Conditions: Chronic Heart Failure With Preserved Systolic Function
Keywords: heart failure dapagliflozin SGLT-2 inhibitors
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 324
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure, disease specific biomarkers, symptoms, health status and quality of life in patients with chronic heart failure with preserved systolic function.

Detailed description:
A 12-week randomized, double-blind, placebo-controlled trial to evaluate the effects of once-daily dapagliflozin 10 mg on heart failure disease-specific biomarkers (NTproBNP and BNP), symptoms, health status, and quality of life in patients with chronic heart failure with preserved systolic function. An imaging substudy will also be conducted to explore the effects of dapagliflozin vs. placebo on various echocardiographic parameters.

Arms:
arm 1: Dapagliflozin 10 mg oral tablet, once daily, for 12 weeks arm 2: Dapagliflozin matching placebo oral tablet, once daily, for 12 weeks

Interventions: intervention 1: Dapagliflozin 10Mg Oral Tablet intervention 2: Dapagliflozin matching placebo
Intervention descriptions: intervention 1: Dapagliflozin 10Mg Oral Tablet intervention 2: Dapagliflozin matching placebo

Protocol document:
Prot_000.pdf: 
EFFECTS OF DAPAGUFLOZIN ON BIOMARKERS, SYMPTOMS AND FUNCTIONAL STATUS IN 
PATIENTS WITH PRESERVED EJECTION FRACTION HEART fAILURE (PRESERVED-HF TRIAL) 
Protocol Number: D1690C00053 
PRESERVED-HF Protocol v3.0 
Page 1 of67 
Version Date March 20, 2020
Protocol
NCT03030235





































































































































SAP_001.pdf: 
PRESERVED-HF SAP 
 
Page 1 of 35 
 
                                 
 
 
Effects of dapagliflozin on biomarkers, symptoms and functional status in patients 
with PRESERVED ejection fraction Heart Failure (PRESERVED-HF trial) 
 
Statistical Analysis Plan (SAP) 
 
            
 
Protocol Number:   D1690C00053 
        
 
                                 
 
                                               
 
                                               
 
                                               
 
 
                    
 
                                               
 
                                               
 
 
Version Number:                Final 
 
Version Date:                      August 12, 2021 
 
 
                      
 
                                                           
 
 
                       
 
 
 
 
NCT03030235


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Abbreviation or 
special term 
Explanation 
AE 
AFib 
Adverse Event  
Atrial fibrillation 
 
 
BMI 
Body mass index 
BNP 
B-type natriuretic peptide 
CRF 
Case Report Form (electronic/paper) 
DBP 
Diastolic Blood Pressure 
DM 
Diabetes mellitus 
EPS 
GFR 
Enrolled Patients Set 
Glomerular filtration rate 
HbA1c 
Hemoglobin A1c 
HDL 
High-Density Lipoprotein 
HF 
Heart failure 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LVEF 
Left Ventricular Ejection Fraction 
ITTS 
Intention to treat set 
IP 
IPDs 
MCAR 
MDRD 
NSVT 
NTproBNP 
NYHA 
Investigational Product 
Important Protocol Deviations 
Missing completely at random 
Modification of Diet in Renal Disease 
Nonsustained ventricular tachycardia 
N-terminal (NT)-pro hormone BNP 
New York Heart Association 
PPS 
PAC 
PTDV 
PVC 
Per protocol set 
Premature atrial contractions 
Premature treatment discontinuation visit 
Premature ventricular contractions 
SAE 
Severe Adverse Event 
SAFS 
Safety Analysis Set 
SAS 
Statistical Analysis Software 
SBP 
Systolic Blood Pressure 


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Abbreviation or 
special term 
Explanation 
SD 
Standard deviation 
SE 
Standard error 
SGLT-2 
Sodium-glucose cotransporter 2 
T2DM 
VF 
VT 
Type 2 Diabetes Mellitus 
Ventricular fibrillation 
Ventricular tachycardia 
 
 
 
 
 
 
 
 
 
 
 


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Contents 
1 INTRODUCTION ................................................................................................................................................ 6 
1.1 
Study Objectives .................................................................................................................................. 6 
1.2 
Study Design ........................................................................................................................................ 7 
1.3 Sample Size and Power ............................................................................................................................ 10 
1.4 Substudy ..................................................................................................... Error! Bookmark not defined. 
2 GENERAL CONSIDERATIONS FOR DATA ANALYSES ........................................................................................ 11 
2.1 Analysis Data Sets .................................................................................................................................... 11 
2.2 Protocol Deviations and Major Eligibility Violations ............................................................................... 12 
2.3 Strata, Covariates, and pre-specified subgroup analyses........................................................................ 12 
2.5 Multiple Testing ....................................................................................................................................... 13 
2.6 Missing Data ............................................................................................................................................ 13 
2.7 Data Handling Conventions and Transformations .................................................................................. 14 
3 SUBJECT DISPOSITION .................................................................................................................................... 14 
3.1 Subject Enrollment .................................................................................................................................. 14 
3.2 Disposition of Subjects ............................................................................................................................ 14 
3.3 Extent of Exposure ................................................................................................................................... 15 
3.3.1 Study Drug Compliance .................................................................................................................... 15 
3.3.2 Duration of Exposure to Study Drug ................................................................................................. 15 
3.3.3 Adherence with Study Drug.............................................................................................................. 15 
4 Endpoints variables ........................................................................................................................................ 16 
4.1 Primary endpoints: .................................................................................................................................. 16 
4.2 Secondary endpoints: .............................................................................................................................. 16 
4.3 Exploratory Outcome Variables ............................................................................................................... 16 
4.4 Substudy Endpoints .................................................................................... Error! Bookmark not defined. 
5 Analyses of Baseline Characteristics ............................................................................................................... 19 
5.1 Demographics and Baseline Characteristics ............................................................................................ 19 
5.2 Medical History .................................................................................................................................... 19 
5.2.1 Diabetes History ............................................................................................................................... 19 
5.2.2 Other Medical History ...................................................................................................................... 19 
5.3 Physical examination ............................................................................................................................... 20 
5.4 Lab results ................................................................................................................................................ 20 


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6 EFFICACY ANALYSES ........................................................................................................................................ 20 
6.1 Analysis of the Primary Efficacy Endpoint ............................................................................................... 20 
6.2 Secondary outcome variables ................................................................................................................. 21 
6.2.1 Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score at 12 weeks .............. 21 
6.2.2 
NTproBNP at 6 and 12 weeks .................................................................................................... 21 
6.2.3 
BNP at 6 and 12 weeks .............................................................................................................. 22 
6.2.4 
Six-minute walk test at 12 weeks .............................................................................................. 22 
6.2.5 
HbA1c at 6 and 12 weeks .......................................................................................................... 22 
6.2.6 
Proportion of patients with a ≥ 5pts increase in KCCQ clinical summary score and KCCQ 
overall summary score at 12 weeks .......................................................................................................... 22 
6.2.7 
Proportion of patients with a ≥ 20% decrease in 6 and 12 weeks average of NTproBNP ........ 22 
6.2.8 
Proportion of patients with a ≥ 5pts increase in KCCQ and a ≥ 20% decrease in 6 and 12 weeks 
average of NTproBNP ................................................................................................................................ 22 
6.2.9 
Weight at 6 and 12 weeks ......................................................................................................... 23 
6.2.10 
Systolic blood pressure at 6 and 12 weeks ................................................................................ 23 
6.3 Exploratory outcome variables ................................................................................................................ 23 
6.3.1 Composite mean hierarchical-rank clinical score. ............................................................................ 23 
6.3.2 Heart failure hospitalizations ........................................................................................................... 23 
6.3.3 Urgent heart failure visits ................................................................................................................. 23 
6.3.4 Heart failure hospitalizations and urgent heart failure visits ........................................................... 23 
6.3.5 Proportion of patients that progress to diabetes during the treatment period (within the subgroup 
of patients without diabetes at baseline only) .......................................................................................... 23 
6.3.6 Change from baseline in average weekly loop diuretic dose (furosemide equivalent) ................... 24 
6.3.7 Change in NYHA Class at 6 and 12 weeks. ........................................................................................ 24 
6.3.8 Left atrial volume index and other measures of left ventricular diastolic function ......................... 24 
6.5 Sub Study Endpoints. .................................................................................. Error! Bookmark not defined. 
7 SAFETY ANALYSES ........................................................................................................................................... 24 
8 REFERENCES .................................................................................................................................................... 25 
9 SOFTWARE ...................................................................................................................................................... 25 
10 APPENDICES .................................................................................................................................................. 26 
10.1 Scoring and Interpreting the KCCQ ....................................................................................................... 26 
10.2 Protocol deviations ................................................................................................................................ 30 


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1 INTRODUCTION    
1.1 Study Objectives  
Primary Study 
Objective 
To evaluate the effects of dapagliflozin vs. placebo on heart failure related 
health status using the Kansas City Cardiomyopathy Questionnaire (KCCQ) 
clinical summary score at 12 weeks. 
 
Secondary Study 
Objectives 
1. To evaluate the effect of dapagliflozin vs. placebo on heart failure 
related health status using the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) overall summary score at 12 weeks  
2. To evaluate the effect of dapagliflozin vs. placebo on NTproBNP at 6 and 
12 weeks  
3. To evaluate the effect of dapagliflozin vs. placebo on BNP at 6 and 12 
weeks  
4. To evaluate the effect of dapagliflozin vs. placebo on 6-minute walk test 
at 12 weeks  
5. To evaluate the effect of dapagliflozin vs. placebo on HbA1c over the 
treatment period (evaluated separately in patients with and without 
type 2 diabetes)  
6. To evaluate the effect of dapagliflozin vs. placebo on proportion of 
patients with a ≥ 5pts increase in KCCQ clinical summary score and KCCQ 
overall summary score at 12 weeks  
7. To evaluate the effect of dapagliflozin vs. placebo on proportion of 
patients with a ≥ 20% decrease in NTproBNP at 6 and 12 weeks  
8. To evaluate the effect of dapagliflozin vs. placebo on proportion of 
patients with a ≥ 5pts increase in KCCQ and a ≥ 20% decrease in 
NTproBNP at 6 and 12 weeks  
9. To evaluate the effect of dapagliflozin vs. placebo on weight at 6 and 12 
weeks  
10. To evaluate the effect of dapagliflozin vs. placebo on systolic blood 
pressure at 6 and 12 weeks  
 
Exploratory 
objectives 
 
1. To evaluate the effect of dapagliflozin vs. placebo on composite 
hierarchical-rank clinical score.  
2. To evaluate the effect of dapagliflozin vs. placebo on heart failure 
hospitalizations  
3. To evaluate the effect of dapagliflozin vs. placebo on urgent heart 
failure visits  
4. To evaluate the effect of dapagliflozin vs. placebo on heart failure 
hospitalizations and urgent heart failure visits  


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5. To evaluate the effect of dapagliflozin vs. placebo on the proportion of 
patients that progress to diabetes during the treatment period (within 
the subgroup of patients without diabetes at baseline only)  
6. To evaluate the effect of dapagliflozin vs. placebo on weekly loop 
diuretic dose (furosemide equivalent)  
7. To evaluate the effect of dapagliflozin vs. placebo on NYHA Class at 6 
and 12 weeks.  
8. To evaluate the effect of dapagliflozin vs. placebo on left atrial volume 
index and other measures of left ventricular diastolic function (among 
Echocardiography sub study participants only) 
 
 
1.2 Study Design     
Design 
Configuration and 
Subject Population 
Randomized, double-blind, placebo-controlled trial. The control group will 
receive placebo administered orally once daily for 12 weeks plus standard of 
care. The treatment group will receive dapagliflozin 10 mg administered 
orally once daily for 12 weeks plus standard of care. A follow-up visit at week 
13 will be performed to evaluate markers of renal function. 
Treatment Groups 
Dapagliflozin 10 mg or matching placebo administered orally once daily for 
12 weeks, in addition to standard of care for chronic heart failure with 
preserved systolic function. 
Inclusion criteria 
1. Age > 18 and < 120 at the screening visit  
2. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-
cardiac or ischemic explanation for dyspnea  
3. Ejection fraction (EF) ≥ 45% as determined on imaging study within 24 
months of enrolment with no change in clinical status suggesting 
potential for deterioration in systolic function  
4. Elevated NT-proBNP (≥ 225 pg/ml) or BNP (≥ 75 pg/ml) Ŧ  
5. Stable medical therapy for heart failure for 15 days as defined by:  
i. 
No addition or removal of ACE, angiotensin receptor blockers 
(ARBs), valsartan/sacubitril, beta-blockers, calcium channel blockers 
(CCBs) or aldosterone antagonists  
ii. 
No substantial change in dosage (100% or greater increase or 
decrease from baseline dose) of ACE, ARBs, beta-blockers, CCBs or 
aldosterone antagonists  
6. On a diuretic ≥15 days prior to screening visit and a stable diuretic 
therapy for 7 days  
7. At least one of the following:  
i. Hospitalization for decompensated HF in the last 12 months  
ii. Acute treatment for HF with intravenous loop diuretic or 
hemofiltration in the last 12 months  


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iii. Mean pulmonary capillary wedge pressure ≥15 mmHg or LV end 
diastolic pressure (LVEDP) ≥15 mmHg documented during 
catheterization at rest, or pulmonary capillary wedge pressure or 
LVEDP ≥25 mmHg documented during catheterization with 
exercise.  
iv. Structural heart disease evidenced by at least one of the following 
echo findings (any local measurement made within the 24 months 
prior to screening visit):  
1) left atrial (LA) enlargement defined by at least one of the 
following: LA width ≥3.8cm or LA length ≥5.0 cm or LA area ≥20 
cm2 or LA volume ≥55 mL or LA volume index ≥29 mL/m2  
2) OR left ventricular hypertrophy (LVH) defined by septal 
thickness or posterior wall thickness ≥1.1 cm.  
Exclusion 
criteria 
1. Decompensated heart failure (hospitalization for heart failure within 7 
days prior to screening)  
2. History of type 1 diabetes  
3. History of diabetic ketoacidosis  
4. Estimated glomerular filtration rate (eGFR) < 20 at the screening visit by 
modified MDRD equation GFR (mL/min/1.73 m2 ) = 175 x (Scr) -1.154 x 
(Age)-0.203 x (0.742 if female) x (1.210 if African American)  
5. Admission for an acute coronary syndrome (ST-elevation MI, non-ST-
elevation MI, or unstable angina), percutaneous coronary intervention, or 
cardiac surgery within 30 days prior to the screening visit.  
6. Admission for cardiac resynchronization therapy (CRT) within 90 days prior 
to the screening visit.  
7. Planned cardiovascular revascularization (percutaneous intervention or 
surgical) or major cardiac surgery (coronary artery bypass grafting, valve 
replacement, ventricular assist device, cardiac transplantation, or any other 
surgery requiring thoracotomy, or transcatheter aortic valve replacement) or 
CRT within the 90 days after the screening visit.  
8. Participation in any interventional clinical trial (with an investigational 
drug or device) that is not an observational registry within 15 days of the 
screening visit.  
9. History of hypersensitivity to dapagliflozin  
10. For women of child-bearing potential: Current or planned pregnancy or 
currently lactating.  
Women of childbearing potential are defined as any female who has 
experienced menarche and who is NOT permanently sterile or 
postmenopausal. Post menopausal is defined as 12 consecutive months 


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with no menses without an alternative medical cause. Women of child-
bearing potential, who are sexually active, must agree to use a 
medically-accepted method of birth control for the duration of the 
study. Acceptable birth control methods include: (1) surgical sterilization 
(such as a hysterectomy or bilateral tubal ligation), (2) progesterone 
hormonal contraceptives (birth control pills or implants), (3) barrier 
methods (such as a condom or diaphragm) used with a spermicide, or 
(4) an intrauterine device (IUD). Women of child-bearing potential will 
have a urine pregnancy test at every clinic visit and it must be negative 
to continue study participation.  
 
11. Life expectancy <1 year at the screening visit  
 
12. Patients who are volume depleted based upon physical examination at 
the time of the screening or randomization visit  
13. BNP <75 pg/mL and NTproBNP<225 pg/mL at the screening visit £  
14. Patients currently being treated with any SGLT-2 inhibitor (dapagliflozin, 
canagliflozin, dapagliflozin, ertugliflozin) or having received treatment with 
any SGLT-2 inhibitor within the 12 weeks prior to the screening visit.  
15. Average supine systolic BP <100 mmHg at the screening or 
randomization visit  
16. Current history of bladder cancer  
17. Donation of blood or bone marrow 12 weeks prior to the screening visit 
and no planned donations during the study period  
18. Heart failure due to restrictive/infiltrative cardiomyopathy, active 
myocarditis, constrictive pericarditis, severe stenotic valve disease, and 
HOCM (hypertrophic obstructive cardiomyopathy).  
19. Heart failure due to severe aortic or mitral regurgitation  
20. Severe COPD thought to be a primary contributor to dyspnea  
21. Isolated right heart failure due to pulmonary disease  
22. Active and significant ischemia thought to be a primary contributor to 
dyspnea  
23. Documentation of previous EF < 45%, under stable conditions, within the 
past 36 months  
24. Complex congenital heart disease  
25. Uncontrolled hypertension, defined as systolic blood pressure ≥200 
mmHg during the screening visit (average value of three blood pressure 
measurements obtained in supine position)  


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26. Any other condition that in the judgment of the investigator would 
jeopardize the patient’s participation in the study or that may interfere with 
the interpretation of study data or if the patient is considered unlikely to 
comply with study procedures, restrictions and requirements  
27. Bariatric surgery within the past 6 months or planned bariatric surgery 
within the study time course.  
28. CardioMems device implantation within previous 4 weeks or planned 
CardioMems implantation during study period  
29. For echo substudy only: patients with ventricular paced rhythm or left 
bundle branch block on the most recent clinically available 12-lead 
electrocardiogram.  
30. For echo substudy only: permanent atrial fibrillation  
 
Ŧ For patients with permanent atrial fibrillation inclusion thresholds will be 
BNP ≥ 100 pg/mL or NTproBNP ≥ 375 pg/mL 
£For patients with permanent atrial fibrillation exclusion thresholds will be 
BNP<100 pg/mL and NTproBNP<375pg/mL 
 
1.3 Sample Size and Power 
Planned Sample 
Size 
Approximately 160 patients will be enrolled in each arm.  
Power Statement 
For the primary endpoint a sample size of 145 for each group will achieve 82% 
power with α=0.05 to detect a 4.7 difference in mean KCCQ CS between 
dapagliflozin group and placebo group at 12 weeks. The assumptions for this 
calculation was derived from DEFINE-HF trial where the adjusted mean 
difference between dapagliflozin group and placebo group is 4.7 and the 
standard deviation is 13.7. Assuming a 10% loss to follow up, we arrive at a 
sample size of ~320 patients. 
 
 
 
 


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2 GENERAL CONSIDERATIONS FOR DATA ANALYSES   
2.1 Analysis Data Sets  
Efficacy and safety analyses will be performed on data from the following analysis sets: 
 
• Enrolled patients set (EPS) will consist of all patients who signed the informed consent. This 
data set will be used to summarize the patient disposition data. 
 
• Modified intention to treat set (modified ITTS) is defined as all patients who have been 
randomized to study treatment, have received at least one dose of study medication, and 
have sufficient evaluable data for endpoint ascertainment during follow up. For clarity, 
patients with no evaluable data for a particular outcome during follow up will be excluded 
from the analyses of these respective endpoints. Subjects will be analysed according to the 
randomization group. The modified ITTS data set will be used for the primary, secondary, 
and selected exploratory (, NYHA class, loop diuretic dose, progress to DM, left atrial 
volume index and other measures of left ventricular diastolic function) efficacy endpoints. 
Progress to DM will be assessed among participants in the modified ITTS who had no 
diabetes at baseline. Left atrial volume index and other measures of left ventricular diastolic 
function will be assessed among participants who are in the modified ITTS dataset and also 
in the Echocardiography sub study. 
 
• On-treatment set (OTS) includes all subjects in the modified ITTS. Primary and secondary 
endpoint measurements will be excluded for the follow-up time point(s) when subjects 
were temporarily or permanently off the study drug at the time the corresponding 
measurements were obtained. The OTS data set will be used for a sensitivity analyses for 
the primary, secondary, and selected exploratory (composite hierarchical rank clinical score, 
NYHA class, loop diuretic dose) efficacy endpoints. 
 
• The per protocol set (PPS) includes all subjects in the modified ITTS who did not have any 
major protocol deviations. Major protocol deviations, which are detailed in section 2.2, will 
be determined prior to unblinding of treatment groups. Subjects will be summarized 
according to actual treatment received regardless of the allocated treatment. This will be 
used for a sensitivity analysis for the primary efficacy endpoints only.  
• The safety analysis set (SAFS) includes all patients who received at least 1 dose of study 
medication. Throughout the safety results sections, erroneously treated patients (eg, those 
randomized to dapagliflozin but actually given placebo) will be accounted for in the actual 
treatment group. If a patient received study drug from the wrong kit for only a part of the 
treatment duration and then switched to another, the associated actual treatment group 
for that patient will be the treatment group the patient had the longest exposure to. The 
main safety analyses will be restricted to adverse events that occurred between 
randomization and the 12-week visit. Adverse events that occurred between 12 weeks and 
13 weeks (after discontinuation of study treatment) will be collected, and presented in a 


PRESERVED-HF SAP 
 
Page 12 of 35 
separate, supplemental analysis. The safety analysis set will be used to summarize safety 
data and patient demography and their baseline characteristics, and to analyze selected 
exploratory endpoints (composite hierarchical-rank clinical score, heart failure 
hospitalizations, urgent heart failure visits, and a composite of heart failure hospitalizations 
or urgent heart failure visits).  If there is a difference between the SAFS and modified ITTS, 
baseline and demography data will also be presented for the IITS.   
2.2 Protocol Deviations and Major Eligibility Violations     
Important Protocol Deviations (IPDs) are defined as those important deviations from the protocol 
that are likely to have an impact on the efficacy and/or safety of study treatments, or integrity of 
study data.  
Protocol deviations will be reviewed in a blinded fashion by the study team prior to database lock. 
All decisions to exclude patients and/or data from the modified ITTS or PPS will be made prior to 
the unblinding of the study and agreed by the study team.  
Error! Reference source not found.10.2 specifies the criteria for IPDs.  
 2.3 Strata, Covariates, and pre-specified subgroup analyses 
All efficacy and safety endpoints will be analyzed in the entire cohort, and then within the 
subgroups of patients with and without diabetes. Analyses for the primary and secondary 
endpoints will be adjusted for the corresponding baseline measurements as well as sex, eGFR, 
diabetes (DM), permanent AFib, and LVEF. Restricted cubic splines will be used for continuous 
variables to accommodate non-linear effects, as appropriate.  
A sensitivity analysis will repeat the primary analysis but will also include site as a random effect to 
account for potential clustering by enrolling centers.  Another sensitivity analysis for the primary 
endpoint will be performed using the imputed KCCQ values as descripted in section 2.6. 
Additionally, the following pre-specified subgroup analyses will be performed for the primary 
endpoints (stratified by the baseline variables below):  
• Baseline NTproBNP (< median, ≥ median)  
• Baseline LVEF (≤60%, > 60%) 
• Atrial fibrillation type (No AFib, permanent/persistent AFib, paroxysmal AFib) 
• Baseline KCCQ overall summary score (<median, ≥median) 
• Baseline eGFR (<60, ≥60 mL/min/1.73 m2) 
• Age (<70, ≥70) 
• Sex (male, female)  
• Race (white, non white)  
• BMI(<median, ≥median) 


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• Furosemide equivalent mean daily dose: ≤ 40 mg, >40 mg 
• NYHA Class (II , III or IV) 
Subgroup analyses will be carried out by augmenting the primary analysis model with terms for 
subgroup and a subgroup-by-treatment interaction. Adjusted point estimates and 95% confidence 
intervals will be calculated for the effect of dapagliflozin compared with placebo within each 
subgroup. An interaction p-value will be provided.  
Due to the large number of study sites and the expected low number of patients per site, site 
effects will not be explored, although study site will be included as a random effect in efficacy 
sensitivity analyses to account for within-site correlations, as specified above.  
2.5 Multiple Testing   
The primary endpoint will be tested at the 2-sided 5% significance level. No adjustments for multiplicity will 
be made for secondary and exploratory endpoints.  
2.6 Missing Data  
There are three possible sources for missing data:  
1. Deaths 
2. Administrative error  
3. Premature study terminations 
Missing data due to deaths is expected to be very low (fewer than 10 patients) because of the short follow-
up period. Missing data due to administrative error is believed to be negligible due to the study 
management procedures and is also believed to be missing completely at random (MCAR). For patients who 
drop out of the study prematurely, a premature treatment discontinuation visit (PTDV) will be scheduled for 
them, whenever possible, to get the last assessment. The PTDV assessment will be carried forward to the 
next follow-up time point. For partially completed KCCQ questionnaires, the scoring algorithm 
accommodates a limited number of skipped responses.  Values that are missing at randomization but 
available at screening will be imputed using the value at screening. Primary, secondary, and exploratory 
endpoints will be analyzed among patients for whom all relevant data for the given endpoint can be 
calculated.  
For KCCQ scores, additional sensitivity analysis will be conducted using multiple imputation to account for 
missing values. IVEware (Raghunathan et al. 2002) will be used to perform the multiple imputation which 
employs iterative sequential regression to sample missing values from the predictive distribution of each 
variable, conditional on all other variables included in the imputation model. The following variables will be 
included in the imputation model: baseline KCCQ scores, sex, baseline eGFR, history of diabetes (DM), 
history of permanent AFib, baseline LVEF, baseline NYHA class, heart failure hospitalization during 
the trial duration , urgent heart failure visit during the trial duration, and covariates used as 
subgroup variables in section 2.3. Additionally, the imputation model will also include all follow up 


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Page 14 of 35 
assessments available for KCCQ scores, eGFR, NTproBNP, BNP, Hgb, loop Diuretic dose, 6-minute 
walk test.  
2.7 Data Handling Conventions and Transformations  
Diabetes duration will be calculated as (Consent date – DM diagnosis date) / 365.25. It will be rounded to 
the whole year.  
Body mass index (BMI) will be calculated as weight (kg) / [height (m)]2. It will be displayed to 1 decimal place 
in listings, but will not be rounded or truncated prior to summarization 
Estimated glomerular filtration rate (eGFR) will be calculated using the MDRD-4 equation: GFR in mL/min 
per 1.73 m2 = 175 x SerumCr-1.154 x age-0.203 x 1.212 (if patient is African American) x 0.742 (if female). 
Patients with missing data in Creatinine Serum, age, race, or gender will not have eGFR calculated.  
If urine microalbumin value is reported as being too high for the laboratory to calculate a UACR, 5000 mg 
value for UACR will be used. 
3 SUBJECT DISPOSITION      
3.1 Subject Enrollment      
The number and percent of subjects randomized for each site will be summarized overall and by treatment 
group.  The denominator for the percent calculation will be number of subjects screened. 
3.2 Disposition of Subjects    
A summary of subject disposition will be provided overall and by treatment group, as appropriate. This 
summary will present the number of subjects screened, randomized, included in the safety analysis set, and 
the number and percent of subjects meeting the following criteria: 
• 
Had known vital status at the end of the study 
• 
Died 
• 
Completed the study drug treatment (defined as on study drug at week 12 visit) 
• 
Did not complete the study drug treatment (with summary of reasons for not completing the study 
treatment) 
• 
Completed the study (defined as with visit at week 12) 
• 
Completed the study (defined as with visit at week 12) and completed the study drug (defined as on 
study drug at week 12 visit) 
• 
Had at least one in-person visit 
• 
Had visit at week 6 and week 12 
• 
 
• 
 
 
The denominator for the percent of subjects in each category will be the number of subjects randomized.  


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Page 15 of 35 
 
No inferential statistics will be generated. A data listing of reasons for premature study treatment/study 
discontinuation will be provided. 
3.3 Extent of Exposure 
3.3.1 Study Drug Compliance 
Study drug compliance will be derived using the Study Drug Accountability at 12 weeks. Proportion of study 
drug compliance is defined as proportion of patients respond ‘Currently taking study drug’ at 12 weeks. 
Summaries will be provided by treatment group for the safety analysis set. 
3.3.2 Duration of Exposure to Study Drug 
Duration of exposure to study drug will be defined as (last dose date – first dose date of double-blind 
treatment phase + 1), regardless of temporary interruptions in study drug administration, and will be 
expressed in weeks (shown to one decimal place, e.g., 4.5 weeks).  
Duration of exposure to study drug will be summarized using descriptive statistics (sample size, mean, 
standard deviation, median, first quartile (Q1), third quartile (Q3), minimum, and maximum). 
Summaries will be provided by treatment group for the safety analysis set. 
3.3.3 Adherence with Study Drug  
• 
The actual number of tablets ingested will be calculated using the Study Drug Accountability CRF:  
                            Total number of tablets dispensed - total number of tablets returned. 
• 
The expected number of tablets ingested will be calculated based on the Study Drug Dispensed CRF 
and Study Drug Accountability CRF:  
Total number of days supposed on study drug ([date of last dose of study drug - start date + 
1]) 
• 
Adherence rate  
             100(total number of tablets ingested) / (expected number of tablets ingested). 
Adherence will be capped at 100% for summarization. Patients with unreturned bottles will be excluded 
from adherence calculations.  
Descriptive statistics for adherence (sample size, mean, standard deviation, median, Q1, Q3, minimum, and 
maximum) will be provided by treatment group and overall for the safety analysis set.  


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4 Endpoints variables 
4.1 Primary endpoints:  
•  Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score at 12 weeks  
4.2 Secondary endpoints:  
• Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score at 12 weeks  
• NTproBNP at 6 and 12 weeks 
• BNP at 6 and 12 weeks 
• Six-minute walk test at 12 weeks 
• HbA1c at 6 and 12 weeks 
• Proportion of patients with a ≥ 5pts increase in KCCQ clinical summary score at 12 weeks 
and proportion of patients with a ≥ 5pts increase in KCCQ overall summary score at 12 
weeks  
• Proportion of patients with a ≥ 20% decrease in 6 and 12 weeks NTproBNP 
• Proportion of patients with a ≥ 5pts increase in KCCQ at 12 weeks and a ≥ 20% decrease in 6 
and 12 weeks NTproBNP 
• Weight at 6 and 12 weeks 
• Systolic blood pressure at 6 and 12 weeks.  
Average of the three measures of supine systolic blood pressure at each time point will be 
used. 
4.3 Exploratory Outcome Variables  
• Composite mean hierarchical-rank clinical score. 
All patients will receive a global rank endpoint based on time to death (tier 1), time to HF 
hospitalization or urgent HF visit (tier 2), or change in KCCQ clinical summary score from 
baseline to 12 weeks. The variable for ranking the patients will be derived as follows. 
o Patients dying during the study will have a value of 0 + (study days from randomization 
to death). Patients with missing vital status at the end of trial will be excluded from the 
analysis. Patient dying during the study but with no mortality date will use the average 
of the last known alive date and the patient’s scheduled 12 weeks follow-up date.  


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o Patients who did not die but had multiple occurrences of HF hospitalization or urgent HF 
visit will have a value of 200 – number of occurrences. 
o Patients who did not die but have only one HF hospitalization or urgent HF visit will have 
a value of 200 + (study days from randomization to the occurrence of HF hospitalization 
or urgent HF visit). Patients known to have an event but event date is unknown will be 
imputed using the median rank based on the rank of other patients in this category.  
o Patients who did not die and did not experience HF hospitalization or urgent HF visit will 
have a value of 400 + (change in KCCQ clinical summary score from baseline to week 
12). 
Patients with missing KCCQ at 12 weeks who didn’t die and didn’t have HF events will be 
excluded. A sensitivity analysis will be performed where these patients will be kept in 
the analysis and the KCCQ values will be imputed using multiple imputation as described 
in section 2.6. 
• Number of heart failure hospitalizations and proportion of patients experienced heart 
failure hospitalizations 
• Number of urgent heart failure visits and proportion of patients with urgent heart failure 
visits 
• Total number of heart failure hospitalizations and urgent heart failure visits and proportion 
of participants who experienced any heart failure hospitalizations and urgent heart failure 
visits.  
For the four endpoints above, only events positively adjudicated by the clinical event 
committee will be included. Events that occurred between screening and randomization, 
and between 12 weeks and 13 weeks will be excluded from this analysis. Events that 
occurred between the week 12 and week 13 study visits will be reported in a separate, 
supplemental analysis. 
• Proportion of patients that progress to diabetes during the treatment period (within the 
subgroup of patients without diabetes at baseline only). Progression to diabetes is defined 
as a HbA1c of 6.5 or greater at either 6 week or 12 week follow-up.  
• Average daily loop diuretic dose (furosemide equivalent)  
The following equations will be used to convert doses to Furosemide equivalent:  
• 40 mg Furosemide = 20 mg Torsemide = 2 mg Bumetanide = 50 mg 
Ethacrynic Acid 
• When patient is not on a loop diuretic, dose = 0 mg. 


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• For subjects with dosing schedule reported as “as needed (prn)”, we will 
assume a twice a week dosing regimen for loop diuretic at the recorded 
dose.  
In addition to comparing daily loop diuretic dose between treatment arms, we will also 
compare the proportion of patients who had their loop diuretic dose reduced or 
discontinued at any time during the treatment period.  
• Change in NYHA Class at 6 and 12 weeks.  
A 3-level categorical variable: 1) Decrease, 2) No change, 3) Increase. For patients missing 
NYHA class at 12 weeks, value at 6 weeks will be used. 
• Echocardiography sub study endpoints: left atrial volume index and other measures of left 
ventricular diastolic function 
Primary Endpoint  
Left atrial volume index at 12 weeks  
Exploratory endpoints:  
• 
BSA 
  
• 
LVEDD   
• 
LVESD   
• 
IVSd 
• 
PWd 
• 
Relative Wall Thickness   
• 
LV Mass 
  
• 
LV Mass Index   
• 
Left ventricular end diastolic volume 
  
• 
Left ventricular end systolic volume 
  
• 
Estimated LVEF 
• 
LVEF Calculated 
• 
Left atrial dimension 
• 
Left atrial volume 
• 
Left atrial volume index 
• 
E 
  
• 
E/A 
  
• 
E/E' medial 
• 
E/E' lateral 
• 
Tricuspid regurgitant velocity 
  
• 
Longitudinal strain 


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5 Analyses of Baseline Characteristics  
Patient demographics, baseline clinical characteristics, medical histories, and baseline labs will be described 
overall and by treatment group. Continuous measures will be summarized by mean ± standard deviation 
and compared using Student’s T-tests.  Categorical variables will be summarized by frequency and percent 
and compared using 𝜒2or Fisher’s exact tests, as appropriate. 
5.1 Demographics and Baseline Characteristics       
• 
Age 
• 
Sex 
• 
Race/Ethnicity 
 
5.2 Medical History 
5.2.1 Diabetes History 
• 
Diabetes duration 
• 
History of diabetic peripheral neuropathy 
• 
History of diabetic autonomic neuropathy 
• 
History of diabetic retinopathy 
• 
History of diabetic ketoacidosis (DKA) event 
• 
History of hyperosmolar hyperglycemic syndrome (HHS) event 
• 
History of severe hypoglycemic event(s) 
• 
History of amputation 
5.2.2 Other Medical History 
• 
History of heart failure 
• 
NYHA Class 
• 
Most Recent LVEF Assessment 
• 
History of PAD 
• 
History of hypertension 
• 
History of coronary artery disease 
• 
History of dyslipidemia 
• 
History of angina 
• 
History of atrial fibrillation 
• 
History of atrial flutter 
• 
History of MI 
• 
History of PCI 
• 
History of CABG 
• 
History of ventricular tachycardia 
• 
ICD implanted 


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• 
Permanent pacemaker implanted 
• 
History of valve disease 
5.3 Physical examination 
• 
Body Mass Index 
• 
Sitting Pulse and Blood Pressure 
• 
Supine Pulse and Blood Pressure 
• 
Standing Pulse and Blood Pressure 
5.4 Lab results        
• 
HbA1c 
• 
BNP 
• 
NT pro-BNP 
• 
Glucose (mg/dL) 
• 
BUN - urea nitrogen (mg/dL) 
• 
Creatinine (mg/dL) 
• 
Estimated Glomerular Filtration Rate (eGFR) 
• 
Sodium (mmol/L) 
• 
Potassium (mmol/L) 
• 
Chloride (mmol/L) 
• 
Carbon Dioxide (mmol/L) 
• 
Calcium (mg/dL) 
• 
Phosphate - as phosphorus (mg/dL) 
• 
Albumin (g/dL) 
• 
Random Urine Creatinine (mg/dL) 
• 
Random Urine Microalbumin < 0.2 mg/dL 
• 
Random Urine Microalbumin (mg/dL) 
• 
Enter Urine Albumin result, if measurable. 
• 
Random Urine Albumin/Creatinine Ratio (mcg/mg creat) 
6 EFFICACY ANALYSES 
6.1 Analysis of the Primary Efficacy Endpoint       
Analysis of the primary efficacy endpoints will be performed on the modified ITT data set, first on the entire 
cohort, then within the subgroups of patients with and without diabetes, and then within other subgroups 
as specified in section 2.3. Sensitivity analyses will be performed as outlined in section 2.3; in addition, 
supportive analyses will be repeated using the same models on the on-treatment set (OTS) and per-protocol 
set (PPS), as applicable. 
Mean, standard deviation, median, and interquartile range (IQR) will be reported for KCCQ clinical summary 
score and for its change at 12-week follow-up, for the entire cohort and by treatment group. 


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An ACCOVA model will be used to estimate the effect of dapagliflozin on the 12-week KCCQ clinical 
summary score, adjusting for baseline KCCQ clinical summary score, sex, eGFR, Diabetes status, permanent 
atrial fibrillation status, and LVEF. Patient participation in the Echocardiography sub-study will not be 
controlled for because we don’t hypothesize that participation in the Echocardiography sub-study is 
associated with the primary outcome (KCCQ CS). 
A sensitivity analysis will repeat the primary analysis but will also include site as a random effect to account 
for potential clustering by enrolling center. Another sensitivity analysis will be performed using the imputed 
KCCQ values as described in section 2.6. 
6.2 Secondary outcome variables 
The following secondary outcomes will be analyzed on the intention to treat (modified ITT) data set, first on 
entire patient cohort and then within subgroups of patient with or without diabetes.  
6.2.1 Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score at 12 weeks  
KCCQ overall summary score at 12 weeks will be analyzed in a manner analogous to that of the primary 
endpoint. 
6.2.2 
NTproBNP at 6 and 12 weeks  
Mean, standard deviation, median, and interquartile range (IQR) will be reported for NT pro-BNP and for its 
change from baseline at 6- and 12-week follow-up, for the entire cohort and by treatment group. 
A generalized linear mixed model will be used to estimate the treatment effect on 6- and 12-week NT pro-
BNP values, adjusting for log baseline NT pro-BNP, sex, eGFR, diabetes (DM), permanent AFib, and 
LVEF. Patient will be included as a random effect. A gamma distribution and log link function will be used to 
account for the skewed nature of NT pro-BNP. The model is as follows:  
E(yijk) = μijk,
Var(yijk) = μijk
2 ϕ, 
log(μijk) = β0 + β1Trtij + β2𝑡𝑘+ β3Trtij ∗𝑡𝑘+ 𝛃𝐱+ γij, 
γij ~ N(0, σ2), 
where,  μijk denotes the expected NT pro-BNP level for patient j from site i at time k, Trtij is a 0/1 variable 
denoting treatment group (dapagliflozin vs. placebo), 𝑡𝑘 indicates the follow-up assessment time (6 week: 
t_𝑘 = 1 ; 12week: 𝑡𝑘= 0), and 𝐱 is the design matrix for log baseline NT pro-BNP, age,  DM,  and baseline 
eGFR. γij are patient random effects with variance σ2. ϕ is a scale factor. With this parameterization, the 
quantities exp(β1) and exp(β1 + β3) represent the corresponding relative effects at 6 and 12 weeks, 
respectively. 
A few sensitivity analyses will be performed:  
• 
Repeat the model above but also include site as a random effect to account for potential clustering 
by enrolling center.  


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• 
Repeat the model above on the on-treatment set (OTS). 
6.2.3 
BNP at 6 and 12 weeks  
BNP at 6 and 12 weeks will be analyzed in a manner analogous to that of NT pro-BNP.  
6.2.4 
Six-minute walk test at 12 weeks  
Six-minute walk test at 12 weeks will be analyzed in a manner analogous to that of the primary endpoint. 
6.2.5 
HbA1c at 6 and 12 weeks  
HbA1c at 6 and 12 weeks will be analyzed in a manner analogous to that of NT pro-BNP, although 
appropriate distributions and link functions will be chosen for the given outcomes. Models will also provide 
separate effect estimates for the 6- and 12-week time points 
6.2.6 
 Proportion of patients with a ≥ 5pts increase in KCCQ clinical summary score and KCCQ overall 
summary score at 12 weeks  
Proportion of patients achieving a ≥ 5pts increase in KCCQ clinical summary score at 12 weeks  
Unadjusted proportion of patients achieving a ≥ 5pts increase in KCCQ clinical summary score at 12 weeks, 
will be reported for the treatment group and placebo group. A logistic regression model will be used to 
assess the treatment effect. Model will be adjusted for baseline measurement, sex, eGFR, diabetes (DM), 
permanent AFib, and LVEF.Several sensitivity analyses will be performed:  
• 
Repeat the model above but also include site as a random effect to account for potential clustering 
by enrolling center.  
• 
Repeat the model above on the on-treatment set (OTS). 
• 
Repeat the model above excluding patients with baseline KCCQ clinical summary score of over 90 (as 
these patients will have a limited opportunity for improvement in KCCQ) 
• 
Repeat the analysis using the imputed KCCQ values as described in section 2.6. 
Proportion of patients achieving a ≥ 5pts increase in KCCQ overall summary score at 12 weeks  
Proportion of patients achieving a ≥ 5pts increase in KCCQ overall summary score at 12 weeks will be 
analyzed in a manner analogous to that of proportion of patients achieving a > 5pts increase in KCCQ clinical 
summary score at 12 weeks. 
6.2.7 
Proportions of patients with a ≥ 20% decrease at 6 and 12 weeks NTproBNP 
This end point will be analyzed in a manner analogous to 6.2.6.  
6.2.8 
Proportions of patients with a ≥ 5pts increase in KCCQ and a ≥ 20% decrease in 6 and 12 weeks 
NTproBNP 
This end point will be analyzed in a manner analogous to 6.2.6. Proportion will be calculated for patients 
with a ≥ 5 pts increase in KCCQ and a ≥ 20% decrease in NTproBNP at 6 weeks, and separately for patients 
with a ≥ 5 pts increase in KCCQ and a ≥ 20% decrease in NTproBNP at 12 weeks.  


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6.2.9 
Weight at 6 and 12 weeks  
Weight at 6 and 12 weeks will be analyzed in a manner analogous to that of NT pro-BNP, although 
appropriate distributions and link functions will be chosen for the given outcomes. Models will also provide 
separate effect estimates for the 6- and 12-week time points 
6.2.10 Systolic blood pressure at 6 and 12 weeks  
Systolic blood pressure at 6 and 12 weeks will be analyzed in a manner analogous to that of NT pro-BNP, 
although appropriate distributions and link functions will be chosen for the given outcomes. Models will also 
provide separate effect estimates for the 6- and 12-week time points 
6.3 Exploratory outcome variables 
6.3.1 Composite mean hierarchical-rank clinical score.  
The composite hierarchical-rank clinical score will be analyzed on the safety dataset. Patients with missing 
KCCQ values at 12 weeks will be excluded unless they died or had HF hospitalizations or urgent HF visits. Win 
ratio will be used to compare the rank score of each patient in the dapagliflozon arm with each patient in 
the placebo group.  Each comparison will result in a “win”, “loss” or “tie” for the patient in the dapagliflozin 
group if the analysis value of the patient in the dapagliflozin group is higher, lower or equal to the analysis 
value of the patient in the placebo group, respectively. Within the dapagliflozin group, total number of wins 
will be divided by the total number of losses (ties are split evenly between wins and losses) to form the Win 
Ratio statistic of the dapagliflozin group against the placebo group (Pocock et al 2012). The confidence 
interval of the win ratio statistic will be calculated as described in Gasparyan et al 2020 (see APPENDIX). 
6.3.2 Heart failure hospitalizations  
Number of heart failure hospitalizations and proportion of patients with any heart failure hospitalizations 
during the length of follow-up will be summarized descriptively for the treatment and placebo group on the 
safety dataset. This will be completed first on the entire cohort and then within subgroups of patients with 
or without diabetes.  Both endpoints will be summarized by frequency and percent and compared using 
𝜒2or Fisher’s exact tests, as appropriate.  
In addition, a Cox proportional hazard model will be used to assess the effect of treatment vs. placebo on 
the time to the first occurrence of heart failure hospitalization, adjusting for sex, eGFR, diabetes (DM), 
permanent AFib, and LVEF. A second sensitivity analysis will be performed using stratified Cox 
proportional model conditional on site to account for clustering.  
6.3.3 Urgent heart failure visits  
Will be analyzed in a manner analogous to that described in 6.3.2.  
6.3.4 Heart failure hospitalizations and urgent heart failure visits  
Will be analyzed in a manner analogous to that described in 6.3.2.  
6.3.5 Proportion of patients that progress to diabetes during the treatment period (within the 
subgroup of patients without diabetes at baseline only)  
Will be analyzed in a manner analogous to that described in 6.3.2.  


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6.3.6 Change from baseline in average weekly loop diuretic dose (furosemide equivalent)  
Change in daily loop diuretic dose will be summarized descriptively for the treatment and placebo group on 
the intention to treat dataset. This will be completed first on the entire cohort and then within subgroups of 
patients with or without diabetes.  Additionally, among patients who were on loop diuretic at 
randomization, we will also compare the proportion of patients who had loop diuretic dose reduced or 
discontinued (using the average of 6- and 12-week doses, and also separately at 6 and 12 weeks). 
Furthermore, daily loop diuretic dose will be also analyzed using generalized mixed models as the model 
used for NTproBNP, although appropriate distributions and link functions will be chosen for the given 
outcomes.  
6.3.7 Change in NYHA Class at 6 and 12 weeks.  
Proportion of patients with a Decreased, No change, and Increased NYHA at 6 and 12 weeks will be 
summarized for the treatment and placebo group on the intention to treat dataset and compared 
using 𝜒2or Fisher’s exact tests, as appropriate. This will be completed first on the entire cohort and then 
within subgroups of patients with or without diabetes.   
Additionally, NYHA change category will be analyzed in a manner analogous to that of NT pro-BNP, although 
appropriate distributions and link functions will be chosen for the given outcome. 
6.3.8 Echocardiography sub study endpoints: left atrial volume index and other measures of left 
ventricular diastolic function 
 
Echocardiography sub study endpoints will be analyzed among patients enrolled in the Echocardiography 
sub study and in the modified ITTS dataset. 
Continuous variables will be analyzed in a manner analogous to that of the primary endpoint. Categorical 
variables will be analyzed in a manner analogous to that described in 6.2.6. 
 
7 SAFETY ANALYSES     
Safety analyses will be performed on the safety analysis set (SAF). Total number of adverse events as well as 
number and proportion of patients developing adverse event(s) will be compared by treatment group. For 
patient level analyses multiple events will be counted once only per subject in each summary. The following 
safety variables will be included:  
1. All cause death 
2. Cardiovascular death 
3. Non-fatal myocardial infarction (MI) 
4. Stroke 
5. Acute kidney injury (defined as doubling of serum creatinine based on the modified RIFLE criteria) 
6. Adverse events (AEs).  
• 
Adverse events of special interest 
o Diabetic Ketoacidosis 


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o Volume Depletion Event (defined as hypotension, syncope, orthostatic hypotension 
or dehydration) 
o Severe Hypoglycemic Event 
o Lower Limb Amputations 
• 
Drug Adverse Event 
• 
Serious Adverse event 
o Resulted in death 
o In-patient hospitalization or prolonging of existing in-patient hospitalization 
o Persistent or significant disability 
o Life-threatening  
o Congenital anomaly/birth defect 
o Important medical event 
Safety analyses will be restricted to adverse events that occurred between randomization and 12 weeks. 
Adverse events occurred between 12 weeks and 13 weeks will be presented separately in a supplemental 
analysis. As a sensitivity analysis, the above analysis will be repeated with events that occur 2 days after 
patients discontinue study drug being excluded.  
8 REFERENCES  
1. Green CP1, Porter CB, Bresnahan DR, Spertus JA., Development and Evaluation of the Kansas City 
Cardiomyopathy Questionnaire: A New Health Status Measure for Heart Failure, J Am Coll Cardiol. 
2000 Apr;35(5):1245-55 
2. Hunger,M et all, Longtitudinal beta regression models for analyzing health-related quality of life 
scores over time Medical Research Methodology, 2012; 12:144 
3. Pocock et al 2012 Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the 
analysis of composite endpoints in clinical trials based on clinical priorities. European heart journal 
2012, 33(2), 176-182. 
4. Gasparyan SB, Folkvaljon F, Bengtsson O, Buenconsejo J, Koch GG. Adjusted Win Ratio with 
Stratification: Calculation Methods and Interpretation. Stat Methods Med Res, DOI: 
10.1177/0962280220942558. 
5. Raghunathan, T. E., Solenberger, P. W., & Van Hoewyk, J. V. (2020). IVEware: Imputation and 
Variance Estimation Software User’s Guide (Version 0.3). Ann Arbor, MI: Institute for Social Research, 
University of Michigan. https://www.src.isr.umich.edu/software/iveware/ 
 
9 SOFTWARE      
All analyses will be performed using SAS 9.4 or higher.  
 


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10 APPENDICES      
10.1 Scoring and Interpreting the KCCQ 
There are 10 summary scores within the KCCQ, which are calculated as follows: 
A. Physical Limitation 
 
The Physical Limitation score corresponds to questions 1a through 1f. Responses to questions 1a through 1f 
should be coded numerically as follows: 
 
 
 
1 = Extremely Limited 
 
 
 
2 = Quite a bit Limited 
 
 
 
3 = Moderately Limited 
 
 
 
4 = Slightly Limited 
 
 
 
5 = Not at all Limited 
 
 
 
6 = Limited for other reasons or did not do the activity 
 
If the responses to questions 1a through 1f are not values 1, 2, 3, 4 or 5 then the response is set to missing. 
Note that a response of 6 (Limited for other reasons or did not do the activity) is treated as a missing value. 
If at least three responses to questions 1a-1f are not missing, then the physical limitation score is computed 
by calculating the mean response and standardizing the result as follows:  
Physical Limitation = 100*(Mean Response – 1)/4 
 
B. Symptom Stability  
 
The Symptom Stability score corresponds to question 2. Responses to question 2 should be coded 
numerically as follows: 
 
 
 
1 = Much Worse 
 
 
 
2 = Slightly Worse 
 
 
 
3 = Not Changed 
 
 
 
4 = Slightly Better 
 
 
 
5 = Much Better 
 
 
 
6 = I’ve had no symptoms over the last 2 weeks 
If the response is 6 (no symptoms over last 2 weeks) then set the response to 3 (not changed). If question 2 
is not missing then the symptom stability score is computed by standardizing the result as follows: 
Symptom Stability = 100*(Response – 1)/4 
 
 


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C. Symptom Frequency 
 
The Symptom Frequency score corresponds to questions 3, 5, 7 and 9. The responses should be coded 
sequentially (1, 2, 3…) in order of increasing health status as follows: 
 
 
 
Question 3 
 
 
 
1 = Every Morning 
 
 
 
2 = 3 or more times per week, but not every day 
 
 
 
3 = 1-2 times a week 
 
 
 
4 = Less than once a week 
 
 
 
5 = Never over the past 2 weeks 
 
 
 
Questions 5 and 7 
 
 
 
1 = All of the time 
 
 
 
2 = Several times per day 
 
 
 
3 = At least once a day 
 
 
 
4 = 3 or more times per week, but not every day 
 
 
 
5 = 1-2 times per week 
 
 
 
6 = Less than once a week 
 
 
 
7 = Never over the past 2 weeks 
 
 
 
Question 9 
 
 
 
1 = Every night 
 
 
 
2 = 3 or more times a week, but not every day 
 
 
 
3 = 1-2 times a week 
 
 
 
4 = Less than once a week 
 
 
 
5 = Never over the past 2 weeks 
If two or more responses are missing then symptom frequency cannot be computed and will be missing. 
Otherwise, the symptom frequency is computed by calculating the mean of the standardized responses and 
multiplying by 100 as follows: 
Symptom Frequency = 100*Mean((Q3 – 1)/4, (Q5 – 1)/6, (Q7 – 1)/6, (Q9 – 1)/4) 
 
D. Symptom Burden 
 
The Symptom Burden score corresponds to questions 4, 6 and 8. The responses should be coded numerically 
as follows: 
 
 
 
1 = Extremely Bothersome 
 
 
 
2 = Quite a bit Bothersome 
 
 
 
3 = Moderately Bothersome 
 
 
 
4 = Slightly Bothersome 


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Page 28 of 35 
 
 
 
5 = Not at all Bothersome 
 
 
 
6 = I’ve had no swelling (fatigue, shortness of breath) 
 
If a response is 6 (none) then set the response to 5 (not at all). If at least one response is present then 
symptom burden score is computed by calculating the mean response and standardizing the result as 
follows: 
Symptom Burden = 100*(Mean Response – 1)/4 
 
E. Total Symptom Score 
 
The total symptom score is calculated as the mean of the symptom frequency score and symptom burden 
score. 
 
F. Self-Efficacy 
 
The Self-Efficacy score corresponds to questions 10 and 11. Responses to questions 10 and 11 should be 
coded sequentially (1, 2, 3, 4, 5) in order of increasing health status, with 1 denoting the response associated 
with the lowest health status. If at least one question response is present then the self-efficacy score may be 
computed by standardizing the mean response as follows: 
Self-Efficacy = 100*(Mean Response – 1)/4 
 
G. Quality of Life 
 
The Quality of Life score corresponds to questions 12, 13 and 14. Responses to questions 12, 13 and 14 
should be coded sequentially (1, 2, 3, 4, 5) in order of increasing health status, with 1 denoting the response 
associated with the lowest health status. If at least one question response is present then the quality of life 
score may be computed by standardizing the mean response as follows: 
 
Quality of Life = 100*(Mean Response – 1)/4 
 
 
 


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H. Social Limitation  
 
The Social Limitation score corresponds to questions 15a through 15d. These responses should be coded 
numerically as follows: 
 
 
 
1 = Severely Limited 
 
 
 
2 = Limited Quite a bit 
 
 
 
3 = Moderately Limited 
 
 
 
4 = Slightly Limited 
 
 
 
5 = Did Not Limit at All 
 
 
 
6 = Does not apply or did not do for other reasons 
If the responses to questions 15a through 15d are not values 1, 2, 3, 4 or 5 then the response is set to 
missing. Note that a response of 6 is treated as a missing value. If at least two question responses are 
present then the social limitation score may be computed by standardizing the mean response as follows: 
Social Limitation = 100*(Mean Response – 1)/4 
 
I. 
Clinical Summary Score 
 
The clinical summary score is calculated as the mean of the physical limitation score and total symptom 
score. 
 
J. Overall Summary Score 
 
The overall summary score is calculated as the mean of the physical limitation score, total symptom score, 
quality of life score and social limitation score. 
 
 
 
 
 
 
 
 


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10.2 Protocol deviations      
 
Number 
Important Protocol Deviations Criteria 
Major Impact 
on Analysis 
(MIA)/Other  
Exclusion level 
1. Did not fulfil eligibility criteria – inclusion criteria: 
1.1 
Ability to provide informed consent prior to 
initiating screening visit procedures 
MIA 
Complete exclusion 
from PPS and 
MODIFIED ITTS 
1.2 
Age > 18 and < 120 at the screening visit  
Other 
No exclusion  
1.3 
Ejection fraction (EF) ≥ 45% as determined on 
imaging study within 24 months of enrolment with 
no change in clinical status suggesting potential for 
deterioration in systolic function  
Other 
 
To be decided on a 
case by case basis 
1.4 
Elevated NT-proBNP (≥ 225 pg/ml) or BNP (≥ 75 
pg/ml)  
Other 
To be decided on a 
case by case basis 
1.5 
Stable medical therapy for heart failure for 15 days  Other 
To be decided on a 
case by case basis 
1.6 
On a diuretic ≥15 days prior to screening visit and 
a stable diuretic therapy for 7 days  
Other 
To be decided on a 
case by case basis 
1.7 
At least one of the following:  
1. Hospitalization for decompensated HF in 
the last 12 months  
2. Acute treatment for HF with intravenous 
loop diuretic or hemofiltration in the last 
12 months  
3. Mean pulmonary capillary wedge pressure 
≥15 mmHg or LV end diastolic pressure 
(LVEDP) ≥15 mmHg documented during 
catheterization at rest, or pulmonary 
capillary wedge pressure or LVEDP ≥25 
mmHg documented during catheterization 
with exercise.  
4. Structural heart disease  
 
 
To be decided on a 
case by case basis 


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Number 
Important Protocol Deviations Criteria 
Major Impact 
on Analysis 
(MIA)/Other  
Exclusion level 
2. Did not fulfil eligibility criteria – exclusion criteria: 
2.0 
Decompensated heart failure (hospitalization 
for heart failure within 7 days prior to 
screening)  
Other 
To be decided on a 
case by case basis 
2.1 
History of type 1 diabetes  
Other 
To be decided on a 
case by case basis 
2.2 
History of diabetic ketoacidosis  
 
Other 
To be decided on a 
case by case basis 
2.3 
Estimated glomerular filtration rate (eGFR) < 20 
at the screening visit by modified MDRD 
equation GFR (mL/min/1.73 m2 ) = 175 x (Scr) -
1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if 
African American)  
Other 
To be decided on a 
case by case basis 
2.4 
Admission for an acute coronary syndrome (ST-
elevation MI, non-ST-elevation MI, or unstable 
angina), percutaneous coronary intervention, or 
cardiac surgery within 30 days prior to the 
screening visit.  
Other 
To be decided on a 
case by case basis 
2.5 
Admission for cardiac resynchronization 
therapy (CRT) within 90 days prior to the 
screening visit.  
Other 
To be decided on a 
case by case basis 
2.6 
Planned cardiovascular revascularization 
(percutaneous intervention or surgical) or 
major cardiac surgery (coronary artery bypass 
grafting, valve replacement, ventricular assist 
device, cardiac transplantation, or any other 
surgery requiring thoracotomy, or transcatheter 
aortic valve replacement) or CRT within the 90 
days after the screening visit.   
Other 
To be decided on a 
case by case basis 
2.7 
Participation in any interventional clinical trial 
(with an investigational drug or device) that is 
not an observational registry within 15 days of 
the screening visit.  
Other 
To be decided on a 
case by case basis 
2.8 
History of hypersensitivity to dapagliflozin  
Other 
To be decided on a 
case by case basis 
2.9 
For women of child-bearing potential: Current 
or planned pregnancy or currently lactating  
Other 
To be decided on a 
case by case basis 


PRESERVED-HF SAP 
 
Page 32 of 35 
Number 
Important Protocol Deviations Criteria 
Major Impact 
on Analysis 
(MIA)/Other  
Exclusion level 
2.10 
Life expectancy <1 year at the screening visit  
Other 
To be decided on a 
case by case basis 
2.11 
Patients who are volume depleted based upon 
physical examination at the time of the 
screening or randomization visit  
Other 
To be decided on a 
case by case basis 
2.12 
Patients currently being treated with any SGLT-2 
inhibitor (dapagliflozin, canagliflozin, 
empagliflozin, ertugliflozin) or having received 
treatment with any SGLT-2 inhibitor within the 12 
weeks prior to the screening visit.  
Other 
To be decided on a 
case by case basis 
2.13 
Average supine systolic BP <100 mmHg at the 
screening or randomization visit  
Other 
To be decided on a 
case by case basis 
2.14 
Current history of bladder cancer  
Other 
To be decided on a 
case by case basis 
2.15 
Donation of blood or bone marrow 12 weeks 
prior to the screening visit and no planned 
donations during the study period  
Other 
To be decided on a 
case by case basis 
2.16 
Heart failure due to restrictive/infiltrative 
cardiomyopathy, active myocarditis, 
constrictive pericarditis, severe stenotic valve 
disease, and HOCM (hypertrophic obstructive 
cardiomyopathy).  
Other 
To be decided on a 
case by case basis 
2.17 
Heart failure due to severe aortic or mitral 
regurgitation  
Other 
To be decided on a 
case by case basis 
2.18 
Severe COPD thought to be a primary 
contributor to dyspnea  
Other 
To be decided on a 
case by case basis 
2.19 
Isolated right heart failure due to pulmonary 
disease  
Other 
To be decided on a 
case by case basis 
2.20 
Active and significant ischemia thought to be a 
primary contributor to dyspnea  
Other 
To be decided on a 
case by case basis 
2.21 
Documentation of previous EF < 45%, under stable 
conditions, within the past 36 months  
Other 
To be decided on a 
case by case basis 


PRESERVED-HF SAP 
 
Page 33 of 35 
Number 
Important Protocol Deviations Criteria 
Major Impact 
on Analysis 
(MIA)/Other  
Exclusion level 
2.22 
Complex congenital heart disease  
Other 
To be decided on a 
case by case basis 
2.23 
Uncontrolled hypertension, defined as systolic 
blood pressure ≥200 mmHg during the screening 
visit (average value of three blood pressure 
measurements obtained in supine position)  
Other 
To be decided on a 
case by case basis 
2.24 
Any other condition that in the judgment of the 
investigator would jeopardize the patient’s 
participation in the study or that may interfere 
with the interpretation of study data or if the 
patient is considered unlikely to comply with study 
procedures, restrictions and requirements  
Other 
To be decided on a 
case by case basis 
2.25 
Bariatric surgery within the past 6 months or 
planned bariatric surgery within the study time 
course.  
Other 
To be decided on a 
case by case basis 
2.26 
CardioMems device implantation within previous 4 
weeks or planned CardioMems implantation 
during study period  
Other 
To be decided on a 
case by case basis 
2.27 
For echo substudy only: patients with ventricular 
paced rhythm or left bundle branch block on the 
most recent clinically available 12-lead 
electrocardiogram  
Other 
To be decided on a 
case by case basis 
2.30 
For echo substudy only: permanent atrial 
fibrillation  
Other 
To be decided on a 
case by case basis 
 
 


PRESERVED-HF SAP 
 
Page 34 of 35 
3. Patient developed discontinuation of investigational product criteria but dosing continued 
3.0 
Subject experienced an Adverse Event which in the 
opinion of the Investigator and/or 
, 
contraindicated further dosing 
Other 
To be reviewed on the 
case by case basis 
3.1 
Pregnancy confirmed by a positive pregnancy test 
or other examinations 
Other 
Complete exclusion 
from PPS 
3.2 
Donation of blood or bone marrow during the 
study period  
 
Other 
To be decided on a 
case by case basis 
3.3 
Admission for an acute coronary syndrome (ST-
elevation MI, non-ST-elevation MI, or unstable 
angina), percutaneous coronary intervention, or 
cardiac surgery during the study period.  
 
Other 
To be decided on a 
case by case basis 
 
4. Patient received prohibited concomitant medication but study treatment not discontinued: 
4.4.1 
SGLT2 inhibitors 
Other 
Only the efficacy 
endpoints before the 
start of prohibited 
medication  will be 
included in PPS 
analysis 
5. Patient received incorrect investigational treatment/dose  
5.0 
Patient took incorrect treatment or damaged 
Investigational Drug Kit 
MIA 
To be decided on a 
case by case basis 
5.1 
Major compliance issues <80% or >120% 
compliance with IP dosing in double blind 
treatment period 
MIA 
To be decided on a 
case by case basis 
5.2 
Patient randomized but never took IP 
MIA 
To be decided on a 
case by case basis 


PRESERVED-HF SAP 
 
Page 35 of 35 
5.3 
Overdose 
 
MIA  
To be decided on the 
case by case basis 
6. Protocol-required procedure not adhered to: 
6.0 
Study data collection has not been stopped when 
subject decided to withdraw their consent from 
the study completely 
Other 
No exclusion from PPS 
Data collected after 
consent withdrawal to 
be excluded from data 
base 
6.1 
Patients with absence of NT-proBNP data at 
randomization visit and having values at Screening 
visit.   
Other 
No exclusion from PPS 
Values from screening 
visit will be used to 
impute the values at 
randomization visit. 
6.2 
Patients with absence of baseline NT-proBNP data 
at both screening and randomization visits  
Other 
Excluded from the NT-
proBNP analyses 
6.3 
Patients with no NT-proBNP values after 
randomization 
Other 
Excluded from the NT-
proBNP analyses 
6.4 
Patients with absence of baseline KCCQ clinical 
summary score at randomization visit 
Other 
Excluded from the 
ITTS KCCQ analyses  
6.5 
Patients with no KCCQ clinical summary score 
after randomization 
Other 
Excluded from ITTS 
KCCQ analyses  
6.6 
Patients with absence of baseline 6-minute walk 
assessment at randomization visit 
Other 
Excluded from the 6-
minute walk analyses 
6.7 
Patients with no 6-minute walk assessment after 
randomization 
Other 
Excluded from 6-
minute walk analyses  
6.8 
Patients with missing values in the covariates:, 
gender, Hx AFib, AFib type, Hx DM, eGFR at 
randomization, lvef at randomization  
Other 
No exclusion from PPS 
Excluded from the 
first and second 
primary analysis