Clinical trial NCT04730947
Conditions: Heart Failure With Preserved Ejection Fraction
Sponsor: Mayo Clinic
Start date: 2021-02-24; Completion date: 2022-11-17
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether treatment with Dapagliflozin (DAPA) for 6 months will improve pulmonary capillary wedge pressure (PCWP) during exercise in heart failure/preserved ejection fraction (HFpEF) and improve cardiac metabolism.

Detailed description:

Arms: arm 1: Subjects with HFpEF will take the study drug dapagliflozin daily arm 2: Subjects with HFpEF will take a placebo daily
Interventions: intervention 1: Dapagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: 10 mg orally once a day intervention 2: Taken orally once a day, the placebo looks identical to the study drug but it contains no active ingredient

Protocol documents:
Prot_SAP_000.pdf: 
 
Evaluation of the Cardiac and 
Metabolic Effects of 
Dapagliflozin in Heart Failure 
with preserved Ejection 
Fraction (CAMEO-DAPA):  
A Phase II, Prospective, Double-
Blind Study 
 
NCT# 04730947 
 
January 13, 2022 


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Principal Investigator: Barry Borlaug, MD 
 
CONFIDENTIAL 
 
 
Evaluation of the Cardiac and Metabolic Effects of Dapagliflozin in 
Heart Failure with preserved Ejection Fraction (CAMEO-DAPA):  
A Phase II, Prospective, Double-Blind Study  
 
 
 
Regulatory Sponsor: 
Barry A. Borlaug, MD  
Mayo Clinic 
Department of Cardiovascular Medicine  
200 First Street SW 
Rochester, MN 55905 
(507) 255-1051 
 
Funding Sponsor: 
 
AstraZeneca 
 
Study Product: 
Dapagliflozin (DAPA) 
Protocol Number: (IRBe) 
20-005646 
IND Number: 
IND Exempt 
 
 
 
 
 
Initial version: September 22, 2020 Version (1.0)  
Revised: 
December 8, 2020 Version (2.0) 
Revised: 
February 2, 2021 Version (3.0) 
Revised:  
April 5, 2021 Version (4.0) 
Revised: 
August 5, 2021 Version (5.0) 
Revised: 
October 12, 2021 Version (6.0) 
Revised 
January 13, 2022 Version (7.0) 
 
 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 5 
1 
INTRODUCTION ................................................................................................................................. 6 
1.1 
BACKGROUND .................................................................................................................................... 6 
1.2 
INVESTIGATIONAL AGENT .................................................................................................................... 6 
1.3 
CLINICAL DATA TO DATE..................................................................................................................... 6 
1.4 
DOSE RATIONALE................................................................................................................................ 7 
1.5 
RISKS AND BENEFITS ........................................................................................................................... 7 
2 
STUDY OBJECTIVES .......................................................................................................................... 8 
3 
STUDY DESIGN ................................................................................................................................... 9 
3.1 
GENERAL DESCRIPTION ....................................................................................................................... 9 
3.2 
NUMBER OF SUBJECTS ....................................................................................................................... 10 
3.3 
DURATION OF PARTICIPATION ............................................................................................................ 10 
3.4 
PRIMARY STUDY ENDPOINTS .............................................................................................................. 10 
3.5 
SECONDARY STUDY ENDPOINTS ......................................................................................................... 10 
3.6 
PRIMARY SAFETY ENDPOINTS ............................................................................................................ 10 
3.7 
IDENTIFICATION OF SOURCE DATA ...................................................................................................... 11 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ...................................................... 12 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 12 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 12 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ....................................................................... 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS .................................................................................................... 12 
5 
STUDY DRUG .................................................................................................................................... 13 
5.1 
DESCRIPTION .................................................................................................................................... 13 
5.2 
TREATMENT REGIMEN ....................................................................................................................... 13 
5.3 
METHOD FOR RANDOMIZING SUBJECTS TO TREATMENT GROUPS ........................................................... 13 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ......................................................................... 13 
5.5 
SUBJECT COMPLIANCE MONITORING ................................................................................................... 13 
5.6 
PRIOR AND CONCOMITANT THERAPY .................................................................................................. 14 
5.7 
PACKAGING ...................................................................................................................................... 14 
5.8 
MASKING/BLINDING OF STUDY........................................................................................................... 14 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................................. 14 
6 
STUDY PROCEDURES ...................................................................................................................... 15 
6.1 
VISIT 1 ............................................................................................................................................. 15 
6.2 
VISIT 2 ............................................................................................................................................. 16 
6.3 
REMOTE TELEPHONE/VIDEO VISITS .................................................................................................... 16 
6.4 
VISITS 3 & 4 ..................................................................................................................................... 16 
7 
STATISTICAL PLAN ......................................................................................................................... 19 
7.1 
INTRODUCTION TO THE STATISTICAL DESIGN ....................................................................................... 19 
7.2 
RANDOMIZATION AND BLINDING ........................................................................................................ 19 
7.3 
DATA MANAGEMENT PLAN ................................................................................................................ 19 
7.4 
OUTCOMES ....................................................................................................................................... 18 
7.5 
SAMPLE SIZE ESTIMATION ................................................................................................................. 18 
7.6 
PRIMARY ANALYSIS .......................................................................................................................... 20 
7.7 
MODERATORS OF TREATMENT EFFECT ................................................................................................. 21 
7.8 
ANALYSIS SETS ................................................................................................................................. 21 


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8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 20 
8.1 
DEFINITIONS ..................................................................................................................................... 20 
8.2 
RECORDING OF ADVERSE EVENTS ....................................................................................................... 23 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .......................................... 24 
8.4 
PREGNANCY ..................................................................................................................................... 26 
8.5 
UNMASKING/UNBLINDING PROCEDURES ............................................................................................. 25 
8.6 
STOPPING RULES ............................................................................................................................... 25 
8.7 
MEDICAL MONITORING ..................................................................................................................... 27 
9 
DATA HANDLING AND RECORD KEEPING .................................................................................. 27 
9.1 
CONFIDENTIALITY ............................................................................................................................. 27 
9.2 
SOURCE DOCUMENTS ........................................................................................................................ 26 
9.3 
CASE REPORT FORMS ........................................................................................................................ 28 
9.4 
RECORDS RETENTION ........................................................................................................................ 28 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 28 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 28 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 28 
11 
ETHICAL CONSIDERATIONS ......................................................................................................... 27 
12 
STUDY FINANCES ............................................................................................................................ 30 
12.1 
FUNDING SOURCE ......................................................................................................................... 30 
12.2 
CONFLICT OF INTEREST ................................................................................................................. 30 
12.3 
SUBJECT STIPENDS OR PAYMENTS .................................................................................................. 30 
13 
PUBLICATION PLAN ....................................................................................................................... 30 
14 
REFERENCES ................................................................................................................................... 31 
15 
ATTACHMENTS .................................................................... ERROR! BOOKMARK NOT DEFINED. 
15.1 
APPENDIX I SHORT FORM 36 (SF-36) QUESTIONNAIRE ..................... ERROR! BOOKMARK NOT DEFINED. 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DAPA 
Dapagliflozin 
DEXA 
Dual Energy X-ray Absorptiometry 
DSMP 
Data and Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HFpEF 
Heart Failure with Preserved Ejection Fraction 
HFrEF 
Heart Failure with Reduced Ejection Fraction 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
NYHA 
New York Heart Association 
PCWP 
Pulmonary Capillary Wedge Pressure 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SF-36 
Short Form 36 Questionnaire 
 
 
 


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Study Summary 
Title 
Evaluation of the Cardiac and Metabolic Effects of Dapagliflozin in 
Heart Failure with preserved Ejection Fraction (CAMEO-DAPA):  
A Phase II, Prospective, Double-Blind Study 
Running Title 
CAMEO-DAPA 
Protocol Number 
20-005646 
Phase 
Phase II 
Methodology 
Randomized, double blind placebo control 
Overall Study 
Duration 
24 months 
Subject Participation 
Duration 
Approximately 7 months 
Single or Multi-Site  
Single 
Objectives 
To determine whether treatment with DAPA for 6 months will improve 
pulmonary capillary wedge pressure (PCWP) at rest and during 
exercise in HFpEF and improve cardiac metabolism. 
Number of Subjects 
Up to 41 Subjects fully completing trial, up to 46 accrual, to account 
for dropouts 
Diagnosis and Main 
Inclusion Criteria 
HFpEF subjects with obesity defined by clinical symptoms of HF: 
Dyspnea (NYHA II-IV without cardiac or ischemia explanation), EF ≥ 
50%  
Study Product, Dose, 
Route, Regimen 
Dapagliflozin (DAPA) 10 mg once daily versus matching placebo 
Duration of 
Administration 
6 months 
Reference therapy 
Placebo 
Statistical 
Methodology 
The principal comparisons will be a comparison of pulmonary 
capillary wedge pressure incorporating values measured at rest and 
during exercise using mixed effects model analysis of covariance.  
 


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1 Introduction 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  
 
1.1 
Background 
 
Over 70% of individuals above the age of 65 years with heart failure (HF) have preserved 
ejection fraction (HFpEF).1 There is currently no proven treatment that improves 
symptoms or outcome in this population.1-3  The vast majority (75%) of patients with 
HFpEF are obese.4-6 Inflammation and metabolic stress secondary to excess body mass are 
strongly implicated in the pathophysiology of the obese phenotype of HFpEF, leading to 
alterations in cardiac function that cause abnormal hemodynamics, which then cause 
symptoms, morbidity and increased mortality. 
 
Despite these signals from various studies, predominantly in animal models, the 
mechanisms by which SLGT2 inhibitors improve outcome in HF, or whether they 
improve clinical status in HFpEF, remain unclear. As such, characterization of the 
mechanisms by which dapagliflozin affects cardiac function and metabolism remains a 
critical unmet need. The most likely mechanisms involve improvements in hemodynamics 
that drive symptoms (through improvements in cardiac function and reduction in plasma 
volume) and improvements in myocardial metabolism, specifically alterations in the 
uptake and utilization of free fatty acids (FFA) vs other substrates. 
 
The gold standard to assess each of these components is through invasive hemodynamic 
assessment, simultaneous echocardiography, and transcardiac blood sampling (arterial and 
coronary sinus), all performed at rest and during supine exercise (where symptoms 
develop in HFpEF). This study will test the effects of treatment with dapagliflozin for 6 
months on cardiac hemodynamics, structure, function and metabolism using these 
methods, as compared placebo. 
 
1.2 
Investigational Agent 
Dapagliflozin 10 mg tablet or matching placebo. 
 
1.3 
Clinical Data to Date 
SGLT2 inhibitors such as dapagliflozin have been shown to reduce incident HF events.7-9 
SGLT2 inhibitors are known to reduce body weight, ventricular mass, enhance insulin 
sensitivity, reduce plasma volume expansion and blood pressure, and improve renal 
outcomes.10-15 Each of these abnormalities has been shown to play a pivotal role in 
patients with the obese phenotype of HFpEF.5, 6, 16   
 
People with obesity display increased free fatty acid (FFA) uptake, which is associated 
with reduced myocardial efficiency.17 Treatment with DAPA may favorably alter 
myocardial substrate utilization by decreasing reliance on FFA and switch to alternative 
sources such as glucose oxidation or utilization of ketone bodies.18, 19 
 


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Dapagliflozin has been shown in a large placebo controlled trial (DAPA-HF) to improve 
the combined primary endpoint of HF hospitalization or cardiovascular mortality in 
patients with HF and reduced ejection fraction (HFrEF, defined by EF<40%).20 Patients 
randomized to dapagliflozin had a statistically significant 26% reduction in the primary 
outcome, with a 30% reduction in HF hospitalization, 18% reduction in cardiovascular 
death, and a 17% reduction in all-cause mortality in patients receiving dapagliflozin. 
Importantly, the beneficial effects were similar in patients with and without diabetes. The 
frequency of adverse events related to volume depletion, renal dysfunction, and 
hypoglycemia did not differ between patients randomized to dapagliflozin or placebo.20 
 
More recently, a second pivotal trial has evaluated a related SGLT2 inhibitor, 
empagliflozin, in the EMPEROR-Reduced trial.21 In this study, 3730 patients with HFrEF 
were treated with empagliflozin (10 mg once daily) or placebo. Consistent with the 
DAPA-HF trial, treatment with the SGLT2 inhibitor empagliflozin was associated with a 
25% reduction in the primary outcome of cardiovascular death or hospitalization for 
worsening heart failure.  Efficacy and safety were similar in patients with and without 
diabetes mellitus. Total hospitalizations were HF were reduced by 30%, and there was a 
significant reduction in the annual rate of decline in the estimated glomerular filtration 
rate. 
 
These data have led to a new indication from the FDA to use dapagliflozin as a treatment 
for patients with HFrEF. While the data from DAPA-HF in HFrEF are supportive of a 
potential benefit in HFpEF, it is well-known that treatments that are effective in HFrEF 
are often not effective in HFpEF due to multiple fundamental pathophysiologic 
differences between the two HF phenotypes.22 Furthermore, the potential mechanisms of 
effect on hemodynamic abnormalities and cardiac metabolism (in any type of HF) remain 
unclear, forming the basis for the present study. 
 
1.4 
Dose Rationale  
This study will test the same 10 mg dose of dapagliflozin (once daily) that was shown to 
be safe and effective in the DAPA-HF trial.20 
 
1.5 
Risks and Benefits 
Dapagliflozin has been well-tolerated in patients with HFrEF in both the DAPA-HF trial20 
and the EMPEROR-Reduced trials.21 Risks reported across all studies include genital and 
urinary tract infections, and diabetic ketoacidosis. The frequency of adverse events related 
to volume depletion, renal dysfunction, and hypoglycemia did not differ between patients 
randomized to dapagliflozin or placebo.20, 21 A recent meta-analysis combining results 
from both DAPA-HF and EMPEROR-Reduced (n=8474) has confirmed an excellent 
safety profile, with lower rate of serious adverse events among patients randomized to 
active therapy in both trials, as shown in the Table below from Zannad et al.23 
 
The potential benefits from dapagliflozin include an improvement in symptoms of 
dyspnea and fatigue, increase in exercise capacity, improved quality of life, reduction in 
the risk of HF hospitalization, and reduction in the risk of death. In the meta-analysis 
combining the results from both DAPA-HF and EMPEROR-Reduced, there was an 


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estimated 13% reduction in all-cause death, 14% reduction in cardiovascular death, 26% 
relative reduction in the combined risk of cardiovascular death or first hospitalization for 
heart failure, and 25% decrease in the composite of recurrent hospitalizations for heart 
failure or cardiovascular death.23 Benefits were consistent across all subgroups based on 
age, sex, diabetes, treatment with angiotensin-neprilysin antagonists, and at different 
values of baseline kidney function. 
 
The table below presents the summary safety data for DAPA-HF and EMPEROR-
Reduced, taken from Zannad et al. Lancet, 2020.23 
 
 
Given the strong evidence of both safety and efficacy in a related form of heart failure, 
along with the fact that dapagliflozin is FDA approved for both HFrEF and diabetes, the 
risk-benefit ratio very much favors benefits in the present study testing DAPA in patients 
with heart failure and preserved EF. 
 
2 Study Objectives 
 
Primary Objective 
To determine whether treatment with DAPA for 6 months will improve pulmonary capillary 
wedge pressure (PCWP) during exercise in HFpEF.  
 
Secondary Objectives 
1. To determine whether treatment with DAPA for 6 months can improve myocardial 
metabolism and substrate utilization, shifting from high uptake of free fatty acids to favor 
glucose utilization. 
2. To determine whether treatment with DAPA for 6 months will improve other 
hemodynamic markers of HF severity (at rest and with exercise) in HFpEF. 
3. To determine whether treatment with DAPA for 6 months can improve ventricular 
function and functional reserve as assessed by tissue Doppler echocardiography and 
strain imaging. 
4. To determine whether treatment with DAPA for 6 months can reduce plasma volume 
assessed by labelled albumin indicator dilution technique. 


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5. To determine whether treatment with DAPA for 6 months can improve exercise capacity 
and quality of life in HFpEF, and explore how these clinical changes relate to changes in 
hemodynamics, cardiac function, and cardiac metabolism. 
 
3 Study Design 
 
3.1 
General Description 
This is a mechanistic phase II placebo-controlled trial designed to determine whether treatment 
with dapagliflozin for 6 months will improve exercise hemodynamics, cardiac metabolism, and 
clinically relevant endpoints in patients with HFpEF.  
 
Brief Synopsis of Methods:  
1) 
Enroll subjects with HFpEF. Some patients will have previously been identified and 
some will have be referred to the catheterization lab for evaluation of dyspnea and 
suspected HFpEF. The latter patients will only qualify for randomization if they meet 
hemodynamic entry criteria for HFpEF (PCWP of ≥25 mmHg with exercise).  
2) 
Safety lab sampling (complete blood count, creatinine, blood urea nitrogen, sodium, 
potassium, aspartate aminotransferase, alanine aminotransferase, total, direct and 
indirect bilirubin) hs-CRP, HgA1c, NTproBNP will be performed. Values may be 
used up to a week prior to study if the same bloods have already been drawn.  
3) 
In the preparation area, an IV cannula will be inserted in a forearm vein for initiation 
of isotope infusion ([U-13C] palmitate), allowing for attainment of steady-state prior 
to transfer to the catheterization laboratory (~60 min). Isotope infusions will be 
continued until blood sampling studies have been completed.  
4) 
Assess hemodynamics at rest and during exercise using gold standard invasive 
techniques in patients with HFpEF. Venous, arterial and coronary sinus blood 
samples obtained at rest and during exercise. Focused echocardiography examination 
with measurement of LV and RV tissue Doppler echocardiography and cardiac 
volumes will be performed. This will conclude the invasive catheterization visit.  The 
patient will be monitored per standard clinical protocols following right heart 
catheterization and discharged the same day. 
5) 
At a separate visit following cardiac catheterization, but prior to receipt of study drug, 
participants will have a QOL assessment, dual energy X-ray absorptiometry (DEXA), 
and measurement of plasma volume using the labelled albumin indicator dilution 
technique. Study coordinator will review patient preferences regarding contact during 
the study including video teleconference (preferred) or phone call.  
6) 
Patients will be randomized in a double-blind fashion to dapagliflozin 10 mg once 
daily or matching placebo.  Study drug dispensed by research pharmacy. 
7) 
Telephone visits will be conducted at 2 days, 1 week, 2 weeks, and then every 4 
weeks thereafter, for a total of 24 weeks. One week after visit 4, there will be an 
additional telephone visit for safety after patient is no longer on study drug. All phone 
visits will have a window of +/- 3 days. Participants will be contacted by phone or 
through videoconference visits (based upon patient preference) to evaluate for 
AEs/SAEs, and encourage compliance with the study medication. Adverse events will 
be determined using a general approach, asking participants if there have been any 
changes to their overall health since the prior visit, including any unplanned hospital 


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or clinic visits. At 2 weeks, as part of standard of care, patients will undergo 
laboratory draw from complete blood count, electrolytes and renal function at their 
local lab, with results reviewed by the study teamIf needed, a physician on the trial 
can put in a referral order for the lab work. 
8) 
At the conclusion the 24 week treatment period, participants will return to complete 
the same invasive hemodynamic assessments and noninvasive assessments as 
described in steps (1) through (5) above (2 visits). Patient must remain on study drug 
through Visit 4, and may be on drug up to 7 days after the 24 week mark. 
9) 
A follow up telephone/videoconference visit will be scheduled 1 week after 
completion of the trial to evaluate for AEs/SAEs following completion. This will 
have a window of +/- 3 days. 
 
3.2 Number of Subjects 
 
Up to 60 subjects will sign consent and be screened and an anticipated 46 subjects will be 
randomized and will complete the first part of the study assessments.  It is anticipated that 
41 subjects will be needed to be randomized to account for drop outs, in order to have 41 
subjects complete all study assessments. 
 
3.3 
Duration of Participation 
Subjects will participate in this study for up to 28 weeks. 
 
3.4 
Primary Study Endpoints 
The primary endpoint will be the PCWP incorporating values at rest, with feet elevated, 
and at 20 Watts exercise after treatment with study drug for 6 months relative to the 
respective PCWP values at each stage in the initial assessment prior to study drug. This 
will be analyzed using a mixed model with repeated measures (MMRM). 
 
3.5 
Secondary Study Endpoints 
Secondary exploratory endpoints will include:  
1. Trans-cardiac uptake of free fatty acids (FFA), glucose, and ketone bodies uptake 
relative to O2, as determined using arterial and coronary sinus blood sampling, at rest 
and with exercise  
2. Changes in resting PCWP after study drug as well as rest and exercise changes in right 
atrial pressure and pulmonary artery pressures, rest and exercise cardiac output, and 
other derived hemodynamic indices. 
3. Rest and exercise tissue Doppler diastolic (e') and systolic function (s'), LV global 
longitudinal strain at rest and with exercise. 
4. Peak oxygen consumption (VO2) during exercise, along with related cardiopulmonary 
indices. 
5. Plasma volume and blood volume and quality of life (QOL) using SF-36. 
6. Body composition including fat mass and fat free mass by DEXA scan 
 
3.6 
Primary Safety Endpoints 
Safety endpoints of special interest will include symptoms suggestive of volume depletion 
or genitourinary infections, and laboratory abnormalities including renal function. These 
adverse events were not more common that placebo in DAPA-HF and will be therefore 


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ascertained remotely via telephone/video-teleconference for patient convenience and 
reduce travel burden. 
 
3.7 
Identification of Source Data 
Study outcome data will be captured on electronic or paper case report forms and entered 
into REDCap database for subsequent analysis. 
 
 


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4 Subject Selection Enrollment and Withdrawal 
 
4.1 
Inclusion Criteria 
Subjects are eligible to be randomized in the study only if all of the following inclusion 
criteria and none of the exclusion criteria apply: 
1. Signed informed consent prior to any study specific procedures 
2. Male or female subject  
3. Age ≥ 18 
4. Symptoms of dyspnea (NYHA II-III) with no non-cardiac or ischemia explanation 
5. EF ≥50%  
6. Elevated pulmonary capillary wedge pressure (PCWP) during exercise (≥25 mmHg) 
ascertained at Visit 1. Patients that have consented to study procedures but do not 
meet this invasive criterion will be considered as screen failures and will not be 
randomized. 
 
4.2 
Exclusion Criteria 
1. Type I diabetes 
2. Type II diabetes with poor control (HgbA1c≥10%) 
3. Recent hospitalization (<30 days) or revascularization (<90 days)  
4. Primary cardiomyopathy (such as amyloid) 
5. Constrictive pericarditis  
6. Dyspnea due to primary lung disease or myocardial ischemia in the opinion of the 
investigator 
7. Severe anemia (hemoglobin <9 gm/dl) 
8. Significant left-sided valvular heart disease (>moderate  stenosis, >moderate 
regurgitation) 
9. Severe kidney disease (estimated GFR<30) or liver disease 
10. Women of child bearing potential not willing to use a medically accepted method of 
contraception OR who are currently pregnant (confirmed with positive pregnancy 
test) or breast feeding. 
11. History of serious hypersensitivity reaction to dapagliflozin 
12. Subjects on dialysis 
13. Subjects with severe hepatic impairment (Child-Pugh class C ) 
14.  Currently taking Empagliflozin or Canagliflozin  
 
4.3 
Subject Recruitment, Enrollment and Screening 
Eligible patients will be identified from screening of the patients listed for exercise right 
heart catheterization as well as patients with known HFpEF at the Mayo Clinic in 
Rochester, Minnesota.    
 
4.4 
Early Withdrawal of Subjects 
 
4.4.1 When and How to Withdraw Subjects 
Development of any condition that requires study withdrawal related to safety, disease 
progression, subject decision or failure to adhere to protocol requirements could qualify 
as reason to withdraw from the study. 


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4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Subjects withdrawing from the study will be contacted 2 weeks following study drug 
administration to collect any adverse events.  Participants that withdraw may be replaced 
to allow for achievement of target enrollment. 
 
5 Study Drug  
 
5.1 
Description 
Dapagliflozin is a highly potent, selective, and reversible inhibitor of SGLT2 that improves 
glycemic control in patients with diabetes mellitus and provides cardio-renal benefits in 
patients with T2DM and without diabetes. Dapagliflozin is orally available and requires 
once-daily dosing. 
 
Dapagliflozin is currently approved in 100 countries for the treatment of T2DM as an 
adjunct to diet and exercise and is also indicated for the treatment of HFrEF. 
 
Dapagliflozin film-coated tablets used in clinical studies are available in strengths of 2.5, 
5, and 10 mg. The tablets contain dapagliflozin propanediol (BMS-512148) drug 
substance, microcrystalline cellulose, anhydrous lactose, crospovidone, silicon dioxide, 
magnesium stearate, and coating material (Opadry® II). The tablets are supplied in HDPE 
bottles. The chemical composition is C21H25ClO6•C3H8O2•H2O, Formula weight 
502.98, Molecular weight 408.87 (dapagliflozin), Appearance is white to off-white powder 
which may contain lumps, pH 6.9 (1.5 mg/mL), pKa: Non-ionizable compound. 
 
Look-alike placebo tablets are supplied in the same container/closure system. The placebo 
tablets contain lactose monohydrate, microcrystalline cellulose, magnesium stearate, and 
coating material (Opadry® II). 
 
5.2 
Treatment Regimen 
Participants will receive dapagliflozin 10 mg by mouth once daily or matching placebo for 
24 weeks. 
 
5.3 
Method for Assigning Subjects to Treatment Groups 
Patients will be randomized 1:1 in a blinded fashion to dapagliflozin or placebo with 
blinding and randomization performed by the Mayo Clinic Research Pharmacy.  
 
5.4 
Preparation and Administration of Study Drug 
The IMP will be provided in bulk from AstraZeneca, to be labeled by the sponsor with a 
study specific label. Separate instructions for preparation and handling of the IMP will be 
provided by AstraZeneca in a Handling instruction. 
 
5.5 
Subject Compliance Monitoring 
Compliance will be monitored and encouraged through frequent telephone 
calls/videoconference visits throughout the course of the study. 
 


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5.6 
Prior and Concomitant Therapy 
Participants’ chronic medications will not be changed for the purposes of this study. They 
will continue taking their home medications as prescribed, including on procedure dates 
unless contraindicated as clinical standards. Data for baseline medication usage will be 
obtained. 
 
5.7 
Packaging 
The oral dapagliflozin tablets (10 mg) or matching placebo will be provided in bulk by 
AstraZeneca, and then shipped to the Research pharmacy at the Mayo Clinic.  Appearance 
of active drug and placebo will be identical. 
 
5.8 
Masking/Blinding of Study  
Only research pharmacy staff will be aware of randomization scheme and all study personnel 
and subjects will remain blinded to the identity of study drug.  Placebo and dapagliflozin 
tablets have an identical appearance assuring maintenance of the blind. 
 
5.9 
Receiving, Storage, Dispensing and Return 
 
5.9.1 Receipt of Drug Supplies 
The oral dapagliflozin tablets (10 mg) or matching placebo will be provided in bulk by 
AstraZeneca, and then shipped to the Research pharmacy at the Mayo Clinic.  
Appearance of active drug and placebo will be identical. It is important that the 
designated study staff counts and verifies that the shipment contains all the items noted in 
the shipping invoice. Any discrepancies, damaged or unusable study drug in a given 
shipment (active drug or placebo) will be documented in the study files. The sponsor-
investigator must be notified immediately of any discrepancies, damaged or unusable 
products that are received. 
 
5.9.2 Storage 
The study drug will be securely stored as recommended according to the instructions on 
the label.  
 
5.9.3 Dispensing of Study Drug 
Study drug (12 week supply plus 10 days additional for unavoidable events) will be 
provided by research pharmacy following randomization.  A second 12-week supply of 
study drug will be may be mailed to participants prior to the 12 week point in the trial 
schedule.  
 
Regular study drug reconciliation will be performed to document drug assigned, drug 
dispensed, drug returns, and drug remaining.  This reconciliation will be logged on the 
drug reconciliation form, and signed and dated by the study team. 
 
5.9.4 Return or Destruction of Study Drug 
Participants are instructed to return all used, partly used and unused trial product at the 
final on-site study visit.  Returned trial product(s) (used, partly used or unused including 
empty packaging material) must be stored separately from the non-allocated trial 


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product(s) until drug accountability has been reconciled. The investigators will keep track 
of all received, used, partly used and unused trial products. 
 
6 Study Procedures 
 
6.1 
Visit 1 
At Visit 1, subjects will provide written informed consent.  Medications will be 
documented and history and physical exam performed.  Routine blood tests including 
complete blood count, creatinine, blood urea nitrogen, sodium, potassium, aspartate 
aminotransferase, alanine aminotransferase, total, direct and indirect bilirubin, hsCRP, 
NTproBNP, and HgbA1c will be performed up to 7 days before catheterization, if the same 
labs are drawn for other clinical appointments, study may use those values to save the 
patient an extra blood draw in addition to pregnancy test for women of child bearing 
potential. 
 
In the preparation area, an IV cannula will be inserted in a forearm vein for initiation of 
isotope infusion ([U-13C] palmitate) to quantify free fatty acid (FFA) uptake during the 
procedure, allowing for attainment of steady-state prior to transfer to the catheterization 
laboratory (~60 min). Isotope infusions will be continued until blood sampling studies 
have been completed.  
 
In the laboratory, right heart catheterization with simultaneous limited echocardiography 
and expired gas analysis will then be performed at rest and during supine cycle ergometer 
exercise as per standard practice. Pressures are measured in the right atrium, right 
ventricle, pulmonary artery, pulmonary artery wedge position, and radial artery are 
measured at end expiration at rest and throughout each stage of exercise.  Cardiac output is 
measured using the direct Fick method. 
  
After resting hemodynamic assessments have been performed, a 6 Fr MPA catheter will be 
advanced from the right internal jugular vein to the coronary sinus (CS) under fluoroscopic 
guidance, with CS location confirmed by oximetry (O2 saturation<45%). Blood samples 
from the radial artery and CS will be drawn in triplicate (3 ml each) and averaged to 
measure blood gases (trans-myocardial O2 uptake and CO2 release based upon the 
difference between artery and CS tensions) along with glucose, lactate, triglyceride, 
pyruvate, ketone, and FFA uptake (total FFA and [U-13C]palmitate – enrichment in arterial 
and CS blood)). Additional mandatory research blood samples will be drawn frozen and 
stored for future discovery analysis. Samples will come from the CS, vein and artery once 
at the beginning of the procedure for future research.  Samples will be transferred in iced 
tubes, centrifuged at 4˚C and stored at -80˚C for analysis.  
 
Following resting metabolic assessments, participants will exercise at 20W workload on a 
supine ergometer for 3 minutes with the CS catheter in place, after which time arterial and 
CS sampling will be repeated during exercise in the same manner as at rest. The MPA 
catheter is then removed from the CS and exercise hemodynamic measurements are 
obtained. After obtaining exercise hemodynamic data at the 20W workload, workload is 


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increased in 20 W stages (3 minutes each) to volitional exhaustion. Hemodynamics and 
arterial and mixed venous blood samples are obtained at each stage. 
 
Following exercise, catheters are removed and the patient is observed in the recovery area 
as per standard clinical practice prior to discharge.   
 
6.2 
Visit 2 
At a second visit, typically the following day from the invasive catheterization  can occur 
the day before visit 1 to allow flexibility, but no later than one week later, the patient will 
undergo plasma volume and blood volume assessment using the radiolabeled iodinated 
albumin (131I, 5–25 μCu) indicator dilution technique (BVA-100 Blood Volume Analyzer, 
Daxor Corp, NY) as is used clinically at Mayo Clinic and as we have described.16 Patients 
will also undergo a DEXA scan in the Mayo CRTU. 
 
At this visit QOL will be assessed using the SF-36 Questionnaire. Participants will receive 
the first 12 week supply of study drug as allocated in the randomization, and review study 
procedures and preferences for remote visits throughout the study period. 
6.3 
Remote Telephone/Video Visits  
Multiple visits will occur through videoconference (preferred) or telephone to assess for 
adverse events and ensure compliance with medication adherence. These visits will occur 
at the following timepoints: 2 day post procedure and 1, 2, 6, 10, 14, 18, & 22 weeks post 
procedure.  
 
A final remote telephone/video visit will occur 1 week following the final on-site study 
visit to assess if there is any clinical change following discontinuation of study treatment.   
 
6.4 
Visits 3 & 4 
These visits will be identical to visits 1 and 2, with the exception that study drug will be 
returned at the final on-site study visit. 
 
 


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Test Schedule 
 
 
Study Activity 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Screen  
Procedure 
1-7 days 
following Visit 1 
or 1 day prior to 
Visit 1 
Week 24 (+/- 2 
weeks) 
1-7 days 
following Visit 
3, or 1 day prior 
to Visit 3 
Informed consent1 
X 
 
X 
 
 
History 
X 
 
 
 
 
Concurrent meds 
X 
 
X 
X 
X 
Physical exam (Ht, Wt, 
BSA, VS) 
X 
 
 
X 
 
Adverse event 
evaluation 
 
X 
X 
X 
X 
NYHA Classification 
X 
 
 
X 
 
Blood Draw  
X2 
X3 
 
X1 
 
Serum pregnancy 4 
X 
 
X 
X 
 
RHC 
 
X 
 
X 
 
Exercise study with 
hemodynamics 
 
X 
 
X 
 
Blood gasses 
 
X 
 
X 
 
Limited Echo 
 
X 
 
X 
 
Blood volume test 
 
 
X 
 
X 
SF-36 Questionnaire 
 
 
X 
 
X 
DEXA 
 
 
X 
 
X 
 
1 Consent can occur on Visit 1 or Visit 2 and must occur before any research activities take place. 
2 Pre-procedure: CBC, creatinine, BUN, sodium, potassium, aspartate aminotransferase, alanine aminotransferase, 
total, direct and indirect bilirubin, hsCRP, NTproBNP, and HgbA1c as part of clinical care 
3 Research blood will be drawn, processed, stored and tested in Dr. Michael Jensen’s lab. 
4 For women of childbearing potential, required to be done once before any research assessments, either Visit 1 or 
Visit 2. 


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DAPA/Placebo  
 
X5 
X5 
X6 
X6 
 
5 12 week supply dispensed once Visit 1 and  Visit 2 are complete and 12 week supply mailed to patient at 12 weeks 
after remote visit 
6 Study drug returned at either Visit 3 or 4, whichever is later  


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7 Statistical Plan 
 
7.1 
Introduction to the Statistical Design 
This study will use a 1:1 randomization to active therapy or control. The control group is 
scientifically necessary because it is expected that there will be longitudinal changes in 
cardiac function and hemodynamics in the absence of intervention that need to be 
accounted for in the analysis. The primary endpoint is left ventricular filling pressure, 
specifically pulmonary capillary wedge pressure (PCWP) measured invasively in the 
cardiac catheterization lab. Within each endpoint assessment period (described in section 
6), a baseline (resting) and exercise assessment of PCWP will be gathered. The analysis 
plan described below will detail how the longitudinal measurements will be used to 
objectively test for differences both within group over time and between groups over time. 
 
7.2 
Randomization and Blinding 
Scientific rigor is enhanced by randomization and blinding. Mayo Research Pharmacy will 
be provided a block randomization sequence that will be used by pharmacy to randomize 
enrolled subjects 1:1.  Medical staff and patients will be both blinded about the 
randomization to achieve the most unbiased results. 
 
7.3 
Data Management Plan 
The data will be secured in a central registry using REDCap. The principle investigator will 
be responsible for proper data quality assurance (data matching, source verification, and 
deidentification). Data will be stored on password protected computers with access only 
allowed to the investigators. The investigator will maintain records and essential 
documents related to the conduct of the study.  These will include subject case histories and 
regulatory documents. 
 
The investigator will retain the specified records and reports during the study and for a 
period of 2 years after the latter of the following two dates: The date on which the 
investigation is terminated or completed, or the date that the records are no longer required 
for purposes of supporting a premarket approval application or a notice of completion of a 
product development protocol. 
 
7.4 
Outcomes 
The complete list of primary and secondary outcome measures is provided in the Outcomes 
section of the application (section 3.4-3.5). The primary outcome measure for this 
mechanistic trial is the PCWP assessed at baseline and 6 months after treatment under rest 
and exercise within the same catheterization session. 
 
7.5 
Sample Size Estimation 
Based on preliminary data from our previous studies (Borlaug et al 2015, 2016), we know 
the PCWP is positively correlated within individuals between rest and exercise. 
Furthermore, the standard deviation of PCWP has been consistently ~5 mmHg, with some 
proportionality to the mean (i.e., more variability in those with pulmonary hypertension). 
To initially frame the sample size, we first focus on the exercise PCWP. We expect little, if 


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any, improvement in PCWP in the control group (some improvement possible due to the 
Hawthorn effect). We assume the average exercise PCWP in obese HFpEF patients is 30 
mmHg and expect a 20% (6 mmHg) reduction in exercise PCWP in patients treated with 
DAPA compared with patients with placebo. The test-retest variability in exercise PCWP is 
<5 mmHg. 
 
Based on two sample t test, 36 patients (18 receiving DAPA and 18 placebo) would 
provide 93% power to detect a difference of 6mmHG or greater in PCWP during exercise 
workloads between the DAPA and placebo groups, with a common standard deviation of 5 
mmHg, at 0.05 significance level.  By including resting values of PCWP in the mixed 
model with repeated measures, this is expected to increase the power further. 
 
7.6 
Primary Analysis 
The primary analysis will be conducted using a mixed model using all available data. There 
will be main effects and interactions used to classify the PCWP as of randomized treatment 
DAPA/control, exercise yes/no, and baseline yes/no. A random subject effect will be 
utilized to block data on individual participant. The model configured this way provided 
the means to conduct a likelihood ratio test for the importance of DAPA on altering the 
PCWP profiles as the test for the primary hypothesis. Statistical contrasts will be utilized to 
compare PCWP under exercise at the end of the treatment period between groups and the 
differences in the change in PCWP over the study period between groups. These two 
hypotheses are a priori specified and will not be adjusted for multiple comparisons as they 
are intrinsically linked to the primary likelihood ratio test. This statistical model does not 
per se adjust for measured covariates as fixed effects in the model. The model, however, 
does include the random effect that effectively “adjusts for baseline” using a random 
variance term.  However, it is acknowledged while the design is randomized, the sample 
size is relatively small to rely on the large sample balancing properties of randomization to 
account for all confounding in the study.  To this end, we will compute standardized 
differences for all putative confounding variables captured at baseline prior to 
randomization. Absolute values for the standardized mean differences (SMD) <10% will be 
considered support for “balance” between the groups. If there are plausible confounding 
variables with SMD >10%, sensitivity analyses will be conducted using standard covariate 
adjustment methods including propensity score analysis. The propensity score analysis is to 
help mitigate the number of estimated parameters in the mixed model to help ensure 
convergence of the estimation process.   
 
For the more general patient reported outcomes and other clinical assessment that have >2 
replications, we will use a more generalized modeling framework that accounts for the 
actual time from baseline in the repeated measures model. Time varying covariates (e.g., 
marking the period of bariatric surgery) will also be considered to provide a model 
framework for the data over time. As with the primary analysis, the treatment group by 
time interaction terms will serve as the main statistical tests of the treatment effect.  As 
with the primary analysis, additional adjustment for imbalance that was not controlled via 
randomization will be implemented.  
 


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Missing data occur. We will conduct sensitivity analyses using modern machine learning 
based imputation approaches including chained equations and random forest imputation. 
Differences in estimates between the imputed and the observed data will be examined 
through pattern mixture models. Lack of consistency of results may indicate an internal 
bias, so therefore we will disclose our findings by reporting data analysis under the various 
data imputation strategies.  
 
Reproducible research principles will be integrated throughout the statistical analysis 
process. The two primary statistical languages of SAS and R will be utilized. In both cases, 
version controlled datasets will be utilized for any formal statistical reports. Programming 
code will be written such that all derivations and assumptions are documented within the 
source code and accompanying materials (i.e., no human manipulation of raw data values 
once entered into the master REDCap database). R markdown reports are the preferred 
study report formats as they allow for each communication of interpretation, raw numeric 
results and figures/tables.  
 
7.7 
Moderators of treatment effect 
It is plausible that increased obesity may result is differential responses to the DAPA 
treatment. We will test this using splined fits of BMI. In addition, age group will be 
examined a priori. The type III estimates of the treatment effect will be compared to the 
unadjusted analysis to assess the robustness of the randomization process. Graphical 
displays such as the customary forest plot will be used to present the means and 95% 
confidence intervals for the estimated responses in these subgroups. Likewise, additional 
subgroups based on baseline demographic and medical history will be plotted for 
completeness.  
 
7.8 
Analysis Sets 
The primary efficacy and safety analyses will be conducted according to “Intention-to-
Treat” (ITT) principles; that is, each subject will be analyzed according to the randomized 
sequence using all available data collected.  
 
8 Safety and Adverse Events 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition can 
be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered. Common adverse events of 
DAPA include genital and urinary tract infections, and diabetic ketoacidosis, and 
pollakiuria/polyuria. 
 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  


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• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: 
(1) death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, 
or prolonged; (4) disability/incapacity - persistent or significant; (5) birth 
defect/anomaly; (6) breach of confidentiality and (7) other problems, events, or new 
information (i.e. publications, DSMB reports, interim findings, product labeling 
change) that in the opinion of the local investigator may adversely affect the rights, 
safety, or welfare of the subjects or others, or substantially compromise the research 
data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
 
Adverse Event 
An untoward or undesirable experience associated with the use of a medical product (i.e. 
drug, device, biologic) in a patient or research subject. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be 
well defined and include; 
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant disability or incapacity 
• birth defect/anomaly 
• an important medical event that may jeopardize the participant or may require 
medical treatment to prevent one of the outcomes listed above and/or per protocol 
may be problems/events that in the opinion of the sponsor-investigator may have 
adversely affected the rights, safety, or welfare of the subjects or others, or 
substantially compromised the research data. 
 
All adverse events that do not meet any of the criteria for serious, should be regarded as 
non-serious adverse events.  
 
Adverse Event Reporting Period 
 
Preexisting Condition 


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A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an adverse event must also be recorded and documented as an 
adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the sponsor-investigator until the 
events are resolved, the subject is lost to follow-up, or the adverse event is otherwise 
explained.  At the last scheduled visit, the sponsor-investigator should instruct each subject 
to report, to the sponsor-investigator, any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this 
study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if there is a 
clinically significant change compared to the baseline values.  This may include measures 
of renal function such as creatinine or electrolyte levels.  The clinical significance of any 
change will be determined by the principal investigator.  
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise 
in this protocol.  Any condition responsible for surgery should be documented as an 
adverse event if the condition meets the criteria for an adverse event.  
 
8.2 
Recording of Adverse Events 
Adverse Events will be collected from the time of enrollment, throughout the treatment 
period and including the follow-up phone call/remote visit 1 week after Visit 4). SAEs will 
be recorded from the time of signing of informed consent form. If the investigator becomes 
aware of an SAE with a suspected causal relationship to the investigational medicinal 
product that occurs after the end of the clinical study in a participant treated by him or her, 
the investigator shall, without undue delay, report the serious adverse event. At each 
contact with the subject, the study team must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate 
adverse event section of the case report form (CRF).  All clearly related signs, symptoms, 
and abnormal diagnostic, laboratory or procedure results should recorded in the source 
document. 
 
All adverse events occurring during the study period must be recorded.  The clinical course 
of each event should be followed until resolution, stabilization, or until it has been 


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ultimately determined that the study treatment or participation is not the probable cause.  
Serious adverse events that are still ongoing at the end of the study period must be followed 
up, to determine the final outcome.  Any serious adverse event that occurs during the 
Adverse Event Reporting Period and is considered to be at least possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event 
(SAE) Worksheet and log.  The sponsor-investigator will evaluate the event and determine 
the necessary follow-up and reporting required.  Additionally, AstraZeneca will be 
informed of the SAE.  All SAEs have to be reported to AstraZeneca, whether or not 
considered causally related to the investigational product.   
 
SAEs related to the Investigational Product (IP) must be provided to AstraZeneca in an 
ongoing basis as individual case reports.  
 
SAEs unrelated to the IP must be provided to AstraZeneca as a quarterly line listing. 
 
At the end of the study a final unblinded summary line listing of all SAEs notified to the 
regulatory authority and/or AstraZeneca during the study, must be provided to the 
Company to enable reconciliation of safety information held by Company for its 
product(s). 
 
Send SAE reports (individual case reports and line listings) and accompanying cover page 
by way of fax to AstraZeneca’s designated fax line: +1 302 886 4114 or Email:
 AEmailboxclinicaltrialTCS@astrazeneca.com  
 
SAEs that do not require expedited reporting to the Regulatory Authority/IRB still need to 
be reported to AstraZeneca as a quarterly listing.  
  
Suspected Unexpected Serious Adverse Reactions (SUSARs) must be reported to 
Company at the same time these events are notified to the Regulatory Authority. 
 
In the case of blinded trials, AstraZeneca may request that the Sponsor either provide a 
copy of the randomization code/ code break information or unblind those SAEs which 
require expedited reporting. 
 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-
UPIRTSOs according to the Mayo IRB Policy and Procedures. 
 
Information collected on the adverse event worksheet (and entered in the research 
database):  
• Subject’s name:  
• Medical record number:  


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• Disease/histology (if applicable):  
• The date the adverse event occurred:  
• Description of the adverse event:  
• Relationship of the adverse event to the research (drug, procedure, or 
intervention):  
• If the adverse event was expected:  
• The severity of the adverse event: (use a table to define severity scale 1-5) 
• If any intervention was necessary:  
• Resolution: (was the incident resolved spontaneously, or after discontinuing 
treatment) 
• Date of Resolution:  
 
The sponsor-investigator will review all adverse event reports to determine if specific 
reports need to be made to the IRB.  The sponsor-investigator will sign and date the 
adverse event report when it is reviewed.  For this protocol, only directly related 
SAEs/UPIRTSOs will be reported to the IRB. 
 
Relationship Index Example 
The relationship of an AE to the Investigational Drug is a clinical decision by the 
sponsor-investigator (PI) based on all available information at the time of the completion 
of the CRF and is graded as follows: 
 
1. Not related: a reaction for which sufficient information exists to indicate that the 
etiology is unrelated to the study drug; the subject did not receive the study 
medication or the temporal sequence of the AE onset relative to administration of 
the study medication is not reasonable or the event is c1early related to other 
factors such as the subject’s clinical state, therapeutic intervention or concomitant 
therapy. 
2. Unlikely: a clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship improbable 
and in which other drugs, chemicals, or underlying disease provide plausible 
explanations. 
3. Possible: a clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug but which could also be explained by 
concurrent disease or other drugs or chemicals; information on drug withdrawals 
may be lacking are unclear. 
4. Probable: a clinical event including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals and which follows a clinically 
reasonable response on withdrawal (de-challenge): re-challenge information is not 
required to fulfi1 this definition. 
5. Definite: a reaction that follows a reasonable temporal sequence from 
administration of the drug, or in which the drug level has been established in body 
fluids or tissues, that follows a known or expected response pattern to the 


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suspected drug, and that is confirmed by improvement on stopping or reducing 
the dosage of the drug, and reappearance of the reaction on repeated exposure (re-
challenge). 
 
Severity Index Example 
The maximum intensity of an AE during a day should be graded according to the 
definitions below and recorded in details as indicated on the CRF. If the intensity of an 
AE changes over a number of days, then separate entries should be made having distinct 
onset dates.  
 
1. Mild: AEs are usually transient, requiring no special treatment, and do not 
interfere with patient’s daily activities. 
2. Moderate: AEs typically introduce a low level of inconvenience or concern to the 
patient and may interfere with daily activities, but are usually ameliorated by 
simple therapeutic measures. 
3. Severe: AEs interrupt a patient's usual daily activity and traditionally require 
systemic drug therapy or other treatment. 
 
8.4 
Pregnancy 
All pregnancies must be reported to AstraZeneca. The Pregnancy and breast-feeding 
exclusion criterion should be used in combination with the discontinuation criterion for 
pregnancy If a patient becomes pregnant during the course of the study, investigational 
product should be discontinued immediately and an AZ representative notified. Pregnancy 
itself is not regarded as an AE unless there is a suspicion that the investigational product 
under study may have interfered with the effectiveness of a contraceptive medication. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and 
documented, even if the patient was discontinued from the study. 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca's 
designated fax line: +1 302 886 4114 or email: 
AEmailboxclinicaltrialTCS@astrazeneca.com 
 
8.5 
Unmasking/Unblinding Procedures 
The investigators will be given access to the treatment code for their Participants for 
emergency un-blinding. Any suspected study drug-related events should be treated as 
though the Participant received active therapy. 
 
Randomization data are kept strictly confidential, accessible only to authorized persons, 
until the time of un-blinding. 
 
8.6 
Stopping Rules  
The study may be terminated prematurely if: 
• The PI (sponsor) and AstraZeneca assess that the number and/or severity of AEs 
justify discontinuation of the study. For instance if there were a case of fatal SAE or 2 
cases of other SAEs that were considered related by the Investigator and AstraZeneca. 


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• AstraZeneca considers the applied doses of the study drug to be no longer relevant. 
• The PI (sponsor) decides to discontinue the study. 
• Data not known before become available and raise concern about the safety of study 
drug so that continuation would pose potential risks to the subjects. 
• Premature termination of the study must be mutually agreed upon by the PI (sponsor) 
and AstraZeneca and must be documented. However, study results will be reported 
according to the requirements outlined in this clinical study protocol as far as 
applicable. 
 
8.7 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his 
site.  This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site data 
and safety-monitoring plan (see section 10  “Study Monitoring, Auditing, and Inspecting”).  
Medical monitoring will include a regular assessment of the number and type of serious 
adverse events. 
 
9 Data Handling and Record Keeping 
 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (long term 
survival status that the subject is alive) at the end of their scheduled study period. Data will 
be stored on password protected computers with access only allowed to the investigators. 
 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents, and 
data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical trial. 


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9.3 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF will be recorded.  All missing data will be explained. 
REDCap is the research data base that will be used to create the CRF’s and securely store 
the data.   
 
9.4 
Records Retention 
The sponsor-investigator will maintain records and essential documents related to the 
conduct of the study.  These will include subject case histories and regulatory documents. 
 
The sponsor-investigator will retain the specified records and reports for; 
1. Up to 2 years after the marketing application is approved for the drug; or, if a 
marketing application is not submitted or approved for the drug, until 2 years after 
shipment and delivery of the drug for investigational use is discontinued. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717  
whichever is longer. 
 
10 Study Monitoring, Auditing, and Inspecting 
 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities.  The 
Investigator will also ensure that the monitor or other compliance or quality assurance 
reviewer is given access to all the study-related documents and study related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the monitoring 
visit. 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
the sponsor, and government regulatory agencies, of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data etc.).  The 
investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
 
11 Ethical Considerations 
 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 


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study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the Approved IRB consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject or the subject’s legally authorized representative, and the individual obtaining the 
informed consent. 
 
 


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12 Study Finances 
 
12.1 Funding Source 
This study is financed through AstraZeneca. Study drug dapagliflozin and placebo will be 
provided by AstraZeneca. 
 
12.2 Conflict of Interest 
Any study team member who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must have the conflict reviewed by a properly constituted Conflict of Interest Committee 
with a Committee-sanctioned conflict management plan that has been reviewed and 
approved by the study sponsor-investigator prior to participation in this study. 
 
12.3 Subject Stipends or Payments 
Participants will receive payment for study participation of up to $400 in total, $100 after 
completion of visit 1, $100 after completion of visit 2, $100 after completion of visit 3 and 
a final payment of $100 after completion of visit 4. 
 
13 Publication Plan 
The primary responsibility for publication of the results lies with the principal investigator.  The 
trial will be registered on ClinicalTrials.gov: https://register.clinicaltrials.gov/. 
 


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14 References 
1. 
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2. 
Shah SJ, Borlaug BA, Kitzman DW, McCulloch AD, Blaxall BC, Agarwal R, Chirinos JA, 
Collins S, Deo RC, Gladwin MT, Granzier H, Hummel SL, Kass DA, Redfield MM, Sam F, 
Wang TJ, Desvigne-Nickens P and Adhikari BB. Research Priorities for Heart Failure With 
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3. 
Pfeffer MA, Shah AM and Borlaug BA. Heart Failure With Preserved Ejection Fraction In 
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Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, Levine JA, Koepp GA, Givertz MM, Felker 
GM, LeWinter MM, Mann DL, Margulies KB, Smith AL, Tang WHW, Whellan DJ, Chen 
HH, Davila-Roman VG, McNulty S, Desvigne-Nickens P, Hernandez AF, Braunwald E and 
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Clinical Trial. JAMA. 2018;320:1764-1773. 
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in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-
HEART CardioLink-6 Randomized Clinical Trial. Circulation. 2019;140:1693-1702. 
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22. Borlaug BA and Redfield MM. Diastolic and systolic heart failure are distinct phenotypes 
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AP, Pfarr E, Jamal W and Packer M. SGLT2 inhibitors in patients with heart failure with 


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reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. 
Lancet. 2020. 
 
 
 
 
 


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