Effect of Exenatide on 24h-UAER in Patients With Diabetic Nephropathy

Study Overview
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Brief Summary
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This is a multi-center, randomized, parallel study to evaluate effect of exenatide on 24h-UAER in patients with diabetic nephropathy. Screening will be made to select eligible participants before intervention. The trial will include 2-week run-in period of stable doses of glargine plus lispro insulin and 24-week treatment period. After the run-in period, patients were randomly assigned to one of two groups for antihyperglycaemic therapies for a total of 24-weeks: glargine plus exenatide and continued glargine plus lispro insulin. The treatment of exenatide will be initiated by 5ug bid, and uptitrated to 10 ug bid after 4 weeks and then maintained at 10ug bid until the completion of the study. Lispro insulin will be initially treated according to the insulin dosage of previous antihyperglycaemic therapies, and further titrated up at 4-week intervals until to reach the target fasting blood glucose (FPG).

Detailed Description
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Objective: To evaluate effect of exenatide on 24-UAER in patients with diabetic nephropathy Hypothesis: Compared with glargine plus lispro group, at 24 weeks, glargine plus exenatide group can: 1) take more significant reduction of 24h-UAER; 2) take more reduction of ACR; 3) take more weight loss, blood pressure reduction; 4) take lower hypoglycemia incidence and less insulin dosage. Primary endpoint： The proportion of reduction of 24h-UAER(urinary albumin excretion rates) Secondary endpoints： 24h-UAER at 24 weeks; the rate of urinary albumin to creatinine ratio(ACR) change at 24 weeks; HbA1c, FPG,PPG, weight , BP Treatment duration： 24weeks Patient/Sites： 90 patients / 3 sites Timeline (best case)： Planed duration of recruitment period: 6 month Planed date for first screening: 1 October 2015 Planed completion of the last subject: 1 March 2017 Planned completion of clinical trial report: 30 October 2017

Official Title
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Effect of Exenatide on 24h-UAER in Patients With Diabetic Nephropathy: a 24- Week Study

Conditions
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Diabetic Nephropathies

Intervention / Treatment
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* Drug: Exenatide
* Drug: Lispro


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study specific procedures. Diagnosed with type 2 diabetes with HbA1c ≥ 7.0% and ≤ 11.0% at screening (the result is valid for seven days). Men and women (non-pregnant and using a medically approved birth-control method) aged from 18 to 80 at screening. Body mass index (BMI) ≥18 and ≤35 kg/m2. Blood Pressure (BP) ≥ 90/60mmHg and ≤160/100mmHg. 6.24h urinary albumin excretion rate (UAE) >0.3g/24h after 3 months treatment with several hypoglycemic agents (sulphonylureas, metformin, AG-inhibitor, meglitinides or insulin), ACEI/ARB and salt restriction(the result is valid for seven days). 7.eGFR >30ml/min(the result is valid for seven days). Exclusion Criteria: 1．Women who are pregnant, intending to become pregnant during the study period, currently lactating females, or women of child-bearing potential not using highly effective, medically approved birth control methods. 2. Diagnosis or history of: Type 1 diabetes mellitus, diabetes resulting from pancreatic injury or secondary forms of diabetes, eg, acromegaly or Cushing's syndrome. Acute metabolic diabetic complications such as ketoacidosis or hyperosmolar coma within the past 6 months. 3. Previous treatment with any Thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP4) inhibitor or GLP-1 receptor agonists within the past 3 months. 4. History of hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to exenatide. 5. Blood amylase and/or lipase > 2 times the upper limit of the normal (ULN) laboratory range. 6. Hyperkalemia (K+>5.5mmol/L). 7. eGFR <30ml/min/1.73m2. 8. Patients without diabetic retinopathy. 9. Triglycerides (fasting) > 4.5 mmol/L (400 mg/dL) at screening or within 4 weeks prior to screening (by local laboratory). 10. Patients with clinically apparent liver disease characterized by ALT or AST > 3ULN confirmed on two consecutive measurements (by local laboratory) within 4 weeks prior to screening period. 11. Significant cardiovascular history within the past 3 months prior to screening defined as: myocardial infarction, coronary angioplasty or bypass graft(s), valvular disease or repair, unstable angina pectoris, transient ischemic attack, or cerebrovascular accident. 12. Congestive heart failure defined as New York Heart Association (NYHA) class III or IV. 13. History of chronic pancreatitis or idiopathic acute pancreatitis. 14. History of medullary thyroid carcinoma.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lispro<br>Patients are treated with Glargine (Lantus, Sanofi-Aventis), the dosage is initiated according to the previous treatment plan and weight of the patients, injection before bed time, titration following FPG <7.2mmol/L and >4.4mmol/L. | Drug: Lispro<br>* Lispro (Eli Lilly), the dosage is initiated according to the previous treatment plan and weight of the patients, distribute the dosage to 1:1:1 before 3 meals, titration following PPG <10.0mmol/L.<br>* Other names: Humalog;|
| Experimental: Exenatide<br>Patients are treated with Glargine (Lantus, Sanofi-Aventis), the dosage is initiated according to the previous treatment plan and weight of the patients, injection before bed time, titration following FPG <7.2mmol/L and >4.4mmol/L. | Drug: Exenatide<br>* Exenatide (Astrazeneca ) 5 μg(initial dose)/10ug(maintenance dose) Subcutaneous injection Bid<br>* Other names: Byetta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the percentage change of 24h-UAER(urinary albumin excretion rates) from baseline at Week 24 | the percentage change of 24h-UAER=(24h-UAERweek24 - 24h-UAERbaseline)/ 24h-UAERbaseline | from baseline at Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the percentage change of ACR | the percentage change of ACR=(ACRweek24 - ACRbaseline)/ ACRbaseline | from baseline at Week 24 | 
| Change in 24h-UAER | Change in 24h-UAER =24h-UAERweek24 - 24h-UAERbaseline | from baseline at Week 24 | 
| Change in HbA1c | Change in HbA1c=HbA1cweek24-HbA1cbaseline | from baseline at Week 24 | 
| Change in FPG | Change in FPG=FPGweek24-FPGbaseline | from baseline at Week 24 | 
| Change in Weight | Change in weight=Weightweek24-Weightbaseline | from baseline at Week 24 | 
| Change in Blood pressure | Change in blood pressure=SBPweek24-SBPbaseline | from baseline at Week 24 |