Clinical trial NCT02251431
Conditions: Type 2 Diabetes Mellitus Chronic Kidney Disease Left Ventricular Diastolic Dysfunction
Keywords: diabetes mellitus chronic kidney disease diastolic function cardiac fibrosis cardiac strain cardiac biomarker renal biomarker
Sponsor: Baylor Research Institute
Start date: 2015-11-01; Completion date: 2019-12-01
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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).

Arms: arm 1: Exenatide-extended release (BYDUREON™) 2 mg subcutaneously once per week x 38 weeks arm 2: Matching placebo subcutaneously once per week x 38 weeks
Interventions: intervention 1: BYDUREON intervention 2: Placebo
Intervention descriptions: intervention 1: Exenatide-extended release, Cohorts A and B intervention 2: Cohort A only

Protocol documents:
Prot_SAP_000.pdf: 
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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 
 
INVESTIGATORS:   
Peter A. McCullough, MD, MPH, Baylor Scott & White Heart and Vascular Institute 
Kristen Tecson, PhD, Baylor Scott & White Heart and Vascular Institute 
Teodoro Bottiglieri, PhD, Institute for Metabolic Disease 
Deepika Gopal, MD, Baylor Scott & White Heart Hospital Plano 
Haojie Wang, MD, Baylor Scott & White Heart and Vascular Hospital – Dallas 
 
 
 
 
Correspondence:  Peter A. McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF 
Consultant Cardiologist 
Baylor Scott & White Heart and Vascular Institute 
621 N. Hall St., H030 
Dallas, TX 75226 
Cell:  248-444-6905 
e-mail:  peteramccullough@gmail.com 
Background/Rationale 
There has been considerable attention given to the cardiovascular safety of antidiabetic 
therapeutic agents in recent years.1  Some agents, in post-approval studies were linked to higher 
rates of myocardial infarction, heart failure, and cardiovascular death.  In addition, modern 


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strategy trials linked tight glycemic control to risk of hypoglycemic events and cardiovascular 
death.2  Many of the issues that came out of the debate dealt with a lack of biologic plausibility 
for specific agents and atherosclerotic or myocardial disease progression as well as statistical 
uncertainty of the post-marketing studies where events were not adjudicated at occurred at very 
low frequencies over short durations of followup.3  In response, the U.S. Food and Drug 
administration issued guidance for sponsors of pharmaceutical trials in terms of acceptable rates 
of myocardial infarction, stroke, and cardiovascular death in randomized controlled trials.4  
Importantly, heart failure was not addressed in this guidance, and as a result, two recent trials 
have raised concerns regarding increased risks of heart failure with new drugs recently approved 
(alogliptin, saxagliptin).5  6  Hence, there is a need for high-quality trials in patients with diabetes 
evaluating treatment effects on the myocardium with the most sophisticated imaging and 
molecular measurements. 
We are in the midst of chronic disease epidemics of type 2 diabetes mellitus (T2DM) and heart 
failure (HF).  It is recognized that approximately half of all patients diagnosed with HF have 
preserved left ventricular ejection fraction (HFpEF), otherwise known as diastolic HF (DHF).  
For the sake of this proposal, which will evaluate diastolic function in detail, the abbreviation 
DHF will be used.  The determinants, pathophysiology, contribution of ischemia, and 
relationship to arrhythmias with DHF are all incompletely understood.7  It is believed that a core 
pathophysiologic process involved in DHF is cardiac fibrosis and the crosslinking of procollagen 
to collagen which is regulated in part, by the renin-angiotensin aldosterone system.8  Once this 
structural event has occurred in the interstitium of the myocardium, it is unlikely that any form of 
neurohumoral modification will reverse, degrade, or influence the cross-linked collagen matrix.  
Thus, there is considerable interest in upstream use of neurohumoral antagonism to prevent or 
retard the progression of cardiac fibrosis in patients who ultimately develop DHF.  There are 
currently no approved therapies for DHF and trials of conventional agents used in systolic HF 
have not led to reductions in heart failure hospitalizations or HF death.  These data all support 
the notion that therapies may be applied too late in the course of DHF. 
There is now widespread recognition that chronic kidney disease (CKD) contributes to the 
initiation and progression of HF.  Cardiorenal syndrome type 4 is the clinical circumstance in 
which the progression of CKD directly leads to derangements in cardiac function and ultimately 
sodium and water retention, volume overload, neurohumoral changes, micronutrient 
abnormalities, all of which result in DHF. 
Recent data suggest glucagonlike peptide-1 (GLP-1) agonists may have anti-apoptotic effects on 
cardiomyocytes in the setting of HF.9  Vyas and colleagues recently conducted a study in a 
murine model where the GLP-1 agonist exenatide was administered twice daily to a mice with 
dilated cardiomyopathy (TG9) starting at 56 days of life.10 TG9 mice develop congestive heart 
failure and secondary insulin resistance in a highly predictable manner with death by 12 weeks 


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of age. Glucose homeostasis was assessed by measuring glucose tolerance at 8 and 10 weeks and 
tissue 2-deoxyglucose uptake at 75 days. Exenatide treatment improved glucose tolerance, 
myocardial GLUT4 expression and 2-deoxyglucose uptake, cardiac contractility, and survival 
over control vehicle-treated TG9 mice. Phosphorylation of AMP kinase and AKT was also 
increased in exenatide-treated animals. Total myocardial GLUT1 levels were not different 
between groups.  Lui and coworkers recently studied the potential of GLP-1 cardioprotective 
effects in an animal model of myocardial infarction (MI).11  The hypothesis was that chronic 
treatment with GLP-1 or the exenatide analog AC3174 would improve cardiac function, cardiac 
remodeling, insulin sensitivity, and exercise capacity (EC) in rats with MI-induced chronic heart 
failure (HF) caused by coronary artery ligation.  Two weeks post-MI, male Sprague-Dawley rats 
were treated with GLP-1 (2.5 or 25 pmol/kg/min), AC3174 (1.7 or 5 pmol/kg/min) or vehicle via 
subcutaneous infusion for 11 weeks. Cardiac function and morphology were assessed by 
echocardiography during treatment. Metabolic, hemodynamic, exercise-capacity, and body 
composition measurements were made at study end.  Compared with vehicle-treated rats with 
HF, GLP-1 or AC3174 significantly improved cardiac function, including left ventricular (LV) 
ejection fraction, and end diastolic pressure. Cardiac dimensions also improved as evidenced by 
reduced LV end diastolic and systolic volumes and reduced left atrial volume. Vehicle-treated 
HF rats exhibited fasting hyperglycemia and hyperinsulinemia. In contrast, GLP-1 or AC3174 
normalized fasting plasma insulin and glucose levels. GLP-1 or AC3174 also significantly 
reduced body fat and fluid mass and improved exercise capacity and respiratory efficiency. Four 
of 16 vehicle control HF rats died during the study compared with 1 of 44 rats treated with GLP-
1 or AC3174. The cellular mechanism by which GLP-1 or AC3174 exert cardioprotective effects 
appears unrelated to changes in GLUT1 or GLUT4 translocation or expression.  Lui concluded 
that chronic treatment with either GLP-1 or AC3174 showed promising cardioprotective effects 
in a rat model of HF.  There are a variety of additional proposed mechanisms for the myocardial 
effects of exenatide as GLP-1 receptor agonist as shown in the figure ranging from 
cardioprotection after an acute ischemic event to fundamental changes in substrate utilization by 
myocardial cells.  Of note, because transport of glucose and potassium can affect the QT interval, 
investigators have evaluated the impact of exenatide on the QTcorrected and have demonstrated 
no significant change.12  Hence, GLP-1 receptor agonists may represent a novel approach for the 
treatment of patients with HF or cardiovascular disease associated with type 2 diabetes. 


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Best and colleagues have recently demonstrated in the LifeLink database that use of exenatide 
twice daily in 21,754 patients compared to non-use in 361,771 using propensity matching was 
associated with a 19% reduction in cardiovascular events, p=0.01.13  These observations have 
been extended by Best and coworkers using the General Electric database where exenatide use 
was associated with an adjusted risk hear failure, OR=0.46, 95% CI 0.38-0.56, for all patients 
who received twice daily exenatide (n = 103,776).14  Of note, this protective effect was greater 
for those who were receiving concomitant insulin therapy compared to those without.  There 
have been consistent cardiovascular benefits seen in the integrated database assembled for safety 
for exenatide over the course of many clinical trials as shown in the Figure.15 
 


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The clinical development of exenatide has progressed to a once-weekly subcutaneous 
formulation, BYDUREON™, (Exenatide extended release for injectable suspension) approved 
by the US FDA for clinical use in January, 2012, which produces elevated and steady state levels 
of the drug over time as shown in the Figure.  This provides theoretical rationale that constant 
agonism at the GLP-1 receptors on myocardial cells may provide the best overall opportunity to 
evaluate changes in structure, function, and satellite cell activation over time as a result of 
exenatide. 
 


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There are new laboratory and imaging technologies that reveal the presence of cardiac and 
possibly renal fibrosis.  The 2013 guidelines for HF from the American College of Cardiology 
recommend several biomarkers for the assessment and management including natriuretic 
peptides (B-type natriuretic peptide [BNP], N-terminal pro B-type natriuretic peptide [NT-
proBNP]), ultrasensitive troponin I or T, galectin-3 and ST2.16  Numerous studies have 
demonstrated the usefulness of chronic serial measurements of BNP or NT-proBNP in the 
monitoring of myocardial disease.17 18  In addition, either peptide has proven to be useful as entry 
criteria for clinical trials HF patients, primary to exclude HF mimics.  With the advent of more 
sensitive assays for troponin, it has been shown that the majority of patients with HF have 
chronic elevations which are related in a graded fashion to heart failure hospitalization and 
death.19 20  Galectin-3, a novel biomarker produced by cardiac macrophages and pericytes, is a 
member of the family of animal lectins, which selectively binds β-galactoside residue on the cell 
surface of fibroblasts, and via the transforming growth factor-beta pathway, signals the 
production and secretion of procollagen in the extracellular space.21  Galectin-3 has been 
demonstrated to be elevated in blood in the presence of HF and is prognostically related to death 
independently and complementary to the natriuretic peptides.22  Soluble ST2 is a decoy ligand 
for the interleukin-33 receptor present in the myocardium and its levels are quantitatively related 
to the severity of HF and are predictive of future HF hospitalizations and death.23 24  
Interestingly, among young individuals in the Framingham Heart Study, ST2 levels anticipate the 
future development of HTN during adulthood.25  In simplistic terms, ST2 can be thought of as a 
link between the immune system and left ventricular dysfunction.   All four markers, 
ultrasensitive troponin I or T, BNP or NT-proBNP, galectin-3 and ST2 can be integrated into a 
chronic Myocardial Injury Summary Score (MISS) as shown below. 
Cardiac magnetic resonance imaging MRI using gadolinium has demonstrated that the presence 
of late gadolinium enhancement is indicative of myocardial tissue fibrosis and is prognostic for 
cardiac arrhythmias and death in a variety of cardiomyopathies.26  There is a new technology that 
complements MRI using ultrasonography with strain rate imaging for assessment of cardiac 


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fibrosis.  In order to determine the health of the heart during treatment, ultrasound imaging will 
be used to measure the function of the myocardium and those changes will be monitored over 
time. Given that the muscle fibers of the left ventricle are laid out in a cross hatch formation 
from the apex to the base (near the mitral valve) and that the chambers are synchronized in their 
pumping, the overall expansion and contraction of the muscle follows a very complex sequence 
of events.  Any damage to the myocardium due to lack of blood, infection or other events will 
change this expansion and contraction significantly.  Ultrasound strain imaging provides a non-
invasive, non-radiation method to assess the heart’s ability to expand and contract properly and 
can detect subtle changes in these events.  Strain rate imaging is emerging as the most sensitive 
technique to evaluate the subtle effects of DM on myocardial function with the ability to detect 
physiologic changes that cannot be seen on conventional echocardiography or cardiac MRI.27 
Finally, there are a host of renal biomarkers in development that will complement the urine 
albumin:creatinine ratio in the detection of chronic renal injury including those outlined below 
which can be organized into a chronic Kidney Injury Summary Score (KISS): 
 Tissue Inhibitor of MetalloProteinases-2 (TIMP-2) x Insulin-like Growth Factor Binding 
Protein-7 (IGFBP-7), also known as the commercially available NephroCheck® Test 
 Neutrophil gelatinase associated lipocalin (NGAL):creatinine (Cr) ratio 
 Kidney injury molecule-1 (KIM-1):Cr ratio 
 L-Fatty acid binding protein:Cr ratio 
 Interleukin-18:Cr ratio 
 Alpha glutathione S-transferase (αGST):Cr ratio 
 Pi glutathione S-transferase (piGST):Cr ratio 
 N-acetyl-β-D-glucosaminidase (NAG):Cr ratio 
 Cystatin-C:Cr ratio (uCysC:Cr) 
 Albumin:Cr ratio (ACR) 
 
One of the difficulties faced by small trials measuring multiple biomarkers is the integration of 
multiple markers in order to interpret a therapeutic signal of benefit or harm.  This protocol will 
use an integrative approach for both the myocardial and renal markers as indicated below.  Since 
most of these markers have a skewed distribution to the right, they are amenable to logarithmic 
transformation, and hence, can be put on a summative scale in order to detect harm (movement 
to the right or positive) or benefit, movement to the left or negative from zero.  The four cardiac  


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markers will be integrated into a MISS score and the renal markers, similarly will be integrated 
into a KISS score as follows: 
The method involves calculation of a biomarker index, representing from one or more 
biomarkers.   The basic metric is the ratio of the peak value for a biomarker seen after a 
treatment to the baseline value before treatment.    Both the baseline and post-treatment values 
may represent single assay measurements, or a single value determined from multiple 
measurements with rules used to ensure robust assay estimates. 
The basic component for the score is defined as:     Biomarker(i)Peak /  Biomarker(i)Baseline 
The composite score across multiple biomarkers (i) for a given patient (j) would be defined as: 
 
MISS or KISS(j)   =      log10  [  Biomarker(i)Peak /  Biomarker(i)Baseline ]/n,   i = 1, 
n=number of individual biomarker terms 
The composite score has these features: 
1. Individual biomarker values, which may be measured on different scales, are normalized 
to a ratio value, without units, which can be combined.   Use of ratios addresses, in part, 
the fact that the variability associated with individual biomarkers may be dependent on 
the magnitude of the values themselves, which make some statistics based on original 
values (especially, mean values) less suitable for comparing differences between 
treatment groups. 
2. The MISS and KISS values will be estimated at a patient level, so that a lack of change in 
some biomarkers can be compensated for by increases by others in the panel of 
biomarkers, reflecting different patient-to-patient expressions of biomarker changes.  
3. The logarithmic transformation addresses the observed right-skewing in the distribution 
of underlying biomarker values, which are bounded by zero but may have relatively large 
values compared to mean or expected values.   Log10 values between -1 and +1 cover the 
range from original ratios of 0.1 to 10 for individual biomarkers.   No change in a 
biomarker value from baseline to post-treatment use would result in a ratio of 1 and a log 
score of zero (which is appealing).   Thus the overall MISS and KISS values will have a 
range from -1 to +1 and the null hypothesis will be represented by a zero in each score.  
4. The MISS and KISS values can be treated as ordinary statistics for purposes of summary, 
analysis, or sample size estimation for future trials.    
Thus, we propose a phase II translational study evaluating Exenatide extended-release, with 
assessment of its impact, if any, on human measures of cardiac and renal fibrosis in Type 4 
cardiorenal syndrome. 
Primary Aim 


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Among adult individuals with T2DM and at risk for early DHF  with mildly reduced 
renal filtration function (Type 4 cardiorenal syndrome), to evaluate the quantitative 
impact on the MISS cardiac biomarker score, cardiac fibrosis by MRI, cardiac strain by 
ultrasonography and strain rate imaging, and KISS kidney biomarker score after A) 38 
weeks of treatment with exenatide extended-release or placebo or B) 38 weeks of 
treatment with BYDUREON™ (exenatide extended-release). 
 
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 early DHF 
(Type 4 cardiorenal syndrome). 
 
Inclusion Criteria 
 
o Age ≥ 18 
o Type 2 diabetes mellitus with hemoglobin A1C 6.6-12.0% with or without the use 
of insulin 
o Estimated glomerular filtration rate (eGFR) between 50 and 130  ml/min/1.73 m2 
 
 
Exclusion Criteria 
 
o Allergy or intolerance to gadolinium 
o Implanted cardiac pacemaker, defibrillator, loop recorder, or other implanted 
metallic device 
o Any other metallic implanted device that is a contra-indication to MRI scanning 
o eGFR < 50 ml/min/1.73 m2 
o eGFR > 130 ml/min/1.73 m2 
o 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 
o 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. 
o Disorders of iron metabolism 
o Collagen vascular diseases 
o Myocardial infarction 


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o New York Heart Association Class III or IV Heart Failure 
o Current use of DPP4 inhibitors and PPAR gamma agonists  
o Pregnancy or planned pregnancy during the trial period 
o Hemoglobin A1C of ≥ 12.0% or <6.6% 
o Fasting glucose ≥ 250mg/dl 
o Clinically significant abnormal baseline laboratories 
o Morbid obesity or body girth that prohibits the ability to undergo 
echocardiography or MRI scanning with high-quality image results 
o Renal transplantation 
o Severe gastrointestinal, liver, or neurodegenerative disease 
o Decompensated liver cirrhosis (Child-Pugh score >7) 
o Patients have alanine aminotransaminase (ALT) greater than 5 times the upper 
limit of the reference range. 
o Prior pancreatitis 
o Personal or family history of medullary thyroid adenoma or carcinoma (MTC)  
o Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). 
o History of severe hypoglycemia 
o Prior bariatric surgery 
 
Study Restricted Drugs:  DPP4 inhibitors (Januvia, Onglyza, Galvus, Tradjenta, Nesina) and 
PPAR gamma agonists (Actos, Avandia).  Subjects may be reconsidered for enrollment upon 
successful withdrawal and washout of these drugs. 
 
Study Design/Methods 
 
Prospective, 2 cohort trial:  
Cohort A:  double blind, randomized, parallel group, placebo controlled  
Intervention: Drug: Exenatide-extended release (BYDUREON™) 2 mg subcutaneously once per 
week x 38 weeks 
Matching placebo subcutaneously once per week x 38 weeks 
Subject Enrollment: approximately 56 subjects will be enrolled 
 
Cohort B: open-label  
Intervention: Drug: Exenatide-extended release (BYDUREON™) 2 mg subcutaneously once per 
week x 38 weeks (single group, open-label, blinded outcome) 
Subject Enrollment:  approximately 48 subjects will be enrolled  
Prescreening:  presence of type 2 diabetes mellitus, eGFR 50-130 ml/min/1.73 m2 within the last 
year will be the principal prescreening data used by study coordinators to identify potential 
candidates for the trial.  There will be a two week washout of study restricted medications listed 


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above. Subjects that agree to withdrawal of study restricted medications will be monitored by the 
investigator.  Monitoring will be based on blood sugar values with medication changes as needed 
as determined by the investigator.  An extended pre-screening period of 2-4 weeks will be 
granted to subjects with high HbA1cs > 12.0% and fasting glucoses > 250 to improve glycemic 
control by improving anti-diabetic medication compliance. Subjects will then be rescreened at 
the end of this period to verify improved compliance. Formal screening will occur as indicated in 
the chart of events.  Blood and urine biomarkers and cardiac MRI with gadolinium will be 
measured at baseline and nine months.  All urine and blood specimens will be processed and 
aliquoted and stored.  In general, patient samples will be collected and stored in a -20 or -80 
freezer for later use.  Samples for some biomarkers may be shipped on dry ice to be processed by 
a commercial lab or core facility.  Other samples will be processed in-house using commercially 
available sandwich ELISA (enzyme-linked immunosorbent assay) kits.  Briefly, a sandwich 
ELISA is an analytic biochemistry assay that detects the presence of an analyte in a sample. The 
antibody (Ab) specific for the analyte is bound to the wells of a 96-well plate.  Samples 
containing the analyte of interest are added to the wells.  A second Ab, specific for that analyte 
and conjugated to an enzyme is then added.  Finally, a chromogen (colorless enzymatic 
substrate) is added.  The Ab coupled enzyme converts the substrate into a colored product, 
indicating the proportion of analyte present in the sample.  The amount of product is then 
quantified by measuring the optical density at a specific wavelength utilizing a microplate reader.  
Detailed laboratory methods and description of the cardiac echocardiography and MRI protocols 
will be produced for a full trial protocol and manual of operations, and the protocols are briefly 
outlined below. 
Cardiac MRI protocol: 
Cardiac MRI will be performed at baseline and at 38 weeks following therapy. The same 
protocol will be used for baseline MRI scan and at 38 weeks. 
Cardiac MRI images will be acquired on a 1.5-T scanner (Philips Achieva 1.5 Tesla for Cohort A 
and Siemens Aera 1.5 Tesla for Cohort B).  
Global and Regional LV function: Steady-state free precession cine images will be acquired in 
the two, three and four chamber long axis views, and stacked short axis views covering the entire 
left ventricle.  
Late enhancement scan will be acquired per routine protocol following IV administration of 
gadolinium in the two, three and four chamber views, and stacked short axis views. Standard late 
gadolinium enhancement imaging will be performed after at least 10 minutes after the dose of 
contrast agent is administered using spoiled gradient echo segmented inversion recovery and 
phase-sensitive inversion recovery segmented gradient echo sequences. In patients with renal 
insufficiency with eGFR<50, contrast will not be administered.  


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Cardiovascular magnetic resonance Functional Analysis: Post processing of the MRI images will 
be performed on a separate workstation. Left ventricular mass index (LVMI) g/m2, left 
ventricular volumes, ejection fraction, and percentage of scar tissue and fibrosis will be 
calculated using Circle CMR software and/or Precession software. 
Echocardiography Protocol: 
Standard TTE echocardiogram will be performed at baseline and at 38 weeks following 
treatment. The same protocol will be used at baseline and at 38 weeks following therapy. 
Echocardiography will be performed using standard 2D, color and spectral Doppler acquisitions 
in the parasternal, apical and subcostal views. Recordings will be made on a GE Vivid 7 machine 
for Cohort A and a Philips Epiq 7 machine for Cohort B. All data will be stored on a workstation 
(EchoPAC for offline analysis). Analysis will be performed by an experienced 
echocardiographer. For each patient conventional analysis of the echocardiography precedes LV 
strain analysis. 
LV systolic and diastolic function, LV ejection fraction (biplane Simpsons), LV volumes, LV 
mass index LVMI, E/A ratio, Tissue Doppler e- prime, E/e-prime, and pulmonary venous 
Doppler will be determined.  
Mitral inflow E and A wave velocities were measured by the pulse wave Doppler method. 
Doppler tissue imaging was recorded at level of the septal and lateral mitral annulus.  
Strain measurement is based on speckle tracking approach. Global longitudinal, circumferential 
and radial myocardial deformation will be evaluated from standard 2 D images using 2D strain 
software. Two dimensional data sets for speckle tracking analysis include three short axis views 
(basal, midventricular and apical) and three apical longitudinal views (four, three and two 
chamber). Adjustments to be made in sector depth and angle to yield a temporal resolution of 
about 80 to 100 frames/sec. By tracing endocardial borders on the end systolic frame, the 
software automatically tracks the contour on the subsequent frames. Tracking will be confirmed 
in real time and manually corrected if necessary. Global longitudinal strain (GLS) is the average 
of the segment strains from the apical four-chamber view. Global radial strain and Global 
circumferential strain are the averages of the segment strains in the mid parasternal short axis 
view at an image frame rate between 60-90 Hz. Images will be analyzed offline on a separate 
EchoPac analysis package. 
12-Lead Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed at screening to rule out baseline atrial 
fibrillation and confirm the subject in sinus rhythm.  An additional ECG be performed at 38 
weeks again to confirm sinus rhythm as well as to evaluate changes in chamber dimension, 


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ventricular axis, intervals, and the development of conduction delays if any.  If atrial fibrillation 
develops during the course of treatment, then usual care will be provided and at week 38 efforts 
will be made at rate control to ensure the highest fidelity echocardiography with strain and 
cardiac MRI studies. 
Body Weight 
Body weight in kilograms will be recorded at every clinical visit and the body mass index will be 
calculated.  Studies of exenatide have shown that subjects lost an average of six pounds over 24 
weeks, and thus, a change in weight is an anticipated confounder in the analyses evaluating 
cardiac imaging measures and potentially the cardiac and renal biomarkers. 
Concomitant Medications 
Concomitant medications will be assessed at every study visit.  If a contra-indicated medication 
has been started by a treating physician (e.g. BYETTA™ (exenatide), BYDUREON™ 
(Exenatide extended-release), VICTOZA™ (liraglutide), or taspoglutide), then the treating 
physician will be contacted by the principal investigator and the contra-indicated medication will 
be suggested for discontinuation.  If there is either hyper- or hypo-glycemia that has signaled a 
change in anti-diabetic agents, then a drug from an allowed class will be selected or deselected in 
the management (e.g. metformin, secretogogues, insulin). 
Liver Function Testing 
Exenatide is primarily cleared by the kidney and does not carry high risks of hepatotoxicity.  
Liver function testing will be measured at screening, and then 4, 16, and 38 weeks.  If either the 
AST or ALT elevate > 3 X the ULN or the bilirubin exceeds 2 X the ULN, then testing will be 
repeated in two weeks and if elevations remain, the study drug will be discontinued and the tests 
will again be repeated in two weeks.  If they remain elevated, then study subjects will be referred 
to their primary care physician or hepatologist for evaluation.  
Patient Follow-Up: 
A retrospective chart review of medical records and the national death registry to capture, 
medical history, demographic information, outcomes, laboratory and procedure results, 
medications usage, hospitalizations, new diagnoses, and long-term survival data.  
 
A follow-up phone call will be completed between week 16 and week 38 visits to assess AE’s, 
ConMeds, and study drug compliance.  
Patients who wish to withdraw from the study will complete all early term procedures listed in 
the schedule of events. Additional MRI/Echo scans and/or urine and blood biomarkers may be 
collected per PI discretion.  


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Areas of Special Concern 
Risk off Thyroid C-cell Tumors 
In both genders of rats, exenatide extended-release caused a dose-related and treatment-duration– 
dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) at 
clinically relevant exposures compared to controls. A statistically significant increase in 
malignant thyroid C-cell carcinomas was observed in female rats receiving exenatide extended-
release at 25-times clinical exposure compared to controls and higher incidences were noted in 
males above controls in all treated groups at ≥ 2-times clinical exposure. The potential of 
exenatide extended-release to induce C-cell tumors in mice has not been evaluated. Other GLP-1 
receptor agonists have also induced thyroid C-cell adenomas and carcinomas in male and female 
mice and rats at clinically relevant exposures. It is unknown whether BYDUREON will cause 
thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human 
relevance of exenatide extended-release–induced rodent thyroid C-cell tumors could not be 
determined by clinical or nonclinical studies. Serum calcitonin was not assessed in the clinical 
trials supporting the approval of BYDUREON. 
Serum calcitonin is a biological marker of MTC. Patients with MTC usually have calcitonin 
values > 50 ng/L. Patients with thyroid nodules noted on physical examination (to be performed 
at screening weeks 4, 16, and 38) or on neck imaging done as a part of concurrent clinical care 
will be referred to an endocrinologist for further evaluation. Routine monitoring of serum 
calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients 
treated with BYDUREON and will not be performed in the study. Such monitoring may increase 
the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for 
MTC and a high background incidence of thyroid disease. If serum calcitonin is measured as a 
part of concurrent clinical care and found to be elevated, the patient should be referred to an 
endocrinologist for further evaluation. 
Acute Pancreatitis 
Based on postmarketing data, exenatide has been associated with acute pancreatitis, including 
fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYDUREON, 
patients should be carefully observed for signs and symptoms of pancreatitis (including 
persistent severe abdominal pain, sometimes radiating to the back, which may or may not be 
accompanied by vomiting). If pancreatitis is suspected, BYDUREON should promptly be 
discontinued and appropriate management should be initiated. If pancreatitis is confirmed, the 
study drug will not be restarted. 
Hypoglycemia 


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The risk of hypoglycemia is increased when exenatide is used in combination with a 
sulfonylurea. Therefore, patients receiving BYDUREON and a sulfonylurea may require a lower 
dose of the sulfonylurea to minimize the risk of hypoglycemia. It is also possible that the use of 
BYDUREON with other glucose-independent insulin secretagogues (e.g., meglitinides) could 
increase the risk of hypoglycemia. 
Renal Impairment 
Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.  
BYDUREON should not be used in patients with severe renal impairment (creatinine clearance < 
30 mL/min) or end-stage renal disease and should be used with caution in patients with renal 
transplantation because of the risks of increased nausea, vomiting, and hypoglycemia.  Estimated 
glomerular filtration rate will be assessed at every clinical visit and if the eGFR falls below 30 
ml/min/1.73 m2, then the study drug will be discontinued 
Primary Endpoints 
1) Serum cardiac biomarker MISS score (derived from changes in ultrasensitive troponin, 
BNP, galectin-3, and ST2) 
2) Urine renal biomarker KISS score (derived from 10 renal biomarkers) 
3) Mean paired percent change in left ventricular myocardial fibrosis (% of left ventricular 
mass) 
4) Mean paired change in left ventricular strain (%) by strain-rate imaging 
Secondary Endpoints 
1) Individual components of cardiac biomarker MISS score, mean paired change from 
baseline 
 Ultrasensitive troponin 
 BNP 
 Galectin-3 
 ST2 
 
2) Individual components of the urine renal biomarker KISS score (derived from 10 renal 
biomarkers), mean paired change from baseline 
 Tissue Inhibitor of MetalloProteinases-2 (TIMP-2) x Insulin-like Growth Factor Binding 
Protein-7 (IGFBP-7), also known as the commercially available NephroCheck® Test 
 Neutrophil gelatinase associated lipocalin (NGAL):creatinine (Cr) ratio 
 Kidney injury molecule-1 (KIM-1):Cr ratio 


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 L-Fatty acid binding protein:Cr ratio 
 Interleukin-18:Cr ratio 
 Alpha glutathione S-transferase (αGST):Cr ratio 
 Pi glutathione S-transferase (piGST):Cr ratio 
 N-acetyl-β-D-glucosaminidase (NAG):Cr ratio 
 Cystatin-C:Cr ratio (uCysC:Cr) 
 Albumin:Cr ratio (ACR) 
 
3) Mean paired change in secondary MRI measurements including left ventricular mass 
index (LVMI) (g/m2) 
4) Mean paired change in Doppler echocardiographic measurements:  EF, E/A ratio, tissue 
Doppler e-prime, and LVMI 
5) Left ventricular strain and strain rate curve analysis  
6) Mean paired change in eGFR 
7) Mean paired change in hemoglobin A1C from baseline to 16 weeks 
8) Mean paired change in fasting glucose from baseline to 16 weeks 
 
Future Biomarker and Genetic Testing 
 
The Baylor Scott & White Institute of Metabolic Disease is actively involved in many types of 
research in both common and rare diseases. Subjects will be asked to give consent to use any 
leftover blood and urine in this research for future studies of diabetes, heart, and kidney disease. 
At each time point that blood and urine samples are taken in this study, there is an opportunity to 
save some of the fluid for up to 50 years in order to run future tests related to diabetes, heart, and 
kidney disease.  Subjects will be asked to consent to long-term sample storage. The subjects will 
be asked to give consent to use stored samples to test for genomic biomarkers (mutations) 
depending on future advancements in laboratory technology.  The urine and blood samples 
collected from subjects in this study may be used to establish a cell line that could be patented 
and licensed.  After 50 years or sooner if the samples are depleted, the remainder of the fluid will 
be destroyed.  Samples will be stored at the Baylor Scott & White Institute of Metabolic Disease. 
 
How Many People Will Take Part In The Study? 
 
This is a single site study that will enroll up to 104 subjects from 2 consecutive cohorts.  


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Safety Endpoints Harmonized to the EXenatide Study of Cardiovascular Event Lowering 
(EXSCEL) Trial28 
 
1) Death 
2) Hospitalization for acute coronary syndrome 
3) Hospitalization for heart failure 
 
ADVERSE EVENTS 
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of investigational product, whether or not considered related to the 
investigational product. 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more AEs.) 
 
Serious Adverse Events 
 
A serious AE (SAE) is any untoward medical occurrence that at any dose:  
• 
results in death 
• 
is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect  
• 
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 


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result in hospitalization.)  Potential drug induced liver injury (DILI) is also considered an 
important medical event.  (See below for the definition of potential DILI.) 
 
Suspected transmission of an infectious agent (e.g., any organism, virus or infectious particle, 
pathogenic or non-pathogenic) via the study drug is an SAE. 
 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs.  (See below 
for reporting pregnancies.) 
 
The following hospitalizations are not considered SAEs in AstraZeneca (AZ) clinical studies:  
 a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered "important medical event" or event life threatening) 
 elective surgery, planned prior to signing consent 
 admissions as per protocol for a planned medical/surgical procedure 
 routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy) 
 medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these cases 
 admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative). 
 
Serious Adverse Event Collection and Reporting 
 
Following the subject’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening 
period and within 30 days of discontinuation of dosing.  If applicable, SAEs must be 
collected that relate to any later protocol-specified procedure (e.g., a follow-up skin biopsy).  
The investigator should report any SAE occurring after these time periods that is believed to 
be related to study drug or protocol-specified procedure.  
 
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness.  
 
If the investigator believes that an SAE is not related to the study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy, or a 


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complication of a study procedure), the relationship should be specified in the narrative 
section of the SAE Report Form. 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to AZ 
(or designee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies 
on a Pregnancy Surveillance Form (electronic or paper forms).  When using paper forms, the 
reports are to be transmitted via email or confirmed facsimile (fax) transmission to: 
AZ Patient Safety and other reports Email 
Address:AEMailboxClinicalTrialTCS@astrazeneca.com 
SAE Facsimile Number:   +01 302 886 8987 
 
For studies capturing SAEs/pregnancies through electronic data capture (EDC), electronic 
submission is the required method for reporting. The paper forms should be used and 
submitted immediately, only in the event the electronic system is unavailable for 
transmission. When paper forms are used, the original paper forms are to remain on site. 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to AZ (or 
designee) using the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
Nonserious Adverse Events 
 
A nonserious adverse event is an AE not classified as serious. 
       
Nonserious Adverse Event Collection and Reporting 
 
The collection of nonserious AE information should begin at initiation of study drug. 
Nonserious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see within). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug, or those that are present at the end of study 
treatment as appropriate. All identified nonserious AEs must be recorded and described on 
the nonserious AE page of the CRF (paper or electronic).  
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study. 
 


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Laboratory Test Abnormalities 
 
The following laboratory abnormalities should be captured on the nonserious AE CRF Page 
or SAE Report Form (paper or electronic) as appropriate: 
• 
Any laboratory test result that is clinically significant or meets the definition of an SAE  
• 
Any laboratory abnormality that required the subject to have the study drug discontinued 
or interrupted 
• 
Any laboratory abnormality that required the subject to receive specific corrective 
therapy. 
 
It is expected that wherever possible, the clinical, rather than the laboratory term would be 
used by the reporting investigator (e.g., anemia versus low hemoglobin value). 
 
Pregnancy 
 
A serum pregnancy test will be done in appropriate subjects to exclude pregnancy with the 
initial study laboratory tests.  If, following initiation of the investigational product, it is 
subsequently discovered that a study subject is pregnant or may have been pregnant at the 
time of investigational product exposure, including during at least 6 half lives after product 
administration, the investigational product will be permanently discontinued in an 
appropriate manner (e.g., dose tapering if necessary for subject safety). Protocol-required 
procedures for study discontinuation and follow-up must be performed on the subject unless 
contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy follow-up 
procedures should be considered if indicated. 
 
The investigator must immediately notify the AZ (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to AZ (or designee) within 24 
hours and in accordance with SAE reporting procedures described within.  
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the 
Pregnancy Surveillance Form. 
 
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 6 half lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner (e.g., dose 
tapering if necessary for subject safety). Protocol-required procedures for study 
discontinuation and follow-up must be performed on the subject unless contraindicated by 


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pregnancy (e.g., x-ray studies). Other appropriate pregnancy follow-up procedures should be 
considered if indicated. 
 
The investigator must immediately notify the AZ (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to AZ (or designee) within 24 
hours and in accordance with SAE reporting procedures described within this document.  
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the 
Pregnancy Surveillance Form. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported 
to the sponsor. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
 
Overdose 
 
All occurrences of overdose must be reported as SAEs (see within for reporting details). 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE (see within for reporting details.). 
 
Potential Drug Induced Liver Injury (DILI) 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs (see within. for reporting 
details). 
 
Potential drug induced liver injury is defined as  
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase), 
AND 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
 
Other Safety Considerations 


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Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious 
AE, as appropriate, and reported accordingly.  
 
SAE’s will be reported using MedWatch forms and graded using the severity scale published 
by the National Cancer Institute.  The terms are provided as Attachment A and can be 
reviewed at the following link.   
https://wiki.nci.nih.gov/display/VKC/Common+Terminology+Criteria+for+Adverse+Events
+FAQ#CommonTerminologyCriteriaforAdverseEventsFAQ-AdverseEventTerms  
 
Data Monitoring Committee 
After funding and contract execution, but before the first subject is screening, a data monitoring 
committee will be formed consisting of five voting members including one statistician.  A 
charter will be drafted governing the committee’s activities which will cover the conventional 
domains of study execution and subject safety. 


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Proposed Schedule of Events  
 
Screening 
 
Follow-Up 
Study Assessments  
Day -365 
to 1a 
Day 1a 
 
 
 
4 
weeks 
16 
Weeksb 
30 
Weeks 
FU 
Phone 
Call (+1 
week)g 
38 
weeks 
(1 
week) 
4 weeks after final dose 5 
daysg/ or early withdrawal 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
Medical and disease history 
X 
 
 
 
 
 
 
Estimated GFR 
X 
X 
X 
X 
 
X 
 
HbA1C(%) 
X 
X 
X 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
X 
 
Echocardiogram with Strain 
Rate 
 
X 
 
 
 
X 
 
Cardiac MRI with gadolinium 
 
X 
 
 
 
X 
 
Serum  pregnancy test 
X 
 
 
 
 
 
 
Physical exam 
 
X 
X 
X 
 
X 
 
Weight  
 
X 
X 
X 
 
X 
X 
Vital signs  
 
X 
X 
X 
 
X 
X 
Hematologyc 
 
X 
 
X 
 
X 
 
Blood chemistryd  
 
X 
X 
X 
 
X 
 
Liver functione 
 
X 
X 
X 
 
X 
 
BNP 
 
X 
 
X 
 
X 
 
Biomarker panelf 
 
Xf 
 
Xf 
 
Xf 
 
Adverse & clinical endpoint 
events 
X 
X 
X 
X 
x 
X 
Xg 
Concomitant medication 
X 
X 
X 
X 
x 
X 
Xg 
Randomizationh 
 
X 
 
 
 
 
 
Study drug administration 
instructions 
 
X 
X 
X 
 
X 
 
Study drug compliancei 
 
 
X 
X 
x 
X 
 
Day 1 is first day of study drug.  Therefore all required elements listed for the Screening visit will be required for patients not seen and 
consented prior to Day 1. All elements of this evaluation must be obtained prior to study drug administration. 
a    May be obtained from medical record and if not present then drawn for study purposes 
b    May be scheduled ± 1 week 
c Hematology panel: complete blood count (CBC) with differential and platelets 
d Blood chemistry panel: sodium, potassium, chloride, carbon dioxide, blood urea nitrogen (BUN), serum creatinine, glycohemoglobin, cystatin 
C and glucose  
e Liver function: serum albumin, total protein, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin  
f Blood and urine biomarker panels used to calculate cardiac MISS and renal KISS scores 
g May be assessed by telephone. Coordinator to document on progress note 
h    Not applicable to open-label cohort (Cohort B) 
i   To be collected any time after last dose 


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Statistical Description 
Before the last subject has completed the trial, a full statistical analysis plan will be written and 
agreed to by the investigators.  Intent-to-treat principles will be used.  The anticipated dropout-
rate with incomplete biomarker and or MRI data is 15%.  Last observation carried forward will 
be used to use as many subjects as possible in the evaluable dataset.  In addition, both the MISS 
and KISS scores are robust to missing individual biomarker data and can collapse down to a 
scale of -1 to +1 for one marker and its change, up to our proposed -10 to +10 for the ten 
component KISS score.  Univariate statistics will be reported in means with standard deviations 
or counts with proportions as appropriate with comparisons by one-way analysis of variance or 
Chi-square (Exact) for dichotomous variables.  Bivariate statistics will include Pearson’s 
correlation for continuous variables.  Those subjects on insulin at baseline will be considered an 
a priori subgroup for analysis.  Multivariate analysis for the secondary aims will include the 
general linear model for continuous outcomes with forward selection of significant predictor 
variables as determined from the univariate analysis.  
3:1 allocation: The randomization goal from the original, 1:1 randomized trial is approximately 
50% complete. As it was a blocked randomization scheme, the number of patients who have 
received placebo is equal to the number of patients who have received drug. For the remaining 
50% of the trial, the design will change from a 1:1 randomization (drug: placebo) to a drug-only 
assignment with continued blinded assessment of the outcomes. Doing so will yield a drug: 
placebo ratio of 3:1. We acknowledge that confounding factors may be present in trials, and 
particularly so for non-randomized designs. Accordingly, we will test for the presence of 
systematic bias induced via non-randomization prior to analyzing the data under a pooled 3:1 
assignment. 
 
To do so, we will examine baseline data of the patients who received drug according to 
the phase of the trial, randomized vs. nonrandomized. Continuous variables will be presented as 
mean ± standard deviation, or median [quartile 1, quartile 3], if skewed. Categorical data will be 
presented as frequency and percentage. Differences between the groups will be assessed via two-
sample t tests and Chi-Square tests, or Wilcoxon Rank Sum tests and Fisher’s Exact tests, as 
appropriate. Tests will be assessed assuming a Type I error rate of 5% and a two-sided 
hypothesis. If statistically significant differences are observed between the randomized and 
nonrandomized cohorts, further exploration of the significance level under a preserved family 
wise error rate construct, with a Bonferroni adjustment, will be conducted.  
 
If it is determined that the patients who received drug during the randomized and 
nonrandomized phases of the trial are sufficiently different, we will perform 2 identical, but 
separate analyses: randomized drug vs. randomized placebo and nonrandomized drug vs. 
randomized placebo. The results of these 2 analyses will then be evaluated in a meta-analytic 


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framework, with a secondary consideration of pooling based on a heterogeneity term. Results 
will be visualized with a Forest Plot. 
If it is determined that the patients who received drug during the randomized and 
nonrandomized phases of the trial do not differ significantly, we will perform the analysis as 
described in the original protocol, but will do so under a 3:1 drug: placebo assignment instead of 
a 1:1. 
 
Sample Size 
Using i = 1,…, n recorded biomarkers for a given patient (j), we calculate the Myocardial Injury 
Summary Score (MISS) and the Kidney Injury Summary Score (KISS) as follows:  
MISSj or KISSj = 
. 
Using the log10 transformation on ratios bounded by (0.1, 10) yields a range of possible values of 
(-1, 1). If no change is observed between the biomarker value from baseline to post-treatment use 
(i.e. 
), then the log of that ratio is 0. Defining the 
MISS and KISS scores as averages of log10 ratios enables them to be robust to missing biomarker 
values. For example, suppose 2 of the 10 individual biomarker components of the KISS score are 
unavailable. Then in the calculation, we adjust n = 10 to n = 8 and the range of possible KISS 
scores is still (-1, 1), meaning it is essentially unaffected by the missing biomarkers. 
Because the MISS and KISS scores are novel metrics, we have no prior knowledge with which 
to estimate their standard deviations. Thus, we use the range rule of thumb to yield plausible 
estimates for the standard deviations. In so doing, we find a conservative estimated standard 
deviation of 2/6 = 0.33. 
1:1 allocation: We will need a sample size of 104 subjects to yield an evaluable dataset of 90 (45 
in each arm) in order to have 99% power to detect 20% difference from zero in the MISS score 
in any one of the treatment arms at p=0.05.   With this sample size, there will be >99% power for 
the KISS score outcome and all continuous MRI and strain rate imaging variables 
Originally, the trial was powered under a 1:1 randomization assumption. The trial has now 
shifted to a 3:1 allocation of drug: placebo (assuming the pooling assumption is met, as discussed 
previously). Table 1 below provides a range of empirical power to detect a significant 
treatment*time interaction in a linear mixed model, treating subjects as a random variable, with 
varied effect size and within-subject correlations, assuming a Type I error of 5%, two-sided 
alternative hypothesis, 69 participants on drug, and 23 participants on placebo. These results 
were generated in R via simulation with 100 replications each. 


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Table 1. Empirical power from linear mixed model simulation under varying effect size and 
within-subject correlations 
Effect Size = Difference of 
means/standard deviation 
Within-subject correlation 
Empirical 
Power 
 
0.61 = .2/.33 
 
0.4 
57% 
0.6 
77% 
0.8 
98% 
 
0.91 = .3/.33 
0.4 
93% 
0.6 
99% 
0.8 
100% 
 
Preliminary Publication Plan 
This will be the first trial of a specific therapy in Type 4 Cardiorenal Syndrome at risk for DHF, 
and thus, will be required to file an Investigational New Drug Application (IND) or IND 
Exemption with the US Food and Drug Administration.  Abstracts with primary results will be 
presented at the Late Breaking Clinical Trials Sessions of the American College of Cardiology, 
American Heart Association, American Diabetes Association, American Society of Nephrology, 
or other relevant meetings depending on which outcomes are highlighted.  Because of the novel 
nature of this translational project, publication is expected in a series of manuscripts that will be 
targeted for widely read journals including the New England Journal of Medicine, Journal of the 
American Medical Association, Lancet, Annals of Internal Medicine, Circulation, and the 
Journal of the American College of Cardiology. 
Investigator Comments 
This trial will be conducted by hospitals that are owned and operated by Baylor Scott & White 
Health System, the largest health system in Texas. Dr. McCullough will have a clinical presence 
at the Baylor University Medical Center in Dallas and will be available for oversight of the all 
aspects of the trial.    
Several methods to identify and recruit potential subjects will be used; these methods may 
include evaluation of patients from physicians' existing clinical practice, or referrals from other 


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physicians, medical record search, and/or review of available databases, phone screening, and 
inpatient screening for patients with this condition for example:  
Approach 1: 
The physician’s office visit schedule, which includes patient names, date of birth, and problem 
list, is reviewed daily for potential candidates based on matching entry criteria.  The potential 
subjects are then screened in greater detail, via the electronic medical record (EMR), based upon 
complete inclusion/exclusion criteria. 
 Approach 2: 
The OR schedule, nursing charge reports which includes patient names, date of birth, and 
problem list, is reviewed daily for potential candidates based on matching entry criteria.  The 
potential subjects are then screened in greater detail, via the EMR, based upon complete 
inclusion/exclusion criteria. 
 Approach 3: 
A physician and/or a member of the clinic treatment team identify a potential patient and refers 
them to be evaluated by research staff for inclusion/exclusion criteria. The potential subjects are 
then screened in greater detail, via the EMR, based upon complete inclusion/exclusion criteria. 
Contacting a patient identified in Approach 1, 2, or 3 
When a patient is identified that might qualify, unless the  patient is scheduled to see the 
physician within the next two weeks in clinic, the Baylor Scott & White Research Institute 
(BSWRI) staff supervised by the investigators will obtain approval from the physician prior to 
study start-up to approach any patient who appears to qualify.  BSWRI staff will indicate they 
are calling/approaching for trial consent on behalf of the physician and explain to them that they 
may qualify for this study. 
For patients that are scheduled to see the physician within the next two weeks in clinic the 
BSWRI staff will alert the physician and request that they talk to the patient at the next visit. 
Please see Approach 4. 
 Approach 4 
If during any of the above approaches, the BSWRI staff identifies a patient who will be seen in 
the next two weeks  for a regularly scheduled visit, the physician will have the option to discuss 
the study with his/her patient during that visit. 
 During a clinic visit with patient still present, the physician will obtain verbal consent from the 
patient that the research staff may speak to them about the study. If patient is interested, research 


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staff will begin thorough informed consent process during a scheduled face-to-face meeting with 
the potential candidate. Only the designated research personnel listed on this application will be 
exposed to any subject protected health information (PHI) for recruitment purposes. 
The imaging visits for echocardiography and MRI will occur at the Center for Advanced Cardiac 
Care (CACC) at the Baylor Scott & White Heart Hospital in Plano for cohort A and Baylor Scott 
& White Heart and Vascular Hospital – Dallas for cohort B.  The Data Coordinating Center 
(DCC) will be housed by the Baylor Scott & White Heart and Vascular Institute, which will be 
under the supervision of Dr. McCullough.  This center will be responsible for the electronic case 
report form development, database construction, analysis, and results reporting.  This center will 
also develop a site monitoring program. A centralized Research Pharmacy will be employed at 
the Baylor University Medical Center in Dallas.  This center will be responsible for the 
randomization, blinding, drug distribution and pharmacovigilance.  A Data Safety Monitoring 
plan will be developed with adverse and serious adverse events reported to the DCC, sponsor, 
and FDA when indicated. 
There will be two treatment cohorts. The first cohort was a prospective, double-blind, placebo 
controlled, parallel group, randomized group of BYDUREON™ (Exenatide extended-release) 
versus placebo. There are approximately 56 patients randomized in this cohort. Randomization to 
treatment groups of active study drug or matching placebo was performed with a permuted block 
design with block sizes of 4.  
The second cohort will be a prospective, single-arm, open-label trial of BYDUREON™ 
(Exenatide extended-release) that will comprise the remaining patients. This second cohort is 
necessitated by a change in availability of the matching placebo.  
 
 


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References 
                                                 
1 Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes drugs--insights from the rosiglitazone 
experience. N Engl J Med. 2013 Oct 3;369(14):1285-7. 
2 Genuth S, Ismail-Beigi F. Clinical implications of the ACCORD trial. J Clin Endocrinol Metab. 2012 
Jan;97(1):41-8. doi: 10.1210/jc.2011-1679. 
3 McCullough PA, Lepor NE. The rosiglitazone meta-analysis. Rev Cardiovasc Med.  2007 Spring;8(2):123-6. 
4 Hennekens CH, Hebert PR, Schneider WR, O'Brien P, Demets D, Borer JS. Academic perspectives on the United 
States Food and Drug Administration's guidance for industry on diabetes mellitus. Contemp Clin Trials. 2010 
Sep;31(5):411-3. 
5 White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, 
Kupfer S, Wilson C, Cushman WC, Zannad F; EXAMINE Investigators. Alogliptin after acute coronary syndrome 
in patients with type 2 diabetes. N Engl J Med. 2013 Oct 3;369(14):1327-35. 
6 Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P,  Frederich R, Wiviott SD, 
Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; SAVOR-
TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 
diabetes mellitus. N Engl J Med. 2013 Oct 3;369(14):1317-26. 
7 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.    
 
8 Chinnaiyan KM, Alexander D, McCullough PA.  Role of Angiotensin II in the Evolution of Diastolic Heart 
Failure.  J Clin Hypertens (Greenwich). 2005 Dec;7(12):740-7.   
 
9Davidson MH. Cardiovascular effects of glucagonlike peptide-1 agonists. Am J Cardiol. 2011 Aug 2;108(3 
Suppl):33B-41B. 
10 Vyas AK, Yang KC, Woo D, Tzekov A, Kovacs A, Jay PY, Hruz PW. Exenatide improves glucose homeostasis 
and prolongs survival in a murine model of dilated 
cardiomyopathy. PLoS One. 2011 Feb 17;6(2):e17178. 
11 Liu Q, Anderson C, Broyde A, Polizzi C, Fernandez R, Baron A, Parkes DG. Glucagon-like peptide-1 and the 
exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart 
failure.  Cardiovasc Diabetol. 2010 Nov 16;9:76. 
12 Linnebjerg H et al. Presented at ADA, 69th Scientific Sessions; New Orleans, LA; data on file, Amylin 
Pharmaceuticals Inc 
13 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. 


30 | P a g e  
 
2 6  F e b  2 0 1 9  
 
                                                                                                                                                             
14 Best JH  et  al. Presented at ADA, 71st Scientific Sessions; 2011; San Diego, CA (1133-P) 
15 Shen L, et al. Cardiovascular Safety of Exenatide BID:  An Integrated-Analysis from Long- term Controlled 
Clinical Trials in Subjects With Type 2 Diabetes. Diabetes. 2009;58(Suppl 1):A96-97. Abstract 366-OR. Data on 
file Amylin Pharmaceuticals, Inc 
16 WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, 
Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper  EK, Levy WC, Masoudi FA, McBride PE, 
McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL. 2013 
ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013 Oct 15;128(16):e240-
319. 
17 McCullough PA, Neyou A.  Comprehensive Review of the Relative Clinical Utility of B-Type Natriuretic 
Peptide and N-Terminal Pro-B-Type Natriuretic Peptide Assays in Cardiovascular Disease.  Open Heart Failure 
Journal, 2009, 2, 6-17. 
18 Savarese G, Trimarco B, Dellegrottaglie S, Prastaro M, Gambardella F, Rengo G, Leosco D, Perrone-Filardi P. 
Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2,686 patients in 12 randomized trials. 
PLoS One.  2013;8(3):e58287. 
19 Gravning J, Askevold ET, Nymo SH, Ueland T, Wikstrand J, McMurray JJ, Aukrust P, Gullestad L, Kjekshus J. 
Prognostic Impact of High-sensitive Troponin T Assessment in Elderly Patients with Chronic Heart Failure: Results 
from the CORONA Trial. Circ Heart Fail. 2013 Nov 27. [Epub ahead of print] 
20 Masson S, Anand I, Favero C, Barlera S, Vago T, Bertocchi F, Maggioni AP, Tavazzi L, Tognoni G, Cohn JN, 
Latini R; Valsartan Heart Failure Trial (Val-HeFT) and Gruppo Italiano per lo Studio della Sopravvivenza 
nell'Insufficienza Cardiaca–Heart Failure (GISSI-HF) Investigators. Serial measurement of cardiac troponin T using 
a highly sensitive assay in patients with chronic heart failure: data from 2 large randomized clinical trials. 
Circulation. 2012 Jan 17;125(2):280-8. 
21 de Boer RA, Voors AA, Muntendam P, van Gilst WH, van Veldhuisen DJ.  Galectin-3: a novel mediator of heart 
failure development and progression.  Eur J Heart Fail. 2009 Sep;11(9):811-7. Epub 2009 Jul 31. 
22 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. 
23 Ciccone MM, Cortese F, Gesualdo M, Riccardi R, Di Nunzio D, Moncelli M, Iacoviello M, Scicchitano P. A 
Novel Cardiac Bio-Marker: ST2: A Review.  Molecules. 2013 Dec 11;18(12):15314-28. 
24 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. 
25 Ho JE, Larson MG, Ghorbani A, Cheng S, Vasan RS, Wang TJ, Januzzi JL Jr. Soluble ST2 predicts elevated SBP 
in the community. J Hypertens. 2013 Jul;31(7):1431-6; discussion 1436. 
26 Jellis C, Martin J, Narula J, Marwick TH.  Assessment of nonischemic myocardial fibrosis.  J Am Coll Cardiol. 
2010 Jul 6;56(2):89-9. 
 


31 | P a g e  
 
2 6  F e b  2 0 1 9  
 
                                                                                                                                                             
27 Roos CJ, Scholte AJ, Kharagjitsingh AV, Bax JJ, Delgado V. Changes in multidirectional LV strain in 
asymptomatic patients with type 2 diabetes mellitus: a 2-year follow-up study. Eur Heart J Cardiovasc Imaging. 
2014 Jan;15(1):41-7. 
28 http://www.clinicaltrials.gov/ct2/show/NCT01144338?term=EXSCEL&rank=1