxagliptin tablet 5mg p.o. qd. for 104 weeks after randomization.; Other Names: Onglyza; Dipeptidyl peptidase 4 (DPP-4) inhibitor; Drug: Insulin; 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.; Other Names: Recombinant Human Insulin, Insulin analogue.; Drug: Metformin; 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.; Other Names: Metformin Hydrochloride tablet; Drug: Vitamin D3; Take vitamin D drops 2000 IU p.o. qd. for 104 weeks after randomization.; Other Names: Cholecalciferol
ACTIVE_COMPARATOR: Metformin (and insulin); Patients who have diagnosed LADA are assigned to receive Metformin 1.5g/d(and insulin at individual dose) for 104-week.	Drug: Insulin; 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.; Other Names: Recombinant Human Insulin, Insulin analogue.; Drug: Metformin; 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.; Other Names: Metformin Hydrochloride tablet

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Second Xiangya Hospital of Central South University
• Collaborators: The First Affiliated Hospital with Nanjing Medical University; Beijing Hospital; The First Affiliated Hospital of Henan University of Science and Technology; First Affiliated Hospital of Chongqing Medical University

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (ACTUAL): December 30, 2020
• Study Completion (ACTUAL): December 31, 2020

Study Registration Dates

• First Submitted: March 31, 2015
• First Submitted That Met QC Criteria: March 31, 2015
• First Posted (ESTIMATE): April 3, 2015

Study Record Updates

• Last Update Posted (ACTUAL): April 20, 2021
• Last Update Submitted That Met QC Criteria: April 18, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: vitamin D3; saxagliptin; LADA; C-Peptide
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Incretins; Insulin; Insulin, Globin Zinc; Vitamin D; Cholecalciferol; Metformin; Dipeptidyl-Peptidase IV Inhibitors; Saxagliptin
• Other Study ID Numbers: NCRCMD LADA SAX 2015

Drug and device information, study documents

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