Conditions: Heart Failure Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 240
Healthy volunteers: no

Brief summary:
This is a randomized trial of the addition of dapagliflozin to patients with or without type 2 diabetes hospitalized with acute decompensated heart failure (ADHF). Participants will be recruited following an initial standard evaluation in the ED and randomized within 24 hours of presentation for ADHF in a 1:1 fashion to protocolized diuretic therapy or dapagliflozin + protocolized diuretic therapy.

Detailed description:
Patients with acute decompensated HF (ADHF) are generally admitted due to symptoms of congestion and 90% are treated with a loop diuretic. However at least one-third of these patients are inadequately decongested due primarily to "diuretic resistance" and/ or "cardiorenal syndrome". The inability to achieve decongestion is associated with a worse prognosis and a higher rate of re-hospitalization for ADHF. More than 40% of all patients admitted with ADHF have diabetes and that percentage is growing both in Heart Failure with Reduced Ejection Fraction (HFrEF) and Preserved Ejection Fraction (HFpEF).

The admission blood glucose is elevated in approximately one-half of ADHF hospitalizations. We recently demonstrated the admission blood glucose was within 50mg/dl of the chronic average blood glucose in 66% of patients with diabetes admitted with ADHF. The median (IQR) admission blood glucose change from the chronic blood glucose was only -7 (-29, 26) mg/dl. Thus, the acute glucose in patients with T2DM presenting with acute heart failure is most often related to poor chronic glucose control suggesting that these patients would benefit from attempts to initiate therapies to improve chronic glucose control while in the hospital.

No new therapies have been introduced in the United States for ADHF in several decades. Natriuretic peptides such as nesiritide and ularitide have failed to improve outcomes in either the chronic or acute heart failure patients. Diuretic resistance and hyperglycemia are common problems in ADHF admissions and represent a therapeutic opportunity for new therapies.

The sodium-glucose cotransporter-2(SGLT2) inhibitors, now approved for the anti-hyperglycemic therapies also have an osmotic diuretic and natriuretic effect. In the chronic setting SGLT2 inhibitors reduce weight with modest decrements in systolic and diastolic blood pressure with a marked drop in albuminuria and a small drop in estimated GFR (-5 mL min-1.1.73 m-2) which returns to baseline over time. In patients with diabetes the SGLT2 transporter likely accounts for as much as 14% of total sodium chloride absorption. In the acute setting following a single dose, SGLT2 inhibitors did not increase urine volume. However, the acute diuretic effects have not been studied in a population with heart failure with or without concomitant hyperglycemia who are undergoing diuresis. To our knowledge, no current trials are investigating the effects of SGLT2 inhibition in ADHF. The current studies planned in HF are investigating the acute effects of SGLT2 on stable HF (NCT03027960), the chronic effects of SGLT2 inhibition in compensated, chronic HF (NCT03619213, NCT02653482, NCT03030235, NCT03057977), changes in pulmonary pressure hemodynamics in patients monitored by CardioMEMs devices (NCT03030222), and effects on cardiopulmonary exercise fitness in chronic HF (NCT02862067).

Congestion remains the major cause of hospital readmission for heart failure and an inpatient plan of care that allowed more effective decongestion would be rapidly and widely adopted by the medical community. Therefore, we propose to test the decongesting effects of the SGLT2 inhibitor dapagliflozin in patients with or without Type II diabetes admitted with an acute decompensation of chronic heart failure.

Arms:
arm 1: The patients with diabetes will receive standard of care point of care blood glucose monitoring 4 times daily (before meals and at bedtime) and sliding scale insulin.

The initial loop diuretic regimen after enrollment:

Loop diuretic naïve: If the patient does not take a scheduled loop diuretic as an outpatient, the initial IV loop diuretic dose will be 40mg of furosemide equivalents every 12 hours.

Chronic, oral loop diuretic therapy: If the patient takes a scheduled loop diuretic regimen as an outpatient prior to hospital admission, the initial IV loop diuretic daily dose will be 2 times the total daily home regimen dose. Diuretic therapy will be titrated to goal urine output using a standardized diuretic protocol. arm 2: The patients with diabetes will receive standard of care point of care blood glucose monitoring 4 times daily (before meals and at bedtime) and sliding scale insulin.

The initial loop diuretic regimen after enrollment:

Loop diuretic naïve: If the patient does not take a scheduled loop diuretic as an outpatient, the initial IV loop diuretic dose will be 40mg of furosemide equivalents every 12 hours.

Chronic, oral loop diuretic therapy: If the patient takes a scheduled loop diuretic regimen as an outpatient prior to hospital admission, the initial IV loop diuretic daily dose will be 2 times the total daily home regimen dose. Diuretic therapy will be titrated to goal urine output using a standardized diuretic protocol.

The patient will receive SGLT2 inhibitor therapy with dapagliflozin 10 mg orally once daily until 5 days or hospital discharge.

Interventions: intervention 1: Dapagliflozin 10 MG intervention 2: Protocolized Diuretic Therapy
Intervention descriptions: intervention 1: SGLT2 inhibitors being investigated for its diuretic and natriuretic effects on top of protocolized diuretic therapy. intervention 2: Structured usual care arm with protocolized diuretic therapy based on urine output.

Protocol document:
Prot_000.pdf: 
Version 4.0 
9-21-2021 
1
Efficacy and Safety of Dapagliflozin in Acute Heart Failure  
DICTATE-AHF 
NCT 04298229  
Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 4.0 
9-21-2021 
2
A Randomized, Open-label Study of Dapagliflozin in Patients with or without  
Type 2 Diabetes Admitted with Acute Heart Failure 
 
 
Principal Investigator: 
JoAnn Lindenfeld, MD 
Director, HF and Transplant Section 
Vanderbilt Heart and Vascular Institute 
Vanderbilt University 
1215 21st Ave South 
Nashville, TN 37212 
 
Co - Principal Investigator: 
Zachary Cox, PharmD 
Clinical Pharmacy Specialist 
Vanderbilt University 
1215 21st Ave South 
Nashville, TN 37212 
 
Site Investigators: 
Zachary Cox, Pharm.D. – Vanderbilt University Medical Center 
Mark Aaron, M.D. - St Thomas Hospital System 
A. Tom McRae, M.D. – Centennial Hospital 
Gabriel Hernandez, MD  – University of Mississippi 
Luke Cunningham – Integris Baptist Medical Center 
Kirkwood Adams – University of North Carolina 
 
 
Clinical Coordinating Center: 
Sean Collins, MD; Christy Kampe; Karen Miller 
 
Data Coordinating Center: 
Chris Lindsell, Frank Harrell, Cathy Jenkins 
 
Sponsor:  
Vanderbilt University Medical Center 
 
 


Version 4.0 
9-21-2021 
3
PROTOCOL VERSION AND AMENDMENT TRACKING 
 
Version Number/Amendment 
Approval Date 
1.4/ Original protocol 
2.10.2020 
2.0/Amendment One 
1.4.2021 
3.1/Amendment Two 
6.14.2021 
4.0/Amendment Three 
9.21.2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 4.0 
9-21-2021 
4
Abbreviations 
 
ADHF 
Acute Decompensated Heart Failure 
BNP 
B-type natriuretic peptide 
BP  
Blood pressure 
CCC  
Clinical Coordinating Center 
CEC 
Clinical Events Committee 
DCC 
Data coordinating center 
DSMB 
Data and Safety Monitoring Board 
ED 
Emergency department 
FENa 
Fractional excretion of sodium 
HFpEF 
Heart failure with preserved ejection fraction 
HFrEF 
Heart failure with reduced ejection fraction 
ICU  
Intensive care unit 
IV  
Intravenous 
LVEF 
Left ventricular ejection fraction 
PI 
Principal Investigator 
VUMC 
Vanderbilt University Medical Center 
WHF 
Worsening Heart Failure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 4.0 
9-21-2021 
5
CLINICAL TRIAL SUMMARY  
Title 
A Randomized, Pilot Study of Dapagliflozin in Patients with or 
without Type 2 Diabetes Admitted with Acute Heart Failure 
Study 
Objectives 
The primary endpoint is to determine the cumulative change in 
weight (kilograms) per 40mg of IV furosemide equivalents from 
enrollment to day 5 or discharge (if earlier) between: 1) protocolized 
diuretic therapy and 2) dapagliflozin plus protocolized diuretic 
therapy guided by urine output.  
 
Secondary endpoints include comparing differences among the two 
arms in the following:  
• Incidence of worsening heart failure during hospitalization 
requiring IV inotropic therapy, new admission to an 
intensive care unit, new non-invasive positive pressure 
ventilation with bi-level positive airway pressure, or 
increase in the IV diuretic protocol intensity by 2 rows 
after Study Day 1 as adjudicated by the Clinical Event 
Committee 
• Hospital readmission within 30 days of discharge for heart 
failure or diabetic reasons as adjudicated by the Clinical 
Event Committee 
 
Exploratory endpoints include comparing difference among the two 
arms in the following: 
• NT-proBNP at baseline to discharge adjusted for baseline 
• Urine-output based Diuretic efficiency:  24-h total urine 
output (ml) per 40mg of IV furosemide equivalents on day 
2 of IV diuretic therapy from 24-h urine collection 
(collected day 2-day 3) 
• Fractional excretion of sodium (FENa)-based diuretic 
efficiency on day 2 of IV therapy: FENa per 40mg of IV 
furosemide equivalents of bolus loop dose using spot 
urine collected 2 hours after bolus loop dose 
• Urinary Na/K ratio at day 2 of IV therapy adjusted for 
baseline 
• Calculated 6-hour sodium output on day 2 of IV therapy 
using spot urine sodium collected 2 hours after bolus loop 
dose 
• Length of hospital stay, measured as days from 
admission to discharge 
• Presence of symptoms of congestion and dyspnea at 
discharge, measured via blinded-physician exam and 
patient reported congestion scores 


Version 4.0 
9-21-2021 
6
• Hospital readmission within 30 days of discharge for any 
cause 
• Number of days at home without hospitalization or 
emergency room visit during 30-day follow up period 
• Mean serum glucose during therapy  
• Amount of total daily insulin doses (units) utilized per day 
during therapy among patients with diabetes, compared 
between treatment arms and to a prior to enrollment 
outpatient insulin regimen 
• serum potassium covariate adjusted for baseline with 
attention to both elevation and depression 
 
Safety endpoints from study medication administration to hospital 
discharge: 
• estimated Glomerular Filtration Rate by the MDRD 
equation at discharge adjusted for baseline 
• Incidence of ketoacidosis 
• Serum glucose covariate adjusted for baseline with 
attention to both elevation (> 400mg/dl) and depression 
(< 70mg/dl) 
• Incidence of hypovolemic hypotension, defined as 
symptomatic hypotension with a sustained systolic blood 
pressure less than 90 mmHg over 30 minutes requiring 
fluid administration  
• Inpatient mortality 
Study Design 
This is a randomized trial of the addition of dapagliflozin to patients 
with or without diabetes hospitalized with AHF. Participants will be 
recruited following an initial standard evaluation in the ED and 
randomized within 24 hours of presentation for AHF in a 1:1 fashion 
to protocolized diuretic therapy or dapagliflozin + protocolized 
diuretic therapy. 
Number of 
Participants 
240 participants will be randomized 
Trial Location 
Up to six sites including but not limited to:  
• Vanderbilt University Medical Center 
• St Thomas Hospital System 
• Centennial Hospital 
• University of Mississippi 
• Integris Baptist Medical Center 


Version 4.0 
9-21-2021 
7
• University of North Carolina 
Inclusion 
Criteria 
1) Age of 18 years or older  
2) Randomized within 24 of presentation during a hospital 
admission for hypervolemic decompensated heart failure defined as 
either: 
• pulmonary artery catheterization with a pulmonary capillary 
wedge pressure greater than 19mmHg plus a systemic 
physical exam finding of hypervolemia (peripheral edema, 
ascites, or pulmonary edema on auscultation)  
• in the absence of pulmonary artery catheterization data 2 of 
the following signs or symptoms: peripheral edema, ascites, 
jugular venous pressure > 10mmHg, orthopnea, paroxysmal 
nocturnal dyspnea, 5-pound weight gain, or signs of 
congestion on chest x-ray or lung ultrasound 
3) Planned or current use of IV loop diuretic therapy during current 
hospitalizaiton 
4) eGFR > 25 ml/min/1.73m2 by the MDRD equation 
 
Exclusion 
Criteria 
Type 1 diabetes 
Serum glucose < 80mg/dl at enrollment  
Systolic blood pressure < 90mmHg at enrollment 
Requirement of intravenous inotropic therapy at enrollment or 
anticipated need of therapy during the study period 
History of hypersensitivity to any SGLT2 inhibitors 
Women who are pregnant or breastfeeding 
Severe anemia (Hemoglobin < 7.5g/dl) 
Severe uncorrected aortic or mitral stenosis 
Inability to perform standing weights or measure urine output 
accurately 
History of diabetic ketoacidosis  
Chronic combination nephron blockade with loop and thiazide 
therapy as an outpatient scheduled daily for more than 7 days prior 
to admission (Does not include HCTZ < 50mg for blood pressure) 
Diffuse anasarca with 4+ edema and projected hypervolemia 
exceeding 40-pounds 
Severe hepatic impairment (Child-Pugh class C if severity of hepatic 
failure is in question) 
Clinical picture consistent with acute myocardial infarction including 
troponin elevation or ischemic changes on electrocardiogram 
Site investigator determines the subject is not a good candidate to 
participate in study at this time  


Version 4.0 
9-21-2021 
8
Primary 
Endpoint 
cumulative change in weight (kilograms) per 40mg of IV furosemide 
equivalents from enrollment to day 5 or discharge (if earlier) 
between protocolized diuretic therapy and dapagliflozin plus 
protocolized diuretic therapy guided by urine output 
Assessment 
Schedule 
(Appendix A) 
Baseline: standing weight, NT-proBNP, BMP, hemoglobin A1c, spot 
urine values of sodium, potassium, and creatinine (calculate urine 
sodium/potassium ratio, FENa), vital signs, study loop diuretic and 
diabetic medication orders, congestion score, document baseline 
HF and diabetic medications, start urine output quantification, urine 
biobanking for future investigations including urinary exosomes. 
Daily: standing weight, BMP, vital signs, urine output quantification, 
titration of study loop diuretic and diabetic medication orders, 
document HF and diabetic medications, adverse event assessment 
Day 2: daily assessments as above plus 2-hour post loop diuretic 
spot urine sodium, potassium, and creatinine. Calculate FENa, 6-hr 
sodium output, urine sodium/potassium ratio, 24-hour urine 
collection for quantification and diuretic efficiency calculation, urine 
biobanking for future investigations including urinary exosomes. 
Day 5 or Discharge: standing weight, NT-proBNP, BMP, vital signs, 
urine output quantification, document HF and diabetic medications, 
congestion score, outcomes assessment, remind primary team to 
schedule standard-of-care 3-7-day follow-up visit with endocrinology 
(if patient has diabetes) and HF 
30-day phone follow-up: document HF and diabetic medications, 
outcomes assessment 
Study Duration 
Enrollment is anticipated to occur over 14 months with the end of 
study occurring at hospital discharge and a 30-day phone-call 
follow-up  
 
Clinical Event 
Committee 
The following events will be adjudicated by a Clinical Event 
Committee blinded to patient assignment:  
• Worsening heart failure defined as inpatient administration of 
an IV inotrope with dobutamine, milrinone, or dopamine, new 
admission to an intensive care unit, new non-invasive 
positive pressure ventilation with bilevel positive airway 
pressure, or increase in the IV diuretic protocol intensity by 2 
rows after Study Day 1 
• 30-day hospital readmissions due to heart failure or diabetes-
related events 


Version 4.0 
9-21-2021 
9
• Prolonged hospitalization as a result of hypoglycemia 
requiring medical intervention  
• Prolonged hospitalization as a result of hypotension requiring 
medical intervention  
• In-hospital incidence of ketoacidosis 
• Inpatient mortality 
Data and 
Safety 
Monitoring 
Board 
An independent Data and Safety Monitoring Board will advise the 
principal investigator on safety aspects and overall progress of the 
study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 4.0 
9-21-2021 
10
Table of Contents: 
 
1.0 
Background and rationale 
2.0 
Study outcomes 
3.0 
Inclusion/Exclusion criteria 
4.0 
Patient screening, consent, and randomization 
5.0 
Study Procedures 
6.0 
Risks 
7.0 
Reporting of adverse events 
8.0 
Data collection and record keeping 
9.0 
Study withdrawal 
10.0 Statistical methods  
11.0 References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 4.0 
9-21-2021 
11
1.0 Background and Rationale: 
Patients with acute decompensated HF (ADHF) are generally admitted due to 
symptoms of congestion and 90% are treated with a loop diuretic.1 However at least 
one-third of these patients are inadequately decongested due primarily to “diuretic 
resistance” and/ or “cardiorenal syndrome”.2,3 The inability to achieve decongestion is 
associated with a worse prognosis and a higher rate of re-hospitalization for ADHF.2 
More than 40% of all patients admitted with ADHF have diabetes and that percentage is 
growing both in Heart Failure with Reduced Ejection Fraction (HFrEF) and Preserved 
Ejection Fraction (HFpEF).4  
The admission blood glucose is elevated in approximately one-half of ADHF 
hospitalizations. 5,6 We recently demonstrated the admission blood glucose was within 
50mg/dl of the chronic average blood glucose in 66% of patients with diabetes admitted 
with ADHF.7 The median (IQR) admission blood glucose change from the chronic blood 
glucose was only -7 (-29, 26) mg/dl.7 Thus, the acute glucose in patients with T2DM 
presenting with acute heart failure is most often related to poor chronic glucose control 
suggesting that these patients would benefit from attempts to initiate therapies to 
improve chronic glucose control while in the hospital.   
No new therapies have been introduced in the United States for ADHF in several 
decades. Natriuretic peptides such as nesiritide and ularitide have failed to improve 
outcomes in either the chronic or acute heart failure patients.8,9 Diuretic resistance and 
hyperglycemia are common problems in ADHF admissions and represent a therapeutic 
opportunity for new therapies.5,10 
The sodium-glucose cotransporter-2(SGLT2) inhibitors, now approved for the anti-
hyperglycemic therapies also have an osmotic diuretic and natriuretic effect.11 In the 
chronic setting SGLT2 inhibitors reduce weight with modest decrements in systolic and 
diastolic blood pressure with a marked drop in albuminuria and a small drop in 
estimated GFR (-5 mL min-1.1.73 m-2) which returns to baseline over time.11  In patients 
with diabetes the SGLT2 transporter likely accounts for as much as 14% of total sodium 
chloride absorption. In the acute setting following a single dose, SGLT2 inhibitors did 
not increase urine volume.12 However, the acute diuretic effects have not been studied 
in a population with heart failure with or without concomitant hyperglycemia who are 
undergoing diuresis. To our knowledge, no current trials are investigating the effects of 
SGLT2 inhibition in ADHF. The current studies planned in HF are investigating the 
acute effects of SGLT2 on stable HF (NCT03027960), the chronic effects of SGLT2 
inhibition in compensated, chronic HF (NCT03619213, NCT02653482, NCT03030235, 
NCT03057977), changes in pulmonary pressure hemodynamics in patients monitored 
by CardioMEMs devices (NCT03030222), and effects on cardiopulmonary exercise 
fitness in chronic HF (NCT02862067).  
 
Congestion remains the major cause of hospital readmission for heart failure and an 
inpatient plan of care that allowed more effective decongestion would be rapidly and 
widely adopted by the medical community. Therefore, we propose to test the 


Version 4.0 
9-21-2021 
12
decongesting effects of the SGLT2 inhibitor dapagliflozin in patients with or without 
Type II diabetes admitted with an acute decompensation of chronic heart failure. 
2.0  Study Outcomes: 
2.1 Primary Outcome 
• The change in weight in kilograms per 40mg of IV furosemide equivalents from 
enrollment baseline to day 5 or discharge (if earlier) 
o Standing weights will be performed by study personnel using the same 
scale throughout the study period with the same clothing (hospital gown 
without shoes). The patient will be requested to empty their bladder and 
bowels if needed prior to each weight assessment. 
o The cumulative loop diuretic dose includes all IV and oral doses 
administered in the study period, converted to IV furosemide equivalents. 
Diuretic conversion: 80mg oral furosemide = 40mg IV furosemide = 20mg 
oral torsemide = 1mg oral/IV bumetanide 
 
This primary outcome investigates the decongestive potential of dapagliflozin by its 
impact on diuretic efficiency. Higher diuretic efficiency has been associated with better 
outcomes in multiple AHF populations.13,14 The primary outcome does not quantify the 
importance of initiating a mortality reducing therapy during hospitalization, which 
increases chronic adherence. Therefore, even if dapagliflozin does not meet the primary 
endpoint, this study would still be beneficial to establish the safety and best practices of 
initiating dapagliflozin during an AHF hospitalization, setting the stage for continuing it 
into the outpatient setting. The established benefits of such a strategy would emerge 
over the coming months to years. In addition to mechanistic and diuretic endpoints, 
additional secondary outcomes are designed to establish the safety across 
hemodynamic, renal, and glycemic outcomes. 
2.2 Secondary Outcomes: Compared between treatment arms 
• Incidence of worsening heart failure during hospitalization requiring IV 
inotropic therapy, new admission to an intensive care unit, new non-invasive 
positive pressure ventilation with bilevel positive airway pressure, or increase 
in the IV diuretic protocol intensity by 2 rows after Study Day 1 as adjudicated 
by the Clinical Event Committee 
• Hospital readmission within 30 days of discharge for heart failure or diabetic 
reasons as adjudicated by the Clinical Event Committee 
2.3 Exploratory Outcomes: Compared between treatment arms 
• NT-proBNP at discharge adjusted for baseline   
• Urine-output based Diuretic efficiency:  24-h total urine output (ml) per 40mg 
of IV furosemide equivalents on day 2 of IV diuretic therapy from 24-h urine 
collection (collected day 2-day 3) 


Version 4.0 
9-21-2021 
13
• Fractional excretion of sodium (FENa)-based diuretic efficiency on day 2 of IV 
therapy: FENa per 40mg of IV furosemide equivalents of bolus loop dose 
using spot urine collected 2 hours after bolus loop dose 
• Urinary Na/K ratio at day 2 of IV therapy adjusted for baseline 
• Calculated 6-hour sodium output on day 2 of IV therapy using spot urine 
sodium collected 2 hours after bolus loop dose 
• Increase in IV loop diuretic titration grid for urine output below the goal range  
• Length of hospital stay, measured as days from admission to discharge 
• Hospital admission within 30 days of discharge for any cause 
• Number of days at home without hospitalization or emergency room visit 
during 30-day follow up period 
• Presence of symptoms of congestion and dyspnea at discharge, measured 
via physical exam congestion scores15 
o Edema will be categorized as trace/mild (0 points), moderate (1 point), 
or severe (2 points).  
o Orthopnea will be characterized as present if the patient needed at 
least 2 pillows to breathe comfortably (2 points) or absent (0 points). 
o The Orthodema Score will be generated by the sum of the individual 
orthopnea and edema scores as in the table below: 
 
Orthodema Score15 
Mild edema 
No orthopnea 
0 
No congestion 
Moderate edema 
No orthopnea 
1 
Low-grade orthodema 
Severe edema or orthopnea 
2 
Moderate edema and orthopnea 
3 
High-grade orthodema 
Severe edema and orthopnea 
4 
Mild edema = below the knee with minimal denting 
Moderate edema = below the knee with significant pitting 
Severe edema = above the knee 
 
• Mean Serum glucose during therapy  
• Amount of total daily insulin doses (units) utilized per day during therapy 
among patients with type 2 diabetes, compared between treatment arms and 
to a prior to enrollment outpatient insulin regimen 
• serum potassium covariate adjusted for baseline with attention to both 
elevation and depression 
Single-Center Exploratory Outcomes at Vanderbilt University Medical Center 
The following exploratory outcomes will only be performed in patients at Vanderbilt 
University Medical Center who elect to participate in a sub-study. Patients can decline  
to participate in this sub-study and still participate in parent clinical trial. To explore 


Version 4.0 
9-21-2021 
14
changes in the plasma proteome during IV diuresis, we will collect one 15mL blood 
sample (10mL in purple top EDTA tube and 5mL in red top tube) at baseline and on the 
final study day (Day 5 or discharge).  
2.4 Safety Outcomes: Compared between treatment arms during the index stay from 
signing of informed consent to hospital discharge 
• Change in the estimated Glomerular Filtration Rate by the MDRD equation at 
discharge adjusted for baseline 
• Incidence of ketoacidosis, identified by the study team as elevated ketones in 
the urine and an arterial blood pH < 7.35 and adjudicated by the Clincal 
Events Committee 
• Serum glucose covariate adjusted for baseline with attention to both elevation 
(> 400mg/dl) and depression (< 70mg/dl) 
• Potential prolonged hospitalization as a result of hypoglycemia requiring 
medical intervention as adjudicated by the Clinical Events Committee 
• Potential prolongation of hospitalization as a result of incidence of 
hypovolemic hypotension, defined as a symptomatic hypotension with a 
sustained systolic blood pressure less than 90 mmHg over 30 minutes and 
requiring medical intervention as adjudicated by the Clinical Events 
Committee. All hypotension episodes requiring medical intervention will be 
evaluated by the Clinical Events Committee. 
• Inpatient mortality 
 
 
3.0  Inclusion/Exclusion criteria 
 
• Inclusion Criteria 
• Age of 18 years or older  
• Randomized within 24 hours of presentation during a hospital 
admission for hypervolemic decompensated heart failure defined as 
either: 
• pulmonary artery catheterization with a pulmonary capillary 
wedge pressure greater than 19mmHg plus a systemic physical 
exam finding of hypervolemia (peripheral edema, ascites, or 
rales on auscultation)  
• in the absence of pulmonary artery catheterization data 2 of the 
following signs or symptoms: peripheral edema, ascites, jugular 
venous pressure > 10mmHg, orthopnea, paroxysmal nocturnal 
dyspnea, 5-pound weight gain, or signs of congestion on chest 
x-ray or lung ultrasound  
 


Version 4.0 
9-21-2021 
15
• Standard-of-care monitoring on an inpatient ward and standard-of-care 
basic metabolic panel laboratory assessment once daily during the 
study period 
• Planned or current use of IV loop diuretic therapy during current 
hospitalization 
• eGFR > 25 ml/min/1.73m2 by the MDRD equation 
 
• Exclusion Criteria 
• Type 1 diabetes 
• Serum glucose < 80mg/dl at enrollment  
• Systolic blood pressure < 90mmHg at enrollment 
• Requirement of intravenous inotropic therapy at enrollment or 
anticipated need of therapy during the study period 
• History of hypersensitivity to any SGLT2 inhibitors 
• Women who are pregnant or breastfeeding 
• Severe anemia (Hemoglobin < 7.5g/dl) 
• Severe uncorrected aortic or mitral stenosis 
• Inability to perform standing weights or measure urine output 
accurately 
• History of diabetic ketoacidosis  
• Chronic combination nephron blockade with loop and thiazide therapy 
as an outpatient scheduled daily for more than 7 days prior to 
admission (Does not include HCTZ < 50mg for blood pressure) 
• Diffuse anasarca with 4+ edema and projected hypervolemia 
exceeding 40-pounds  
• Severe hepatic impairment (Child-Pugh class C if hepatic impairment 
is in question) 
• 
Clinical picture consistent with acute myocardial infarction including 
troponin rise and fall or ischemic changes on electrocardiogram  
• 
Site investigator determines the subject is not a good candidate to 
participate in study at this time  
 
4.0 Patient screening, consent, and randomization 
We will perform a randomized, open-label, multicenter trial to investigate the safety and 
clinical effects of initiating dapagliflozin vs standard of care in patients admitted to the 
hospital with ADHF with protocolized diuretic therapy in both treatment arms.  
4.1 Screening 
To identify candidates, we will collaborate with our Emergency Department. We are able 
to screen, consent, and randomized study candidates in the Emergency Department. 
Additionally, patients with ADHF will be screened on the HF team daily by a member of 


Version 4.0 
9-21-2021 
16
the HF team. Finally, we will utilize an electronic HF dashboard embedded within the 
electronic medical record to identify candidates across the medical center by their 
International Classification Disease code history, natriuretic peptide concentration 
adjusted for body-mass index, and use of intravenous loop diuretic therapy.  
We will utilize up to 5 additional sites for enrollment including but not limited to:  
• Mark Aaron - St Thomas Hospital System in Nashville, TN 
• A. Tom McRae – Centennial Hospital in Nashville, TN 
• Gabriel Hernandez – University of Mississippi in Jackson, MS 
• Luke Cunningham – Integris Baptist Medical Center 
• Kirkwood Adams – Univeristy of North Carolina 
4.2 Consent 
The study will be reviewed with the prospective participant (surrogate) by the 
investigator or study personnel. The prospective study participant (surrogate) will be 
given adequate time to read the written consent form.  The investigator or study 
personnel will be available to answer questions about the study including procedures, 
risks, and alternatives. The informed consent form will be signed and dated by the 
patient or legally authorized representative as per local regulation. 
The consent will allow for protected health information (PHI) to be transferred to 
REDCap to be analyzed by the Biostatistical team. All privacy regulations will be 
followed (i.e., Health Insurance Portability and Accountability Act [HIPAA]). 
4.3 Randomization 
Randomization will occur during the hospitalization within 24 hours of evaluation of 
AHF. Enrollment and randomization will be accomplished by study personnel logging 
into REDCap, confirming the inclusion and exclusion criteria have been satisfied, and 
using the REDCap randomization engine. Participants will then be randomized to either 
dapagliflozin or standard-of-care and will be registered as randomized.  
5.0 Study Procedures 
All patients will receive a low sodium diet (2g/day) with a 2000ml fluid restriction. 
Patients will receive standard-of-care laboratory monitoring (including at minimum once 
daily basic metabolic panel and baseline complete metabolic panel), vital sign 
monitoring, and strict urine output monitoring/quantification. 
5.1 Diabetic Therapies for patients with a diagnosis of Type 2 diabetes 
After enrollment, all previous diabetic therapies will be discontinued. Patients will be 
randomzed in a 1:1 ratio to standard of care with protocolized diuretic therapy or 
standard of care with protocolized diuretic therapy plus the addition of open label 
SGLT2 inhibitor therapy with dapagliflozin 10 mg orally once daily for the duration of the 
study, which will be until 5 days or hospital discharge. The patient will receive standard 


Version 4.0 
9-21-2021 
17
of care point of care blood glucose monitoring 4 times daily (before meals and at 
bedtime) and correctional insulin according to a blood glucose scale. For patients 
requiring large doses of basal insulin, the patient will be continued on a reduced dose of 
basal insulin. Insulin initiation and titration algorithms are in Appendix B.  
 
 
 
Non-insulin hypoglycemic: chronic, outpatient oral hypoglycemic medications which 
may include but are not limited to sulfonylureas, DPP-4 inhibitors, and/or metformin. 
 
5.2 Heart Failure Therapies 
The titration of non-diuretic heart failure therapies will be left to the direction of the 
treating physician. 
5.3 Diuretic Therapies 
5.3.1 Initial loop diuretic regimen 
If the patient has received loop diuretic dose(s) prior to randomization, proceed to 
Section 5.3.2 and titrate the current loop diuretic regimen according to diuretic protocol 
provided. 
If the patient’s first IV loop diuretic dose is after enrollment, the initial loop diuretic 
regimen after enrollment will be as follows: 


Version 4.0 
9-21-2021 
18
Loop diuretic naïve: If the patient does not take a scheduled loop diuretic as an 
outpatient, the initial IV loop diuretic dose will be 40mg of furosemide equivalents every 
12 hours. (1mg IV bumetanide = 40mg IV furosemide) 
Chronic, oral loop diuretic therapy: If the patient takes a scheduled loop diuretic regimen 
as an outpatient prior to hospital admission, the initial IV loop diuretic daily dose will be 
2 to 2.5 times the total daily home regimen dose. The calculated daily dose will be given 
as 50% the total daily dose as an IV bolus dose every 12 hours. Individual bolus doses 
exceeding 200mg IV furosemide equivalents will be capped to 200mg IV furosemide 
equivalents, so that the highest initial regimen will be 200mg IV every 12 hours. 
Diuretic conversion: 80mg oral furosemide = 40mg IV furosemide = 20mg oral 
torsemide = 1mg oral/IV bumetanide 
5.3.2 Loop diuretic titration 
Diuretic therapy can be titrated every 12 - 24 hours. Diuretic titration recommendations 
will be provided per the table below to first maximize IV loop diuretic therapy before 
addition of combination nephron blockade to limit non-loop diuretic therapy impact.  
Goal urine output 
Suggested Diuretic Regimen Titration 
Over 12 h 
Over 24 h 
< 1.5 liters 
< 3 liters 
Move down diuretic grid 1 row to increase diuretic intensity 
1.5 – 2.5 liters 
3-5 liters 
Continue on same diuretic regimen 
> 2.5 liters 
> 5 liters 
Move up diuretic grid 1 row to decrease diuretic intensity 
 
Current IV Diuretic Regimen 
(Furosemide IV Equivalent mg/day) 
Suggested New IV Diuretic Regimen 
(Furosemide IV Equivalent in mg) 
≤ 80 mg /day 
160mg daily: 80mg IV Q12H  
81-200mg/day 
320mg daily: 160mg IV Q12H 
201-320mg/day 
480mg daily: 240mg IV Q12H or 20mg/h infusion* 
321-480mg/day 
600mg daily: 300mg IV Q12H or 25mg/h infusion* 
481-600mg/day 
720mg daily: 30mg/h infusion* 
601-720mg/day 
960mg daily: 40mg/h infusion* 
721-960mg/day 
1,440mg daily: 60mg/h infusion* + metolazone 5 mg daily 
>960mg/day 
1,920mg daily: 80mg/h infusion* + metolazone 10 mg daily 
*Continuous IV infusions will be preceded by a 80mg IV furosemide loading dose unless a bolus dose 
was given in the previous 2 hours. 
Non-study diuretic therapies 
Use of non-study diuretic therapies including: spironolactone doses ≥100mg/day, 
eplerenone ≥ 100mg/day, non-study thiazides (metolazone or HCTZ> 12.5mg or other 
thiazide), non-study loop diuretics, systemic acetazolamide, triamterene, or amiloride 
therapy is discouraged and considered a protocol deviation.  
5.4 Clinical Event Committee 
The CEC will consist of 3 independent clinicians, which will consist of at least one 
endocrinologist and at least one heart failure specialist. The members of this committee 


Version 4.0 
9-21-2021 
19
will be independent of the study implementation teams and will be blinded to study arm 
assignment. This committee will review abstracted clinical data to determine when 
primary endpoints and major events have occurred. The CEC will review data for the 
following study outcomes: 
• Potential inhospital worsening heart failure events identified by the following 
criteria: 
o New intravenous inotropic therapy 
o New admission to an intensive care unit 
o New non-invasive positive pressure ventilation with bilevel positive airway 
pressure 
o 2 or more increases in IV diuretic protocol intensity after Study Day 1 
• 30-day readmission events for heart failure or diabetes-related care 
• Prolonged hospitalization as a result of the following safety outcomes: 
hypotension requiring medical intervention or hypoglycemia requiring medical 
intervention 
• In-hospital incidence of ketoacidosis 
• Inpatient mortality for causality  
 
All criteria and definitions will be pre-specified in detail in the Clinical Events Committee 
Charter. Only outcomes adjudicated as such by the Clinical Events Committee will be 
considered. If there are valid reasons for questioning an adjudication, such as an 
inexplicable outlier during analysis, the Principal Investigator may formally request a 
review of the case. In such situations, the Clinical Events Committee has final 
determination. 
6.0 Risks 
This study will evaluate the addition of oral dapagliflozin to standard-of-care heart failure 
therapies in patients with hypervolemic heart failure. We do not expect the risk of the 
dapagliflozin treatment arm will be different than the standard of care treatment arm. 
Dapagliflozin has a lower hypoglycemia risk than standard of care insulin therapy. Study 
procedures are designed to manage and minimize risks through careful selection of the 
patients who participate in the trial. We have developed a standardized protocol for 
diabetic therapies with endocrinology to minimize hypoglycemia risk in patients with 
diabetes. Participants will be monitored throughout the treatment phase of the study, 
throughout hospitalization, and at 30-day follow-up. Further, an independent DSMB will 
monitor safety of the participants throughout the study. 
 
7.0 Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
 
An Adverse Event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 


Version 4.0 
9-21-2021 
20
pharmaceutical product, whether or not considered causally related to the product. An 
undesirable medical condition can be symptoms (eg, nausea, chest pain), signs (eg, 
tachycardia, enlarged liver) or the abnormal results of an investigation (eg, 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. The term AE is used to include both serious 
and non-serious AEs. The time period of AE evaluation in this study will start after 
signature of the informed consent and will conclude at the end of the follow up period 30 
days after hospital discharge. 
 
 
 
7.1 Safety Standards 
The determination of adverse event severity rests on medical judgment of a medically 
qualified investigator. The severity of AEs will be graded using the following definitions: 
• Mild: awareness of sign, symptom, or event, but easily tolerated; 
• Moderate: discomfort enough to cause interference with usual activity and may 
warrant intervention; 
• Severe: incapacitating with inability to do usual activities or significantly affects 
clinical status, and warrants intervention. 
 
A Serious Adverse Event (SAE) is an adverse event that: 
• Results in death 
• Is life-threatening 


Version 4.0 
9-21-2021 
21
• Requires prolongation of hospitalization which is not specifically required by the 
protocol nor is it elective 
• Results in permanent impairment of a body function or permanent damage to a 
body structure 
• Requires medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure 
Additionally, important medical events that may not result in death, be life-threatening, 
or prolong hospitalization may be considered SAEs when they jeopardize the patient or 
require medical or surgical intervention to prevent one of the serious outcomes listed 
above.  Example of such medical events include: allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in prolonged hospitalization, or the development of drug dependency 
or drug abuse. Medical and scientific judgment must be exercised when classifying 
events as serious. 
Serious Adverse Events (SAE) related to dapagliflozin will be categorized as: 
• Suspected Unexpected Serious Adverse Reaction (SUSAR):  
o unintended response to dapagliflozin, which is not listed in the applicable 
product labeling, and meets the severity definition(s) of a SAE as above 
• Suspected Serious Adverse Reaction (SSAR): 
o unintended response to dapagliflozin, which is listed as a potential 
adverse reaction in the product labeling, and meets the severity 
definition(s) of a SAE as above 
7.2 Adjudication and Reporting of Re-hospitalizations during the 30-day follow-up period 
We will evaluate all re-hospitalizations occurring 30-days from the date of discharge 
from index hospitalization during which the study occurred. Thirty-day 
rehospitalizations are very common and expected in patients with heart failure. The 
purpose of this is to clarify if the hospitalization is a study outcome, AE, or both.  


Version 4.0 
9-21-2021 
22
 
*Definitely or possibly related to study drug = the rehospitalization was related to known 
or potential adverse events from dapagliflozin as defined in the U.S. marketed 
dapagliflozin package insert or according to investigator judgement in accordance with  
Section 7.3 below.  
Rehospitalizations that are within 7 days of the last study day and are definitely/possibly 
related to the study drug will be reported as Adverse Events according the procedures 
detailed in protocol Section 7.4. All other rehospitalizations will be documented as study 
outcomes and adjudicated by the CEC according to protocol Section 5.4.  
7.3 Assessment of Causality and Expectedness 
A medically-qualified investigator must assess the relationship of any AE to the use of 
study drug, based on available information, using the following guidelines: 
Causality 
Possibly Related - There is a reasonable possibility that the adverse event may 
have been caused by the study drug. The temporal relationship of the adverse 
event to study drug administration makes a causal relationship possible, and 
other drugs, therapeutic interventions or underlying conditions do not provide 
sufficient explanation for the observed event. 
Not Possibly Related- It is unlikely that the event was caused by the study drug. 
The temporal relationship of the adverse event to the study drug administration 
makes causal relationship unlikely and other drugs, therapeutic interventions or 
underlying conditions provide a more likely explanation for the event. 
Expectedness  


Version 4.0 
9-21-2021 
23
The expectedness of an adverse event or suspected adverse reaction shall be 
determined according to the package insert for U.S. marketed furosemide and 
dapagliflozin. Any AE that is not identified in nature, severity, or specificity in the 
current U.S. package insert is considered unexpected. Events described in the 
U.S. package insert as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but not specifically mentioned as 
occurring with the particular drug under investigation are considered unexpected. 
 
7.4 Reporting of Adverse Events and SAEs 
All adverse events occurring from signing of the Informed Consent through the 30-day 
follow-up period will be collected and reported. The Site Investigator is responsible for 
monitoring the safety of patients enrolled into the study. The following adverse events 
are anticipated, disease related-events in patients with decompensated heart failure; 
however, they should still be reported on the Adverse Event form in the REDCAP 
Database (some may require reporting as study endpoints): 
• New Ventricular Arrhythmia: Ventricular tachycardia lasting longer than 30 
seconds, or frequent non-sustained VT causing hemodynamic instability with 
MAP < 60 mmHg requiring intervention or > 1 intra-cardiac defibrillation or 
external cardiac defibrillation shock or ventricular fibrillation requiring defibrillation 
or requiring transfer to the intensive care unit 
• Hypotension: SBP < 90 for 2 repeated measurements within 30 minutes or 
lasting at least 30 minutes or symptomatic hypotension necessitating clinical 
intervention (defined as vasopressor support, intravenous fluid boluses, or 
initiation of inotropes) 
o Hypovolemic hypotension: subset of “hypotension” requiring fluid 
administration for hypovolemia 
• Cardiac arrest: any ventricular arrhythmic or pulseless electrical event that 
requires immediate life-sustaining medical therapies 
• Acute kidney injury requiring renal replacement therapy: an acute renal failure 
event that began during the study period and necessitates new renal 
replacement therapy during the hospitalization 
• Prolonged hospitalization as a result of the following safety outcomes: 
hypotension requiring medical intervention or hypoglycemia requiring medical 
intervention 
• Diabetic ketoacidosis as adjudicated by the CEC 
• Death 
 
All serious adverse events must be recorded in the Adverse Event Record of the 
patient’s REDCAP database. All serious adverse events should be monitored until 
stabilization or resolution. 
The process of reporting of SAEs will be as follows: 


Version 4.0 
9-21-2021 
24
1. The investigator team informs the site investigator of an SAE 
2. The site investigator reports the SAE to the local IRB and to the coordinating 
center and PI within 24 hours of being aware of the event. The site investigator 
will electronically submit the necessary supporting documentation to the 
coordinating site. 
3. The coordinating center and PI will report the SAE to AstraZeneca. 
4. If the coordinating set determines the SAE is a SUSAR, the coordinating site will 
report the SUSAR to the FDA. 
 
Reporting to the Coordinating Site 
All serious adverse events will be reported to the coordinating center (Vanderbilt) by the 
investigational site within 24 business hours of being aware of the event.  
Reporting to Local IRB. Investigators are also responsible for promptly reporting 
unexpected adverse events (serious and non-serious) to their reviewing IRB in 
accordance with local requirements. The Vanderbilt investigational site will report DSMB 
reports to the Vanderbilt IRB annually at the time of continuing review at a minimum. 
SAEs will be reported to the local IRB within 24 business hours of being aware of the 
event. 
Reporting to the Data Safety Monitoring Board 
Adverse event reports will be generated and presented to the DSMB at each meeting 
for review. The DSMB will also be alerted to SAEs prior to scheduled meetings if the 
number of individual SAEs in the data safety and monitoring plan are met.   
Reporting to AstraZeneca 
The coordinating center will notify AstraZeneca of each SAE. The SAE will be submitted 
as an individual case report. The causality of SAEs (their relationship to all study 
treatments/procedures) will be assessed by the investigator(s) and communicated to 
AstraZeneca. The Investigator is responsible for informing the local authorities (FDA) 
and ethical committees, of any SAEs as per local requirements, and concurrently 
AstraZeneca. When reporting to AstraZeneca, a cover page will accompany the SAE 
form indicating the following: 
• External Sponsored Research (ESR) 
• The site investigator’s and coordinating center’s name and address  
• The trial name/title and AstraZeneca ESR reference number 
SAEs will be reported by way of fax to AstraZeneca’s designated fax line: +1 302 886 
4114 or email if a secure is set up: AEMailboxClinicalTrialTCS@astrazeneca.com 
 
7.5 Study Termination 
The study may be terminated based on the DSMB review of serious adverse events and 
unexpected events.  


Version 4.0 
9-21-2021 
25
7.6 Non-serious Adverse Events 
Non-serious AEs will be reported to the IRB and AstraZeneca in annual scheduled 
reports. Additionally, the investigator will notify AstraZeneca of all non-serious AEs as a 
line item list at the end of the study. Non-serious AEs will be presented to the DSMB at 
each interim analysis. 
The following events are examples of potential non-serious suspected adverse 
reactions unless the seriousness meets criteria for a SAE as defined above.  
•  Incidence of mycotic genital infection, defined as a new symptomatic 
infection requiring treatment 
• Incidence of symptomatic cystitis, defined as new symptoms of dysuria, 
frequency, and/or urgency, plus a urine culture with at least 102 colony 
forming units of a uropathogen requiring treatment with antibiotic therapy 
• Incidence of symptomatic pyelonephritis, defined as new symptoms of 
dysuria, frequency, and/or urgency plus acute flank pain, plus a urine culture 
with at least 102 colony forming units of a uropathogen requiring treatment 
with antibiotic therapy  
7.7 Pregnancy  
Pregnancy is an exclusion criteria for this trial. It is unlikely that a patient would become 
pregnant during this study, as it takes place during hospitalization for acute heart failure. 
If a patient becomes pregnant during the course of the study, dapagliflozin will be 
discontinued immediately and an Astra Zeneca representative notified. Pregnancy itself 
is not regarded as an AE unless there is a suspicion that dapagliflozin 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) will be followed up and documented even if the patient 
was discontinued from the study. All pregnancies and outcomes of pregnancy will be 
reported to AstraZeneca’s designated fax line: +1 302 886 4114 or email: 
AEMailboxClinicalTrialTCS@astrazeneca.com  
 
8.0 Data Handling and Record Keeping 
The primary data collection system for our study will be the REDCap system, which 
uses a web-based electronic data capture. All data collected at any point in the trial are 
entered into this EDC system. At regular intervals, all data will be transferred from the 
EDC database for statistical summarization, data description, and data analysis.  
Further crosschecking of the data will be performed, and discrepant observations 
flagged and appropriately resolved through a data query system. The biostatistical team 
will perform internal database quality-control checks, and data audits throughout the 
course of the trial. 
 


Version 4.0 
9-21-2021 
26
8.1 Data Confidentiality and Retention 
Computerized data will be accessible only by password, and a centralized monitoring 
system will record and report all access to data. Electronic CRFs (eCRFs) will be 
identified by study number only, to ensure participant anonymity. No participant 
identifiers will be used in the presentation of data. Study records that might identify 
participants will be kept confidential as required by law. Except when required by law, 
participants will not be identified by name, personal identification number (e.g. social 
security number, social insurance number), address, telephone number, or any other 
direct personal identifier in study records. Participants will be informed that the study 
physician and his/her study team will report the results of study-related tests to the 
investigators and to the NIH. Participants will be informed that their records may be 
reviewed in order to meet federal, state or regional/local regulations. Reviewers may 
include the study team monitors, IRBs/ECs, the NIH, other government regulators as 
dictated by local law, or their delegates. Study records will be maintained by the 
investigators for a period of six (6) years following the expiration of the grant or length of 
time as required by local regulations, whichever is longer. 
9.0 Study Withdrawal/Discontinuation 
A patient may withdraw at the study at any time. The patient will inform the site 
investigator of their desire to withdraw. All study-based therapy will stop at this point, 
and the attending cardiologist will perform any further care. All study data collected to 
that time point will be included in the analysis. The withdrawal reason will be 
documented. All patients will be followed per the study protocol through Day 30. 
 
10.0 Statistical Methods 
The full statistical methods are detailed separately in the Statistical Analysis Plan. 
The primary analysis model will be the semiparametric proportional odds (PO) ordinal 
logistic regression model16 for continuous outcome variables17.  The PO model does not 
make any distributional assumption for the response variable,  is robust to extreme 
values, and is invariant to transformations of the response variable.  It is also extremely 
efficient when compared to linear regression if normality holds. The Wilcoxon 
nonparametric two-sample test is a special case of the PO model, but the PO model 
allows for baseline covariate adjustment.   Note that we use covariate adjustment 
instead of change from baseline so as to not assume that (1) the baseline variable is 
linearly related to the response variable and (2) the slope of the baseline variable is 1.0. 
 
For binary outcomes we will use the special case of the PO model that is the binary 
logistic regression model. 
 


Version 4.0 
9-21-2021 
27
For safety analysis of clinical lab variables we use the most powerful and least arbitrary 
continuous variable analyses and include the empirical cumulative distribution function 
of post-randomization values of these variables.  These continuous analyses will also 
provide estimates of incidence of such outcomes as hyper- and hypo-kalemia, but will 
be more sensitive than using only binary responses. 
Changes in body weight from admission to discharge in previous literature 
Trial 
Experimental 
agent 
Mean decrease in 
weight (kg) 
Experimental, (%) 
Mean decrease in 
weight 
Control, (%) 
Within group SD 
in Experimental 
Group (kg) 
TRUE-AHF8 
Ularitide 
--- 
--- 
--- 
RELAX-AHF18 
Serelaxin 
3.6 
3.0 
4.4 
ASCEND-HF9 
Nesirtide 
--- 
--- 
--- 
EVEREST19 
Tolvaptan 
3.3 
2.7 
3.3 
 
TACTICS20 
Tolvaptan 
3.7 
2.5 
4.4 
Secrets of 
HF21 
Tolvaptan 
3.5 
2.4 
2.0 
ROSE-HF22 
Nesiritide 
3.25 
3.5 
0.9 
ROSE-HF22 
Dopamine 
3.4 
3.5 
0.9 
MEAN 
3.5 
2.9 
2.7 
 
Changes in weight by IV 40mg Furosemide Equivalents (FE) 
Trial 
Experimental 
agent 
Duration 
(days) 
Daily IV loop 
diuretic dose in 
FE, mean or 
median (IQR)* 
Median (IQR) decrease in 
weight (kg)/40mg IV FE 
 
Difference associated with 
adverse HF outcomes 
RELAX-AHF23 
Serelaxin 
5 
80 
0.42 (1.00, 0.14) 
Below median value 
DIUR-HF14 
None 
3-5 
137  
(100, 200) 
0.20 (0.281, 0.082) 
Below median value 
ASCEND-HF24 
Nesiritide 
2 
---- 
0.42 (1.0, 0.05) 
Below median value 
PROTECT25 
Rolofylline 
4 
80 (47, 133) 
0.38 (0.8, 0.13) 
Below median value 
EVEREST19,26 
Tolvaptan 
4 
80 
0.30 (0.79, 0.03) 
Below median value 
Average across clinical trials 
0.34 (0.78, 0.09) 
 
FE= Furosemide Equivalents (FE) 
 
Multiple clinical trials have examined and validated the diuretic efficiency metric of mean 
weight loss (kg)/40mg IV furosemide in contemporary AHF study populations. 14 14 14 14 
The average cumulative median weight loss/40mg furosemide across these trials was 
0.34 (IQR 0.78, 0.09) kg/40mg. Patients with this diuretic efficiency metric in the lower 
two quartiles had higher incidence of adverse outcomes including hospitalization and 
mortality across time frames of 30 to 180 days after multivariate analyses. These 
findings have been confirmed by diuretic efficiency metrics using urine output/40mg IV 
furosemide in several other populations. In an AHF population at our medical center, we 
also found a the weight based diuretic efficiency to be similar, with a mean 0.25 
kg/40mg but a higher standard deviation (0.47 kg/40mg).  


Version 4.0 
9-21-2021 
28
We anticipate dapagliflozin to increase the weight loss while decreasing the cumulative 
furosemide dose required to achieve euvolemia. On the basis of the historical literature, 
we project an increase in diuretic efficiency by 0.1kg/40mg IV furosemide in the 
dapagliflozin arm to be a clinically meaningful difference.  We project that our diuretic 
protocol will decrease variations in loop diuretic dosing, which drive large standard 
deviations.  We project a normally distributed standard deviation within each arm to be 
0.25kg/40mg.  A sample size of 120 experimental subjects and 120 control subjects will 
have 87% power to detect a probability of 0.611 that an observation in the dapagliflozin 
arm is less than an observation in the standard of care arm using a Wilcoxon (Mann-
Whitney) rank-sum test with a 0.05 two-sided significance level. 
 
For descriptive statistical analyses of baseline characteristics we will compute 
proportions for categorical data. Continuous variables will be described by sample 
quantiles, mean, and Gini's mean differencewill be descrbied using sample quantiles.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 4.0 
9-21-2021 
29
References: 
1. 
Adams KF, Jr., Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients 
hospitalized for heart failure in the United States: rationale, design, and preliminary 
observations from the first 100,000 cases in the Acute Decompensated Heart Failure National 
Registry (ADHERE). American heart journal. 2005;149(2):209-216. 
2. 
Chioncel O, Mebazaa A, Maggioni AP, et al. Acute heart failure congestion and perfusion status - 
impact of the clinical classification on in-hospital and long-term outcomes; insights from the 
ESC-EORP-HFA Heart Failure Long-Term Registry. European journal of heart failure. 2019. 
3. 
Damman K, Testani JM. The kidney in heart failure: an update. European heart journal. 
2015;36(23):1437-1444. 
4. 
Echouffo-Tcheugui JB, Xu H, DeVore AD, et al. Temporal trends and factors associated with 
diabetes mellitus among patients hospitalized with heart failure: Findings from Get With The 
Guidelines-Heart Failure registry. American heart journal. 2016;182:9-20. 
5. 
Mebazaa A, Gayat E, Lassus J, et al. Association between elevated blood glucose and outcome in 
acute heart failure: results from an international observational cohort. Journal of the American 
College of Cardiology. 2013;61(8):820-829. 
6. 
Kosiborod M, Inzucchi SE, Spertus JA, et al. Elevated admission glucose and mortality in elderly 
patients hospitalized with heart failure. Circulation. 2009;119(14):1899-1907. 
7. 
Cox ZL, Lai P, Lewis CM, Lindenfeld J. Change in Admission Blood Glucose from Chronic Glycemic 
Status in Acute Heart Failure Hospitalization and 30-day Outcomes: A retrospective analysis. 
International journal of cardiology. 2019;in press. 
8. 
Packer M, O'Connor C, McMurray JJV, et al. Effect of Ularitide on Cardiovascular Mortality in 
Acute Heart Failure. The New England journal of medicine. 2017;376(20):1956-1964. 
9. 
O'Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute 
decompensated heart failure. The New England journal of medicine. 2011;365(1):32-43. 
10. 
Cox ZL, Lenihan DJ. Loop diuretic resistance in heart failure: resistance etiology-based strategies 
to restoring diuretic efficacy. Journal of cardiac failure. 2014;20(8):611-622. 
11. 
Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium Glucose Cotransporter 2 
Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential 
Mechanisms, and Clinical Applications. Circulation. 2016;134(10):752-772. 
12. 
Heise T, Seewaldt-Becker E, Macha S, et al. Safety, tolerability, pharmacokinetics and 
pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with 
type 2 diabetes. Diabetes Obes Metab. 2013;15(7):613-621. 
13. 
Testani JM, Brisco MA, Turner JM, et al. Loop diuretic efficiency: a metric of diuretic 
responsiveness with prognostic importance in acute decompensated heart failure. Circulation 
Heart failure. 2014;7(2):261-270. 
14. 
Palazzuoli A, Testani JM, Ruocco G, Pellegrini M, Ronco C, Nuti R. Different diuretic dose and 
response in acute decompensated heart failure: Clinical characteristics and prognostic 
significance. International journal of cardiology. 2016;224:213-219. 
15. 
Lala A, McNulty SE, Mentz RJ, et al. Relief and Recurrence of Congestion During and After 
Hospitalization for Acute Heart Failure: Insights From Diuretic Optimization Strategy Evaluation 
in Acute Decompensated Heart Failure (DOSE-AHF) and Cardiorenal Rescue Study in Acute 
Decompensated Heart Failure (CARESS-HF). Circulation Heart failure. 2015;8(4):741-748. 
16. 
Walker SH, Duncan DB. Estimation of Probability of an Event as a Function of Several 
Independent Variables. Biometrika. 1967;54:167-+. 
17. 
Harrell FE. Regression Modeling Strategies: With Applications to Linear Models, Logistic and 
Ordinal Regression, and Survival Analysis, 2nd Edition. Springer Ser Stat. 2015. 


Version 4.0 
9-21-2021 
30
18. 
Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment 
of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet. 
2013;381(9860):29-39. 
19. 
Konstam MA, Gheorghiade M, Burnett JC, Jr., et al. Effects of oral tolvaptan in patients 
hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA : the journal of the 
American Medical Association. 2007;297(12):1319-1331. 
20. 
Felker GM, Mentz RJ, Cole RT, et al. Efficacy and Safety of Tolvaptan in Patients Hospitalized 
With Acute Heart Failure. Journal of the American College of Cardiology. 2017;69(11):1399-1406. 
21. 
Konstam MA, Kiernan M, Chandler A, et al. Short-Term Effects of Tolvaptan in Patients With 
Acute Heart Failure and Volume Overload. Journal of the American College of Cardiology. 
2017;69(11):1409-1419. 
22. 
Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute 
heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA : the 
journal of the American Medical Association. 2013;310(23):2533-2543. 
23. 
Voors AA, Davison BA, Teerlink JR, et al. Diuretic response in patients with acute 
decompensated heart failure: characteristics and clinical outcome--an analysis from RELAX-AHF. 
European journal of heart failure. 2014;16(11):1230-1240. 
24. 
ter Maaten JM, Dunning AM, Valente MA, et al. Diuretic response in acute heart failure-an 
analysis from ASCEND-HF. American heart journal. 2015;170(2):313-321. 
25. 
Valente MA, Voors AA, Damman K, et al. Diuretic response in acute heart failure: clinical 
characteristics and prognostic significance. European heart journal. 2014;35(19):1284-1293. 
26. 
Ter Maaten JM, Valente MA, Damman K, et al. Combining Diuretic Response and 
Hemoconcentration to Predict Rehospitalization After Admission for Acute Heart Failure. 
Circulation Heart failure. 2016;9(6). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 4.0 
9-21-2021 
31
Appendix A: Schedule of study assessments 
Assessment 
Screening 
Baseline 
(may be Day 
1) 
Day 1 
Day 2 
Days 3-4 
(if not 
discharged) 
Day 5 or 
discharge  
30-days 
post 
discharge 
Inclusion /exclusion 
 
X 
 
 
 
 
 
Consent 
 
X 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
Study drug dose 
 
 
#1 
#2 
#3, #4 
#5 
 
Laboratory Assessments 
HgbA1c 
 
X 
 
 
 
 
 
NT-proBNP 
 
X 
 
 
 
X 
 
Serum chemistries 
X 
 
 
X 
X 
X 
 
Pregnancy test 
X 
 
 
 
 
 
 
VUMC proteomic sub-study† 
 
X 
 
 
 
X 
 
Urine Assessments  
Urine measurement 
 
 
X 
X 
X 
X 
 
24-h urine 
collection*** 
 
 
 
X 
 
 
 
Spot urine electrolytes 
and creatinine*  
 
X 
 
X 
 
 
 
VUMC urine biobanking† 
 
X 
 
X 
 
 
 
Medication Assessments 
Loop diuretic titration 
per protocol 
 
 
X 
X 
X 
X 
 
Insulin titration per 
protocol among 
diabetics only 
 
 
X 
X 
X 
X 
 
CV medication 
reconciliation 
 
X 
X 
X 
X 
X 
X 
Diabetic medication 
reconciliation 
 
X 
X 
X 
X 
X 
X 
Other Assessments  
Vital signs** 
X 
X 
X 
X 
X 
X 
 
Standing weight** 
 
X 
X 
X 
X 
X 
 
Congestion score 
 
X 
 
 
 
X 
 
Adverse Event 
assessment 
 
 
X 
X 
X 
X 
X 
Study outcomes 
 
 
X 
X 
X 
X 
X 
HgbA1c= hemoglobin A1c; BNP= b-type natriuretic peptide; CV = cardiovascular  
* Urine sodium, urine potassium, and urine creatinine collected approximately 2 hours after an IV loop diuretic 
dose. For baseline, this can be 2 hours after the first open-label IV loop diuretic dose prior to randomization. 
**Vital Signs and weights are done as close to randomization time as possible for each day 
***24 h urine collection started on day 2 plus or minus 6 hours from randomization 
† At Vanderbilt University Medical Center study site only 


Version 4.0 
9-21-2021 
32
 
Appendix B: Insulin algorithms for patients with Type 2 diabetes 
Insulin lispro is listed as the rapid acting insulin but may be substituted with a equivalent 
rapid acting insulin for formulary differences across investigation sites 
Insulin glargine is listed as the long acting insulin but may be substituted with a 
equivalent long acting insulin for formulary differences across investigation sites 
*Correctional Insulin regimens based upon blood glucose measured 4 times daily 
(before meals and at bedtime or every 6 hours if NPO): 
Blood Glucose 
 
Moderate dose correctional scale 
< 70 mg/dl 
Hypoglycemia protocol per hospital protocol 
70 -139mg/dl 
No action 
140 - 159mg/dl 
1 unit insulin lispro 
160 - 189 mg/dl 
2 units insulin lispro 
190- 219 mg/dl 
3 units insulin lispro 
220 - 249 mg/dl 
4 units insulin lispro 
250 - 279mg/dl 
5 units insulin lispro  
280 - 309mg/dl 
6 units insulin lispro 
310 - 339mg/dl 
7 units insulin lispro 
340 - 369mg/dl 
8 units insulin lispro 
370 - 379mg/dl 
9 units insulin lispro 
>380mg/dl 
10 units insulin lispro and notify medical team 
 
Blood Glucose 
High dose correctional scale 
< 70 mg/dl 
Hypoglycemia protocol per hospital protocol 
70 -139mg/dl 
No action 
140 - 159mg/dl 
2 units insulin lispro 
160 - 179 mg/dl 
3 units insulin lispro 
180 - 199 mg/dl 
4 units insulin lispro 
200 - 219 mg/dl 
5 units insulin lispro 
220 - 239mg/dl 
6 units insulin lispro 
240 - 259mg/dl 
7 units insulin lispro 


Version 4.0 
9-21-2021 
33
260 - 279mg/dl 
8 units insulin lispro 
280 - 299mg/dl 
9 units insulin lispro 
300 - 319mg/dl 
10 units insulin lispro 
300 - 319mg/dl 
10 units insulin lispro 
320 - 339mg/dl 
11 units insulin lispro 
340 - 359mg/dl 
12 units insulin lispro 
360 - 379mg/dl 
13 units insulin lispro 
380 - 399mg/dl 
14 units insulin lispro 
>400mg/dl 
15 units insulin lispro and notify medical team 
Blood Glucose 
Very high dose correctional scale 
< 70 mg/dl 
Hypoglycemia protocol per hospital protocol 
70 -139mg/dl 
No action 
140 - 174mg/dl 
3 units insulin lispro 
175 - 204 mg/dl 
5 units insulin lispro 
205 - 234 mg/dl 
7 units insulin lispro 
235 - 264mg/dl 
9 units insulin lispro 
265 - 294mg/dl 
11 units insulin lispro 
295 - 324mg/dl 
13 units insulin lispro 
325 - 354mg/dl 
15 units insulin lispro 
355 - 384mg/dl 
17 units insulin lispro 
385 - 399mg/dl 
19 units insulin lispro 
>400mg/dl 
20 units insulin lispro and notify medical team 
 
#Basal insulin regimen 
Glargine once daily - starting daily dose: 
• Patients with BG between 140-200 mg/dL= 0.2 units per kg weight per day. 
• Patients with BG between 201-400 mg/dL= 0.25 units per kg weight per day. 
• Glargine insulin will be given once daily, at the same time of the day. 
• Patients will receive the full-dose of glargine insulin (even if NPO) except for 
those that have GFR <50 ml/min.  
• Patients with GFR <50ml/min will receive only one-half of the calculated insulin 
dose 
Supplemental (correction) insulin: 
• Give supplemental insulin lispro following the “correctional scale” protocol* for 
elevated blood glucose  
• If a patient is able and expected to eat all, give supplemental lispro insulin after 
each meal and at bedtime following the high dose correctional scale 
• If a patient is not able to eat, give supplemental lispro insulin every 6 hours (6-
12-6-12) following the moderate dose correctional scale 
Daily insulin adjustment: 
• Fasting and pre-meal BG between 100-140 mg/dl without hypoglycemia the 
previous day: no change 


Version 4.0 
9-21-2021 
34
• Fasting and pre-meal BG between 141-180 mg/dl: increase glargine dose by 
10% every day 
• Fasting and pre-meal BG >180 mg/dl: increase glargine dose by 20% every 
day 
• Fasting and pre-meal BG between 70-99 mg/dl: decrease glargine dose by 
10% every day 
• If a patient develops hypoglycemia (BG <70 mg/dL), decrease glargine dose by 
20%. 
• If a patient develops hypoglycemia (BG <40 mg/dL), decrease glargine dose by 
30-40%. 
Blood glucose monitoring: 
• Measure BG before each meal and at bedtime (or every 6 hours if a patient is 
not eating) using a glucometer. 
 
$Basal and Bolus Meal Coverage Insulin 
Glargine once daily - starting daily dose: 
• Patients with BG between 140-200 mg/dL= 0.4 units per kg weight per day. 
• Patients with BG between 201-400 mg/dL= 0.5 units per kg weight per day. 
• Half the total insulin daily dose will be given as glargine and the other half as 
lispro. 
• Glargine insulin will be given once daily, at the same time of the day. 
• Patients will receive the full-dose of glargine insulin (even if NPO) except for 
those that have GFR <50 ml/min.  
• Patients with GFR <50ml/min will receive only one-half of the calculated insulin 
dose 
• Insulin lispro will be given in three equally divided doses after each meal. To 
prevent hypoglycemia, if a subject is not able to eat, the dose of lispro will be 
held. Patients with GFR <50ml/min receive one-half of the calculated insulin 
dose. 
Supplemental (correction) insulin: 
• Give supplemental insulin lispro following the “correctional scale” protocol* for 
elevated blood glucose  
• If a patient is able and expected to eat all, give supplemental lispro insulin after 
each meal and at bedtime following the high dose correctional scale 
• If a patient is not able to eat, give supplemental lispro insulin every 6 hours (6-
12-6-12) following the moderate dose correctional scale 
Daily insulin adjustment: 
• Fasting and pre-meal BG between 100-140 mg/dl without hypoglycemia the 
previous day: no change 
• Fasting and pre-meal BG between 141-180 mg/dl: increase glargine dose by 
10% every day 
• Fasting and pre-meal BG >180 mg/dl: increase glargine dose by 20% every 
day 


Version 4.0 
9-21-2021 
35
• Fasting and pre-meal BG between 70-99 mg/dl: decrease glargine dose by 
10% every day 
• If a patient develops hypoglycemia (BG <70 mg/dL), decrease glargine dose by 
20%. 
• If a patient develops hypoglycemia (BG <40 mg/dL), decrease glargine dose by 
30-40%. 
Blood glucose monitoring: 
• Measure BG before each meal and at bedtime (or every 6 hours if a patient is 
not eating) using a glucometer. 
 

SAP_001.pdf: 
Version 2.0 
Page 1 
 
 
Efficacy and Safety of Dapagliflozin in Acute Heart Failure  
DICTATE-AHF 
NCT 04298229  
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 2.0 
Page 2 
 
Version 
Number/Amendment 
Approval 
Date 
Summary of Changes 
1.0/ Original protocol 
10.2021 
Not applicable 
2.0/Amendment One 
3.2023 
1. Modified text to include patients without diabetes 
2. Sensitivity endpoint analysis - changed diuretic 
dose analyses to be centered on 40mg IV 
furosemide from 20mg 
3. Defined serum potassium values to define 
severity categories of hypokalemia 
4. Defined serum glucose values to define severity 
categories of hypoglycemia and subsequent 
analyses changes for these new categories 
5. Added eGFR calculation to also be done with the 
CKD-EPI calculation 
6. Primary Analysis: changed the covariates to only 
be baseline weight (removing other covariates) 
7. Exploratory Outcome: Altered analysis of 30-day 
readmission to include death as a competing risk 
8. Exploratory Outcome: clarified total daily insulin 
doses will be compared between treatment arms 
and prior to enrollment 
9. Exploratory Outcome: Added 24-hour and spot 
urine sodium measures  
10. Added Heterogenicity of Treatment Effect 
analyses  
11. Added changes in serum chemistries by treatment 
arm 
 
 
 
 
 
 
 
 


Version 2.0 
Page 3 
 
Introduction 
This document describes the statistical analysis plan (SAP) for a randomized, open-label, multi-center 
trial studying the sodium-glucose cotransporter-2 inhibitor (SGLT2), Dapagliflozin, in patients with or 
without Type II diabetes (T2DM) admitted with acute decompensated heart failure (ADHF). 
Patients with ADHF are typically admitted to the hospital due to symptoms of congestion with loop 
diuretics being the primary mode of treatment; however, loop diuretics are not always sufficient in 
helping patients achieve adequate decongestion.1,2,3 In fact, congestion remains the major cause of 
hospital readmission for heart failure.  In addition, an increasing percentage of patients admitted with 
ADHF also have T2DM.  It has been shown that SGLT2-inhibitors, approved for anti-hyperglycemic 
therapies, also have diuretic and natriuretic effects.4 The acute diuretic effects in a population with 
ADHF, with or without concomitant hyperglycemia, undergoing intravenous diuresis are currently 
unknown.  This trial hypothesizes patients randomized to receive dapagliflozin will have improved 
decongestion when compared to those receiving structured usual care. 
Treatment arms 
Patients with or without T2DM hospitalized with ADHF will be randomized within 24 hours of 
evaluation of ADHF in 1:1 ratio to either intervention or structured usual care defined as follows: 
a) Intervention:  Previous diabetic therapies will be discontinued, and patients will receive 
protocolized diuretic therapy plus the addition of open label SGLT2 inhibitor therapy with 
dapagliflozin 10 mg orally once daily for the duration of the study – the minimum of 5 days or 
hospital discharge. 
b) Structured usual care: Previous diabetic therapies will be discontinued, and patients will receive 
protocolized diuretic therapy. 
Endpoints 
Primary Endpoint: 
The primary endpoint is to determine the cumulative change in weight (kg) per 40mg of IV furosemide 
equivalents from enrollment to the minimum of Day 5 or discharge between 1) protocolized diuretic 
therapy (structured usual care) and 2) dapagliflozin plus protocolized diuretic therapy guided by urine 
output. 
Sensitivity Endpoint: 
The cumulative change in weight (kg) per doubling of the cumulative loop diuretic (analyzed as log2 of 
the cumulative loop diuretic dose centered on 40mg of IV furosemide equivalent and winsorized at 40mg) 
from enrollment to Day 5 or discharge between 1) structured usual care and 2) dapagliflozin plus 
structured usual care 
Secondary Endpoints:  Comparing differences among the two arms in the following: 
a) Incidence of worsening heart failure during hospitalization requiring i) IV inotropic therapy, ii) 
new admission to an intensive care unit (ICU), iii) new non-invasive positive pressure ventilation 
with bi-level positive airway pressure, or iv) increase in the IV diuretic protocol intensity by 2 
rows after Study Day 1 as adjudicated by the Clinical Event Committee (CEC). 


Version 2.0 
Page 4 
 
b) Hospital readmission within 30 days of discharge for ADHF or diabetic reasons as adjudicated by 
the CEC. 
Exploratory Endpoints:  Comparing differences among the two arms in the following: 
a) NT-proBNP at baseline to discharge adjusted for baseline. 
b) Urine-output based diuretic efficiency defined as the Day 2 24-hour total urine output (ml) per 
40/mg of IV furosemide equivalents  
a. Repeated as per doubling of the cumulative loop diuretic dose (log2 cumulative loop 
diuretic dose centered at 40mg) 
c) Urine sodium-based diuretic efficiency defined as the Day 2 24-hour total urine sodium excretion 
(mmol) per 40mg of IV furosemide equivalents (total loop diuretic dose over Day 2) 
a. Repeated as per doubling of the cumulative Day 2 loop diuretic dose (log2 cumulative 
loop diuretic dose centered at 40mg) 
d) Spot urine sodium-based diuretic efficiency defined as the spot urine sodium concentration 
(mmol/L) on Day 2 per 40mg of IV furosemide equivalents (preceding loop diuretic dose) 
e) Fractional excretion of sodium (FENa)-based diuretic efficiency on Day 2 of IV therapy defined 
as the FENa from a spot urine test on Day 2 of IV therapy collected ~2 hours after bolus loop 
dose per 40 mg of IV furosemide equivalents.  
a. Repeat as per doubling of the cumulative loop diuretic dose (log2 cumulative loop 
diuretic dose centered at 40mg) 
f) Urinary Na/K ratio at Day 2 of IV therapy adjusted for baseline.  
g) Calculated 6-hour sodium output on Day 2 of IV therapy using spot urine sodium collected 2 
hours after bolus loop dose.  
h) Length of hospital stay, measured as days from admission to discharge 
i) Presence of symptoms of congestion and dyspnea at discharge, measured via blinded-physician 
exam and patient reported congestion scores. 
j) Hospital readmission within 30 days of discharge for any cause.  
k) Number of days at home without hospitalization or emergency room visit during 30-day follow 
up period.  
l) Mean serum glucose during therapy 
m) Amount of total daily insulin doses (units) utilized per day during therapy, compared between 
treatment arms and to a “prior to enrollment” outpatient insulin regimen. 
n) Analyze the change in basic metabolic panel laboratory values and hemoglobin from baseline to 
end of study 
o) Serum potassium covariate with attention to both elevation and depression.  
Hypokalemia levels are defined as  
a. Not hypokalemic:  serum potassium > 3.4 mEq/L 
b. Mild:  serum potassium 3.0 – 3.4 mEq/L 
c. Mod-Severe:  serum potassium < 3.0 mEq/L 
Hyperkalemia levels are defined as 
a. Not hyperkalemic:  serum potassium < 5.1 mEq/L 
b. Mild:  serum potassium 5.1 – 5.5 mEq/L 
c. Severe:  serum potassium > 5.5 mEq/L 
 
 


Version 2.0 
Page 5 
 
Safety Endpoints:  Comparing differences among the two arms in the following: 
a) Estimated Glomerular Filtration Rate by the MDRD equation at discharge adjusted for baseline.  
A sensitivity analysis of eGFR by the CKD-EPI equation will also be done. 
b) Incidence of ketoacidosis as adjudicated by the CEC 
c) Serum glucose with attention to both elevation and depression.   
a. Hypoglycemia is defined as: 
i. Not hypoglycemic:  serum glucose > 70 mg/dl 
ii. Mild:  serum glucose 54-69 mg/dl 
iii. Mod-Severe:  serum glucose < 54 mg/dl 
b. Hyperglycemia is defined as: 
a. Not hyperglycemic:  serum glucose < 200 mg/dl 
b. Mild:  serum glucose 200-300 mg/dl 
c. Severe:  serum glucose > 300 mg/dl 
d) Incidence of hypovolemic hypotension, defined as symptomatic hypotension with a sustained 
systolic blood pressure less than 90 mmHg lasting at least 30 minutes requiring fluid 
administration. 
e) Inpatient mortality 
Design Considerations 
Randomization 
Patients will be randomized in a 1:1 ratio to receive either intervention or structured usual care.  
Randomization will use block randomization stratified by site with block sizes of 4. 
Power and Sample Size 
We anticipate dapagliflozin will increase the weight loss while decreasing the cumulative furosemide 
dose required to achieve euvolemia.  On the basis of the historical literature, we project an increase in 
diuretic efficiency by 0.1kg/40mg IV furosemide in the Dapagliflozin arm to be a clinically meaningful 
difference.  We project that our diuretic protocol will decrease variations in loop diuretic dosing, which 
drive large standard deviations.  We project a normally distributed standard deviation within each arm to 
be 0.25kg/40mg.  A sample size of 120 experimental subjects and 120 control subjects will have 87% 
power to detect a probability of 0.611 that an observation in the Dapagliflozin arm is less than an 
observation in the structured usual care arm using a Wilcoxon (Mann-Whitney) rank-sum test with a 0.05 
two-sided significance level. 
Statistical Approach 
Descriptive Analysis 
Initially, we will describe the study cohort pooled across all sites, both overall and grouped by treatment 
assignment.  To characterize the study sample, demographic, clinical, and lab data will be described 
overall and by treatment arm.  Categorical variables will be described using frequencies and proportions; 
continuous variables will be described using means and standard deviations as well as medians and 
interquartile ranges (IQR).  Missingness will be recorded for each variable.  To further assess the 
distribution of variables, graphical summaries will be displayed using graphs such as box-plots, dot-plots, 


Version 2.0 
Page 6 
 
violin-plots, and/or histograms.  No statistical testing will be done to compare characteristics across 
groups. At a minimum, the following baseline variables will be described: 
• 
Age (years) 
• 
Sex 
• 
Race (American Indian or Alaskan Native; Asian; Black or African American, Haitian; Native 
Hawaiian or Pacific Islander; White Origins in Europe, Middle East, North Africa; Other; 
Declined to disclose) 
• 
Medical history (Yes/No) 
o Heart failure 
o Myocardial infarction 
o Chronic kidney disease (CKD) 
o Chronic obstructive pulmonary disease (COPD) 
o Hypertension 
o Atrial fibrillation or flutter 
• 
Description of Heart failure 
o Ejection Fraction (%) 
o Ischemic cardiomyopathy 
o Implantable cardiac defibrillator therapy 
o Cardiac resynchronization therapy 
• 
Enrollment vitals 
o Weight (kg) 
o BMI (kg/m2) 
o Systolic blood pressure (SBP) 
o Diastolic blood pressure (DBP) 
o Heart rate 
o Respiratory rate 
o Temperature (ºC) 
• 
Enrollment labs 
o Sodium 
o Potassium 
o Chloride 
o Serum Bicarbonate 
o Glucose 
o BUN 
o Calcium 
o Creatinine 
o eGFR 
o BNP 
o NT-proBNP 
o Troponin 
o Hemoglobin A1c 
• 
Home Medications 
o Home diabetes medications 


Version 2.0 
Page 7 
 
§ 
Metformin n (%) 
§ 
Sulfonylurea n (%) 
§ 
DPP-4 inhibitor n (%) 
§ 
SGLT2-inhibitor n (%) 
§ 
GLP-1 receptor agonist n (%) 
§ 
Insulin n (%) 
• 
Total daily insulin dose (units) 
o Home heart failure medications n (%) 
§ 
ACEI/ARB/ARNI 
§ 
Beta blocker 
§ 
Aldosterone Antagonist (mra’s) 
§ 
Oral loop diuretic total daily dose in furosemide equivalents (mg) 
• 
In-hospital Medications at Baseline n (%) 
o IV furosemide as total daily dose (mg) 
o Beta Blocker 
o ACEI 
o ARB 
o ARNI 
o Aldosterone Antagonist 
o Long acting (Basal) insulin 
o Rapid acting (meal time) insulin  
o Total daily insulin dose (units) as sum of all insulin products in a day 
Description of Endpoints 
Inpatient and 30-day endpoints of interest will be summarized overall and by treatment assignment.  
Categorical variables will be described using frequencies and proportions; continuous variables will be 
described using means and standard deviations as well as medians and interquartile ranges (IQR).  
Missingness will be recorded for each variable.  For those endpoints that are a composite of multiple 
endpoints, such as incidence of worsening heart failure (requiring IV inotropic therapy, new admission to 
an ICU, new non-invasive positive pressure ventilation with bi-level positive airway pressure, or increase 
in the IV diuretic protocol intensity by 2 rows after Day 1 as adjudicated by the CEC) and hospital 
readmission within 30 days of index hospitalization discharge (for heart failure-related reasons or diabetic 
reasons), frequencies will be summarized overall and for each level. 
No statistical testing will be done to compare characteristics across groups.  
Main Analysis 
All model results (unadjusted and adjusted) will be summarized with point estimates, 95% confidence 
intervals (CIs), and p-values displayed in tabular form or graphically, along with appropriate model fit 
statistics.  Missingness in adjusting covariates will be addressed using multiple imputation based on 
predictive mean matching.   
Primary Analysis:  Our main analysis will be a covariate-adjusted proportional odds (PO) regression 
model with our outcome being cumulative change in weight per 40mg of IV furosemide equivalents from 


Version 2.0 
Page 8 
 
enrollment to the minimum of Day 5 or discharge and the main predictor being treatment assignment.  
Adjusting covariates will be pre-specified and include baseline weight. Baseline weight will be fit with 
restricted cubic splines with 3 knots to relax the linearity assumptions.   
Secondary Analyses:  
Appropriate model diagnostics will be run to assess model fit.  If model diagnostics suggest the planned 
approach violates necessary assumptions, alternative methods will be pursued.  
a) Binary logistic regression will be used to assess the association of the incidence of worsening 
heart failure as adjudicated by the CEC with treatment assignment.   
b) A time to event analysis is proposed to assess the association of 30-day hospital readmission for 
ADHF or diabetes-related reasons.  Cumulative incidence of hospital readmission for heart failure 
or diabetes-related reasons will be graphed by treatment arm death as a competing risk.  
Multivariable Cox proportional hazards models stratified by enrollment site will be fit to assess 
the association of time to hospital readmission for reasons of interest with treatment assignment. 
Exploratory Analyses:   
Appropriate model diagnostics will be run to assess model fit.  If model diagnostics suggest the planned 
approach violates necessary assumptions, alternative methods will be pursued.  
a) The association of NT-proBNP at discharge with treatment arm will be modeled using covariate-
adjusted PO regression, adjusting for NT-proBNP at baseline (Day 1). 
b) The association of Day 2 24-hour total urine output per the following methods in which diuretic 
dose is centered at 40mg and values less than 40mg are winsorized to 40mg: 
a. 40 mg of IV furosemide equivalents will be analyzed using the Wilcoxon Rank Sum test 
b. Doubling of the loop diuretic dose to account for the logarithmic dose-response curve 
will be analyzed using the Wilcoxon Rank Sum test.  
c) Urine sodium-based diuretic efficiency defined as the Day 2 24-hour total urine sodium excretion 
(mmol) per 40mg of IV furosemide equivalents (total loop diuretic dose over Day 2) will be 
analyzed using the Wilcoxon Rank Sum test. 
a. Repeated as per doubling of the cumulative Day 2 loop diuretic dose (log2 cumulative 
loop diuretic dose centered at 40mg) will be analyzed using the Wilcoxon Rank Sum test. 
d) Spot urine sodium-based diuretic efficiency defined as the spot urine sodium concentration 
(mmol/L) on Day 2 per 40mg of IV furosemide equivalents (preceding loop diuretic dose) will be 
analyzed using the Wilcoxon Rank Sum test. 
e) The association of Day 2 fractional excretion of sodium (FENa)-based diuretic efficiency 
determined from spot urine collected 2 hours after bolus loop dose with treatment arm will be 
analyzed using the Wilcoxon Rank Sum test.  
f) The association of Day 2 urinary Na/K ratio with treatment arm will be analyzed using covariate-
adjusted PO regression, adjusting for baseline (Day 1) urinary Na/K ratio.  
g) The association of calculated Day 2 6-hour sodium output with treatment assignment will be 
analyzed using the Wilcoxon Rank Sum test 
h) The association of length of hospital stay with treatment assignment will be analyzed using the 
Wilcoxon Rank Sum test 


Version 2.0 
Page 9 
 
i) The association of presence of symptoms of congestion and dyspnea at discharge measured via 
blinded physician exam and patient reported congestion scores with treatment assignment will be 
analyzed using the Pearson chi-square test.  A proportional odds model will be used to assess the 
association of discharge congestion score with treatment assignment, adjusting for baseline 
congestion. 
j) Cumulative incidence of all cause hospital readmission within 30 days of index hospitalization 
discharge will be graphed by treatment arm treating death as a competing risk.  The association of 
all cause hospital readmission within 30 days of index hospitalization discharge with treatment 
assignment will be analyzed using the Pearson chi-square test.   
k) The association of number of days at home without hospitalization or emergency room visit during 
the 30-day follow-up period with treatment assignment will be analyzed using the Wilcoxon Rank 
Sum test.  For purposes of analysis, subjects who died within 30 days of the index hospital 
discharge will be assigned a value of 0 days at home 
l) The association of mean serum glucose during therapy with treatment assignment will be analyzed 
using the Wilcoxon Rank Sum test 
m) Total daily insulin doses (units) utilized per day during therapy will be compared between 
treatment arms in all comers and in those with diabetes at baseline using a Wilcoxon Rank Sum 
Test.  Total daily insulin doses utilized per day during therapy will be compared to a ‘prior to 
enrollment’ utilization using the Wilcoxon Signed Rank Test. 
n) The change in basic metabolic panel laboratory values and hemoglobin from baseline to the end of 
study will be compared across treatment groups using the Wilcoxon Rank Sum test. 
o) Serum potassium trends over time by treatment assignment will be graphed. Descriptive statistics 
of the daily raw potassium values and kalemic status during hospitalization by treatment group 
will be reported and compared across treatment assignments by Wilcoxon Rank Sum tests and 
Pearson’s chi-square tests, respectively. 
Safety Analyses: 
All multivariable models will adjust for the same key covariates as specified for the primary outcome, as 
sample size permits.  Appropriate model diagnostics will be run to assess model fit.  If model diagnostics 
suggest the planned approach violates necessary assumptions, alternative methods will be pursued.  
a) The association of estimated Glomerular Filtration Rate (eGFR) at discharge, calculated using the 
MDRD equation, with treatment assignment will be modeled using covariate-adjusted PO 
regression, adjusting for baseline eGFR.  The analysis will be repeated calculating eGFR using 
the CKD-EPI equation as well. 
b) The association of the incidence of ketoacidosis as adjudicated by the CEC with treatment 
assignment will be analyzed using the Pearson chi-square test. 
c) Serum glucose trends over time by treatment assignment will be graphed.  Descriptive statistics 
of the daily raw glucose values and the glycemic status during hospitalization by treatment group 
will be reported and compared across treatment assignment by Wilcoxon Rank Sum tests and 
Pearson’s chi-square tests, respectively.   
d) The association of incidence of hypovolemic hypotension, defined previously, with treatment 
assignment will be analyzed using the Pearson chi-square test. 


Version 2.0 
Page 10 
 
e) The association of inpatient mortality with treatment assignment will be analyzed using the 
Pearson chi-square test and univariate logistic regression.   
Sensitivity Analyses: 
Our sensitivity analysis will be a covariate-adjusted proportional odds (PO) regression model with our 
outcome being log-transformed weight at the minimum of Day 5 or discharge and the main predictor 
being treatment assignment.  Adjusting covariates will be as defined in the primary analysis. Appropriate 
model diagnostics will be run to assess model fit.  If model diagnostics suggest the planned approach 
violates necessary assumptions, alternative methods will be pursued.  
Heterogenicity of Treatment Effect: 
Heterogenicity of Treatment Effect (HTE) will be assessed refitting the primary model with the covariate 
of interest interacted with treatment assignment.  The HTE analysis will include the following variables: 
• 
Sex (male or female) 
• 
Baseline edema score (No-Mild/Moderate/Severe) 
• 
Baseline NTproBNP  
o Continuous 
o Dichotomize by median NTproBNP [above/below] 
• 
Baseline BMI-adjusted BNP:  defined as a 4% increase in NT-proBNP for every 1 unit increase 
in baseline BMI above a BMI of 20kg/m2 
o Continuous 
o Dichotomize by median BMI-adjusted NTproBNP [above/below] 
• 
Baseline BMI 
o Continuous 
o Dichotomize by median BMI [above/below] 
• 
Baseline eGFR (calculated using MDRD) 
o Continuous 
o Dichotomize by median eGFR [above/below] 
• 
Baseline weight 
o Continuous 
o Dichotomize by median baseline weight [above/below] 
• 
Diabetes comorbidity at baseline (Yes or No) 
• 
Left ventricular ejection fraction  
o <= 40 vs > 40 
o < 50 vs >= 50 
• 
Day 1 Fractional excretion of sodium (FENa)-based diuretic efficiency (per 40mg IV furosemide) 
o Continuous 
o Dichotomize by median FENa [above/below] 
 
 


Version 2.0 
Page 11 
 
References 
1. Adams KF, Jr., Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients 
hospitalized for heart failure in the United States:  rationale, design, and preliminary observations 
from the first 100,000 cases in the Acute Deompensated Heart Failure National Registry 
(ADHERE).  American heart journal.  2005; 149(2):209-216. 
2. Chioncel O, Mebazaa A, Maggioni AP, et al.  Acute heart failure congestion and perfusion status-
impact of the clinical classification on in-hospital and long-term outcomes; insights from the 
ESC-EORP-HFA Heart Failure Long-Term Registry.  European journal of heart failure.  2019.   
3. Damman K, Testani JM.  The kidney in heart failure: an update.  European heart journal.  
2015;36(23):1437-1444. 
4. Heerspink JH, Perkins BA, Fitchett DH, Husain M, Cherney DZ.  Sodium Glucose Cotransporter 
2 inhibitors in the Treatment of Diabetes Mellitus:  Cardiovascular and Kidney Effects, Potential 
Mechanisms, and Clinical Applications.  Circulation.  2016;134(10:752-772.