A Study of Efficacy and Safety of Supaglutide in Type 2 Diabetes Patients On Metformin Treatment

Study Overview
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Brief Summary
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This is a study to evaluate the efficacy and safety of Supaglutide injection in the treatment of type 2 diabetes patients with poor glycemic control after metformin treatment. This trial includes dosage determination (Phase IIb) and efficacy confirmation stage(Phase III ). The primary outcome of the phase IIb period is to preliminarily evaluate the efficacy and safety of Supaglutide combined with metformin and to provide the recommended dosage for the Phase 3 period after 12-week treatment. The primary outcome of the Phase III period is to evaluate the efficacy and safety of Supaglutide combined with metformin treatment after 24-week, double-blind treatment. The secondary outcome is to evaluate the efficacy and safety of Supaglutide combined with metformin during the 24-week, double-blinded plus 28-week, open-label treatment period.

Detailed Description
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This trial includes a 2-week screening period, a 4-week metformin titration and dose-stabilization period, a 4-week induction period, a 24-week double-blind treatment period and a 28-week open-label treatment period, followed by a 4-week follow-up period and a follow-up visit. We calculated that the sample size would need to be 632, including 120 subjects in the period of Phase IIb and 512 subjects in the period of Phase III. During the phase IIb period, subjects were randomly assigned to once-weekly subcutaneously injected Supaglutide 1mg plus metformin, 3mg plus metformin and placebo plus metformin at a ratio of 1:1:1. When the number of participants who have completed the 12-week follow up reached 120, interim analyses will be performed and the results will be evaluated by Independent Data Monitoring Committee experts to determine the recommended phase 3 dosage. During the phase III stage, subjects were randomly assigned 1:1 to the recommended phase 3 dosage + metformin group and the placebo + metformin group.

Official Title
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Efficacy and Safety of Once-weekly Supaglutide Versus Placebo in Patients With Type 2 Diabetes Suboptimally Controlled on Metformin: A Multicenter, Randomized, Double-blind, Placebo-controlled Clinical Trial

Conditions
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Type2 Diabetes

Intervention / Treatment
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* Biological: supaglutide injection+metformin
* Other: placebo+metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged from 18 to 75; Clinical diagnosed of Type 2 diabetes for at least 8 weeks ，receive metformin single treatment ； During screening, HbA1c: 7.5% ≤ HbA1c ≤ 11% ，and before randomization 7.5% ≤ HbA1c ≤ 10.5%; During screening and before randomization: FPG< 13.9 mmol/L； 5.18.5 kg/m2 ≤ BMI ≤ 35 kg/m2; 6. without birth plan and voluntarily take effective contraceptive measures; 7. fully understood the study, signed the informed consent； Exclusion Criteria: Diabetes other than Type 2; Any dipeptidyl peptidase IV and / or glucagon-like peptide-1 （GLP-1）analogues were used within 3 months before screening; Continuous use of insulin for more than 14 days in the previous year; C-Peptide <0.3 nmol/L; Diabetic ketoacidosis, diabetic lactic acidosis or hyperosmolar non ketonic diabetic coma occurred within 6 months before screening; Unstable proliferative retinopathy or macular lesion, severe diabetic neuropathy, intermittent claudication or diabetic foot occurred within 6 months before screening; Severe hypoglycemia occurred within 6 months before screening Severe trauma infection or operation within one month before screening; Blood donation or massive blood loss or transfusion within 3 months ; Suspected active infection ; Growth hormone therapy was performed within 6 months before screening; Patients having received corticosteroid continuous ≥ 7 days through within 2 months ; use any drugs or surgery with weight control effect within 2 months; weight change of more than 5% within 3 months; mean systolic pressure (SBP) ≥ 160mmhg and / or diastolic pressure （DBP） ≥ 90 mmHg at screening, or new/changed antihypertensive drugs or adjusted dosage of antihypertensive drugs within 4 weeks before screening or before induction period with a history of severe cardiovascular disease, high risk of stroke/stroke within 6 months before screening; with a history of acute or chronic pancreatitis, symptomatic gallbladder , pancreatic injury and other risk factors for pancreatitis, or with blood amylase and/or blood lipase ≥1.5 times the upper limit of normal (ULN) at the time of screening or before randomization; Calcitonin level ≥50 ng/L (pg/mL) during screening; with a history of medullary thyroid cancer, multiple endocrine neoplasm (Men) 2A or 2B syndrome, or related family history; with clinically significant abnormal gastric emptying , severe chronic gastrointestinal diseases , long-term use of drugs that have a direct impact on gastrointestinal peristalsis , or having undergone gastrointestinal surgery within 6 months before screening, are not suitable to participate in this clinical study according to the evaluation of the researchers; suffering from hematological diseases or any disease causing hemolysis or erythrocyte instability ; Uncontrolled hyperthyroidism or hypothyroidism; with hemoglobinopathy that may affect the determination of HbA1c levels; HBsAg, Hepatitis C antibody, HIV-Ab, Treponema pallidum antibody or Corona Virus Disease 2019 nucleic acid tested positive; serious mental illness; drinking more than 14 standard units weekly within 6 months before screening ; a history of organ transplantation or other acquired or congenital immune system diseases; allergic to the active ingredients (GLP-1 and GLP-1 analogues) of the study drug; clear contraindications for the use of metformin; clear contraindications for Empagliflozin； Any of the following conditions: the pacemaker was installed when screened; no pacemaker was installed, but 12 lead ECG showed degree II or III atrioventricular block, long QT syndrome or QTc interval ≥ 450ms ; Patients with New York Heart Function Classification III or IV; Or other abnormal cardiac function with clinical significance that is not suitable for clinical research judged by researchers; acute or chronic hepatitis, or whose laboratory examination indexes meet one of the following criteria at the time of screening or before randomization : alanine aminotransferase (ALT) level ≥ 2.5 fold ULN, aspartate aminotransferase (AST) ≥ 2.5 fold ULN, fasting triglyceride (TG) > 5.7 mmol/L or 500 mg/dl; the glomerular filtration rate (EGFR) < 60 ml/min/1.73 square meters was calculated by CKD-EPI (epi - (SCR)) formula; participated in clinical trials of other drugs or devices within 3 months before screening; Medication compliance in the metformin dosage stable period was < 80% or > 120%; Supaglutide placebo injection compliance during the induction period was <75% or>125%, or metformin compliance <80% or >120%; Any other situation that researchers think may affect the patients' informed consent or compliance with the trial protocol;

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
Interventional Model Description: This clinical trial includes dosage determination (Phase IIb) and efficacy confirmation stage(Phase III ). During the phase IIb, subjects were randomly assigned to Supaglutide 1mg + metformin, Supaglutide 3mg + metformin and placebo + metformin according to a 1:1:1 ratio. When 120 subjects complete the 12 weeks of follow-up, Interim analysis will be performed and the results be evaluated by IDMC to confirm the RP3D dose. And then during the phase III, subjects were randomly assigned to Supaglutide RP3D + metformin, placebo + metformin group according to a 1:1 ratio.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: supaglutide RP3D dose+metformin<br>Supaglutide Subcutaneous injection once a week for 52weeks,combined with metformin | Biological: supaglutide injection+metformin<br>* supaglutide subcutaneous injection under RP3D dose combined with metformin treatment<br>|
| Placebo Comparator: placebo+metformin<br>Placebo Subcutaneous injection once a week for 52weeks,,combined with metformin | Other: placebo+metformin<br>* placebo subcutaneous injection combined with metformin treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c | The change in mean HbA1c concentrations (%)from baseline with Supaglutide versus placebo | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| fasting plasma glucose | Changes in fasting plasma glucose (mmol/L) relative to baseline | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| HbA1c<7.0% and <6.5% | The proportion of participants who achieved HbA1c target (HbA1c<7.0% and <6.5% Patient percentage) | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| Fasting insulin | Fasting insulin changes（pmol/L) relative to baseline | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| fasting C-peptide | Fasting C-peptide changes (nmol/L) relative to baseline | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| fasting glucagon | fasting glucagon changes (pg/ml) relative to baseline | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| Area under the curve of blood glucose | Area under the curve of blood glucose (AUC0-120min,mmol/L) during the multi-maneuvering target tracking | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| Area under the curve of insulin | Area under the curve of insulin (AUC0-120min,pmol/L) during the MMTT | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| Area under the curve of C-peptide | Area under the curve of C-peptide (AUC0-120min,nmol/L) during the MMTT | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| Total cholesterol | Changes in total cholesterol (mmol/L) relative to baseline | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| low density lipoprotein | Changes in low density lipoprotein (mmol/L) relative to baseline | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| High density lipoprotein | Changes in high density lipoprotein (mmol/L) relative to baseline | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| triglyceride | Changes in triglyceride(mmol/L) relative to baseline | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| weight | Weight change from baseline(kg) | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III | 
| salvage treatment | Percentage of subjects receiving salvage treatment(%) | 12 weeks for phase IIb; 24weeks and 52 weeks for phase III |