Diabetes Mellitus, Type 2, Non-alcoholic Fatty Liver Disease
Conditions
Keywords
Diabetes, Non-alcoholic Fatty Liver Disease
Brief summary
The purpose of this study is to evaluate whether exenatide is superior to insulin glargine (after 24 weeks) in reducing liver fat content (by MRS) in patients with newly diagnosed type 2 diabetes mellitus and concomitant non-alcoholic fatty-liver disease(NAFLD).
Detailed description
This is a randomized, open-label, parallel-group, active controlled, multi-center clinical trial to investigate whether exenatide is superior to insulin glargine in reducing liver fat content in patients with newly diagnosed type 2 diabetes mellitus and concomitant NAFLD.Patients with type 2 diabetes and concomitant NAFLD from 18-70 years of age, with inadequate glycaemic control defined as 7% ≤ HbA1c ≤ 10% and BMI≥24kg/ m2 at the time of screening. Patients should be on diet and exercise but drug treatment naive, no use of any glucagon-like peptide-1(GLP-1) analogues or insulin within 3 months before enrolment.Patients will have an screening period 2 weeks, and a 24-week open label treatment period. All demographic data variables collected by descriptive analysis tests are used. Qualitative variables use absolute frequency and percentage, and numeric variables use average, mean, median, standard deviation, maximum, minimum, quartiles, etc. Unless specifically stated, statistical significance will be defined as P\<0.05 in the whole analysis procedure.For the primary endpoint of this study, superiority test will be applied to the quantitative data of these two groups. For secondary and exploratory efficacy variables, difference test will be used to analyse repeated measurement data from two groups. For essential Safety parameters, difference test will be used to analyse the differences between two groups.The analysis of all primary and secondary endpoints of efficacy and safety must be based on the Full Analysis Set (FAS). As supporting evidence, the analysis of primary endpoint variables must also comply with the Pre-protocol (PPS) Analysis.
Interventions
DRUGExenatide
The starting dose of exenatide is 5 ug bid, subcutaneously, for 4 weeks, followed by 10 ug bid, subcutaneously, for 20 weeks. If hypoglycaemia (blood glucose\<2.9 mmol/l or \< 3.9 mmol/l at least 2 times) or serious intolerance occurs, the dose will be adjusted to 5 ug bid, subcutaneously.
DRUGinsulin glargine
The starting dose of insulin glargine will depend upon the HbA1c level at screening(HbA1c \<8% use 0.1 -0.2 U/kg per day;HbA1c \>8% use 0.2 -0.3 U/kg per day). Dose adjustment protocol for insulin glargine (at least 3 determinations of fasting blood glucose per week): fasting blood glucose(FBG) \> 180 mg/dL(10 mmol/l): add 4 U; FBG 140-180 mg/dL(7.8-10 mmol/l): add 2 U; FBG 126-139 mg/dL(7.0-7.8 mmol/l): add 1 U. If hypoglycemia, reduce insulin glargine by: blood glucose \<70mg/dl（3.9mmol/l）: 10%-20%; blood glucose \<40mg/dl（2.2mmol/l）: 20%-40%.
Sponsors
Huadong Hospital
Shanghai Minhang Central Hospital
Shanghai 6th People's Hospital
Shanghai Changzheng Hospital
Fudan University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, 18 ≤ age ≤ 70 years old. * Newly diagnosed type 2 diabetes mellitus (WHO Diagnostic criteria for diabetes mellitus, 1999). * Patients with NAFLD, MRS measurement of liver fat content\> 10%. * 7% ≤ HbA1c ≤ 10% * No heavy drinking history within the last 5 years (alcohol intake: male \< 20 g/d, female \< 10 g/d) * HBsAg (-), hepatitis C virus antibody (HCV-Ab) (-) * BMI ≥ 24 kg/m2;
Exclusion criteria
* Pregnancy, lactation, intended pregnancy, or failure to take adequate contraceptive measures taken (contraception measures including sterilization, intrauterine device, oral contraceptives, and persistent use of condoms). * Type 1 diabetes mellitus, gestational diabetes mellitus or other special types of diabetes. * Liver and renal dysfunction (ALT or aspartate aminotransferase(AST) is 2.5 times higher than the upper limit of normal, or total bilirubin is 1.5 times higher than the upper limit of normal, or Cr ≥ 115 μmol/L). * increased amylase (blood amylase is 2.5 times higher than the upper limit of normal) or presence of gastrointestinal disease. * Use of drugs that may affect liver fat content within one month before or during the trial period, such as glucocorticoids, thyroid hormone, etc. * Use of GLP-1 receptor agonist, dipeptidyl peptidase -4 (DPP-4) inhibitors or insulin within 3 months before enrolment * Presence of serious dyslipidemia or other endocrine diseases (hypothyroidism, hypothalamic-pituitary dysfunction, etc). * Fatty liver caused by viral hepatitis, drug, alcohol, Wilson disease or total parenteral nutrition. * Presence of liver cancer, infection, biliary tract disease or recently increased liver enzyme due to medication. * Participation in strenuous exercise or administration of any drugs that affect glucose metabolism. * History of pancreatitis, alcohol abuse, metal disorders or history of allergy to investigational drug. * Congestive heart failure defined as New York Heart Association (NYHA) class III or IV, unstable angina or myocardial infarction in recent 6 months. * Any situation that may affect the implementation or results of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in liver fat content（%） measured by MRS | baseline and 24 weeks | Change in liver fat content（%） measured by MRS |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in intra-abdominal visceral fat content (cm2), abdominal subcutaneous fat content (cm2), and ratio between intra-abdominal visceral fat and subcutaneous fat area by MRI | baseline and 24 weeks | Change in intra-abdominal visceral fat content (cm2), abdominal subcutaneous fat content (cm2), and ratio between intra-abdominal visceral fat and subcutaneous fat area by MRI |
| Change in glucose metabolism (fasting blood glucose, postprandial plasma glucose, HbA1c) | baseline and 24 weeks | Change in glucose metabolism (fasting blood glucose, postprandial plasma glucose, HbA1c) |
| Change in blood lipid profile (total cholesterol, triglyceride, HDL, LDL) | baseline and 24 weeks | Change in blood lipid profile (total cholesterol, triglyceride, HDL, LDL) |
| Change in body weight,waist circumference and hip circumference | baseline and 24 weeks | Change in body weight,waist circumference and hip circumference |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in cardiac function measured by echocardiography | baseline and 24 weeks | Change in cardiac function measured by echocardiography |
| Change in β-cell function (fasting C-peptide, 2-hour postprandial C-peptide) | baseline and 24 weeks | Change in β-cell function (fasting C-peptide, 2-hour postprandial C-peptide) |
| Change in liver enzymes and laboratory parameters (hematology, biochemical tests) | baseline and 24 weeks | Change in liver enzymes and laboratory parameters (hematology, biochemical tests) |
| Incidence of hypoglycaemia events | up to 24 weeks | Incidence of hypoglycaemia events |
| Incidence of adverse events（AEs）and Severe adverse events(SAEs) | up to 24 weeks | Incidence of adverse events（AEs）and Severe adverse events(SAEs) |
Countries
China
Outcome results
None listed