Extended Release Exenatide Versus Placebo In Diabetic Patients With Type 4 Cardiorenal Syndrome

Study Overview
=================
Brief Summary
-----------------
Among adult individuals with type 2 diabetes mellitus and at risk for heart failure with impaired relaxation of the heart mildly reduced kidney filtration function (Type 4 cardiorenal syndrome) this trial will evaluate the quantitative impact of 38 weeks of treatment with exenatide extended-release injections versus placebo. on a cardiac biomarker blood test score, cardiac fibrosis seen on magnetic resonance scanning, cardiac strain identified by ultrasonography and strain rate imaging, and a kidney urine biomarker score.

Detailed Description
-----------------
Primary Aim Among adult individuals with type 2 diabetes mellitus (T2DM) and at risk for diastolic heart failure (DHF) and mildly reduced renal filtration function (Type 4 cardiorenal syndrome), to evaluate the quantitative impact on the MISS (myocardial injury summary score) cardiac biomarker score, cardiac fibrosis by MRI, cardiac strain by ultrasonography and strain rate imaging, and KISS (kidney injury summary score) kidney biomarker score after 38 weeks of treatment with exenatide extended-release or placebo. Secondary Aim To evaluate the inter-relationships between demographic, clinical, and biochemical variables (MISS score, KISS score) and of progressive cardiac fibrosis as assessed by MRI, strain-rate imaging, and in adult individuals with T2DM and at risk for DHF (Type 4 cardiorenal syndrome).

Official Title
-----------------
MB001-067 A PROSPECTIVE, DOUBLE BLIND, PLACEBO CONTROLLED, PARALLEL GROUP, RANDOMIZED TRIAL OF EXTENDED RELEASE EXENATIDE VERSUS PLACEBO (COHORT A) AND A PROSPECTIVE, SINGLE GROUP, OPEN-LABEL, BLINDED OUTCOME TRIAL OF EXTENDED RELEASE EXENATIDE (COHORT B) IN DIABETIC PATIENTS WITH TYPE 4 CARDIORENAL SYNDROME (EXTEND-CRS TRIAL) AMENDMENT 3

Conditions
-----------------
Type 2 Diabetes Mellitus, Chronic Kidney Disease, Left Ventricular Diastolic Dysfunction

Intervention / Treatment
-----------------
* Drug: BYDUREON
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 Type 2 diabetes mellitus with hemoglobin A1C 6.6-9.9% with or without the use of insulin Estimated glomerular filtration rate (eGFR) between 50 and 90 ml/min/1.73 m2 Exclusion Criteria: Allergy or intolerance to gadolinium Implanted cardiac pacemaker, defibrillator, loop recorder, or other implanted metallic device Any other metallic implanted device that is a contra-indication to MRI scanning eGFR < 50 ml/min/1.73 m2 eGFR > 90 ml/min/1.73 m2 Patient has ever been treated with an approved or investigational GLP-1 receptor agonist e.g. BYETTA™ (exenatide), BYDUREON™ (Exenatide extended-release), VICTOZA™ (liraglutide), or taspoglutide Patient is enrolled in another experimental protocol which involves the use of an investigational drug or device, or an intervention that would interfere with the conduct of the trial. Disorders of iron metabolism Collagen vascular diseases Myocardial infarction Use of DDP4 inhibitors, and PPAR gamma agonists Pregnancy or planned pregnancy during the trial period Hemoglobin A1C of ≥ 10.0% or <6.6% Fasting glucose ≥ 260 mg/dl Clinically significant abnormal baseline laboratories Morbid obesity or body girth that prohibits the ability to undergo echocardiography or MRI scanning with high-quality image results Renal transplantation Severe gastrointestinal, liver, or neurodegenerative disease Decompensated liver cirrhosis (Child-Pugh score >7) New York Heart Association Class III or IV heart failure Patients have alanine aminotransaminase (ALT) greater than 5 times the upper limit of the reference range. Prior pancreatitis Personal or family history of medullary thyroid adenoma or carcinoma (MTC) Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). History of severe hypoglycemia Prior bariatric surgery

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exenatide-extended release<br>Exenatide-extended release (BYDUREON™) 2 mg subcutaneously once per week x 38 weeks | Drug: BYDUREON<br>* Exenatide-extended release, Cohorts A and B<br>|
| Placebo Comparator: Placebo<br>Matching placebo subcutaneously once per week x 38 weeks | Drug: Placebo<br>* Cohort A only<br>* Other names: Matching placebo subcutaneous injection;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Galectin-3 | Mean change in plasma galectin-3 (pg/ml) | 38 weeks | 
| ST2 | Mean change in plasma ST2 (pg/ml) | 38 weeks | 
| NGAL | Mean change in urine neutrophil gelatinase associated lipocalin (NGAL):creatinine (Cr) ratio | 38 weeks | 
| KIM-1 | Mean change in urine kidney injury molecule-1 (KIM-1):Cr ratio | 38 weeks | 
| L-FABP | Mean change in urine L-type fatty acid binding protein:Cr ratio | 38 weeks | 
| IL-18 | Mean change in urine interleukin-18:Cr ratio | 38 weeks | 
| Alpha GST | Mean change in urine alpha glutathione S-transferase (αGST):Cr ratio | 38 weeks | 
| Troponin I | Mean change in plasma ultrasensitive troponin I (pg/ml) | 38 weeks | 
| Pi GST | Mean change in pi glutathione S-transferase (piGST):Cr ratio | 38 weeks | 
| NAG | Mean change in urine N-acetyl-β-D-glucosaminidase (NAG):Cr ratio | 38 weeks | 
| Cystatin-C | Mean paired change in urine cystatin-C:Cr ratio (uCysC:Cr) | 38 weeks | 
| BNP | Mean change in plasma B-type natriuretic peptide BNP (pg/ml) | 38 weeks | 
| ACR | Mean change in urine albumin:Cr ratio (ACR) | 38 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
diabetes mellitus, chronic kidney disease, diastolic function, cardiac fibrosis, cardiac strain, cardiac biomarker, renal biomarker