Clinical trial NCT02920918
Conditions: Heart Failure, Systolic Diabetes Mellitus, Type 2
Keywords: Systolic Heart Failure Canagliflozin Sitagliptin Phosphate Type 2 Diabetes SGLT2 inhibitor DPPIV inhibitor
Sponsor: Virginia Commonwealth University
Start date: 2016-10-01; Completion date: 2018-09-01
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Investigator Initiated Study to study the effects of Canagliflozin 100 milligrams (mg) vs Sitagliptin 100 mg on parameters of aerobic exercise capacity (peak oxygen consumption \[VO2\]) and ventilator efficiency (minute ventilation \[VE\]/carbon dioxide production \[VCO2\] slope) at cardiopulmonary exercise test (CPET) after 12 weeks of active treatment (primary endpoints). Blood pressure (BP), body water content, body composition, cardiac function, and diet will be also measured (secondary endpoints).

Detailed description:
Investigator Initiated Study: Randomized, double-blinded, active-control clinical trial to determine the safety and efficacy of Canagliflozin and Sitagliptin in patients with type 2 diabetes and systolic heart failure (HF).

The investigators propose to study the effects of Canagliflozin 100 mg vs Sitagliptin 100 mg (both administered once daily for 12 weeks) on parameters of aerobic exercise capacity and ventilator efficiency by CPET after 12 weeks of active treatment. BP, body water content (Bioelectrical Impedance Analysis \[BIA\]), body composition (Dual-energy X-ray absorptiometry \[DEXA\]), cardiac function, diet and biomarkers will be also measured. Subjects with evidence of left ventricular hypertrophy will undergo cardiac magnetic resonance (CMR) imaging.

Arms: arm 1: Canagliflozin will be administered orally in pill form at 100 mg, daily for 12 weeks. arm 2: Sitagliptin will be administered orally in pill form at 100 mg, daily for 12 weeks.
Interventions: intervention 1: Canagliflozin intervention 2: Sitagliptin
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_ICF_000.pdf: 
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Treatment of Diabetes in Patients 
with Systolic Heart Failure 
 
A Randomized Active-Control Double-Blinded Study 
 
 
 
 
The CANA-HF trial 
 
Canagliflozin in Heart Failure 
 
 
 
 
 
 
 
 
Principal Investigators:  
Antonio Abbate, MD, PhD; Salvatore Carbone, MS 
 
Sponsor: 
Virginia Commonwealth University  
 
Financial support provided by: 
Janssen Scientific Affairs 
 
 
    STUDY PROTOCOL   


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TABLE OF CONTENTS 
 
1) 
PROTOCOL SUMMARY 
2) 
SCHEMATIC OF STUDY DESIGN 
3) 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
4) 
OBJECTIVES 
4.1   Study objectives 
4.2   Study outcome measures  
5) 
STUDY DESIGN 
5.1   Treatment arms 
5.2 
 Randomization 
5.3   Treatment with canagliflozin or sitagliptin 
5.4 
Study assessments  
5.5 
 Study schedule 
6) 
ENROLLMENT IN THE STUDY 
6.1   Screening 
6.2   Inclusion criteria 
6.3   Exclusion criteria 
7) 
POTENTIAL BENEFITS AND RISKS 
7.1   Canagliflozin 
7.2 
 Sitagliptin 
7.3   Social and psychological risks 
7.4   Testing Risks 
7.5 
Direct benefits to study participants 
8) 
ASSESSMENT OF SAFETY 
8.1   Specification of safety parameters 
8.2  
 Methods of timing for assessing, recording, and analyzing safety 
parameters 
8.3   Reporting procedures 
8.4   Regulatory reporting 
8.5 
 Reconciliation of serious AEs 
9) 
DISCONTINUATION OF TREATMENT AND WITHDRAWAL 
10) 
STATISTICAL CONSIDERATIONS 
11) 
REFERENCES 
 
Appendix B - Case report forms 
 
 


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1) 
 PROTOCOL SUMMARY 
 
Title: 
Treatment of Diabetes in patients with Systolic Heart 
Failure 
 
Population: 
88 Patients aged ≥18 years with type 2 Diabetes Mellitus 
and systolic Heart Failure  
 
Study Duration: 
 
24 months 
 
Description:   
Phase IV clinical trial of Canagliflozin vs Sitagliptin for the 
treatment of type 2 diabetes mellitus and systolic heart 
failure.  
 
 
 
 
 
 
Objectives: 
To determine the safety and efficacy of SGLT2 inhibition in 
patients with type 2 diabetes and systolic heart failure in 
terms of aerobic exercise capacity and ventilator efficiency, 
blood pressure, fluid status, body composition and left 
ventricular structure and function. 
 
Study Design: 
Randomized, double-blinded, active-control clinical trial with 
allocation to Canagliflozin 100 mg or Sitagliptin 100 mg daily 
for 12 weeks in a 1:1 ratio. Patients will be assessed at 4, 8 
and 12 weeks after treatment initiation. 
 
 
 
 
 
Estimated Time to  
Complete Enrollment: 
21 months 
 
 


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2)  
SCHEMATIC OF STUDY DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients with Type 2 Diabetes 
and Systolic Heart Failure 
Screening testing (if not already clinically 
available): Biomarkers, Echocardiogram 
A)Canagliflozin 100 mg daily (12 weeks) (44 subjects) 
B)Sitagliptin 100 mg daily (12 weeks) (44 subjects) 
Baseline testing: CPET, DEXA, BIA, Biomarkers, BP, AASI, 
Echocardiogram, Urine Analysis, CMR (substudy), Diet 
8-week testing: Safety assessment, BIA, BP, Biomarkers 
12-week testing: Safety assessment, CPET, DEXA, BIA, 
Biomarkers, BP, AASI, Echocardiogram, Urine Analysis, CMR 
(substudy), Diet 
4-week testing: Safety assessment, BIA, BP, Biomarkers 
Randomization 


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3) BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
Heart Failure (HF) is defined by the ACCF/AHA as “a complex clinical syndrome that 
results from any structural or functional impairment of ventricular filling and/or ejection of 
blood”. It is estimated that about 38 million people worldwide are diagnosed with HF, 5.7 
million in the United States (US) alone with 870,000 new HF cases every year. HF 
patients typically present dyspnea, fatigue, fluid retention and exercise intolerance [1]. 
The pathophysiologic abnormalities driving to the development and progression of HF 
are very complex and partly unknown. HF cannot be exclusively considered a cardiac 
disease, since metabolic abnormalities and disorders, such as insulin-resistance and 
type II diabetes mellitus (T2DM) are highly prevalent [2-4].  
Diabetes mellitus is a “group of metabolic diseases characterized by hyperglycemia 
resulting from defects in insulin secretion and/or insulin action” [5]. About 347 million 
people worldwide have diabetes and 86 million have pre-diabetes. In the US alone 21 
million people have been diagnosed with diabetes, and about 8 million have 
undiagnosed diabetes. Moreover, diabetes is the 7th cause of death in the US [6]. 
Diabetes is associated with many cardiovascular risk factors, which in turn, increase risk 
for the development of HF [6,7]. Diabetes, however, is an independent risk factor for HF 
and both diseases simultaneously affect a large population [7]. Moreover diabetes is an 
independent risk factor for mortality among individuals with diagnosed HF. The survival 
rate in patients with HF and diabetes is significantly lower compared to subjects with HF 
or diabetes alone [8,9]. The concurrent presence of HF and diabetes presents a major 
challenge of improving metabolic control and heart failure symptoms at the same time.   
The majority of patients with diabetes mellitus (about 90%) are affected by type 2 
Diabetes (T2DM), a result of a chronic insulin-resistant state followed by progressive 
dysfunction and finally failure of pancreatic β-cells [10]. Overweight and obesity, 
particularly the excess of body fat, 
represent the major risk factors for 
the 
development 
of 
insulin 
resistance and thus T2DM [6]. 
Several therapies exist for the 
treatment 
of 
T2DM 
aimed 
to 
improved glucose control [11,12] 
reflected in the reduction of the 
HbA1c. Although a reduction in the 
HbA1c has proven to improve 
micro-vascular 
complications 
related to T2DM [11,12], HbA1c 
Figure 1. Reduced hospitalization for HF in patients with T2DM treated with 
empagliﬂozin, an inhibitor of the SGLT2. From Zinman B et al. N Engl J Med 
2015;373(22):2117-28. 


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control has never been shown to reduce macro-vascular complications and/or overall 
mortality [14-16], hypothesizing potential alternative mechanisms by which diabetes 
affects the cardiovascular system. Indeed, only in a recent groundbreaking study [17], 
the inhibition of the SGLT2 has shown for the first time to reduce cardiovascular 
mortality and hospitalizations for HF in T2DM patients (Figure 1) despite a modest 
reduction in HbA1c. 
In 
this 
study 
we 
hypothesize 
that 
Canagliflozin 
(Invokana®) 
will 
improve 
cardiorespiratory fitness in patients with systolic heart failure and type 2 diabetes in 
comparison with Sitagliptin (Januvia®). We also hypothesize that the improved 
cardiorespiratory fitness is related to an improvement in blood pressure, changes in left 
ventricular structure and function, and in body composition and fluid status, and not 
directly to glycemic control.  
SGLTs are membrane proteins involved in the transport of glucose, vitamins, amino 
acids, and ions in the brush border membrane of the gut epithelium, in the proximal 
renal tubules, and recently found in the heart [18-22]. SGLT1 and SGLT2 are located in 
proximal kidney tubule, while SGLT1 is also broadly expressed in the gut and the heart 
[18-22]. SGLT1 is a high-affinity, low capacity transporter while SGLT2 is a low-affinity, 
high capacity transporter. SGLT2 mediates glucose uptake in the early proximal tubule 
and is responsible for the majority of glucose reabsorption at the glomerulus level. The 
remaining glucose (≈10%) is then reabsorbed by the SGLT1 [18-23]. The kidneys 
reabsorb the majority of glucose before the “glucose renal threshold” (GRT) is reached. 
When the amount of glucose exceeds the GRT, the exceeding glucose is excreted in 
the urine proportionally to plasma glucose concentration. The GRT in healthy subjects is 
≈180 mg/dL, meaning that when plasma concentration exceeds such a level, glucose 
begins to be excreted by the kidney into the urine. Importantly, for each molecule of 
glucose, one sodium molecule is also reabsorbed from the SGLT2, while 2 molecules of 
sodium for each molecule of glucose are required for the SGLT1 [18-23]. 
In diabetic patients the glucose renal threshold is significantly increased to roughly 240 
mg/dL, increasing the reabsorption of glucose and contributing to hyperglycemia [23]. 
The mechanisms by which diabetes increases the GRT are still unknown. Researchers 
have been studying ways to reverse the GRT increase, and to possibly even reduce it 
below physiologic levels. That allows to further increase glycosuria, finally lowering 
plasma glucose concentrations.  
The SGLTs are overexpressed in diabetic patients. In animal models lacking SGLT2, 
improvements in glucose control were observed [24]. Inhibitors of the SGLT2 have then 
been proposed as new strategies to improve glucose control in patients with T2DM. To 
date, three SGLT2 inhibitors have been approved by the Food and Drug Administration 
(FDA) in the United States based on their efficacy in improving HbA1c: Empagliflozin, 


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Canagliflozin and Dapagliflozin. SGLT2 inhibitors are neither insulin sensitizers nor 
secretagogues acting in an insulin-independent manner [18,23]. They reduce the GRT, 
thereby increasing the excretion of glucose in the urine by 60-100 g/day, reducing 
plasma glucose concentrations [23,25,26]. 
SGLT2 inhibitors also possess non-glucose related effects. They improve blood 
pressure, arterial compliance, body weight and body composition (fluid status, fat mass, 
lean mass) [23,25-28] suggesting the existence of alternative mechanisms beyond the 
mere reduction in kidney reabsorption of glucose (glucose-lowering effect). The 
definitive proof of extra-glycemic effects was explored in the EMPA-REG OUTCOME 
trial [17] in which the selective inhibition of the SGLT2 with Empagliflozin, when 
compared to standard of care, had exciting beneficial effects on total cardiovascular 
mortality and overall mortality. Moreover, a significant reduction in hospitalization for 
heart failure was reported [17,29]. Interestingly these results seemed to be independent 
of the reduction in the HbA1c that was only slightly reduced compared to standard of 
care. Except for some results seen with metformin on cardiovascular outcomes, the 
EMPA-REG OUTCOME was the first trial in which an anti-diabetic drug showed benefits 
on cardiovascular mortality, total mortality and HF hospitalizations, despite minor 
improvements in glucose control. However, the mechanisms by which SGLT2 inhibition 
improves cardiovascular outcomes are largely unknown. SGLT2 inhibitors can: 1) 
Improve blood pressure possibly through the diuretic and natriuretic effects. Diuretics 
have beneficial effects on mortality in diseases such as hypertension [30], but they have 
never been broadly investigated in randomized placebo-controlled trials in HF [31]. 
Diuretics improve symptoms of congestion and quality of life in HF patients [31], but 
whether these effects translate into improved outcomes remains unknown 2) Improve 
fluid status possibly related to the above-mentioned natriuretic effects 3) Improve body 
weight and body composition by reducing body weight, but more importantly reducing 
fat mass and preserving lean mass, important determinant of cardio-respiratory 
functionality in patients with and without HF [32,33]. The improvements on body 
composition parameters seem to be related to the reduced reabsorption of glucose in 
the kidney, therefore inducing a caloric deficit able to promote weight loss [23,26,27]. 
These improvements could potentially link SGLT2 inhibitors and proposed improved 
fitness 4) Improve arterial compliance; arterial stiffness is related to worse 
cardiovascular outcomes [34]. Selective inhibition of SGLT2 improved arterial stiffness 
in patients with T2DM [27], suggesting an additional mechanism by which SGLT2 
inhibitors affect the vascular tone 5) Reduction in uric acid level. Plasma levels of uric 
acid predict adverse outcomes in heart disease [35]. Recent data showed that SGLT2 
inhibitors could reduce uric acid levels by possibly increasing uric acid excretion [36,37]. 
Whether these improvements translate in improved outcomes in T2DM and/or HF is 
unknown. Therefore we cannot exclude that Canagliflozin will be neutral in patients with 
HF and T2DM. Furthermore, there is a possibility the Canagliflozin may be harmful, 


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potentially by inducing hypovolemia and hypotension, particularly when administered 
concomitantly with other antihypertensive drugs. We believe the potential harmful 
effects, more evident when Canagliflozin was administered at the higher dose (300 mg) 
in prior studies, will be minimized in this trial since we are planning to use the lower 
dose (100 mg).  
Canagliflozin will be compared to Sitagliptin, a dypeptidil peptidase (DPP)-IV inhibitor. 
DPPIV hydrolyzes glucagon-like peptide 1 (GLP1), a gut hormone produced in 
response to glucose ingestion and responsible for about 70% of insulin secretion 
[38,39]. DPPIV activity is increased in diabetic patients, thus reducing the level of active 
GLP1. Therefore by inhibiting DPPIV, there is a significant increase in GLP1 levels to 
physiologic values. That induces an increase in insulin secretion with improvements in 
glucose control, measured by reduction in HbA1c [38,40]. 
As shown in the Diabetes Control and Complication Trial (DCCT) in patients with Type 1 
Diabetes [41], and in the United Kingdom Prospective Diabetes Study (UKPDS) in 
patients with T2DM [42], improvements in glucose control measured by reduction in 
HbA1c result in prevention or reduction in micro-vascular complications [43]. Therefore 
Sitagliptin may improve diabetes micro-vascular complications. Moreover Sitagliptin has 
been tested in several clinical trials and based on its effectiveness and safety has 
become one of the most prescribed anti-diabetic medications in the US [44].  
We are planning to compare doses of Canagliflozin and Sitagliptin that in prior studies 
provided a comparable reduction in HbA1c compared to placebo at 26 weeks (0.79% 
for Canagliflozin 100 mg; 0.82% for Sitagliptin 100 mg) and at 52 weeks (0.73% for 
Canagliflozin 100 mg; 0.73% for Sitagliptin 100 mg)[45]. 
As already described, the mechanisms of action of Canagliflozin are, however, very 
different compared to Sitagliptin. Canagliflozin acts in an insulin-independent manner 
inhibiting the SGLT1 and SGLT2 [18,23], while Sitagliptin increases the production of 
insulin by increasing the levels of GLP1 [38].  
We believe the different mechanisms of action of Canagliflozin may explain the non-
glucose lowering effects seen in patients treated with SGLT2 inhibitors, and not in the 
ones treated with DPPIV inhibitors, like Sitagliptin.  
HF is characterized by impaired aerobic exercise capacity and ventilatory inefficiency 
[46,47]. Similarly to what has been seen in HF, cardio-respiratory fitness (CRF) may 
predict all-cause mortality in diabetics [48,49]. Therefore when HF and T2DM coexist, 
the need for improving CRF and thus prognosis is imperative. Peak aerobic exercise 
capacity is measured using ventilator expired gas analysis and measuring oxygen 
consumption.  Higher peak VO2 reflects better cardiorespiratory fitness in HF, and is an 
independent predictor of mortality in HF [50-54]. Peak VO2 is not biased by 


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overexertion, shows minimal familiarization effects over time, exhibits high intra-class 
correlation coefficients (ICC>0.90) and is insensitive to placebo-effect [46,47,50-54]. 
Ventilatory efficiency is measured using ventilator expired gas analysis and measuring 
peak ventilation (VE) and CO2 elimination (VCO2), a high VE/VCO2 reflects an 
inefficient system requiring larger ventilation for the same degree of CO2 elimination. As 
for peak VO2, also VE/VCO2 slope is an independent prognostic factor in HF, it is not 
biased by overexertion, shows minimal familiarization effects over time, exhibits high 
intra-class correlation coefficients (ICC>0.90) and is insensitive to placebo-effect 
[46,47,50-54].  
 
4) 
OBJECTIVES 
 
 
4.1  
Study Objectives 
We propose to study the effects of SGLT2 inhibition with Canagliflozin 100 mg vs 
Sitagliptin 100 mg on parameters of aerobic exercise capacity (peak VO2) and ventilator 
efficiency (VE/VCO2) at CPET after 12 weeks of active treatment (co-primary 
endpoints). Blood pressure and body water content will be measured at baseline, 4 
weeks, 8 weeks and 12 weeks (secondary endpoints). Body composition, cardiac 
function, left ventricular mass and diet will be measured at baseline and after 12 weeks 
of treatment (secondary endpoints).  
Biomarkers will be collected at baseline and at 12 weeks. Kidney function will be 
additionally measured at 4 weeks and at 8 weeks.  
4.2 
Study Outcome Measures 
Cardiopulmonary Exercise Test (CPET): We will treat patients with T2DM and HF with 
Canagliflozin (n=44) or Sitagliptin (n=44) for 12 weeks, in a double-blinded fashion. We 
will measure CRF with a validated CPET at baseline and after 12 weeks of treatment, to 
determine whether Canagliflozin improves cardiorespiratory fitness assessed by 
changes in peak VO2 and VE/VCO2 slope, in comparison with Sitagliptin, for which we 
do not expect to see changes in cardiopulmonary capacity.  
Blood pressure and Bioelectrical Impedance Analysis (BIA): We will measure resting 
blood pressure and fluid status every 4 weeks. Fluid status will be determined using the 
BIA, to measure changes in total, extracellular and intracellular body water. We expect 
to see improvement in blood pressure and fluid status in patients treated with 
Canagliflozin, while we do not expect significant changes in the Sitagliptin-treated 
group.  
Dual-energy X-ray absorptiometry (DEXA): At baseline (Visit 1) and at 12 weeks (Visit 
4) we will accurately quantify body lean mass (LM) and appendicular LM (ALM) in 


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particular, which correlates best with body strength and functionality [55-61], and we will 
measure also fat mass (FM). We expect to see improvements in body composition in 
the Canagliflozin-treated group (reduction in FM and preservation or increase of ALM) 
and not in the Sitagliptin group.  
Echocardiography: structural and functional echocardiographic parameters include left 
and right ventricular dimensions, mass, systolic and diastolic function, and longitudinal 
strain analysis. These will provide mechanistic insight as to whether the hypothesized 
changes in aerobic exercise performance are dependent upon changes in cardiac 
dimension/function. The data will be collected and electronically stored for further 
analysis at the conclusion of the study.  
FibroScan®: A FibroScan® exam will be performed at baseline (Visit 1) and at 12 
weeks (Visit 4) to determine liver fibrosis and fat content.  
 
Biomarkers: Blood will be collected at each time-point throughout the study (0, 4, 8, and 
12 weeks). At baseline and at 12 weeks a complete panel of biomarkers (i.e., 
inflammatory, metabolic, cardiac, neurohormonal, renal functions, etc…) will be 
measured. At 4 and 8 weeks safety biomarkers will be measured (i.e., renal function). 
Urine analysis: Urine will be collected at baseline and at 12-week to measure 
electrolytes, glucose, volume excretion and renal function. 
Dietary assessment: We will estimate the nutritional components of the diet with a 
standardized 24-hour recall system at baseline and after 12 weeks to measure potential 
changes in dietary intake. 
Ambulatory arterial stiffness index: Patients will undergo an indirect assessment of 
arterial stiffness by the measurement of the ambulatory arterial stiffness index (AASI) at 
baseline and 12 weeks.  
Cardiac Magnetic Resonance (CMR): A pre-specified subgroup of subjects who have 
left ventricular hypertrophy (LVH)(N=32 – Stratus A1) will undergo a CMR imaging with 
intravenous gadolinium infusion using a 3 T magnet in order to quantify left and right 
ventricular mass and volumes, and extracellular volume content at baseline and at 12 
weeks (Visit 4). In order to be included in the sub-study, subjects will need to meet all 
inclusion criteria for the study and also have a determination of LVH by 
echocardiography during the screening process, defined as a left ventricular mass index 
>116 g/m2 in men and >96 g/m2 in women [43]. To reduce the risk of nephrogenic 
systemic fibrosis or dermopathy, only subjects with glomerular filtration rate >60 ml•min-
1/1.73m2 will be considered for the sub-study.   


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Questionnaires: The  Minnesota  Living with  Heart  Failure  questionnaire  (MLHFQ), the 
Duke Activity Status Index (DASI) and the International Physical Activity questionnaire 
(IPAQ) will  be  used  to  measure potential impairments in  quality  of  life and  physical 
activity level at Visit 1 (baseline) and at Visit 4 (12 weeks).  
5) 
STUDY DESIGN 
5.1  Treatment arms 
We  designed  an active-controlled,  double-blinded randomized  study  of Canagliflozin 
versus Sitagliptin in patients with heart failure with reduced ejection fraction or systolic 
heart failure. The study is composed of 2 treatment arms exploring: 
a) Canagliflozin 100 mg once daily for 12 weeks;    
b) Sitagliptin 100 mg once daily for 12 weeks. 
 
Patients  will undergo  baseline  clinical  assessment,  CPET, blood  pressure and  fluid 
status (BIA), body  composition  (DEXA), dietary  assessment, echocardiogram, 
FibroScan, AASI (24-hour ABPM), biomarkers and urine analysis, and CMR (substudy 
in  patients  with  LVH).  After 4 weeks and  8  weeks  of treatment, blood  pressure,  
fluid 
88 subjects 
with T2DM 
and HF 
Baseline 
4 weeks 
8 weeks 
12 weeks 
Figure 2 - Study design. Randomized double-blind ac1ve-controlled trial, daily treatment with Canagliﬂozin 100 mg or Sitaglip1n 
100  mg.  CPET  =  cardio-pulmonary  exercise  test  
(peak  VO2  and  VE/VCO
2);  Ques1onnaires  =  quality  of  
life  
(DASI  and  MLHFQ); 
DEXA = Dual-energy X-ray absorp1ometry (appendicular lean mass, fat mass - body composi1on); BIA = Bioelectrical Impedance 
Analysis (ﬂuid status); HbA1c = glycated hemoglobin, FPG = fas1ng plasma glucose (glucose control); BP = blood pressure; AASI = 
ambulatory  arterial  s1ﬀness  
index;  Biomarkers  =  safety  
(cardiac,  kidney)  and  
inﬂamma1on;  Biomarkers  
(kidney)  = crea1nine, 
eGFR;  Urine  analysis; Fibroscan  =  liver  ﬁbrosis  and  fat  content;  Dietary  assessment  =  24-hour  dietary  recall  CMR  =  cardiac 
magne1c resonance in 32 pa1ents with le` ventricular hypertrophy and eGFR ≥ 60 ml•kg
-1•min-1.  
Canagliﬂozin 100 mg 
N=44 
N=44 
SitaglipIn 100 mg 
Screening 
BP 
Biomarkers 
(kidney) 
HbA1c, FPG 
BP 
Biomarkers 
(kidney) 
BIA 
DEXA, BIA 
CPET and QuesIonnaires 
BP and AASI 
Biomarkers 
HbA1c, FPG, 
Insulin, Lipids 
Echo 
Urine analysis 
Urine analysis 
DEXA, BIA 
Biomarkers 
HbA1c, FPG,  
Insulin, Lipids 
Echo 
Urine analysis 
BP 
Biomarkers 
(kidney) 
BIA 
BP and AASI 
CMR 
CMR 
FibroScan 
FibroScan 
Dietary assessment 
CPET and QuesIonnaires 
Dietary assessment 


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status and kidney biomarkers will be repeated. At 12 weeks (Visit 4), changes in peak 
VO2 and VE/VCO2 slope in Canagliflozin treated patients versus Sitagliptin will be 
determined. At 12 weeks, all the baseline tests will be repeated (DEXA, BIA, dietary 
assessment, blood pressure, echocardiogram, FibroScan, AASI, biomarkers and urine 
analysis, and CMR (substudy)(Figure 2). 
 
At study end, the patients will be transitioned to standard-of-care anti-diabetic treatment 
according to the patient and physician preference. 
 
5.2  
Randomization 
The Investigational Pharmacist not involved in patient care, data gathering, or data 
analysis, will be in charge of randomization. Patients will be randomized 1:1 to 
Canagliflozin 100 mg or Sitagliptin 100 mg. Due to the need of stratification for patients 
with LVH, the Investigational Pharmacist will be notified about presence/absence of 
LVH to stratify 44 patients to stratum A (presence of LVH) and 44 to stratum B (absence 
of LVH). Patients in stratum A will be further stratified in stratum A1 (N=32) who will 
need to have also an estimated glomerular filtration rate >60 ml•min-1/1.73m2 and no 
contraindications to undergo Cardiac Magnetic Resonance (CMR) with intravenous 
gadolinium infusion (see Exclusion criteria), and in stratum A2 (N=12) who will meet 
inclusion in the CANA-HF trial but have contraindications to CMR (i.e., estimated 
glomerular filtration rate <60 ml•min-1/1.73m2, claustrophobia, body weight over CMR 
permitted limit). 
 
5.3 
Treatment with canagliflozin and sitagliptin 
After completion of all baseline testing patients will be given a 12-week supply of 
Canagliflozin 100 mg or Sitagliptin 100 mg. Intermediate visits, 4-week and 8-week will 
be scheduled within respectively 28±7 and 56±7 days after baseline visit. Patients will 
receive instruction from the investigators regarding daily administration of Canagliflozin 
or Sitagliptin. The 12-week visit will be scheduled within 84±10 days after baseline visit.  
Canagliflozin or Sitagliptin are dispensed in non-identifiable capsules over-encapsulated 
by the investigational pharmacist to create the blinded study capsules. The 
Canagliflozin 100 mg or Sitagliptin 100 mg capsules will be indistinguishable. 
Investigational pharmacist will mark capsules containers in a way that neither the 
patient nor the physician will be able to distinguish between the two drugs.  
The investigational Pharmacist at VCU will prepare the randomization. Access to 
randomization log will be restricted and allowed only on an emergency basis, or at the 
end of the study, including all data collection. In case of an emergency, a physician 
treating any patient enrolled in the study may request unblinding of that individual 


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patient if the physician determines that unblinding is necessary to make a treatment 
decision. The PI will contact the VCU Investigational Pharmacy to provide the treatment 
allocation to the PI, who will then relay the information to the treating physician. Upon 
completion of the study (including completion of all data collection and event 
adjudication), the PI will request the complete randomization log from the VCU 
Investigational Pharmacy. 
Patients in the study will receive HF and T2DM guidelines-based medical treatments as 
clinically indicated. Canagliflozin or Sitagliptin will be added in adjunct to standard of 
care. However, the treatment is blinded to patients and investigators involved in patients 
care. To avoid providers prescribing additional SGLT2 inhibitors or DPPIV inhibitors, 
after a subject is enrolled, we will write a note in the clinical chart informing providers 
about the enrollment in the study and the recommendation to not prescribe SGLT2 
inhibitors or DPPIV inhibitors in such patient. That allows avoiding a patient to be 
treated with two drugs belonging to the same class. 
5.4  
Study assessments 
 
Upon completion of screening/enrollment, all subjects will be scheduled for Baseline 
visit (Visit 1) at the cardiopulmonary exercise suite. A supervised maximal aerobic 
exercise test will be administered using a metabolic cart that is interfaced with a 
treadmill. A conservative ramping treadmill protocol will be used. Prior to each test, the 
oxygen and carbon dioxide sensors will be calibrated using gases of known oxygen, 
nitrogen, and carbon dioxide concentrations and the flow sensor will also be calibrated 
using a 3-liter syringe. Subjects will then be briefed regarding the protocol and will be 
requested to exercise to fatigue. 12-lead ECG monitoring will be conducted at baseline, 
throughout the test and into recovery. Blood pressure will be measured every two 
minutes using an automated exercise-compatible device (Tango, SunTech Medical). In 
this technique, expired gases are sampled using a mouthpiece-mounted sensor, and 
analyzed to continuously measure oxygen (O2) uptake; the highest 10-second average 
value for O2 uptake defines peak oxygen consumption (VO2 peak in mL•kg-1•min-1). 
The ventilatory equivalents method will be used to determine VO2 at ventilatory 
threshold. Ten second averaged VE and VCO2 data, from the initiation of exercise to 
peak, were input into spreadsheet software (Microsoft Excel, Microsoft Corp., Bellevue, 
WA) to calculate the VE/VCO2 slope via least squares linear regression (y = mx + b, 
m=slope).  Peak Respiratory Exchange Ratio (VCO2/VO2) will be used for determining 
maximal to near maximal effort.  A peak RER >/=1.10 is well accepted as a criterion for 
maximal effort and a peak RER >/= 1.0 is considered a minimal acceptable threshold. 
American Heart Association guidelines for exercise testing contraindications and 
termination criteria will be followed.  
 


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Upon completion of exercise testing, the results of the cardiopulmonary exercise test 
will be reviewed and discussed with the patients. Patients with angina, abnormal blood 
pressure or heart rate response, or ECG changes suggestive of coronary ischemia will 
be excluded from the study.  
 
Subjects will return to the cardiopulmonary exercise suite for the additional visits upon 
completion of 12 weeks (visit 4, 84±10 days) of treatment with Canagliflozin or 
Sitagliptin. At Visit 1 and Visit 4, subjects will undergo a brief physical exam and repeat 
exercise testing. Raw data from the cardiopulmonary test will be analyzed at the end of 
the study, free of patient identifiers. 
 
Resting blood pressure will be measured at baseline, 4, 8 and 12 weeks. The mean of 
three blood pressure measurements after being seated for 5 minutes will be taken.  
 
Fluid status will also be analyzed. We will measure total body water (TBW) and its 
distribution in the intra- (ICW) and extra-cellular (ECW) compartments by a 
Bioelectrical Impedance Analysis (BIA)(RJL System). BIA introduces (non-invasively) 
into subjects’ body a current at a given single-frequency (50 kHz) passing through a 
source electrode and a detector electrode, located in the homolateral hand and ankle. 
As a result BIA allows the analysis of Resistance (R) and Reactance or Capacitance 
(Xc) and their vector relationship Impedance (Z) [23-26]. R derives from extra- and intra-
cellular fluid while Xc from cell membranes. Based on predictive equation obtained by 
regression analysis BIA estimates TBW, ICW and ECW. BIA is an indirect measure of 
body fluids, which has been validated against several direct measurements such as 
deuterium oxide for the measurement of TBW, bromide dilution for the measurement of 
ECW and total-body potassium for the assessment of ICW [23-26]. 
 
Body composition, particularly LM and FM, are considered better determinants of 
cardio-respiratory fitness (CRF) than body weight and Body Mass Index (BMI)[40-42]. 
Body composition will be measured with the Dual-energy X-ray absorptiometry 
(DEXA) at baseline (visit 1) and after 12 weeks (Visit 4). DEXA allows to estimate 
appendicular LM that describes the amount of LM in the legs and the arms, which are 
considered the major determinants of strength and functionality. The DEXA uses a 
small amount of X-rays of two different photon energy levels that pass through the body 
and are identified by a photon detector. The photon detector measures the attenuation 
(amount of energy absorbed) at each pixel by the bone and the soft tissue, which is 
further divided into fat and lean mass86,87,94. Radiation exposure amount is very low 
(0.02-1-5 mrem) compared to other assessments such as conventional X rays 
technique (25-270 mrem)61. Tests will be completed in the dedicated DEXA suite of the 


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VCU Division of Endocrinology. Subject with body weight exceeding DEXA permitted 
limit will not undergo DEXA. 
 
Dietary intake data gathered by interview is governed by a 5-pass interview approach 
in which items are listed, reviewed, then described in details (including preparation), 
quantified, probed for frequently forgotten foods, and eventually reviewed again [62-65]. 
Data will be collected using Nutrition Data System for Research (NDSR), a computer-
based software application developed at the University of Minnesota Nutrition 
Coordinating Center (NCC). The NCC Food and Nutrient Database serves as the 
source of food composition information in the NDSR. This database includes over 
18,000 foods. Values for 165 nutrient, including carbohydrates, protein, fat and 
electrolytes like sodium and potassium, nutrient ratios and other food components are 
generated [62-65]. The USDA Nutrient Data Laboratory is the primary source of nutrient 
values and nutrient composition. 
 
Prior to initiation of treatment, all subjects will undergo a transthoracic 
echocardiogram to measure left ventricular diastolic and systolic volumes, transmitral 
flow Doppler spectra, mitral and tricuspidal valve annulus tissue Doppler spectra, and 
tricuspidal annulus plane systolic excursion, according to the recommendations of the 
American Society of Echocardiography [66]. The echocardiogram will be repeated at 
12-week visit (Visit 4). All images and loops will be acquired in an electronic format and 
transferred to the VCU Pauley Heart Center for blinded centralized measurements at 
the end of the study. 
 
Biomarkers and urine analysis will be measured by LabCorp (Burlington, NC). Blood 
samples collected from peripheral vein and urine analysis will be performed at baseline 
(Visit 1), and 12 weeks (Visit 4), and used for analysis of complete cell count with 
differential, biomarkers (inflammatory, metabolic, cardiac, kidney, neurohormonal). At 4-
week (Visit 2) and at 8-week (Visit 3), renal function will be monitored. The tubes will be 
collected by trained personnel, and immediately inverted 8-10 times after being drawn. 
Samples are then processed, refrigerated and shipped within 24 hours to LabCorp. 
Some of the cardiac biomarkers (i.e., high-sensitivity Troponin) will be measured in a 
single batch at end of study. After collection, samples will be stored in a freezer located 
our lab. The results from LabCorp will be sent to the PIs and designated investigators 
by email and/or fax. 
 
Ambulatory arterial stiffness index (AASI) will be measure at baseline and 12 weeks. 
AASI will be defined as 1 minus the regression slope of diastolic blood pressure and 
systolic blood pressure measured with a 24-hour ambulatory blood pressure monitor 


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(ABPM)[67]. The patients will be instructed on the use the ABPM. A date, time and 
location will be also scheduled to return the ABPM to the study personnel. 
 
Prior to each cardiopulmonary exercise test, subjects will complete the Minnesota 
Living with Heart Failure and the Duke Activity Status Index (DASI) 
questionnaires, and the International Physical Activity questionnaire (IPAQ). The 
Minnesota Living with Heart Failure questionnaire (MLHFQ) is a 21-question graded 
questionnaire that has been extensively used to measure impairment in quality of life in 
patients with HF [68]. The questions are designed to measure a wide range of physical, 
emotional, social, and mental factors that contribute to overall quality of life. The DASI is 
a twelve-item “yes/no” questionnaire that allows for the calculation of perceived 
functional capacity. Each question describes a different physical activity and asks the 
subjects if they feel they can perform the task. The questions are weighted according to 
their degree of physical exertion. The weighted values from “yes” responses are 
summed to produce a score in metabolic equivalents. The IPAQ-short is a 7-question 
questionnaire that allows the estimation of daily physical activity by asking the subjects 
about duration and intensity of daily physical activity.   
 
Subjects with evidence of LVH will undergo a cardiac magnetic resonance study 
(CMR) including intravenous infusion of gadolinium. CMR studies will be obtained at the 
VCU Collaborative Advanced Research Imaging (CARI) or at the VCU Medical Center. 
The rationale for restricting this analysis to patients with LVH is that a reduction in left 
ventricular mass is associated with more favorable outcomes in patients with LVH, 
whereas it is not expected to occur nor to portend a favorable prognosis in those without 
LVH. The subjects will also be evaluated for additional exclusion criteria preventing the 
completion 
of 
the 
cardiac 
magnetic 
resonance 
(i.e. 
pacemaker/defibrillator, 
claustrophobia, prior metal implants not compatible with magnetic resonance imaging, 
estimated glomerular filtration rate <60 ml•min-1/1.73m2, body weight over CMR 
permitted limit). We will measure cardiac dimensions (volumes and mass) and systolic 
and diastolic function. Regional wall motion abnormalities will be assessed at cine-CMR 
using the 17-segment model [69-71]. Dedicated T1 and T2-weighted acquisition (T2 
mapping) to measure the presence of myocardial fibrosis and edema, and the 
extracellular content.  Paired analysis will be performed to determine changes in cardiac 
dimensions, function or extracellular volume content that can be attributed to study 
treatment. 
 
 


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5.5 
Study Schedule 
 
 
Visit 1 
(Baseline) 
Visit 2 
(28±7 days) 
Visit 3 
(56±7 days) 
Visit 4 
(84±10 days) 
Screening 
X 
 
 
 
Consent 
X 
 
 
 
Clinical assessment 
X 
X 
X 
X 
Medication list 
X 
X 
X 
X 
CPET 
X 
 
 
X 
Questionnaires 
X 
 
 
X 
Blood pressure 
X 
X 
X 
X 
DEXA 
X 
 
 
X 
BIA 
X 
 
X 
(only in CRSU) 
X 
(only in CRSU) 
X 
 
Echocardiogram 
X 
 
 
X 
FibroScan ® 
X 
 
 
X 
CMR (substudy) 
X 
 
 
X 
Biomarkers 
(complete) 
X 
 
 
X 
Biomarkers (kidney) 
 
X 
X 
 
Urine analysis 
X 
 
 
X 
AASI 
X 
 
 
X 
Dietary assessment 
X 
 
 
X 
 
 
6) 
ENROLLMENT IN THE STUDY  
Patients seen in clinic will be screened for inclusion and exclusion criteria. Part of the 
data needed for screening may not be available in the clinical chart, in such cases, after 
the patient has signed the informed consent form, the necessary laboratory and imaging 
studies will be ordered and charged to the research study account.  
6.1 
Screening 
All eligible patients will be screened among the patients seen in clinic. Patients meeting 
inclusion criteria will be approached to obtain informed consent. Patients agreeing to 
participate in the study will sign the informed consent form and will be given a copy of 
the consent form signed by the investigator performing the informed consent process. 
 
 


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6.2 
Inclusion Criteria 
All 5 criteria need to be met for enrollment of the patient in the study 
1) Symptomatic stable HF (NYHA class II-III) with reduced left ventricular ejection 
fraction (LVEF≤40%, measured within 6 months of enrollment – no changes in 
cardiac including anti-hypertensive medications within past 3 months); 
2) Peak exercise limited by shortness of breath and associated with a respiratory 
exchange ratio (RER) >1.00 (reflecting maximal aerobic effort); 
3) Reduced peak aerobic exercise capacity (peak VO2) to less than 80% of predicted 
value by age/gender; 
4) Poorly controlled T2DM (HbA1c levels between 7.0% and 10.0% if on a treatment 
regimen including insulin, or between 6.5% and 10.0% if not on an insulin regimen); 
5) The patient is willing and able to comply with the protocol (i.e, exercise protocol, 
body composition) 
6) Eighteen years of age or older. 
 
6.3 
Exclusion Criteria 
Subjects will not be eligible if they meet any of the following 13 exclusion criteria. 
1) Type I diabetes; 
2) Type II diabetes that is difficult to control (episodes of severe hypoglycemia <50 
mg/dl by history, hypoglycemia unawareness by history, frequent changes in anti-
diabetic regimen class in the past 3 months) or with prior episode of diabetic 
ketoacidosis (any time); 
3) Open label treatment with SGLT2 inhibitors (within the past 3 months); 
4) Current treatment with thiazolidinedione which may induce volume and sodium 
retention (within the past 3 months); 
5) Recent participation in a structured exercise or weight loss program (within the past 
6 months);  
6) Chronic Renal Disease defined as GFR <50 ml•min-1/1.73m2 according to local 
laboratory (since Canagliflozin 100 mg is not indicated for GFR <45 ml•min-1/1.73m2, 
and Sitagliptin 100 mg is not indicated for GFR <50 ml•min-1/1.73m2); 
7) Uncontrolled thyroid dysfunction (TSH<0.4>4.5 mcIU/ml); 
8) Pregnancy or of child-bearing potential or lactating; 
9) Active or recent (within 2 weeks) of genital/urinary infection; 
10) Concomitant conditions or treatment which would affect completion or interpretation 
of the study including physical inability to walk or run on a treadmill such as 
decompensated HF (edema, NYHA class IV), significant ischemic heart disease, 
angina, arterial hypotension (BP systolic <100 mmHg), orthostatic arterial 
hypotension, arterial hypertension (resting BP systolic >160 mmHg), atrial fibrillation 


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with rapid ventricular response, severe valvular disease, severe chronic obstructive 
or restrictive pulmonary disease, moderate-severe anemia (Hgb<10 g/dl), diabetic 
neuropathy or myopathy; 
11) Abnormal blood pressure or heart rate response, angina or ECG changes (ischemia 
or arrhythmias) occurring during baseline cardiopulmonary exercise testing (CPX); 
12) Current or recent (within 2 weeks) use of oral corticosteroids;  
13) Inability to give informed consent.  
 
Exclusion criteria specific to the CMR substudy. 
14) Estimated GFR <60 ml•min-1/1.73m2; 
15) Implantable cardioverter defibrillator, pacemaker or other implantable metal device 
not compatible with CMR scanning; 
16) Severe claustrophobia, inability to lay flat for up to 60 minutes, or other 
contraindication to CMR scanning, including body weight over CMR permitted weight 
limit. 
 
 
7) 
POTENTIAL BENEFITS AND RISKS  
 
 
7.1  
Canagliflozin  
Canagliflozin is a SGLT2 inhibitor (and SGLT1 inhibitor in a smaller extent); it improves 
glucose control, reduces blood pressure, and additionally improves body composition in 
T2DM [13-20]. 
Canagliflozin is orally administered and its safety and efficacy have been broadly 
investigated in healthy subjects and in patients with T2DM in either monotherapy or 
combination with other anti-diabetic drugs. Canagliflozin 100 mg once daily was 
approved by the FDA in 2013 for the treatment of diabetes. Canagliflozin 100 mg is 
associated with a significant reduction in hemoglobin A1c, blood pressure and body 
weight. Considering the increased incidence of hypovolemia observed in patients on 
Canagliflozin, especially if using loop diuretics [72], there will be no uptitration of dose to 
300 mg of Canagliflozin during the study. There is no loading dose and no dose-
adjustments needed with age or weight. Drug-to-drug interactions are very low and are 
not expected to be clinically relevant. Co-administration of Canagliflozin with rifampin 
(UGT enzyme inducer) has shown a reduction of Canagliflozin by 51%, possibly 
decreasing efficacy. Due do its mechanism of action, monitoring glucose control with 
urine glucose test is not recommended in patients taking SGLT2 inhibitors, due to false 
positive results. In subjects taking SGLT2 inhibitors the monitoring of glycemic control 
with 1,5-AG assay is not recommended since considered unreliable.  


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Side effects have been reported with Canagliflozin. The most likely side effects 
associated with the use of Canagliflozin include: 
• In men and women: 
- 
Dizziness or lightheadedness upon standing (up to 1 in 20 people), particularly in 
subjects already treated with diuretics, older patients and with subjects with 
reduced kidney function; 
- 
Hypoglycemia (approximately 4 in 100), particularly if associated with other anti-
diabetic drugs such as sulfonylurea or insulin in which case is more common (5 
in 10 people) and can be serious (up to 2  in 100 people);  
- 
Increased urination and thirst (approximately 1 in 20 people); 
- 
Urinary tract infections (approximately 1 in 20 people); 
- 
Allergic reaction including rash or hives (approximately 1 in 20 people), generally 
shortly after starting Canagliflozin and not associated with serious symptoms; 
- 
Constipation (less than 1 in 25 people); 
- 
Nausea (less than 1 in 25 people); 
- 
Diabetic ketoacidosis (approximately 1 in 1000 people); 
- 
Bone fractures (approximately in 50 people). 
- 
Amputation of the toes (and to a lesser extent the foot or leg) (up to 1 in 150 
people) 
- 
Laboratory changes observed in prior clinical trials with Canagliflozin but not 
associated with clinically significant illnesses: 
o Increase of approximately 4.5% in low-density lipoprotein cholesterol; 
o Increase in serum potassium, phosphate and/or hemoglobin of 
approximately 3.6%, 3.5% and 5% respectively; 
o Decrease of approximately 10% in serum urate.  
- 
Vaginal yeast infections and vaginal itching (<2 in 10 people)(in women); 
- 
Yeast infection at the head of the penis (up to 1 in 20 people), requiring 
circumcision in 0.3% in men who are not circumcised (in men). 
In subjects not enrolled in clinical studies, but who have been prescribed Canagliflozin, 
the following side effects have been reported. It is however unknown if these side 
effects are directly linked to the use of Canagliflozin since not reported in the completed 
clinical trials (serious allergic reactions; severe decrease in kidney function [mostly in 
dehydrated patients]; urosepsis and pyelonephritis).  
 
7.2  
Sitagliptin 
 
Sitagliptin is orally administered and its safety and efficacy have been broadly 
investigated in healthy subjects and in patients with T2DM in either monotherapy or 
combination with other anti-diabetic drugs. The FDA has approved Sitagliptin 100 mg 
for the treatment of diabetes. Sitagliptin 100 mg provides similar glucose-lowering 


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21 
effects of Canagliflozin 100 mg. There is no loading dose and no dose-adjustments 
needed with age or weight in subjects with normal or mildly reduced kidney function. 
Drug-to-drug interactions are very low. Increases in AUC and peak drug concentration 
of digoxin have been reported when administered with Sitagliptin 100 mg for ten days 
[73].  
 
Side effects have been reported with Sitagliptin. The most likely side effects associated 
with the use of Sitagliptin include: 
- 
Hypoglycemia, particularly if associated with other anti-diabetic drugs such as 
sulfonylurea or insulin (2 in 10 people), which can be severe (less than 1 in 100); 
- 
Upper respiratory infection (up to 3 in 50 people); 
- 
Headache (3 in 50 people);  
- 
Nausea, stomach upset and diarrhea (approximately 3 in 100 people) 
 
In subjects not enrolled in clinical studies, but who have been prescribed Sitagliptin, the 
following side effects have been reported. The real incidence is unknown. It is however 
unknown if these side effects are directly linked to the use of Sitagliptin since not 
reported in the completed clinical trials (swelling of the hands or legs, if used with 
another 
anti-diabetic 
drug 
([rosiglitazone]; 
hypersensitivity 
reactions 
including 
anaphylaxis; rash; urticarial; cutaneous vasculitis; exfoliative skin condition (i.e., Steven-
Johnson syndrome); hepatic enzyme elevations; acute pancreatitis; worsening renal 
function (including acute renal failure); constipation; vomiting). 
 
7.3 
Social and psychological risks 
 
There is a social/psychological risk in this study of breaching confidentiality and having 
a patient’s diagnosis discovered. The likelihood of this occurring is very low, and will be 
further lowered by creating a database that does not link patients’ identity with their 
clinical data. Loss of confidentiality is a potential risk. However, except when required 
by law, patients will not be identified by name, social security number, address, or any 
other personal identifier.  
 
7.4 
Testing risks 
 
The following risks pertain to the different tests that are being used for monitoring the 
treatment responses:  
• Blood draw: minor bleeding (rare) and infection (extremely rare) at puncture site. 
• Urine collection: There are no known risks related to the urine collection.  
• Cardio pulmonary exercise test (CPET): very low risk of rhythm disturbance of the 
heart and syncope. With adequate medical supervision extremely low risk of serious 


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complication. A physician will be present during the CPET. Minor arm or 
discomfort/pressure may occur during blood pressure measurement. 
• Echocardiogram: no greater than minimal risk. The patient may feel minor discomfort 
or minor soreness over the area where the ultrasound probe contacts the chest wall, 
and during the application and removal of the electrodes.  
• FibroScan®: there are no known direct risks from the FibroScan® medical device, 
which uses ultrasound waves. The patient may feel minor discomfort or minor 
soreness over the area where the ultrasound probe contacts the abdomen.   
• Dual-energy X-ray Absorptiometry (DEXA): The radiation exposure amount is very 
low (0.02-1-5 mrem) if compared with other assessments such as conventional X 
rays technique (25-270 mrem). The exposure of radiation with DEXA is equivalent to 
the radiation exposure received during a transcontinental plane trip or to a few days 
of natural background. A Radiation Safety Committee approval letter will be obtained 
before study initiation. The duration of the test will be between 10 and 20 minutes, 
the analysis is noninvasive and painless for the participant.  
• Bioelectrical Impedance Analysis (BIA): There are no known risks related to the BIA. 
In patients with defibrillator or pacemaker, however, cardiac activity will be monitored 
for potential interferences of BIA with the devices. 
• 24-hour blood pressure monitor: Risks are related to minor sleep disturbance due to 
the inflation/deflation of the device. 
• Dietary recall: There are no known risks related to the dietary recall. 
• Questionnaires: There are no known risks related to the questionnaires. 
• Cardiac magnetic resonance (CMR) – substudy only: There are no known risks 
related to the CMR. Contraindications include implantable pacemakers and 
defibrillators, neuroaxial stimulators and other conditions in which a metallic implant 
is present, which may be affected by the magnetic fields. The use of gadolinium 
contrast requires the placement of intravenous cannula. The risks of placing this 
cannula are similar to those associated with blood draws (see above). Adverse 
reactions, including allergic reactions, to the gadolinium contrast agent used are 
rare. However, mild side effects may occur and include headache, nausea, 
dizziness, and changes in taste, which are generally self-limited. We will exclude 
patients with moderate to severe impairment (estimated glomerular filtration rate <60 
ml•min-1/1.73m2) because of increased risk of nephrogenic systemic sclerosis.  
 
7.5 
Direct benefits to study participants 
The hypothesis being tested is that SGLT2 inhibition with Canagliflozin will improve 
exercise capacity, blood pressure, fluid status, body composition and left ventricular 
hypertrophy in patients with systolic heart failure and diabetes. In contrast we 
hypothesize that the active control Sitagliptin will be neutral. 


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As for all clinical trials, there is no guarantee that there is a benefit with Canagliflozin. 
We cannot exclude the possibility that Canagliflozin and or Sitagliptin provide harm in 
the investigated population. 
 
 
8)  
ASSESSMENT OF SAFETY 
 
 
8.1 
Specification of safety parameters 
Safety parameters will include data deriving from history and physical examination 
performed at each visit, laboratory data and results of functional and imaging tests. The 
patient will be encouraged to contact the research team at any time with any concern or 
change. 
Disease-related data will be assessed including change in symptoms (or new 
symptoms), change in functional capacity, vital signs   as well as significant changes in 
medications. 
Data specific to the treatment will also be assessed. The patient will be asked about 
symptoms. Changes to treatment for side-effects or unanticipated problems will be 
performed without breaking the randomization code, unless deemed necessary for the 
treatment of the individual patient by the physician caring for him/her, in which case the 
physician will be made aware while the remainder of the team, especially the 
investigators performing and interpreting the tests, will be maintained blinded.  
 The risks of the tests performed have been described above. In order to reduce risk, 
the procedures will be performed by skilled practitioners in the standard clinical fashion.  
8.2 
Methods of timing for assessing, recording, and analyzing 
safety parameters 
8.2.1 Adverse Events 
All Adverse  Events (AEs) (regardless of causality) will be recorded on an AE form. 
An AE is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An AE does not necessarily 
have a causal relationship with the treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational or non- investigational) product, 
whether or not related to that medicinal (investigational or non-investigational) product.  
The occurrence of an AE may come to the attention of study personnel during study 
visits and interviews of a study recipient for medical care, or upon review by an 


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investigator and/or study coordinator. An event that is considered by the investigator(s) 
to be expected and related to the natural history of the disease is NOT considered an 
AE. 
All events considered AEs including local and systemic reactions should be recorded on 
the appropriate AE form. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study intervention (assessed 
only by those with the training and authority to make a diagnosis, which would include a 
physician) and time of resolution/stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
Any medical condition that is present at the time that the patient is screened should be 
considered as baseline and not reported as an AE. However, if it deteriorates at any 
time during the study, it should be recorded as an AE. 
All AEs must be graded for severity and relationship to study product. 
Severity of Event. All AEs will be assessed by the clinician as: 
• Mild: events require minimal or no treatment and do not interfere with the daily 
activities. 
• Moderate: events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning and may require local or systemic drug therapy. 
• Severe: events interrupt a patient’s usual daily activity and will likely require 
systemic drug therapy or other treatment. Severe events are usually 
incapacitating. 
• Life threatening: any adverse drug experience that places the patient or subject, 
in the view of the investigator, at immediate risk of death from the reaction as it 
occurred (it does not include a reaction that had it occurred in a more severe 
form, might have caused death). 
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events 
characterized as intermittent require documentation of onset and duration of each 
episode.  
Relationship to the intervention. All suspected AEs must have their relationship to study 
intervention assessed using the terms: associated or not associated. In a clinical trial, 
the study intervention must always be a suspect. To help assess, the following 
guidelines are used to assess causality: 


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• Definitely related: The event is temporally related to the administration of the 
study intervention and, in the opinion of the investigator, no other etiology 
explains the event. 
• Probably related: The event is temporally related to the administration of the 
study intervention and represents, in the opinion of the investigator, the most 
plausible explanation of the event. 
• Possibly related: The event is temporally related to the administration of the 
study intervention but, in the opinion of the investigator, it does not represent the 
most likely explanation of the event. 
• Definitely Unrelated: The event is temporally independent of study intervention 
and/or the event appears, in the opinion of the investigator, to be explained by 
another etiology. 
All unexpected and severe AE that are possibly, probably or definitely related to 
research will be promptly reported to the IRB, the Janssen Scientific Affairs, and the 
FDA (as applicable). 
The AE form will contain the following criteria to meet regulatory reporting requirements: 
• An identifiable subject (not disclosing the subject’s name and address) 
• An identifiable reporter (investigational site) 
• A potential Janssen medicinal product (Canagliflozin) or active control 
(Sitagliptin) 
• An adverse event, outcome, or certain special situation 
 
The minimum information required is: 
• Suspected Janssen product (doses, indication) 
• Date of therapy (start and end date, if available) 
• Batch or lot number, if available 
• Subject details (subject ID and country) 
• Gender 
• Age at AE onset 
• Reporter ID 
• Adverse event detail (AE verbatim in English), onset date, relatedness, causality, 
action taken, outcome, (if available) 
• Janssen protocol ID 
 
8.2.2  Product quality complaint (PQC) 
A product quality compliant is related to a potential quality issue during manufacturing, 
packaging, release testing, stability monitoring, dose preparation, storage or distribution 


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of the product, or delivery system.  Not all PQCs involve a subject.  Lot and batch 
numbers are of high significance and need to be collected whenever available. 
 
Examples of PQC include but not limited to: 
• Functional Problem: e.g., altered delivery rate in a controlled release product 
• Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• Potential Dosing Device Malfunction: e.g., autoinjector button not working, needle 
detaching from syringe 
• Suspected Contamination 
• Suspected Counterfeit. 
 
8.2.3 Serious adverse events 
A SAE is any adverse event/experience occurring between baseline assessments and 
the patients final study visit that results in any of the following outcomes and is 
considered by the investigator(s) to be unexpected or not consistent with the natural 
history of the disease: 
• Death 
• Life threatening (subject at immediate risk of death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant disability or incapacity 
• Important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered SAEs when, based upon appropriate 
medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
NOTE: Death for any reason should be reported as a serious adverse event. 
For reports of hospitalization, it is the sign, symptom or diagnosis, which led to the 
hospitalization, that is the serious event for which details must be provided. 
Any event requiring in-patient hospital admission (or the prolongation of hospitalization) 
must be reported as an SAE. Events that do not meet the criteria for SAE reporting are: 
• Reasons described in the protocol, e.g. drug administration, protocol-required 
testing 
• Social reasons, e.g. overnight stay because of distance between home and 
hospital 
• Surgery or procedure planned and documented prior to entry into the study 


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Any event requiring hospitalization or prolongation of hospitalization that occurs during 
the study must be reported as a serious adverse event, except hospitalizations for the 
following: 
• Hospitalizations not intended to treat an acute illness or adverse event (e.g., 
social reasons such as pending placement in long-term care facility) 
• Surgery or procedure planned before entry into the study. [Note: Hospitalizations 
that were planned before the start of data collection and where the underlying 
condition for which the hospitalization was planned has not worsened will not be 
considered serious adverse events. Any adverse event that results in a 
prolongation of the originally planned hospitalization is to be reported as a new 
serious adverse event]. 
The cause of death of a subject in a study within 30 days of the last dose of study drug, 
whether or not the event is expected or associated with the study drug, is considered a 
serious adverse event. 
8.2.4 Unlisted (Unexpected) adverse event/reference safety 
information 
An adverse event is considered unlisted if the nature or severity is not consistent with 
the applicable product reference safety information. For a medicinal product(s) with a 
marketing authorization, the expectedness of an adverse event will be determined by 
whether or not it is listed in the applicable product information. 
Safety events of interest for a Janssen medicinal product that require expediting 
reporting and/or safety evaluation include, but are not limited to: 
• Drug exposure during pregnancy (maternal and paternal) 
• Overdose of a Janssen medicinal product  
• Exposure to a Janssen medicinal product from breastfeeding  
• Suspected abuse/misuse of a Janssen medicinal product 
• Inadvertent or accidental exposure to a Janssen medicinal product  
• Any failure of expected pharmacological action (i.e., lack of effect) of a 
Janssen medicinal product 
• Medication error involving a Janssen medicinal product (with or without 
patient exposure to the Janssen medicinal product, e.g., name confusion) 
• Suspected transmission of any infectious agent via a medicinal  
• Unexpected therapeutic or clinical benefit from use of a Janssen medicinal 
product 
These safety events may not meet the definition of an adverse event; however, they are 
treated in the same manner as adverse events. 


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Any special situation that meets the criteria of a serious adverse event should be 
recorded on a Serious Adverse Event Report Form and be reported to Janssen 
Scientific Affairs within 24 hours of becoming aware of the event. 
8.2.5 Pregnancy  
All initial reports of pregnancy must be reported to Janssen Scientific Affairs by the 
Sponsor Investigator within 24 hours of their awareness of the event using the 
Serious Adverse Event Form. Abnormal pregnancy outcomes (e.g. spontaneous 
abortion, stillbirth, and congenital anomaly) are considered serious adverse events and 
must be reported using the Serious Adverse Event Form. Any subject who becomes 
pregnant during the study must be promptly withdrawn from the study and discontinue 
further study treatment. Because the effect of the Janssen medicinal product on sperm 
is unknown, pregnancies in partners of male subjects potentially exposed to a Janssen 
medicinal product will be reported by the Sponsor Investigator within 24 hours of their 
awareness of the event using the Serious Adverse Event Form. Follow-up information 
regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be 
required. 
8.3. 
Reporting Procedures 
8.3.1 Adverse events and pregnancies [and/or pregnancies in 
partners] 
All adverse events, whether serious or non-serious, related or not related, special 
situations, pregnancy exposures and/or pregnancies in partners following exposure to a 
Janssen medicinal product are to be documented by the investigator and recorded in 
the CRF and in the subject’s source records. Investigators must record in the CRF their 
opinion concerning the relationship of the adverse event to a Janssen medicinal 
product.  
All (serious and non-serious) adverse events reported for a Janssen medicinal product 
should be followed-up in accordance with clinical practice. 
 
All serious adverse events that have not resolved by the end of the study, or that have 
not resolved upon discontinuation of the subject's participation in the study, must be 
followed until any of the following occurs: 
• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value/status is available 


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• The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct 
• It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 
 
All serious adverse events that are unexpected and possibly, probably or definitely 
related to research and all pregnancy-related events (including exposures and/or 
pregnancies in partners) will be reported directly by the Sponsor Investigator, within 24 
business hours of becoming aware, to the IRB to the Janssen Scientific Affairs using 
the Janssen Scientific Affairs Serious Adverse Event Report Form, and to the FDA (as 
applicable). Decision to unblind treatment will be made by the investigators on a case-
to-case basis, after consultation with the IRB. 
All follow-up information for serious adverse events that are not resolved at the end of 
the study or by the time of patient withdrawal must be reported directly by the Sponsor 
Investigator, within 24 business hours becoming aware, to the IRB, the Janssen 
Scientific Affairs using the Janssen Scientific Affair’s Serious Adverse Event Report 
Form, and the FDA (as applicable). 
 
8.3.2 Product quality complaints (PQC) for Janssen Medicinal 
Products 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, 
and complete reporting and analysis of PQC information from studies are crucial for the 
protection of patients, investigators, and Janssen Scientific Affairs, and are mandated 
by regulatory agencies worldwide. Janssen Scientific Affairs has established procedures 
in conformity with regulatory requirements worldwide to ensure appropriate reporting of 
PQC information.  Lot and/or Batch #s shall be collected or any reports of failure of 
expected pharmacological action (i.e., lack of effect). 
All initial PQCs involving a Janssen product under study must be reported to Janssen 
Scientific Affairs by the Sponsor Investigator within 24 business hours after being 
made aware of the event. If the defect for a Janssen product under study is combined 
with either a serious adverse event or non-serious adverse event, the Sponsor 
Investigator must report the PQC to Janssen Scientific Affairs according to the serious 
adverse event reporting timelines, and to the FDA (as applicable). A sample of the 
suspected product should be maintained for further investigation if requested by 
Janssen Scientific Affairs. 
 
 


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8.3.3 Maintenance of safety information 
All safety data should be maintained in a clinical database in a retrievable format. The 
Institution and Sponsor Investigator shall provide all adverse events, both serious and 
non-serious, in report format. However, in certain circumstances more frequent 
provision of safety data may be necessary, e.g. to fulfill a regulatory request, and as 
such the data shall be made available within a reasonable timeframe at Janssen 
Scientific Affair’s request. 
8.3.4 Transmission methods: 
The following methods are acceptable for transmission of safety information to Janssen 
Scientific Affairs: 
• Electronically via Janssen SECURE Email service (preferred) 
• For business continuity purposes, if SECURE Email is non-functional: 
• Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report 
• Telephone (if fax is non-functional). 
 
8.4  
Regulatory Reporting 
8.4.1 
Procedures for reporting adverse events (AE), serious 
adverse events (SAE), pregnancy, and product quality 
complaints (PQC) to Janssen Scientific Affairs 
The Institution and the Sponsor Investigator will transmit SAEs that are both unexpected 
and possibly, probably or definitely related to research and Special Situations in a form 
provided by Janssen Scientific Affairs in accordance with Section VIII Transmission 
methods, in English within 24 business hours of becoming aware of the event(s). 
The Institution and/or Sponsor Investigator are responsible for ensuring that these 
cases are complete and if not are promptly followed-up. A safety report is not 
considered complete until all clinical details needed to interpret the case are received. 
Reporting of follow-up information should follow the same timeline as initial reports. 
Copies of any and all relevant correspondences with regulatory authorities and ethics 
committees regarding any and all serious adverse events, irrespective of association 
with the Janssen Product under study, are to be provided to Janssen Scientific Affairs 
using a transmission method in Section 9.4.2 within 24 business hours of such 
report or correspondence being sent to applicable health authorities. 


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The Institution and the Sponsor Investigator will report any suspected PQC to the 
Janssen contact within 24 business hours of becoming aware of the complaint.  
The product should be quarantined immediately and if possible, take a picture. 
8.5 
Reconciliation of SAEs 
At a minimum, on a quarterly basis and at the end of the Study, Janssen Scientific 
Affairs will provide to the Institution and/or Sponsor Investigator, a listing of all SAEs 
reported to Janssen Scientific Affairs.  The Sponsor Investigator will review this listing 
and provide any discrepancies to Janssen Scientific Affairs. 
Upon request, Institution and/or Sponsor Investigator shall provide Janssen Scientific 
Affairs with a summary list of all SAEs, and AEs of Special Interest and Special 
Reporting Situation reports to date, for reconciliation purposes. 
 
9)  
DISCONTINUATION OF TREATMENT AND WITHDRAWAL 
Patients may withdraw from the study at any time. The patient can decide to forgo any 
study procedures that makes him/her uncomfortable or wish not to complete. The study 
doctor may however stop the participation of the patient in this study at any time for 
many reasons including (but not limited to) the study doctor thinks it is necessary for 
patient health or safety, the patient has not followed study instructions, or administrative 
reasons requiring withdrawal.  
Pre-defined reasons for discontinuation of the investigational drug (Canagliflozin or 
Sitagliptin): 
1) Diabetic ketoacidosis; 
2) Reduced eGFR (<45 ml•min-1/1.73m2)*; 
3) Clinically significant hypotension*; 
4) Hypersensitivity reaction; 
* treatment may be restarted after condition resolved 
Loss to follow-up can occur due to patients’ withdrawal or death. Patients that have 
withdrawn from treatment will still be offered to complete all the functional assessment 
to analyze data in an intention-to-treat strategy. If patients are lost to follow up and their 
clinical condition cannot be established (alive vs dead, hospitalized vs not), they will be 
excluded from the initial analysis, and then reintroduced for sensitivity analysis 
considering all potential outcomes. A 10% attrition rate is a reasonable assumption. To 
account for this attrition a larger number of patients will need to be enrolled, resulting in 
a total number of 88 study patients.  
 
 


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10) 
STATISTICAL CONSIDERATIONS  
All statistical analyses will be performed with the SPSS 22.0 package. Continuous data 
will be reported as median and interquartile range for potential deviation for the 
Gaussian distribution, and discrete variables will be reported as N and %. The 
Spearman test will be used to test correlations between 2 continuous variables. We 
expect a baseline peak VO2 of 14.5 ml•Kg-1•min-1 [74]. A sample size of 40 patients per 
group (total of 80 patients) provides sufficient power to detect a mean difference in the 
interval change in peak VO2 of 1.50±1.76 ml•Kg-1•min-1 (primary endpoint) expected 
with Canagliflozin compared to Sitagliptin, which we predict to have no significant effect 
on peak VO2 (0±1.76 ml•Kg-1•min-1)(power of >90%, α value 0.025 two-sided). A 
sample size of 88 patients will allow for a 10% loss to follow up. We also anticipate 
additional 20 screen failure patients based on biomarkers findings that would preclude 
participation in the study (i.e., HbA1c <7% or >10%, eGFR<50 ml•min-1/1.73m2, 
TSH<0.4>4.5 mcIU/ml, etc…) and additional 10 screen failure patients based on 
findings at the cardiopulmonary exercise test (i.e. RER<1.00 indicating a sub-maximal 
aerobic exercise test, peak VO2 >80% than predicted) and at the echocardiogram (i.e., 
LVEF>40%). Therefore, approximately 120 subjects will be screened in this study, and 
of these we expect to enroll 88 subjects and complete 80 cases.  
Baseline measurement and demographic characteristics will be summarized for the 
patients into each of the treatment arms. Descriptive summaries of continuous 
measurements will consist of means, standard deviations and 95% confidence intervals; 
if the measurements have markedly non-normal distributions, then medians and 
interquartile ranges will be provided instead. Descriptive summaries of categorical 
measurements will consist of frequencies, proportions and 95% confidence intervals on 
those proportions. The summaries for each measurement will be provided separately for 
each treatment group.  
The CPET data will be collected and data analyzed at the end of the study. All 
randomized subjects in the study who received at least one dose of study medication  
will be entered in the database and constitute the full analysis set, to be used to the 
assessment of safety. The differences in interval changes between the treatments will 
be compared using a random-effect analysis of variance model for repeated measures 
to analyze the effects of time and group allocation. Unadjusted p values will be reported 
throughout, with statistical significance set at the 2-tailed 0.05 level. Only randomized 
subjects who received at least 1 dose of the study drug and completed the study per 
protocol-specified criteria with available data sufficient to compute the primary endpoints 
(peak VO2 and VE/VCO2 slope at baseline and 12 weeks) will be included in the per 
protocol analysis set. The cases with missing data in the primary endpoint will be 


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omitted from all the remaining per-protocol analyses, and analyzed only for safety as 
part of the full analysis set.   
The data will be collected and electronically stored. The analysis will be performed at 
the conclusion of the study as described above. For statistical analysis, all values will be 
reported as the median and interquartile range for potential deviation from Gaussian 
distribution. The differences between treatment groups will be computed using the 
Wilcoxon signed-rank test for continuous variables or Fisher’s exact test for discrete 
variables. Only cases with available data used to compute the primary endpoint (peak 
VO2 at baseline and 2 weeks) will be included in the analyses of the secondary 
endpoints. Missing data in the data for the analysis of the secondary endpoints will be 
omitted, and not imputed.  
 


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11. REFERENCES 
1) Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti 
S, Després J, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, 
Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire 
DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, 
Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, 
Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB. Heart 
Disease and Stroke Statistics-2015 Update: A Report From the American Heart 
Associaion. Circulation 2015;131(4):e29-322. 
2) Stratmann B, Tschoepe D. Heart in diabetes: not only a macrovascular disease. 
Diabetes Care 2011;34 Suppl 2:S138-44. doi: 10.2337/dc11-s208. 
3) Kasznicki 
J, 
Drzewoski 
J. 
Heart 
failure in 
the diabetic population -
 pathophysiology, diagnosis and management. Arch Med Sci 2014;10(3):546-56. 
doi: 10.5114/aoms.2014.43748. 
4) Perrone-Filardi P, Paolillo S, Costanzo P, Savarese G, Trimarco B, Bonow RO. The 
role of metabolic syndrome in heart failure. Eur Heart J 2015 Oct 14;36(39):2630-4. 
5) Triplitt C, Solis-Herrera C, Reasner C, DeFronzo RA, Cersosimo E. Classification of 
Diabetes Mellitus. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 
2000-. 
6) Centers for Disease Control and Prevention (CDC). 2014 National Diabetes 
Statistics Report. http://www.cdc.gov/diabetes/  
7) Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 
diabetes: prevalence, incidence, 
and risk 
factors. 
Diabetes 
Care 
2001 
Sep;24(9):1614-9. 
8) Dries DL, Sweitzer NK, Drazner MH, Stevenson LW, Gersh BJ. Prognostic impact of 
diabetes mellitus in patients with heart failure according to the etiology of left 
ventricular systolic dysfunction. J Am Coll Cardiol. 2001;38(2):421-8. 
9) Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr. Heart 
failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes 
Care. 2004;27(3):699-703. 
10) World Health Organization. Diabetes. Fact sheet n^312, updated January 2015. 
http://www.who.int/mediacentre/factsheets/fs312/en/ 
11) American Diabetes Association. Standards of Medical Care in Diabetes – 2016. 
Diabetes Care. 2016;39 (Supplement 1). 
12) Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 
diabetes: 
perspectives 
on 
the 
past, 
present, 
and 
future. 
Lancet. 
2014;383(9922):1068-83. doi: 10.1016/S0140-6736(13)62154-6. 
13) King P, Peacock I, Donnelly R. The UK prospective diabetes study (UKPDS): clinical 
and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol. 
1999;48(5):643-8 
14) Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular 
disease in type 
2 
diabetes. 
Eur 
Heart 
J 2015;36(34):2288-96. 
doi: 
10.1093/eurheartj/ehv239. 
15) Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, 
Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein 


VCU Cana-HF Trial - Clinical Protocol 
 
Version #1.1 – 12082016 
 
 
 
 
 
 
 
35 
PP et al; TECOS Study Group. Effect of Sitagliptin on Cardiovascular Outcomes in 
Type 2 Diabetes. N Engl J Med 2015;373(3):232-42. 
16) Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, Lawson FC, 
Ping L, Wei X, Lewis EF, Maggioni AP, McMurray JJ, Probstfield JL, Riddle MC, 
Solomon SD, Tardif JC; ELIXA Investigators. Lixisenatide in Patients with Type 2 
Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015;373(23):2247-57. doi: 
10.1056/NEJMoa1509225. 
17) Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus 
M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG 
OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in 
Type 
2 
Diabetes. 
N 
Engl 
J 
Med 2015;373(22):2117-28. 
doi: 
10.1056/NEJMoa1504720. 
18) Nauck MA. Update on developments with SGLT2 inhibitors in the management of 
type 2 diabetes. Drug Des Devel Ther. 2014; 8: 1335–1380. 
19) DeSouza C, Fonseca V. Therapeutic targets to reduce cardiovascular disease in 
type 2 diabetes. Nat Rev Drug Discov. 2009;8(5):361-7. doi: 10.1038/nrd2872. 
20) Vrhovac I, Balen Eror D, Klessen D, Burger C, Breljak D, Kraus O, Radović N, 
Jadrijević S, Aleksic I, Walles T, Sauvant C, Sabolić I, Koepsell H. Localizations of 
Na(+)-D-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 
in human small intestine, liver, lung, and heart. Pflugers Arch. 2015;467(9):1881-98. 
doi: 10.1007/s00424-014-1619-7. 
21) Mudaliar S, Polidori D, Zambrowicz B, Henry RR. Sodium-Glucose Cotransporter 
Inhibitors: Effects on Renal and Intestinal Glucose Transport: From Bench to 
Bedside. Diabetes Care. 2015;38(12):2344-53. doi: 10.2337/dc15-0642. 
22) Banerjee SK, McGaffin KR, Pastor-Soler NM, Ahmad F. SGLT1 is a novel cardiac 
glucose transporter that is perturbed in disease states. Cardiovasc Res. 
2009;84(1):111-8. doi: 10.1093/cvr/cvp190. 
23) Abdul-Ghani M, Norton L, DeFronzo RA. Role of sodium-glucose cotransporter 2 
(SGLT2) inhibitors in the treatment of type 2 diabetes. Endocr Rev 2011;32: 515–
531. 
24) Jurczak MJ, Lee HY, Birkenfeld AL, Jornayvaz FR, Frederick DW, Pongratz RL, 
Zhao X, Moeckel GW, Samuel VT, Whaley JM, Shulman GI, Kibbey RG. SGLT2 
deletion improves glucose homeostasis and preserves pancreatic beta-cell function. 
Diabetes. 2011;60(3):890-8. doi: 10.2337/db10-1328. 
25) DeFronzo RA, Hompesch M, Kasichayanula S, Liu X, Hong Y, Pfister M, Morrow LA, 
Leslie BR, Boulton DW, Ching A, LaCreta FP, Griffen SC. Characterization of the 
kinetics of renal glucose reabsorption in response to dapagliflozin in healthy subjects 
and subjects with type 2 diabetes. Diabetes Care 2013;36:3169-3176. 
26) Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical 
prospects. Nat Rev Endocrinol 2012;8:495-502. 
27) Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, Johansen OE. 
Effects of empagliflozin on blood pressure and markers of arterial stiffness and 
vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015 
Dec;17(12):1180-93. 


VCU Cana-HF Trial - Clinical Protocol 
 
Version #1.1 – 12082016 
 
 
 
 
 
 
 
36 
28) Tikkanen I, Narko K, Zeller C, et al.; EMPA-REG BP Investigators. Empagliflozin 
reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes 
Care 2015;38:420–428.  
29) Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen 
OE, Woerle 
HJ, Broedl 
UC, Inzucchi 
SE; EMPA-REG 
OUTCOME® 
trial 
investigators. Heart failure outcomes with empagliflozin in patients with type 2 
diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. 
Eur Heart J 2016 Jan 26. pii: ehv728. [Epub ahead of print] 
30) Whitworth JA, Chalmers J. World health organisation-international society of 
hypertension (WHO/ISH) hypertension guidelines. Clin Exp Hypertens. 2004;26(7-
8):747-52. 
31) Abbate A, Van Tassell BW, Canada JM, Dixon DL, Arena RA, Biondi-Zoccai G. 
Pharmacologic and surgical interventions to improve functional capacity in heart 
failure. Heart Fail Clin. 2015;11(1):117-24. doi: 10.1016/j.hfc.2014.08.005. 
32) Cicoira M, Zanolla L, Franceschini L, Rossi A, Golia G, Zamboni M, Tosoni P, 
Zardini P. Skeletal Muscle Mass independently predicts peak oxygen consumption 
and ventilator response during exercise in noncachectic patients with chronic heart 
failure. J Am Coll Cardiol 2001;37(8):2080-5. 
33) Krachler B, Savonen K, Komulainen P, Hassinen M, Lakka TA, Rauramaa R. 
Cardiopulmonary fitness is a function of lean mass, not total body weight: The DR's 
EXTRA 
study. 
Eur 
J 
Prev 
Cardiol. 
2015;22(9):1171-9. 
doi: 
10.1177/2047487314557962. 
34) Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events 
and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. 
J Am Coll Cardiol. 2010;55(13):1318-27 
35) Zhao 
G, Huang 
L, Song 
M, Song 
Y. 
B 
aseline serum uric acid level as 
a predictor of cardiovascular disease related mortality and all-cause mortality: 
a meta-analysis of prospective studies. Atherosclerosis 2013 Nov;231(1):61-8. 
36) Davies MJ, Trujillo A, Vijapurkar U, Damaraju CV, Meininger G.E Effect of 
canagliflozin on serum uric acid in patients with type 2 diabetes mellitus. Diabetes 
Obes Metab. 2015;17(4):426-9. doi: 10.1111/dom.12439. 
37) Chino Y, Samukawa Y, Sakai S, Nakai Y, Yamaguchi J, Nakanishi T, Tamai I. 
SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport 
activity in renal tubule by increased glycosuria. Biopharm Drug Dispos. 
2014;35(7):391-404. doi: 10.1002/bdd.1909 
38) Ahren B. DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab. 2007 
Dec;21(4):517-33.  
39) Nauck M, Sto ̈ ckmann F, Ebert R et al. Reduced incretin effect in type 2 (non-
insulin-dependent) diabetes.  Diabetologia 1986; 29: 46–54.   
40) Tricco AC, Antony J, Khan PA, Ghassemi M, Hamid JS, Ashoor H, Blondal 
E, Soobiah C, Yu CH, Hutton B, Hemmelgarn BR, Moher D, Majumdar SR, Straus 
SE. 
Safety 
and 
effectiveness 
of dipeptidyl 
peptidase-4 
inhibitors versus 
intermediate-acting insulin or placebo for patients with type 2 diabetes failing two 
oral antihyperglycaemic agents: a systematic review and network meta-analysis. 
BMJ Open 2014;4(12):e005752. 


VCU Cana-HF Trial - Clinical Protocol 
 
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37 
41) Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin 
P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Diabetes 
Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive 
diabetes treatment and cardiovascular disease in patients with type 1 diabetes. 
N  Engl J Med 2005 Dec 22;353(25):2643-53. 
42) UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control 
with sulphonylureas or insulin compared with conventional treatment and risk of 
complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–
53.  
43) Udell JA, Cavender MA, Bhatt DL, Chatterjee S, Farkouh ME, Scirica BM. Glucose-
lowering drugs or strategies and cardiovascular outcomes in patients with or at risk 
for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes 
Endocrinol 2015;3(5):356-66. 
44) Plosker GL. Sitagliptin: a review of its use in patients with type 2 diabetes mellitus. 
Drugs 2014 Feb;74(2):223-42. 
45) Lavalle-González FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of 
canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes 
on 
background 
metformin 
monotherapy: 
a 
randomised 
trial. Diabetologia 
2013;56:2582-2592. 
46) Francis DP, Shamim W, Davies LC, Piepoli MF, Ponikowski P, Anker SD, Coats AJ. 
Cardiopulmonary exercise testing for prognosis in chronic heart failure: continuous 
and independent prognostic value from VE/VCO(2)slope and peak VO(2). Eur Heart 
J 2000;21(2):154-61. 
47) Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, Forman D, 
Franklin B, Guazzi M, Gulati M, Keteyian SJ, Lavie CJ, Macko R, Mancini D, Milani 
RV; American Heart Association Exercise, Cardiac Rehabilitation, and Prevention 
Committee of the Council on Clinical Cardiology; Council on Epidemiology and 
Prevention; Council on Peripheral Vascular Disease; Interdisciplinary Council on 
Quality of Care and Outcomes Research. Clinician's Guide to cardiopulmonary 
exercise testing in adults: a scientific statement from the American Heart 
Association. Circulation 2010;122:191-225. 
48) Church TS, Cheng YJ, Earnest CP, Barlow CE, Gibbons LW, Priest EL, Blair SN. 
Exercise capacity and body composition as predictors of mortality among men with 
diabetes. Diabetes Care. 2004;27(1):83-8. 
49) Wei M, Gibbons LW, Kampert JB, Nichaman MZ, Blair SN. Low cardiorespiratory 
fitness and physical inactivity as predictors of mortality in men with type 2 diabetes. 
Ann Intern Med. 2000;132(8):605-11. 
50) Arena R, Sietsema KE. Cardiopulmonary Exercise Testing in the Clinical Evaluation 
of Patients With Heart and Lung Disease. Circulation 2011;123(6):668-80.  
51) Task Force of the Italian Working Group on Cardiac Rehabilitation and Prevention 
(Gruppo Italiano di Cardiologia Riabilitativa e Prevenzione, GICR); Working Group 
on Cardiac Rehabilitation and Exercise Physiology of the European Society of 
Cardiology. Statement on cardiopulmonary exercise testing in chronic heart failure 
due to left ventricular dysfunction: recommendations for performance and 
interpretation Part III: Interpretation of cardiopulmonary exercise testing in chronic 


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heart failure and future applications. Eur J Cardiovasc Prev Rehabil 2006;13(4):485-
94.   
52) Bensimhon DR, Leifer ES, Ellis SJ, Fleg JL, Keteyian SJ, Piña IL, Kitzman DW, 
McKelvie RS, Kraus WE, Forman DE, Kao AJ, Whellan DJ, O'Connor CM, Russell 
SD; HF-ACTION Trial Investigators. Reproducibility of peak oxygen uptake and 
other cardiopulmonary exercise testing parameters in patients with heart failure 
(from the Heart Failure and A Controlled Trial Investigating Outcomes of exercise 
traiNing). Am J Cardiol 2008 15;102(6):712-7. 
53) Van Tassell BW, Arena R, Biondi-Zoccai G, McNair Canada J, Oddi C, Abouzaki 
NA, Jahangiri A, Falcao RA, Kontos MC, Shah KB, Voelkel NF, Dinarello CA, 
Abbate A. Effects of interleukin-1 blockade with anakinra on aerobic exercise 
capacity in patients with heart failure and preserved ejection fraction (from the D-
HART pilot study). Am J Cardiol 2014;113(2):321-7.  
54) Lewis GD, Shah 
R, Shahzad 
K, Camuso 
JM, Pappagianopoulos 
PP, Hung 
J, Tawakol A, Gerszten RE, Systrom DM, Bloch KD, Semigran MJ. Sildenafil 
improves exercise capacity and quality of life in patients with systolic heart failure 
and secondary pulmonary hypertension. Circulation 2007;116(14):1555-62. 
55) Kim TN, Choi KM. Sarcopenia: definition, epidemiology, and pathophysiology. J 
Bone Metab 2013;20(1):1-10. doi: 10.11005/jbm.2013.20.1.1. 
56) Prado CMM, Wells JCK, Smith SR, Stephan BCM, Siervo M. Sarcopenic obesity: a 
clinical appraisal of the current evidence. Clin Nutr 2012;31(5):583-601.   
57) Cruz-Jentoft AJ, Landi F. Sarcopenia. Clin Med 2014;14(2):183-6. 
58) Heymsfield S, Lohman T, Wang ZM, Going S. Human Body Composition. Book. 
2005. ISBN: 9780736046558 
59) Lee SY, and Gallagher D. Assessment methods in human body composition. Curr 
Opin Clin Nutr Metab Care 2008;11(5):566-72.  
60) Fuller NJ, Laskey MA, Elia M. Assessment of the composition of major body regions 
by dual-energy X-ray absorptiometry (DEXA), with special reference to limb muscle 
mass. Clin Physiol 1992;12(3):253-66. 
61) Kim TN, Choi KM. Sarcopenia: definition, epidemiology, and pathophysiology. J 
Bone Metab 2013;20(1):1-10.  
62) Thompson FE, Byers T. Dietary Assessment Resource Manual. J Nutr 1994;124(11 
Suppl):2245S-2317S. 
63) University of Minnesota Nutrition Coordinating Center. Description of 24-hour 
Dietary and Supplement Recall Features of NDSR. http://www.ncc.umn.edu/ 
64) Johnson RK. Dietary intake--how do we measure what people are really eating? 
Obes Res 2002;10 Suppl 1:63S-68S  
65) Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F, 
Fontana L, Mirisola MG, Guevara-Aguirre J, Wan J, Passarino G, Kennedy BK, Wei 
M, Cohen P, Crimmins EM, Longo VD. Low protein intake is associated with a major 
reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older 
population. Cell Metab 2014;19(3):407-17.  
66) Gardin JM, Adams DB, Douglas PS, Feigenbaum H, Forst DH, Fraser AG, Grayburn 
PA, Katz AS, Keller AM, Kerber RE, Khandheria BK, Klein AL, Lang RM, Pierard LA, 
Quinones MA, Schnittger I. Recommendations for a standardized report for adult 
transthoracic 
echocardiography: 
a 
report 
from 
the 
American 
Society 
of 


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Echocardiography's Nomenclature and Standards Committee and Task Force for a 
Standardized Echocardiography Report. J Am Soc Echocardiogr 2002;15:275-90. 
67) Kollias A, Stergiou GS, Dolan E, O'Brien E. Ambulatory arterial stiffness index: a 
systematic review and meta-analysis. Atherosclerosis. 2012;224(2):291-301. 
68) Garin O, Ferrer M, Pont A, Rue M, Kotzeva A, Wiklund I, Van Ganse E, Alonso J. 
Disease-specific health-related quality of life questionnaires for heart failure: a 
systematic review with meta-analyses. Qual Life Res 2009;18:71-85. 
69) Mather AN, Greenwood JP, Plein S. Characterization of acute myocardial infarction 
by magnetic resonance imaging. JACC Cardiovasc Imaging 209 2(9):1141-1143. 
70) Doltra A, Amundsen BH, Gebker R, Fleck E, Kelle S. Emerging concepts for 
myocardial late gadolinium enhancement MRI. Curr Cardiol Rev 2013; 9(3):185-190. 
71) Lorenz CH, Flacke S, Fischer SE. Noninvasive modalities. Cardiac MR imaging. 
Cardiol Clin 2000;18(3):557-570. 
72) Invokana 
® 
[prescribing 
information]. 
www.invokanahcp.com/prescribing-
information.pdf 
73) Januvia 
® 
[prescribing 
information]. 
https://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf 
74) O 'Connor CM, Whellan DJ, Lee KL, Keteyian SJ, Cooper LS, Ellis SJ, Leifer ES, 
Kraus WE, Kitzman DW, Blumenthal JA, Rendall DS, Miller NH, Fleg JL, Schulman 
KA, McKelvie RS, Zannad F, Piña IL; HF-ACTION Investigators. Efficacy and safety 
of exercise training in patients with chronic heart failure: HF-ACTION randomized 
controlled trial. JAMA 2009;301(14):1439-50. doi: 10.1001/jama.2009.454. 
 
 
 


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Appendix B – CASE REPORT FORMS 
 
- 
Screening and Enrollment Form 
- 
Patient Flow Sheet 
- 
Data Collection Form 
- 
Medication charts 
- 
Echocardiographic data 
- 
24-hour dietary recall form 
- 
Event or Drug Discontinuation 
 
 


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VCU Informed Consent Form – Version #1.2 – 12082016 
 
1
RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
 
 
TITLE: 
Treatment of Diabetes in Patients with Systolic Heart Failure: A 
Randomized Active-Control Double-Blinded Study 
 
PROTOCOL NO.: 
VCU Cana-HF 
 
WIRB® Protocol #20161437 
 
HM20007043 
 
SPONSOR: 
Virginia Commonwealth University 
 
INVESTIGATOR: 
Antonio Abbate, MD, PhD  
 
1200 East Broad St., West Hospital, 10th Floor East Wing, Rm. 1041 
 
Richmond, Virginia 23298 
 
United States 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Antonio Abbate, MD, PhD 
 
804-828-0513 
 
804-828-0951 (telepage/24-hours) 
 
 
If any information contained in this consent form is not clear, please ask the study doctor or the 
study staff to explain any information that you do not fully understand.  You may take home an 
unsigned copy of this consent form to think about or discuss with family or friends before 
making your decision. 
 
Diabetes is a medical condition in which the sugar (glucose) level in the blood is high, increasing 
the risk to develop heart disease. Heart failure is a disease of the heart muscle in which the 
heart contractions are weakened, causing tiredness (fatigue) and difficulty breathing (dyspnea). 
 
The purpose of this study it to measure the safety and the effects of two medications used to 
treat diabetes (Canagliflozin or Sitagliptin) in patients with heart failure. You are being asked to 
participate in this study because you are affected by both diabetes and heart failure and you 
may meet the requirements for study participation. 
 
Canagliflozin (Invokana®) is a medication approved by the United States (US) Food and Drug 
Administration (FDA) in 2013 for the treatment of Type 2 Diabetes Mellitus (T2DM) in subjects 
in which blood sugar is not well controlled with diet, exercise and/or other anti-diabetic 
medications. Canagliflozin improves blood sugar by increasing the amount of sugar (glucose) in 
the urine. Sitagliptin (Januvia®) is also a medication approved by the US FDA in 2006 in 
patients in which diabetes is not well controlled with diet, exercise and/or other anti-diabetic 
medication. Sitagliptin improves blood sugar by increasing the level of a hormone (insulin) in 
your body leading to a reduction in blood sugar (glucose) levels. 


 
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Prior studies comparing these two medications have shown similar effects in improving blood 
sugar. This study is designed to measure the effects of Canagliflozin or Sitagliptin given for 12 
weeks on heart function. The different way by which Canagliflozin and Sitagliptin lower blood 
sugar level may determine whether one of the two is better tolerated or more efficacious than 
the other in patients with heart failure.  
 
During participation in this study you will take one pill daily of Canagliflozin (100 mg) or 
Sitagliptin (100 mg). Your assignment to treatment with one of the medications will be 
determined by randomization like the “flip of a coin”. Approximately 44 patients will receive 
Canagliflozin and 44 will receive Sitagliptin. You will not know whether you are receiving one or 
the other medication: the medication will be prepared by the pharmacy in a capsule so that it 
will not be possible to determine which one is which. 
 
During your initial and follow-up visits, you will undergo an exercise test on a treadmill, an 
ultrasound of the heart and the liver, a body scan to measure composition (amount of fat and 
muscle in your body) and fluid status (amount of water in your body). We will ask you questions 
about your diet. You will also receive a portable blood pressure device for 24 hours that you will 
return back to us the following day. You may be asked also to undergo cardiac magnetic 
resonance imaging to measure the thickness of your heart muscle. You will be in the study for 
approximately 12 weeks. During the course of the research, we will inform you (and, if you 
wish, also your doctor) of any significant new findings deriving from these tests (or new data 
derived by other studies published in the meantime) that might affect your willingness to 
continue participation. 
 
PROCEDURES 
If you decide to participate in this research study, you will be asked to sign this consent form 
after you have had all your questions answered. After you sign this consent form, the 
investigators will perform a thorough evaluation to determine your eligibility for the study. This 
evaluation will consist of an interview about your medical history, followed by a brief physical 
exam, a blood draw (2 tablespoons of blood), and, if indicated, a pregnancy test. 
 
If you meet all the requirements to participate in this study, you will be asked to schedule 4 
study visits at the Clinical Research Unit (North Hospital 8th floor) over approximately 12 weeks.  
 
Visit 1  
This visit constitutes your baseline assessment (before initiation of treatment). You will be 
asked to fast for at least 8 hours before the visit. The assessment will occur in the Clinical 
Research Unit (North Hospital, 8th floor), and it will last approximately 2 hours and 30 min. 
Upon arrival, we will measure your body weight, height, waist circumference and blood 
pressure. You will undergo a blood draw (2-3 tablespoons of blood) and urine collection.  
 
You will then undergo an ultrasound of your heart (transthoracic echocardiogram) and of the 
liver (FibroScan®). To perform this ultrasound, you will lie down in a bed while a technician 
applies a small amount of gel to your chest and abdomen and uses a probe on your skin to take 
pictures of your heart. You will be asked to remain still and to hold your breath for 
approximately 10 seconds. These procedures will last approximately 30 to 60 minutes. 


 
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We will measure the amount of fluid (water) in your body using a procedure called bio-
electrical impedance analysis (BIA). This procedure involves placing small adhesive patches on 
your skin that can measure electricity running through the body. You will not be able to sense 
the electricity being delivered or running through the body. This test will last approximately 10 
min, and by examining how the current is distributed it allows us to determine your body’s fluid 
content. Afterwards, the investigators will ask you some questions about your diet, particularly 
regarding what you ate during the 24 hours prior to the visit. You will be asked to complete 
three surveys to evaluate your heart failure symptoms and your physical activity. The Duke 
Activity Status Index (DASI) questionnaire contains 12 questions to which you will answer “yes” 
or “no”. Each question asks you to describe your ability to perform different activities. The 
Minnesota Living with Heart Failure Questionnaire (MLHFQ) contains 21 questions that ask you 
to mark how often you experience symptoms of heart failure (i.e. swelling in your legs, 
shortness of breath). The International Physical Activity Questionnaire-short (IPAQ-short) is a 7-
question questionnaire that asks you about amount and intensity of your daily physical activity. 
These procedures will last approximately 30 minutes.  
 
Upon completion of the questionnaires, a physician-supervised maximal aerobic exercise test 
will be administered using a treadmill. Monitoring with non-invasive blood pressure, heart rate 
and 12-lead electrocardiogram (ECG) will be conducted. This procedure will last approximately 
60 minutes. If you experience any chest discomfort or pain, abnormal blood pressure and heart 
rate response, or ECG signs of poor blood flow to the heart (“ischemia”) that limit your ability to 
complete the exercise test, you will not be permitted to continue the study.  
 
On the same day, or within a few days, you will undergo a low-intensity X-ray routinely used to 
measure the composition of the bones (dual-energy X-ray absorptiometry - DEXA). The DEXA 
can measure the content of fat and muscle in your body. You will be asked to lie flat on a table 
and a machine will take pictures of different areas of the body. This test will last 15 minutes. 
 
We will give you a portable blood pressure measurement device for you to wear for 24 hours. 
After you wear it for 24 hours, you will be asked to return the device to the clinic. 
 
After you complete all evaluations, you will be provided with study medication (90 capsules in a 
bottle) to take home for daily administration for 12 weeks.  
 
If during the echocardiogram or based on prior medical history we find that your heart is 
enlarged (“left ventricular hypertrophy”), we will ask you to undergo a scan of the heart using 
magnetic waves to accurately measure thickness and function of the heart muscle and valves 
(cardiac magnetic resonance - CMR). You will be asked to lie flat on a table in a large metallic 
tube and a machine will take pictures of your body. Before completing the test, you will be 
asked several questions about your health to determine whether you can have a CMR scan 
done (i.e. individuals with a pacemaker cannot have a CMR because the waves would interfere 
with the pacemaker function). You will also have a small cannula inserted into a vein in your 
hand or arm through which a contrast agent, gadolinium, is injected to enhance the quality of 
the images. This test will be performed at the VCU Medical Center or at VCU Collaborative 


 
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Advanced Research Imaging (CARI) site, located at 203 E. Cary Street, Richmond, VA. The test 
will last about 45 minutes.  
 
Visit 2 and Visit 3 
After approximately 4 weeks (Visit 2) and 8 weeks (Visit 3) from when you start the study 
medication, you will be seen in the Clinical Research Unit (North Hospital, 8th Floor), or by your 
own doctor, for a shorter visit (30 minutes) for a brief history and medical examination, and a 
blood draw (1 to 2 tablespoons) to assess for kidney function. If the visit is performed in the 
Clinical Research Unit, the ‘bio-electrical impedance’ test will also be repeated. 
 
Visit 4 
After approximately 12 weeks, you will undergo a complete assessment, as described in Visit 1, 
that will last approximately 2 hours. 
 
Upon completion of Visit 4, your active participation in the study will be over. Treatment with 
the study drug will be terminated. If you agree, the results of the study will be shared with your 
doctor. You and your doctor will discuss how to continue treatment for diabetes, which may 
include the use of one of the drugs used in the study or other drugs.  
 
Study schedule 
Procedure 
Visit 1 
(Baseline) 
Visit 2 
(4 weeks) 
Visit 3 
(8 weeks) 
Visit 4 
(12 weeks) 
Screening 
X 
 
 
 
Consent 
X 
 
 
 
Clinical assessment 
X 
X 
X 
X 
Blood draw 
X 
X 
X 
X 
Urine analysis 
X 
 
 
X 
Fluid status assessment (BIA) 
X 
X  
(only at 
VCU) 
X  
(only at 
VCU) 
X 
Echocardiogram and FibroScan® 
X 
 
 
X 
Dietary recall and surveys 
X 
 
 
X 
Exercise Test 
X 
 
 
X 
Questionnaires (DASI and MLHFQ) 
X 
 
 
X 
24-hour blood pressure measurement 
X 
 
 
X 
Body composition (DEXA) 
X 
 
 
X 
Cardiac magnetic resonance 
(only for a subgroup of subjects) 
X 
 
 
X 
Receive study medication 
X 
 
 
 
 
RISKS AND DISCOMFORTS 
All drugs can cause unwanted effects, called side effects. It is important that you read the risks 
and discomforts listed herein, and discuss with the study doctor or your own doctor if you have 
any questions. 


 
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Side effects that are more likely to occur with Canagliflozin (Invokana®) include: 
- 
Dizziness or lightheadedness upon standing (approximately 1 in 20 people), particularly in 
subjects already treated with diuretics (fluid pill, i.e., Lasix/Furosemide), or older patients or 
patients with impaired kidney function; 
- 
Hypoglycemia (approximately 4 in 100), particularly if associated with other anti-diabetic 
drugs such as sulfonylurea or insulin in which case it is more frequent (up to 5 in 10 people) 
and can be serious (up to 2 in 100 can be severe);  
- 
Increased urination and thirst (approximately 1 in 20 people); 
- 
Urinary tract infections (approximately 1 in 20 people); 
- 
Allergic reaction including rash (approximately 1 in 20 people), generally self-limiting; 
- 
Constipation (less than 1 in 25 people); 
- 
Nausea (less than 1 in 25 people); 
- 
Diabetic ketoacidosis (approximately 1 in 1000 people): 
o The risk of developing diabetic ketoacidosis may be increased with prolonged 
fasting, excessive alcohol consumption, dehydration, sudden reductions in insulin 
dose, or a higher need of insulin due to major surgery or serious illness; 
o Symptoms of diabetic ketoacidosis may include difficulty breathing, nausea, 
vomiting, excessive thirst, rapid weight loss, abdominal pain, confusion, fruity-
smelling breath, a sweet or metallic taste in your mouth, a different odor to your 
urine or sweat, and unusual fatigue or sleepiness. 
- 
Bone fractures (approximately 1 in 50 people):  
- 
Amputation of the toes (and to a lesser extent the foot or leg) could occur in up to 1 in 150 
people per year on canagliflozin.   
o This risk of amputation is greater in those with a prior history of amputation, disease 
of the circulation involving the legs or in those with nerve damage due to diabetes. 
- 
Laboratory changes not associated with clinical adverse events in clinical trials: 
o Increase of approximately 5% in low-density lipoprotein cholesterol; 
o Increase in serum potassium, phosphate and/or hemoglobin of approximately 4%, 
4% and 5% respectively; 
o Decrease of approximately 10% in serum urate.  
- 
Vaginal yeast infections and vaginal itching (up to 2 in 10 women) or yeast infection at the 
head of the penis (up to 1 in 20 men), requiring circumcision in 0.3% in not circumcised. 
 
In subjects not enrolled in clinical studies, but who have been prescribed Canagliflozin, the 
following side effects have also been reported. It is however unknown if these side effects are 
directly linked to the use of Canagliflozin since not reported in the completed clinical trials: 
serious allergic reactions, severe decrease in kidney function (mostly in dehydrated patients—
see below), infections of the urinary tract that can spread to the kidneys or into the 
bloodstream. Symptoms of urinary tract infections may include high fever, increased heart rate 
and breathing, low blood pressure, low urine output and lower back pain. Subjects experiencing 
these symptoms should call their doctor promptly if experiencing these symptoms. 
 


 
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6
As noted above, cases of acute kidney injury, some requiring hospitalization and dialysis, have 
been reported in patients receiving canagliflozin, about half of the cases occurring within 1 
month of starting the drug.  Please seek medical attention immediately if you experience 
decreased urine or swelling of your legs or feet.  Please talk with your study doctor if you are 
eating or drinking less due to illness or fasting, or are losing fluids due to vomiting, diarrhea, or 
excessive heat exposure.  Your health care professional may determine it is appropriate to 
temporarily stop taking the study drug. 
 
Side effects have been reported with Sitagliptin (Januvia®). The most likely side effects 
associated with the use of Sitagliptin include: 
- 
Hypoglycemia, particularly if associated with other anti-diabetic drugs such as sulfonylurea 
or insulin (approximately 2 in 10 people) which can be serious (in less than 1 in 100 people);  
- 
Upper respiratory infection (stuffy or runny nose and sore throat)(up to 3 in 50 people); 
- 
Headache (approximately 3 in 50 people);  
- 
Nausea, stomach upset and diarrhea (approximately 3 in 100 people). 
 
In subjects not enrolled in clinical studies, but who have been prescribed Sitagliptin, the 
following side effects have been reported. It is however unknown if these side effects are 
directly linked to the use of Sitagliptin since not reported in the completed clinical trials: 
hypersensitivity reactions including anaphylaxis, rash, urticarial, cutaneous vasculitis, skin 
condition (i.e., Steven-Johnson syndrome), hepatic enzyme elevation, pancreatitis (acute 
inflammation of the pancreas), worsening renal function (including acute renal failure), 
constipation, vomiting. 
 
Although animal studies do not suggest that either Canagliflozin or Sitagliptin are associated 
with birth defects, human studies have not been performed in this field. Women who are 
pregnant, lactating or intend to become pregnant will not be allowed to be in the study.  
Women who could possibly become pregnant must have a negative pregnancy test (urine test) 
prior to starting on the study medication and report immediately to the study personnel if they 
suspect they are pregnant during the study. If you are able to have children and you are 
heterosexually active, you must use birth control (contraception) during the study.  Birth 
control methods that can be used while in this study include: avoiding sex, birth control pills, 
birth control injections or patch, intrauterine device, barrier method (for example, condoms or 
diaphragm) combined with spermicide (foam, cream, or gel), or your male partner is sterile (e.g. 
sperm tubes are cut or blocked).  The type of birth control you use must be discussed with the 
study doctor before you begin the study. The study doctor must approve the method you use 
before you can enter the study. If you become pregnant during the study, you must tell the 
doctor immediately. You will have to stop taking the study medication.  The doctor will advise 
you about your medical care and will ask you to allow him/her to collect information about 
your pregnancy and the health of your baby. For male subjects, if your partner becomes 
pregnant, you must tell the study doctor immediately. 
 


 
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Risks related to procedures: 
• Blood draw: the discomfort may derive from minor bruising (occasional), bleeding (rare, less 
than 1 in 100), and infection (extremely rare, less than 1 in 1,000) at the puncture site. To 
minimize the potential discomforts, all blood samples will be taken by trained personnel. 
• Urine collection: there are no known risks or discomforts related to the urine collection.  
• Cardio pulmonary exercise test (CPET): with adequate medical supervision, there is 
extremely low risk of serious complications such as heart attack or stroke (less than 1 in 
1,000). Abnormal cardiovascular response during exercise testing (i.e. markedly elevated 
blood pressure or heart rate) may occur (approximately 1 in 10). A physician will be present 
during the CPET. Minor arm or discomfort/pressure may occur during blood pressure 
measurement. 
• Echocardiogram: there are no known risks related to the echocardiogram. Minor discomfort 
is associated with the applying the probe to the chest wall and the placement and removal 
of the electrodes on your skin. 
• FibroScan®: there are no known direct risks from the FibroScan® medical device, which uses 
ultrasound waves. However, you may feel minor discomfort or soreness over the area 
where the ultrasound probe contacts the abdomen. 
• Dual-energy X-ray Absorptiometry (DEXA): as a participant in this study, you will receive 
extra radiation exposure from the scans that are for research purposes only (not for your 
direct clinical benefit). The radiation dose from these procedures is minimal, less than 1% of 
the annual permissible occupational exposure level for radiation workers. These limits are 
defined as the dose of radiation that, in light of present knowledge, is not expected to cause 
appreciable bodily injury to a person at any time during his/her lifetime. The risk of this 
amount of occupational exposure to radiation is, thus, considered to be very small and less 
than that associated with normal everyday activities. 
• Bioelectrical Impedance Analysis (BIA): there are no known risks or discomforts related to 
the BIA. If you have a defibrillator or a pacemaker, the activity of your heart will be 
monitored because BIA may interfere with defibrillator or pacemaker function. Minor 
discomfort is associated with the placement and removal of the electrodes on your skin. 
• 24-hour blood pressure monitor: the blood pressure measurement may provide minor 
discomfort to your arm during cuff inflation and affect your sleep since it will automatically 
inflate every 60 minutes during the night. 
• Cardiac magnetic resonance (CMR): there are no known risks related to the CMR, except for 
the use of gadolinium described below and a potential psychological risk of claustrophobia 
due to the tight space of the CMR machine.  Please alert staff should this be a concern. If 
you have a pacemaker and/or a defibrillator and/or other conditions in which a metallic 
implant is present, you will not undergo CMR. The use of gadolinium contrast may cause 
mild headache, nausea, dizziness, and change in taste – these events are generally mild and 
self-resolving. Gadolinium can cause an allergic reaction in some patients – this is a rare but 
potentially dangerous event, the personnel administering the gadolinium will monitor you 
for side effects, and treat an allergy reaction if it were to occur. A condition known as 
nephrogenic systemic fibrosis has been related to the use of Gadolinium-enhanced MRI, this 
is a rare occurrence and has only been observed in individuals with severe kidney disease.  


 
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Your kidney function will be assessed prior to this testing, and you will be unable to 
participate if it is compromised.  
• Dietary recall: there are no known risks or discomforts related to the 24-hour dietary recall. 
• Questionnaires: there are no known risks or discomforts related to the questionnaires. 
 
There is a social/psychological risk in this study of breaching confidentiality and having your 
diagnosis discovered, which may be stressful. The likelihood of this occurring is very low. 
 
BENEFITS 
There is no guarantee that you will receive any cardiovascular benefit from being in this study. 
Canagliflozin (Invokana®) and Sitagliptin (Januvia®) improve blood sugar in a similar manner. 
Due to the differences in the way the 2 drugs reduce blood glucose levels, Canagliflozin and 
Sitagliptin may be differently tolerated and may be associated with a difference in exercise 
capacity and heart function.   
 
COSTS 
You or your insurance will not be charged for the study visits or any study-related procedures. 
 
PAYMENT FOR PARTICIPATION 
To compensate for your time and travel related expenses (transportation, parking fees etc.), 
you will be paid as follows: $25 for the screening visit, $100 for Visit 1 and 4 each, and $25 for 
Visit 2 and 3 each, for a maximum amount of $275. You will receive a check at home within a 
few weeks of visit 4. 
 
ALTERNATIVE TREATMENT 
You do not have to participate in this study. You will still receive the standard medical 
treatments for heart failure and diabetes whether you participate or not. Your physician may 
decide to prescribe you Invokana® and/or Januvia® outside the study, since both drugs have 
been approved by the FDA for the treatment of diabetes. 
 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH PURPOSES or 
CONFIDENTIALITY 
 
Authority to Request Protected Health Information 
The following people and/or groups may request my Protected Health Information: 
• Virginia Commonwealth University 
• Janssen Scientific Affairs, LLC (funding company) 
and their representatives  
• Research Collaborators  
• Institutional Review Boards 
• Sponsor, Investigators, and Research Staff
• U.S. Food and Drug Administration (FDA) 
• The Western Institutional Review Board® 
(WIRB®) 
• Others as required by law 
 
• Government/Health Agencies in US and in other 
countries 
• Department of Health and Human Services 
(DHHS) agencies 
 


 
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Authority to Release Protected Health Information  
The VCU Health System (VCUHS) may release the information identified in this authorization 
from my medical records and provide this information to:   
• Health Care Providers at the VCUHS 
• Data Safety Monitoring Boards 
• Virginia Commonwealth University 
• Janssen Scientific Affairs, LLC (funding company)  
• Research Collaborators  
• Institutional Review Boards 
• Sponsor, Investigators and Research Staff  
• U.S. Food and Drug Administration (FDA) 
• The Western Institutional Review Board® 
(WIRB®) 
• Others as required by law 
 
• Government/Health Agencies in US and in other 
countries 
• Department of Health and Human Services (DHHS) 
agencies 
 
Once your health information has been disclosed to anyone outside of this study, the 
information may no longer be protected under this authorization. 
 
Type of Information that may be released: complete health record. 
 
Right to Revoke Authorization and Re-disclosure 
You may change your mind and revoke (take back) the right to use your protected health 
information at any time. If you revoke this authorization you may no longer be allowed to 
participate in the research study.  To revoke this authorization, you must write to the Principal 
Investigator(s). 
 
Expiration of This Authorization: this authorization will expire when the research study is 
closed, or there is no need to review, analyze and consider the data generated by the research 
project, whichever is later. 
 
CONFIDENTIALITY 
Potentially identifiable information about you will consist of data abstracted from the medical 
record. Data are being collected only for research purposes. Your data will be identified by ID 
numbers, (will not include your name) and will be stored separately from medical records in a 
locked research area. All personal identifying information will be kept in password-protected 
files. Access to research data will be limited to study personnel.  
 
You should know that research data about you might be reviewed by Virginia Commonwealth 
University. Although results of this research may be presented at meetings or in publications, 
identifiable personal information pertaining to participants will not be disclosed. The 
information from this study will not be stored in your permanent medical record. However, the 
investigators can provide copies of your study information upon request. 
 


 
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COMPENSATION FOR INJURY 
If you are injured by, or become ill, from participating in this study, please contact your study 
doctor immediately.  Medical treatment is available at the Virginia Commonwealth University 
Health System (VCU Health System).  Your study doctor will arrange for short-term emergency 
care at the VCU Health System or for a referral if it is needed. 
 
Fees for such treatment may be billed to you or to appropriate third party insurance.  Your 
health insurance company may or may not pay for treatment of injuries or illness as a result of 
your participation in this study. 
 
To help avoid research-related injury or illness it is very important to follow all study directions. 
 
VOLUNTARY PARTICIPATION AND WITHDRAWAL 
Your participation in this study is voluntary.  You may decide to not participate in this study.  
Your decision not to take part will involve no penalty or loss of benefits to which you are 
otherwise entitled.  If you do participate, you may freely withdraw from the study at any time.  
Your decision to withdraw will involve no penalty or loss of benefits to which you are otherwise 
entitled. You can decide to forgo any study procedures that make you uncomfortable or you 
wish not to complete. The study doctor may however stop your participation in this study at 
any time for reasons including (but not limited to) the study doctor thinks it is necessary for 
your health or safety, you have not followed study instructions, or administrative reasons 
require your withdrawal. 
 
SOURCE OF FUNDING FOR THE STUDY AND DISCLOSURES 
Janssen Pharmaceuticals is the manufacturer of Canagliflozin (Invokana®), one of the drugs 
studied in this trial. Dr. Abbate has served as a paid consultant on an Advisory Board for the 
development of Canagliflozin for heart disease. Please feel free to ask any questions you may 
have about this matter.  
 
QUESTIONS 
If you have any questions, complaints, or concerns about your participation in this research, or 
if you feel you have experienced a research-related injury, contact: 
 
Antonio Abbate, MD, PhD 
Virginia Commonwealth University 
West Hospital 5th Floor – Room 525 
Richmond, VA, 23298 
Phone: (804) 828-0513 
804-828-0951 (telepage/24-hours) 
Fax: (804) 628-3984 
 
Salvatore Carbone, MS 
Virginia Commonwealth University 
West Hospital 5th Floor – Room 520 
Richmond, VA, 23298 
Phone: (804) 628-3980 
Fax: (804) 628-3984 
 
The researchers named above are the best persons to call for questions about your 
participation in this study.  
 


 
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If you have general questions about your rights as a participant in this or any other research, 
you may contact: 
 
Office of Research 
Virginia Commonwealth University 
800 East Leigh Street, Suite 3000 
P.O. Box 980568 
Richmond, VA 23298 
Telephone: (804) 827-2157 
 
Contact this number to ask general questions, to obtain information or offer input, and to 
express concerns or complaints about research. You may also call this number if you cannot 
reach the research team or if you wish to talk to someone else.  
 
General information about participation in research studies can also be found at 
http://www.research.vcu.edu/irb/volunteers.htm. 
 
If you have questions about your rights as a research subject or if you have questions, concerns, or 
complaints about the research, you may contact: 
 
Western Institutional Review Board® (WIRB®) 
1019 39th Avenue SE Suite 120 
Puyallup, Washington  98374-2115 
Telephone:  1-800-562-4789 or 360-252-2500 
E-mail: Help@wirb.com 
 
WIRB is a group of people who perform independent review of research. 
 
WIRB will not be able to answer some study-specific questions, such as questions about 
appointment times.  However, you may contact WIRB if the research staff cannot be reached or 
if you wish to talk to someone other than the research staff.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 


 
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CONSENT 
I have been provided with an opportunity to carefully read this consent form composed of 10 
pages. All of the questions that I wish to raise concerning this study have been answered. 
 
By signing this consent form, I have not waived any of the legal rights or benefits to which I 
otherwise would be entitled. My signature indicates that I freely consent to participate in this 
research study. I will receive a copy of the consent form once I have agreed to participate. 
 
 
________________________________________________ 
Participant Name, printed 
 
 
________________________________________________ 
________________ 
Participant Signature 
Date 
 
 
________________________________________________ 
Name of Person Conducting Informed Consent / Witness 
(Printed) 
 
 
________________________________________________ 
________________ 
Signature of Person Conducting Informed Consent / Witness 
Date 
 
 
________________________________________________ 
________________ 
Principal Investigator Signature (if different from above) 
Date