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

Primary Purpose

Diabetes Mellitus, Type 1

Status

Completed

Phase

Phase 4

Locations

China

Study Type

Interventional

Intervention

Saxagliptin

Vitamin D3

Insulin

Metformin

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 1 focused on measuring LADA, saxagliptin, vitamin D3, C-Peptide

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Peking University People's Hospital
Beijing Hospital of the Ministry of Health
The First Affiliated Hospital of Chongqing Medical University
Quanzhou First Hospital, Fujian
The First Affiliated Hospital of Fujian Medical University
Gansu Provincial Hospital
Dongguan People's Hospital
Guangdong General Hospital
Guangzhou First People's Hospital
The First Affiliated Hospital of Guangzhou Medical University
The First Affiliated Hospital of Guangxi Medical University
Hainan General Hospital
Tangshan Gongren Hospital063000
Tangshan Gongren Hospital
Harbin Medical University
The First Affiliated Hospital of Henan University of Science and Technology
Henan Provincial People's Hospital
The First People's Hospital of Changde
Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University
The First Affiliated Hospital of South China University
The Second Hospital University of South China
The First People's Hospital of Huaihua
The First People's Hospital of Yueyang
The Affiliated Hospital of Inner Mongolia Medical University
Jiangsu Province Hospital
The Northern Jiangsu People's Hospital
The First Affiliated Hospital of Nanchang University
The Third Affiliated Hospital of Nanchang University
The Second Hospital of Jilin University
Jilin Province People's Hospital
The First Hospital of China Medical University
The Affiliated Hospital of Qingdao University
Shanghai Xuhui District Central Hospital
Heping Hospital of Changzhi Medical College
Affiliated Heji Hospital of Changzhi Medical College
The First Affiliated Hospital of The Fourth Military Medical University
First People's Hospital of Yunnan Province
The Second Affiliated Hospital of Zhejiang University School of Medicine
The Second Affiliated Hospital of Wenzhou Medical University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

Metformin (and insulin) + saxagliptin

Metformin(insulin)+saxagliptin +vitamin D3

Metformin (and insulin)

Arm Description

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.

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.

Patients who have diagnosed LADA are assigned to receive Metformin 1.5g/d(and insulin at individual dose) for 104-week.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT02407899

First Posted

March 31, 2015

Last Updated

April 18, 2021

Sponsor

Second Xiangya Hospital of Central South University

Collaborators

Beijing Hospital, The First Affiliated Hospital with Nanjing Medical University, First Affiliated Hospital of Chongqing Medical University, The First Affiliated Hospital of Henan University of Science and Technology

1. Study Identification

Unique Protocol Identification Number

NCT02407899

Brief Title

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

Official Title

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)

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Completed

Study Start Date

March 2015 (undefined)

Primary Completion Date

December 30, 2020 (Actual)

Study Completion Date

December 31, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Second Xiangya Hospital of Central South University

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes Mellitus, Type 1

Keywords

LADA, saxagliptin, vitamin D3, C-Peptide

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

300 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Metformin (and insulin) + saxagliptin

Arm Type

Experimental

Arm Description

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.

Arm Title

Metformin(insulin)+saxagliptin +vitamin D3

Arm Type

Experimental

Arm Description

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.

Arm Title

Metformin (and insulin)

Arm Type

Active Comparator

Arm Description

Patients who have diagnosed LADA are assigned to receive Metformin 1.5g/d(and insulin at individual dose) for 104-week.

Intervention Type

Drug

Intervention Name(s)

Saxagliptin

Other Intervention Name(s)

Onglyza, Dipeptidyl peptidase 4 (DPP-4) inhibitor

Intervention Description

Take saxagliptin tablet 5mg p.o. qd. for 104 weeks after randomization.

Intervention Type

Drug

Intervention Name(s)

Vitamin D3

Other Intervention Name(s)

Cholecalciferol

Intervention Description

Take vitamin D drops 2000 IU p.o. qd. for 104 weeks after randomization.

Intervention Type

Drug

Intervention Name(s)

Insulin

Other Intervention Name(s)

Recombinant Human Insulin, Insulin analogue.

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Metformin

Other Intervention Name(s)

Metformin Hydrochloride tablet

Intervention Description

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.

Primary Outcome Measure Information:

Title

Absolute changes from baseline in Fasting C-peptide levels at week 104.

Description

Time Frame

From baseline to 104 week

Secondary Outcome Measure Information:

Title

Absolute changes from baseline in fasting C-peptide levels and at week 26, 52 and 78.

Description

Time Frame

From baseline to 26, 52, 78 week

Title

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.

Description

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.

Time Frame

From baseline to 26, 52, 78, 104 week

Title

The proportion of subjects with increased (decreased, unchanged) fasting or post-stimulus C peptide level compared with baseline after 104 weeks of treatment.

Description

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.

Time Frame

From baseline to 104 week

Title

The increased percentage of C peptide pre-and post mixed-meal tolerance test (Delta C peptide) after 104 weeks of treatment.

Description

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

Time Frame

From baseline to 104 week

Title

Changes of HbA1c levels from baseline and at week 26, 52, 78 and 104.

Description

Time Frame

26, 52, 78, 104 week

Title

The proportion of subjects responding to glucose therapy (i.e. HbA1c<7%) after 104 weeks of treatment.

Description

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.

Time Frame

104 week

Title

Changes of average daily insulin dose (U/kg/d) from baseline and at week 26, 52, 78 and 104

Description

Time Frame

From baseline to 26, 52, 78, 104 week

Title

Changes of GADA titers from baseline and at week 52 and 104.

Description

Time Frame

From baseline to 52, 104 week

Title

Absolute changes of body weight and BMI level from baseline and at week 26, 52, 78 and 104.

Description

Time Frame

From baseline to 26, 52, 78, 104 week

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Zhiguang Zhou, MD/PhD

Organizational Affiliation

Second Xiangya Hospital of Central South University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Peking University People's Hospital

City

Peking

State/Province

Beijing

ZIP/Postal Code

100044

Country

China

Facility Name

Beijing Hospital of the Ministry of Health

City

Peking

State/Province

Beijing

ZIP/Postal Code

100730

Country

China

Facility Name

The First Affiliated Hospital of Chongqing Medical University

City

Chongqing

State/Province

Chongqing

ZIP/Postal Code

400042

Country

China

Facility Name

Quanzhou First Hospital, Fujian

City

Quanzhou

State/Province

Fujian

ZIP/Postal Code

350005

Country

China

Facility Name

The First Affiliated Hospital of Fujian Medical University

City

Fujian

State/Province

Fuzhou

ZIP/Postal Code

350005

Country

China

Facility Name

Gansu Provincial Hospital

City

Lanzhou

State/Province

Gansu

ZIP/Postal Code

730000

Country

China

Facility Name

Dongguan People's Hospital

City

Dongguan

State/Province

Guangdong

ZIP/Postal Code

523059

Country

China

Facility Name

Guangdong General Hospital

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510080

Country

China

Facility Name

Guangzhou First People's Hospital

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510120

Country

China

Facility Name

The First Affiliated Hospital of Guangzhou Medical University

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510120

Country

China

Facility Name

The First Affiliated Hospital of Guangxi Medical University

City

Nanning

State/Province

Guangxi

ZIP/Postal Code

530021

Country

China

Facility Name

Hainan General Hospital

City

Haikou

State/Province

Hainan

ZIP/Postal Code

570311

Country

China

Facility Name

Tangshan Gongren Hospital063000

City

Tangshan

State/Province

Hebei

ZIP/Postal Code

063000

Country

China

Facility Name

Tangshan Gongren Hospital

City

Tangshan

State/Province

Hebei

ZIP/Postal Code

063000

Country

China

Facility Name

Harbin Medical University

City

Harbin

State/Province

Heilongjiang

ZIP/Postal Code

150081

Country

China

Facility Name

The First Affiliated Hospital of Henan University of Science and Technology

City

Luoyang

State/Province

Henan

ZIP/Postal Code

471023

Country

China

Facility Name

Henan Provincial People's Hospital

City

Zhengzhou

State/Province

Henan

ZIP/Postal Code

450003

Country

China

Facility Name

The First People's Hospital of Changde

City

Changde

State/Province

Hunan

ZIP/Postal Code

415003

Country

China

Facility Name

Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University

City

Changsha

State/Province

Hunan

ZIP/Postal Code

410011

Country

China

Facility Name

The First Affiliated Hospital of South China University

City

Hengyang

State/Province

Hunan

ZIP/Postal Code

421001

Country

China

Facility Name

The Second Hospital University of South China

City

Hengyang

State/Province

Hunan

ZIP/Postal Code

421001

Country

China

Facility Name

The First People's Hospital of Huaihua

City

Huaihua

State/Province

Hunan

ZIP/Postal Code

418000

Country

China

Facility Name

The First People's Hospital of Yueyang

City

Yueyang

State/Province

Hunan

ZIP/Postal Code

414000

Country

China

Facility Name

The Affiliated Hospital of Inner Mongolia Medical University

City

Hohhot

State/Province

Inner Mongolia

ZIP/Postal Code

010050

Country

China

Facility Name

Jiangsu Province Hospital

City

Nanjing

State/Province

Jiangsu

ZIP/Postal Code

210029

Country

China

Facility Name

The Northern Jiangsu People's Hospital

City

Yangzhou

State/Province

Jiangsu

ZIP/Postal Code

225001

Country

China

Facility Name

The First Affiliated Hospital of Nanchang University

City

Nanchang

State/Province

Jiangxi

ZIP/Postal Code

330006

Country

China

Facility Name

The Third Affiliated Hospital of Nanchang University

City

Nanchang

State/Province

Jiangxi

ZIP/Postal Code

330008

Country

China

Facility Name

The Second Hospital of Jilin University

City

Changchun

State/Province

Jilin

ZIP/Postal Code

130000

Country

China

Facility Name

Jilin Province People's Hospital

City

Changchun

State/Province

Jilin

ZIP/Postal Code

130021

Country

China

Facility Name

The First Hospital of China Medical University

City

Shenyang

State/Province

Liaoning

ZIP/Postal Code

110122

Country

China

Facility Name

The Affiliated Hospital of Qingdao University

City

Qingdao

State/Province

Shandong

ZIP/Postal Code

266000

Country

China

Facility Name

Shanghai Xuhui District Central Hospital

City

Shanghai

State/Province

Shanghai

ZIP/Postal Code

200031

Country

China

Facility Name

Heping Hospital of Changzhi Medical College

City

Changzhi

State/Province

Shanxi

ZIP/Postal Code

046000

Country

China

Facility Name

Affiliated Heji Hospital of Changzhi Medical College

City

Changzhi

State/Province

Shanxi

ZIP/Postal Code

140400

Country

China

Facility Name

The First Affiliated Hospital of The Fourth Military Medical University

City

Xi'an

State/Province

Shanxi

ZIP/Postal Code

710032

Country

China

Facility Name

First People's Hospital of Yunnan Province

City

Kunming

State/Province

Yunnan

ZIP/Postal Code

650032

Country

China

Facility Name

The Second Affiliated Hospital of Zhejiang University School of Medicine

City

Hangzhou

State/Province

Zhejiang

ZIP/Postal Code

310009

Country

China

Facility Name

The Second Affiliated Hospital of Wenzhou Medical University

City

Wenzhou

State/Province

Zhejiang

ZIP/Postal Code

325000

Country

China

12. IPD Sharing Statement

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

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