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

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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus; Chronic Kidney Disease; Left Ventricular Diastolic Dysfunction
• Intervention / Treatment: Drug: BYDUREON; Drug: Placebo

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).

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75226
      • Baylor Scott and White Research Institute- Baylor Heart and Vascular Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cystatin-C	Mean paired change in urine cystatin-C:Cr ratio (uCysC:Cr)	38 weeks
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Galectin-3	Mean paired change in plasma galectin-3 (ng/ml)	38 weeks
ST2	Mean paired change in plasma ST2 (ng/ml)	38 weeks
NephroCheck	Mean paired change in urine NephroCheck (Tissue Inhibitor of MetalloProteinases-2 x Insulin-like Growth Factor Binding Protein-7) unitless	38 weeks
NGAL	Mean paired change in urine neutrophil gelatinase associated lipocalin (NGAL):creatinine (Cr) ratio	38 weeks
KIM-1	Mean paired change in urine kidney injury molecule-1 (KIM-1):Cr ratio	38 weeks
L-FABP	Mean paired change in urine L-type fatty acid binding protein:Cr ratio	38 weeks
IL-18	Mean paired change in urine interleukin-18:Cr ratio	38 weeks
Alpha GST	Mean paired change in urine alpha glutathione S-transferase (αGST):Cr ratio	38 weeks
Pi GST	Mean paired change in pi glutathione S-transferase (piGST):Cr ratio	38 weeks
NAG	Mean paired 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
ACR	Mean paired change in urine albumin:Cr ratio (ACR)	38 weeks
LVMI	Mean paired change in ventricular mass index (LVMI) (g/m2) by cMRI	38 weeks
Radial Strain	Mean paired change in radial strain by strain rate echocardiography (unitless)	38 weeks
eGFR	Mean paired change in eGFR (ml/kg/1.72 m2)	38 weeks
Glycohemoglobin	Mean paired change in blood glycohemoglobin (hemoglobin A1C) %	16 weeks
Fasting glucose	Mean paired change in fasting glucose (mg/dl)	16 weeks
Troponin I	Mean paired change in plasma ultrasensitive troponin I (ng/L)	38 weeks
BNP	Mean paired change in plasma B-type natriuretic peptide BNP (pg/ml)	38 weeks

Collaborators and Investigators

• Sponsor: Baylor Research Institute
• Investigators: Study Chair: Peter A McCullough, MD, MPH, Baylor Research Institute

Publications and helpful links

General Publications

• Chinnaiyan KM, Alexander D, Maddens M, McCullough PA. Curriculum in cardiology: integrated diagnosis and management of diastolic heart failure. Am Heart J. 2007 Feb;153(2):189-200. doi: 10.1016/j.ahj.2006.10.022.
• Davidson MH. Cardiovascular effects of glucagonlike peptide-1 agonists. Am J Cardiol. 2011 Aug 2;108(3 Suppl):33B-41B. doi: 10.1016/j.amjcard.2011.03.046.
• Levine GD, Rosai J, Bearman RM, Polliack A. The fine structure of thymoma, with emphasis on its differential diagnosis. A study of ten cases. Am J Pathol. 1975 Oct;81(1):49-86.
• Best JH, Hoogwerf BJ, Herman WH, Pelletier EM, Smith DB, Wenten M, Hussein MA. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database. Diabetes Care. 2011 Jan;34(1):90-5. doi: 10.2337/dc10-1393. Epub 2010 Oct 7.
• McCullough PA, Olobatoke A, Vanhecke TE. Galectin-3: a novel blood test for the evaluation and management of patients with heart failure. Rev Cardiovasc Med. 2011;12(4):200-10. doi: 10.3909/ricm0624. Erratum In: Rev Cardiovasc Med. 2012;13(1):e52.
• Wang YC, Yu CC, Chiu FC, Tsai CT, Lai LP, Hwang JJ, Lin JL. Soluble ST2 as a biomarker for detecting stable heart failure with a normal ejection fraction in hypertensive patients. J Card Fail. 2013 Mar;19(3):163-8. doi: 10.1016/j.cardfail.2013.01.010.
• Jellis C, Martin J, Narula J, Marwick TH. Assessment of nonischemic myocardial fibrosis. J Am Coll Cardiol. 2010 Jul 6;56(2):89-97. doi: 10.1016/j.jacc.2010.02.047.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: September 12, 2014
• First Submitted That Met QC Criteria: September 25, 2014
• First Posted (Estimate): September 29, 2014

Study Record Updates

• Last Update Posted (Actual): May 17, 2023
• Last Update Submitted That Met QC Criteria: April 24, 2023
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: chronic kidney disease; diabetes mellitus; diastolic function; cardiac fibrosis; cardiac biomarker; renal biomarker; cardiac strain
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Endocrine System Diseases; Renal Insufficiency; Heart Failure; Diabetes Mellitus; Diabetes Mellitus, Type 2; Kidney Diseases; Renal Insufficiency, Chronic; Cardio-Renal Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Exenatide
• Other Study ID Numbers: 014-149; D5551L00004/ISSEXEN0013 (Other Grant/Funding Number: AstraZeneca)