Study to Assess the Efficacy and Safety of Liraglutide in the Treatment of Type 2 Diabetes

Study Overview
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Brief Summary
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Liraglutide injection is a glucagon-like peptide-1 (GLP-1) analogue that activates the cyclic adenosine monophosphate (cAMP) and mitogen-activated protein kinase (MAPK) pathway by binding to the GLP-1 receptor (GLP-1R),thus,it has physiological effects such as glucose-dependent insulin synthesis and secretion, inhibition of β-cell apoptosis, promotion of β-cell proliferation and regeneration, inhibition of glucagon secretion, reduction of food intake, delay of gastric emptying, enhancement of glucose utilization in peripheral tissues and reduction of glycogen output. Liraglutide injection,developed and marketed as Victoza® by Novo Nordisk,is indicated for the treatment of patients with type 2 diabetes and was approved by the U.S. Food and Drug Administration in 2010.This 26-week trial compares the effectivity on glycaemic control,safety and immunogenicity of liraglutide injection and Victoza® in patients with type 2 diabetes inadequately controlled by oral metformin alone.

Official Title
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A Phase III,Randomized,Parallel,Open-label,Multicenter Trial to Compare the Efficacy and Safety of Liraglutide and Victoza® in Patients With Type 2 Diabetes Inadequately Controlled by Oral Metformin Alone

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Victoza®.
* Drug: Metformin Hydrochloride
* Drug: TQZ2451


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed as type 2 diabetes. Stably daily dose of metformin alone[between the dose of 1500mg and 2000mg inclusive] for at least 12 weeks prior to day of screening . HbA1c(glycosylated haemoglobin) of 7-11%(both inclusive). Body mass index (BMI) of 18.5-45 kg/m2(both inclusive). The patient must give informed consent to the study before the trial and voluntarily sign the informed consent form. The patient can communicate well with the researcher and complete the study in accordance with the research regulations. Exclusion Criteria: Diagnosed as type 1 or other types of diabetes. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonist, dipeptidyl peptidase-4 (DPP-4) inhibitor and insulin treatment within 3 months before screening.[short term (cumulative use ≤7 days) insulin therapy due to intermittent disease is excluded] Treatment with systemic glucocorticoid therapy within 3 months before screening[topical medication or inhaled product is excluded] . Treatment with Chinese medicine preparations having hypoglycemic effects within 1 month before screening. Patients with recurrent severe or unconscious hypoglycemia within 3 months before screening. Patients with acute metabolic complications (ketoacidosis, lactic acidosis or hypertonic coma, etc.) within 6 months before screening. History of chronic pancreatitis or idiopathic acute pancreatitis, or suffering from acute or chronic pancreatitis during screening, or blood amylase ≥ 3 times of the upper limit of normal value, or triglycerides ≥ 8.0 mmol / L. Fasting blood-glucose(FBG)≥15.0 mmol / L on the day of screening. Personal or family history of medullary thyroid carcinoma (MTC) or type 2 multiple endocrine adenoma (MEN2). Patients with obvious liver and kidney dysfunction (alanine aminotransferase (ALT)> 2.5 × upper normal value (ULN), aspartate aminotransferase (AST)> 2.5 ULN, glomerular filtration rate <60 Milliliter(mL) / min / 1.73m2 Hemoglobin <lower limit of normal value. Hyperthyroidism is being treated or the dosage of hypothyroidism is not stable within 6 months. Uncontrolled or poorly treated hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg). Patients with decompensated heart failure (NYHA grades III and IV), unstable angina, stroke or transient ischemic attack, myocardial infarction, severe arrhythmia, cardiac surgery or vascular reconstruction performed (including coronary artery bypass grafting or percutaneous coronary intervention) within 6 months before screening. Proliferative retinopathy or macular disease (macular edema) that requires urgent treatment. Malignant tumors (except basal cell carcinoma or phosphorous cell skin cancer) diagnosed within the past 5 years. Patients with severe chronic gastrointestinal disease (such as active peptic ulcer) and severe infections. People who are allergic to any of the ingredients in metformin, liraglutide injection and Victoza®. Participated in any other clinical trials within 3 months before screening. Pregnant women, lactating women and women of reproductive age who did not take appropriate contraception (sterilization, intrauterine devices, oral contraceptives or barrier contraception) during the trial. History of psychotropic substance abuse, alcohol abuse or drug addiction. Patients judged as unsuitable participants of the trial by researchers or with poor compliance. According to the investigators' judgment, there are seriously concomitant diseases endanger the safety of the patient or prevent the patient from completing the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: TQZ2451+metformin hydrochloride<br>TQZ2451 injection (0.6mg qd from baseline to week 1;1.2mg qd during week 2;1.8mg qd from week 3 to week 26) + metformin hydrochloride sustained-release tablets (1500-2000mg qd) | Drug: Metformin Hydrochloride<br>* Patients who were receiving metformin prior to study will continue to receive it during the study.<br>Drug: TQZ2451<br>* Patients will receive TQZ2451.Both products will be provided as pen-injector.<br>|
| Active Comparator: Victoza®+metformin hydrochloride<br>Victoza® (0.6mg qd from baseline to week 1;1.2mg qd during week 2;1.8mg qd from week 3 to week 26) + metformin hydrochloride sustained-release tablets (1500-2000mg qd) | Drug: Victoza®.<br>* Patients will receive Victoza®. Both products will be provided as pen-injector.<br>Drug: Metformin Hydrochloride<br>* Patients who were receiving metformin prior to study will continue to receive it during the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| glycated hemoglobin (HbA1c) | Changes in glycated hemoglobin (HbA1c) relative to baseline. | week 0,week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body weight | Changes in body weight relative to baseline. | week 0,week 26 | 
| Proportion of achieving HbA1c target (<7.0% or ≤6.5%) |  | week 0,week 26 | 
| HbA1c change from baseline |  | week 0,week 14 | 
| Changes in fasting venous blood glucose (FPG). |  | week 0,week 14,week 26 | 
| Changes in 2h-Postprandial Blood Glucose(2h-PBG). |  | week 0,week 14,week 26 | 
| Changes in fasting insulin. |  | week 0,week 14,week 26 | 
| Changes in fasting C peptide. |  | week 0,week 14,week 26 | 
| Changes in systolic blood pressure. |  | week 0,week 14,week 26 | 
| Changes in diastolic blood pressure. |  | week 0,week 14,week 26 | 
| Number of adverse events and serious adverse events during exposure to trail product. |  | week 0-26 | 
| Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic episodes during exposure to trail product. |  | week 0-26 | 
| Positive rate of liraglutide anti-drug antibody(ADA). |  | week 0-26 | 
| Percentage of participants with clinically significant change from baseline in vital signs. |  | week 0-26 | 
| Percentage of participants with clinically significant change from baseline in laboratory parameters. |  | week 0-26 |