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

Diabetic Nephropathies Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02690883
• Other study ID #: ESR-14-10425
• Status: Completed
• Phase: Phase 4
• Start date: April 8, 2016
• Est. completion date: December 30, 2019

Study information

• Verified date: March 2020
• Source: Nanfang Hospital of Southern Medical University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 92
• Est. completion date: December 30, 2019
• Est. primary completion date: December 13, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures.

2. Diagnosed with type 2 diabetes with HbA1c = 7.0% and = 11.0% at screening (the result is valid for seven days).

3. Men and women (non-pregnant and using a medically approved birth-control method) aged from 18 to 80 at screening.

4. Body mass index (BMI) =18 and =35 kg/m2.

5. 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:

1. Type 1 diabetes mellitus, diabetes resulting from pancreatic injury or secondary forms of diabetes, eg, acromegaly or Cushing's syndrome.

2. 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.

Related Conditions & MeSH terms

• Diabetic Nephropathies
• Kidney Diseases

Intervention

Drug:
• Exenatide
Exenatide (Astrazeneca ) 5 µg(initial dose)/10ug(maintenance dose) Subcutaneous injection Bid
• Lispro
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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Nanfang Hospital of Southern Medical University

References & Publications (16)

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de Zeeuw D, Parving HH, Henning RH. Microalbuminuria as an early marker for cardiovascular disease. J Am Soc Nephrol. 2006 Aug;17(8):2100-5. Epub 2006 Jul 6. — View Citation

Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86. — View Citation

Filippatos TD, Elisaf MS. Effects of glucagon-like peptide-1 receptor agonists on renal function. World J Diabetes. 2013 Oct 15;4(5):190-201. doi: 10.4239/wjd.v4.i5.190. Review. — View Citation

Imamura S, Hirai K, Hirai A. The glucagon-like peptide-1 receptor agonist, liraglutide, attenuates the progression of overt diabetic nephropathy in type 2 diabetic patients. Tohoku J Exp Med. 2013 Sep;231(1):57-61. — View Citation

KDOQI. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007 Feb;49(2 Suppl 2):S12-154. — View Citation

Kobori H, Mori H, Masaki T, Nishiyama A. Angiotensin II blockade and renal protection. Curr Pharm Des. 2013;19(17):3033-42. Review. — View Citation

Lai X, Zhang AH, Chen SY, He L, Su CY, Fan MH, Wang T. Outcomes of stage 1-5 chronic kidney disease in Mainland China. Ren Fail. 2014 May;36(4):520-5. doi: 10.3109/0886022X.2013.875859. Epub 2014 Jan 23. — View Citation

Lim AKh. Diabetic nephropathy - complications and treatment. Int J Nephrol Renovasc Dis. 2014 Oct 15;7:361-81. doi: 10.2147/IJNRD.S40172. eCollection 2014. Review. — View Citation

Lu B, Song X, Dong X, Yang Y, Zhang Z, Wen J, Li Y, Zhou L, Zhao N, Zhu X, Hu R. High prevalence of chronic kidney disease in population-based patients diagnosed with type 2 diabetes in downtown Shanghai. J Diabetes Complications. 2008 Mar-Apr;22(2):96-103. doi: 10.1016/j.jdiacomp.2007.08.001. — View Citation

Park CW, Kim HW, Ko SH, Lim JH, Ryu GR, Chung HW, Han SW, Shin SJ, Bang BK, Breyer MD, Chang YS. Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice. J Am Soc Nephrol. 2007 Apr;18(4):1227-38. Epub 2007 Mar 14. — View Citation

Tomino Y. Pathogenesis and treatment of chronic kidney disease: a review of our recent basic and clinical data. Kidney Blood Press Res. 2014;39(5):450-89. doi: 10.1159/000368458. Epub 2014 Nov 30. Review. — View Citation

Xu WW, Guan MP, Zheng ZJ, Gao F, Zeng YM, Qin Y, Xue YM. Exendin-4 alleviates high glucose-induced rat mesangial cell dysfunction through the AMPK pathway. Cell Physiol Biochem. 2014;33(2):423-32. doi: 10.1159/000358623. Epub 2014 Feb 11. — View Citation

Yanagisawa K, Ashihara J, Obara S, Wada N, Takeuchi M, Nishino Y, Maeda S, Ishibashi Y, Yamagishi S. Switching to multiple daily injection therapy with glulisine improves glycaemic control, vascular damage and treatment satisfaction in basal insulin glargine-injected diabetic patients. Diabetes Metab Res Rev. 2014 Nov;30(8):693-700. doi: 10.1002/dmrr.2537. — View Citation

Zhang H, Zhang X, Hu C, Lu W. Exenatide reduces urinary transforming growth factor-ß1 and type IV collagen excretion in patients with type 2 diabetes and microalbuminuria. Kidney Blood Press Res. 2012;35(6):483-8. doi: 10.1159/000337929. Epub 2012 Jun 8. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

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