Clinical trial NCT04249778
Conditions: Heart Failure Diabetes
Keywords: hospitalization mortality time of initiation of therapy quality of life cost-effectiveness dapagliflozin clinical trial diabetes
Sponsor: Emory University
Start date: 2020-07-29; Completion date: 2022-03-03
Enrollment: 105 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety and efficacy of dapagliflozin treatment in preventing hospital re-admissions, emergency room (ER) visits, urgent clinic visits, and death in patients with and without type 2 diabetes (T2D) after hospital admission for heart failure.

Detailed description:
The prevalence of both heart failure and type 2 diabetes (T2D) or prediabetes are reaching epidemic proportions globally and in the United States. More than 40% of patients with established heart failure (HF) have diabetes.

Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor (SGLT2-i) indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D mellitus. Treatment with SGLT2-i has been shown to reduce both heart failure hospitalizations and mortality in patients with established heart disease. However, the time of initiation of SGLT2-i therapy has not been evaluated in patients with HF. This study will be the first trial to evaluate the safety and efficacy of dapagliflozin treatment in preventing hospital re-admissions, ER visits, urgent clinic visits, and death in patients with and without T2D after hospital admission for heart failure. In addition, the impact of treatment on HF symptoms quality of life, resource utilization, and cost-effectiveness of dapagliflozin versus placebo will be evaluated. The results of this study have great potential to impact and facilitate care and to change current clinical guidelines in the management of patients with heart failure.

Patients with and without diabetes who have acute decompensated heart failure (ADHF) will be randomized to take either dapagliflozin or placebo daily for 26 weeks, beginning at the time of discharge from from the hospital.

Arms: arm 1: Patients admitted with exacerbation of chronic heart failure by clinical and radiologic features randomized to receive 10 mg of dapagliflozin, once daily for 26 weeks. arm 2: Patients admitted with exacerbation of chronic heart failure by clinical and radiologic features randomized to receive a placebo to match 10 mg of dapagliflozin, once daily for 26 weeks.
Interventions: intervention 1: Dapagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Participants will receive 10 mg/day of dapagliflozin, beginning at hospital discharge, for 26 weeks. intervention 2: Participants will receive a placebo to match 10 mg/day of dapagliflozin, beginning at hospital discharge, for 26 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
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Effect of Dapagliflozin at Discharge on Hospital Re-Admissions in Patients with Acutely 
Decompensated Heart Failure: A Randomized Controlled Study 
 
NCT Number: NCT04249778 
 
 
Protocol date: July 6, 2021 
 
 


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Effect of Dapagliflozin at Discharge on Hospital Re-Admissions in Patients with Acutely 
Decompensated Heart Failure: A Randomized Controlled Study  
Principal Investigator: 
 
 
1Guillermo E. Umpierrez, MD, CDE, FACP, FACE 
 
Sites/Investigators:  
 
Grady M. Hospital:  
Guillermo Umpierrez, MD, CDE (Principal investigator), Modele O. Ogunniyi, MD, MPH, Nanette K. 
Wenger, MD, Georgia Davis, MD, Francisco Pasquel, MD, MPH, Maya Fayfman, MD, Priyathama 
Vellanki, MD, Saumeth Cardona, MD, MPH.  
 
Emory University: Alexandra Migdal, MD (Co-PI), Alanna Morris, MD, Arshed A. Quyyumi, MD, 
Rodolfo Galindo, MD 
 
Emory Saint Joseph’s Hospital: David Markham, MD, Ryan Martin, MD 
 
 
  
Non-Emory/Grady Centers for consideration: 
 
Tulane University: Dragana Lovre, MD (Site PI) 
 
Temple University: Daniel Rubin, MD. (Site PI) 
 
 
 
 
Statistical Support:  
Limin Peng, Ph.D. 
Associate Professor 
Rollins School of Public Health 
Emory University 
 
 
Short Title: Dapagliflozin Heart Failure Readmission 
Correspondence: 
  
 
Guillermo E. Umpierrez, MD, CDE, FACE, FACP 
 
 
Professor of Medicine 
 
 
Director Clinical Research, Center of Diabetes & Metabolism 
Emory University 
Director, Diabetes & Endocrinology 
Grady Health System 
Atlanta, Georgia 


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RESEARCH OBJECTIVES AND SPECIFIC AIMS 
More than 40% of patients with established heart failure (HF) have diabetes 1. Several studies have 
reported that HF patients with diabetes have higher rates of recurrent HF hospitalizations, longer 
durations of hospital stay 2,3, and significantly higher mortality compared to HF patients without 
diabetes 4,5. In a recent 42-month longitudinal study of 902 patients with type 2 diabetes (T2D) and HF, 
30% of patients with T2D and HF died and 60% experienced a composite endpoint of death and 
HF readmission 5. Despite these statistics, remarkably little is known about optimal strategies for the 
management of patients with T2D and HF after hospital discharge.  
There is strong epidemiologic evidence linking poor glycemic control in patients with T2D with the risk 
of hospitalization for HF and higher mortality, regardless of ejection fraction 1,5. A linear relationship 
between glycemic control and HF events has been reported across several observational studies in T2D, 
such that, on average, the risk of HF was increased by 15% for each percentage point higher 
glycosylated hemoglobin (HbA1c) 6,7.  Several clinical trials using traditional glucose lowering drugs 
have failed to demonstrate either reduction of new-onset HF or hospitalization rates in patients with 
established heart disease 8-11. More recently, observational and randomized clinical trials in patients with 
T2D have shown that treatment with sodium glucose co-transporter 2 inhibitors (SGLT2-i) results in a 
substantial reduction in hospitalization for HF and reduced mortality in patients with established heart 
disease 12-15. The osmotic diuretic effect of SGLT2-i may provide a unique benefit to patients with 
coexisting T2D and HF, by lowering blood glucose levels and at the same time promoting reduction in 
plasma volume, weight loss, and lower blood pressure 16. Additional actions on cardiac metabolism and 
neurogenic signaling may also contribute to the observed benefits16-19. The beneficial effects with 
SGLT2-i were present within a few months of commencing therapy and continued with ongoing 
therapy, suggesting that this therapy may be effective in preventing HF admissions in patients with T2D.  
Recent cardiovascular outcome trials using SGLT2-i reported a significant reduction in hospitalization 
for HF 15,20-22. In the DECLARE trial, dapagliflozin resulted in lower rate of hospitalization for heart 
failure compared to placebo (HR, 0.73; 95% CI, 0.61 to 0.88)23. More recently, among patients with 
heart failure and a reduced ejection fraction (HFrEF), the risk of worsening heart failure or death from 
cardiovascular causes was lower among those who received dapagliflozin than among those who 
received placebo, regardless of the presence or absence of diabetes 22. Similarly, in the EMPA-REG 
OUTCOME study with empagliflozin, the HR was 0.65 (95% CI 0.50-0.85) and in the CANVAS 
program with canagliflozin, the HR was 0.67 (95%CI 0.52-0.87). In the Canvas Program, the rate of 
hospitalization was dramatically lower in patients with history of HF (28.1% vs 14.1%) compared to 
those without a history of HF (5.7% vs 4.3%) 11. The consistency across trials, as well as the results of 
observation studies 24 indicate that SGLT2-i will be considered in the management of T2D patients with 
a history of HF 25. It will be noted, however, that the time of initiation of SGLT2-i therapy has yet to be 
formally evaluated in patients with T2D and HF.  
We propose to perform a randomized clinical trial to evaluate the effects of dapagliflozin on hospital 
readmission rates in patients with and without T2D after an admission for acutely decompensated heart 
failure (ADHF). We hypothesize that treatment with dapagliflozin for 26 weeks will reduce the rate of 
readmissions for HF (primary endpoint), and will improve glycemic control, HF symptoms, NT proBNP 
levels, quality of life, resource utilization and hospital charges/costs as compared with placebo. 
Specific Aims: 
Aim 1: To determine whether the composite rate of hospital readmissions, emergency department, 
urgent clinic visits for HF and death are lower in patients with ADHF treated with dapagliflozin 
compared to those treated with placebo.  Patients with and without diabetes ADHF will be 
randomized to receive either dapagliflozin (10 mg once daily) or placebo at hospital discharge for 26 
weeks.     


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Hypothesis: Treatment with dapagliflozin will significantly reduce the composite rate of hospital 
admissions, emergency department visits and urgent clinic visits for HF compared to placebo in patients 
discharged after an ADHF admission. 
 
Aim 2: To determine whether treatment with dapagliflozin compared to placebo will result in 
lower HF disease-specific biomarker (NT proBNP), improvement in glycemic control (HbA1c) in 
T2D patients, and improvement in symptoms and quality of life after hospital discharge in 
patients with ADHF. We will measure changes in HbA1c, NT proBNP levels and HF-specific quality 
of life assessment using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and improvement in 
symptoms using the Chronic Heart Failure Questionnaire (CHQ-SAS). 
Hypothesis: Treatment with dapagliflozin will result in a greater improvement in HbA1c levels (in T2D 
patients), HF disease-specific marker (NT proBNP), quality of life (KCCQ scores), improvement of 
symptoms (CHQ-SAS scores) compared to placebo after hospital discharge at 12 and 26 weeks. 
Aim 3. Evaluate the within-trial cost-effectiveness of dapagliflozin compared to placebo in overall 
healthcare costs in patients with ADHF.  We will prospectively collect information on overall health 
care costs including emergency room visits, urgent clinic visits for HF, and hospitalizations between 
groups during the 6 months of intervention.  
Hypothesis:  Treatment with dapagliflozin will be associated lower resource utilization and health care 
costs compared to placebo after hospital discharge. 
Innovation.  The proposed study will be the first prospective RCT to determine the safety and efficacy 
of dapagliflozin treatment in preventing readmissions/ER visits/urgent clinic visits and death in patients 
with and without T2D after admission for ADHF. Treatment with SGLT2-i has been shown to reduce 
both HF hospitalization and mortality in patients with established heart disease and a history of HF 12-
14,23. More recently, among patients with HFrEF, dapagliflozin was shown to reduce the risk of 
worsening heart failure or death from cardiovascular causes compared to placebo, regardless of the 
presence or absence of diabetes 22. However, the time of initiation of SGLT2-i therapy has yet to be 
formally evaluated in patients with ADHF and is the purpose of this study.  In addition, we will evaluate 
the impact of treatment on HF symptoms quality of life, resource utilization and cost-effectiveness of 
dapagliflozin versus placebo. The results of this study have great potential to influence and facilitate 
care and to change current clinical guidelines in the management of patients with ADHF. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Rationale on Dapagliflozin treatment. Dapagliflozin (Farxiga®) is a highly selective SGLT2-i, given 
in once-daily doses26,27. It is rapidly absorbed with a time to maximum plasma concentration of two 
hours and a half-life of 17 hours, with an absolute oral bioavailability of dapagliflozin following the 
administration of a 10 mg dose of 78%. Dapagliflozin is approximately 91% protein bound. Protein 
binding is not altered in patients with renal or hepatic impairment. The metabolism of dapagliflozin is 
primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. 
Dapagliflozin and related metabolites are mainly eliminated via the renal pathway. The mean plasma 
terminal half-life for dapagliflozin is approximately 12.9 hours following an oral dose of Farxiga 10 mg.   
Clinical trial in ambulatory patients with T2D reported a significant reduction in HbA1c of ~ 0.8%-1.5% 
from baseline in patients with T2D 28-30.  Dapagliflozin as monotherapy and in combination with other 
antidiabetic drugs is well tolerated and associated with very low rates of hypoglycemia31-33.  In addition, 
due to its mechanism of action of increasing urinary glucose excretion, SGLT2-i can reduce systolic 
blood pressure and body weight compared to placebo in patients with T2D34,35. 
In a recent pooled post-hoc analysis of completed clinical trials, treatment with dapagliflozin 10 mg 
produced clinically meaningful reductions in HbA1c and weight vs placebo in patients with concomitant 
T2DM and HF. In the recent DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart 
Failure) trial, 4474 patients with and without diabetes with New York Heart Association class II, III, or 
IV heart failure and an ejection fraction of 40% or less assigned to receive either dapagliflozin (at a dose 
of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a 
composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy 
for heart failure) or cardiovascular death. Over a median of 18.2 months, the risk of worsening heart 
failure or death from cardiovascular causes was significantly lower among those who received 
dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.  
In addition, the trend toward a decrease in systolic blood pressure seen with dapagliflozin occurred 
without an increase in heart rate36.  Similar results were also reported in the DECLARE Trial23 in 17,160 
patients with T2D who had or were at risk for atherosclerotic cardiovascular disease treated either with 
dapagliflozin or placebo. Dapagliflozin resulted in a lower rate of cardiovascular death or hospitalization 
for HF (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate 
of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88). The results of DECLARE 
and DAPA-HF trials, together with previous SGLT2-i trials indicate that in patients with and without 
T2D with or at risk for atherosclerotic cardiovascular disease, treatment with SGLT2-I results in lower 
rate of cardiovascular death or hospitalization for HF.   
 
Study Endpoints: 
Primary outcome is to compare the efficacy of dapagliflozin compared with placebo, on the composite 
rate of hospital admissions, emergency department visits, urgent clinic visits for HF and death after 
admission with ADHF.  
Secondary outcomes are to determine differences between dapagliflozin compared to placebo in: 
1. Change in the KCCQ score between baseline score and the scores at 12, and 26 weeks  
2. Change in the CHQ-SAS score between baseline score and the scores at  12, and 26 weeks 
3. Change in NT proBNP levels between baseline and after 12 and 26 weeks 
4. Change in 6-minute walk distance (6MWD) between baseline and after  12 and 26 weeks 
5. Change in HbA1c between baseline and after 12 and 26 weeks (in T2D patients).   
6. Change in weight between baseline and after 12 and 26 weeks   
7. Change in systolic blood pressure between baseline and after 12 and 26 weeks  
8. Change from baseline in left atrial volume index and other measures of left ventricular systolic 
and diastolic function in patients who may undergo repeated echocardiogram during follow up.  


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9.Change from baseline in serum magnesium at baseline and after 12 and 26 weeks 
 
Safety Variables 
1. All-cause mortality 
2. Cardiovascular death  
3. Non-fatal myocardial infarction (MI)  
4. Stroke  
5. Acute kidney injury (defined as doubling of serum creatinine based on the RIFLE criteria 37. 
6. Adverse events (AEs) and serious adverse events (SAEs). Of special interest are events including 
diabetic ketoacidosis (DKA), volume depletion (defined as hypotension, syncope, orthostatic 
hypotension or dehydration), hypoglycemic events and urinary tract infections. 
Study Methods: 
 
The trial is a 26-week, randomized, double-blind, placebo-controlled trial investigating the efficacy of 
dapagliflozin versus placebo in reducing hospital readmission, ER visits, urgent clinic visits for HF and 
death after discharge, in patients with and without T2D, following an admission with ADHF.   
 
Patients: 
Patients admitted with ADHF will be enrolled after signing an informed consent. Patients will be invited 
to participate during their hospital admission. Those fulfilling the inclusion/exclusion criteria will 
undergo baseline testing at randomization prior to discharge.  
 
We will recruit 392 patients, hospitalized with ADHF.  Patients with T2D can be treated with diet or oral 
antidiabetic drugs (OAD) except TZDs, or SGLT2-i, or on low-dose insulin therapy (total daily dose 
[TDD] ≤0.4 unit/kg/day) prior to admission. 
  
 
 
 
Inclusion Criteria 
1.   Males or females between the ages of 18 and 90 years, with ADHF, and New York Heart 
Association (NYHA) class II, III, or IV symptoms discharged after hospital admission with a clinical 
diagnosis ADHF.   
2. Elevated NT-pro-BNP ≥300 pg/ml or BNP (≥100 pg/ml) on admission.  
3. Interpretable echocardiogram during hospital admission (or within 12 months prior to index 
hospitalization) 
4.  Blood glucose level <400 mg/dL without evidence of diabetic ketoacidosis (serum bicarbonate <18 
mEq/L or positive serum or urinary ketones)- Applies to patients with T2D. 
 
Exclusion Criteria 
1. Age < 18 or > 90 years.  
2. Subjects with a history of type 1 diabetes. 
3. Treatment with TZDs or SGLT2-i during the past 3 months of admission.   
4. Recurrent episodes of severe hypoglycemia or hypoglycemic unawareness. 
5. History of recurrent HF admissions considered to be due to non-compliance (evaluated by the 
research staff for participation)  
6. Patients with clinically significant hepatic disease (cirrhosis, jaundice, end-stage liver disease, portal 
hypertension) and elevated ALT and AST > 3 times upper limit of normal. 
7.   Patients with impaired renal function (GFR < 25 ml/min). 
9. Mental condition rendering the subject unable to understand the nature, scope, and possible 
consequences of the study. 
10. Patients on ventricular assist devices (VADs) 


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11. History of heart transplant or listed for heart transplant 
12. History of cardiac surgery* (within 90 days prior to enrollment) or planned cardiac interventions* 
within the following 6 months 
       *Includes: PCI, ablation, CRT-ICD 
13. HF due to restrictive/infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, severe 
stenotic valvular diseases, hypertrophic cardiomyopathy, or congenital heart disease. 
14. History of SGLT2-i allergy 
15.  Systolic blood pressure < 100 mmHg 
16. Uncontrolled hypertension, defined as a systolic blood pressure > 200 mmHg at randomization 
17. Female subjects who are pregnant or breast-feeding at time of enrollment into the study. 
18. Females of childbearing potential who are not using adequate contraceptive methods (as required by 
local law or practice). 
19. In hospice or expected life expectancy less than 6 months 
20. Patients with diabetic foot infection, osteomyelitis, and history of amputation of lower extremities 
within 6 months of admission 
21. Patients anticipated to undergo major surgical procedures during the following 6 months 
22. Patients with active hematuria, urinary tract infection (UTI), or history of frequent UTIs or genital 
mycotic infections 
23. Uncontrolled atrial fibrillation or atrial flutter with a resting heart rate >110bpm documented by 
ECG at randomization.  
24. Any condition that in the opinion of the investigator would contraindicate the assessment of 6MWD 
25. Chronic pulmonary disease i.e. with known FEV1 <50% requiring home oxygen, or oral steroid 
therapy or current hospitalization for severe COPD thought to be a primary contributor to dyspnea, 
or significant chronic pulmonary disease in the Investigator’s opinion, or primary pulmonary arterial 
hypertension 
26. Patients with active history of bladder cancer.  
27. Patients with previous history of diabetic ketoacidosis, per ADA criteria 38 
 
Investigational Drugs: 
• Group 1.  Dapagliflozin 10 mg once daily (n=196) 
• Group 2.  Placebo once daily (n=196) 
 
Treatment Protocol: 
Patients admitted with exacerbation of chronic heart failure by clinical and radiologic features will be 
considered as candidates for participation.  Patients will be approached and invited to participate during 
the hospital admission. Patients that fulfill inclusion/exclusion criteria will undergo baseline testing and 
will be randomize prior to discharge will be randomized 1:1 to receive either dapagliflozin10 mg/day or 
matching placebo at the time of discharge.  
Inpatient Heart failure treatment.  Patients will receive standard treatment for ADHF by their primary 
care team and/or cardiology service including diet and pharmacological treatment with diuretics, ACE-
I/ARBs, ARNI, beta receptor antagonists, aldosterone antagonists, hydralazine/nitrate combination 
following the ACCF/AHA Guidelines for the Management of Heart Failure 39,40.   
Inpatient T2D Treatment.  Patients with T2D will be treated with a standard insulin regimen during 
the hospital stay 41,42. Prior to hospital discharge, patients will be randomized 1:1 to either dapagliflozin 
or placebo. All patients will receive diabetes education. The day of discharge, dapagliflozin /matching 
placebo will be added to the subject’s pre-admission treatment regimen.  
 


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Hospital Heart Failure Education.  Hospital discharge HF education will be conducted by the 
Advanced Practice Providers. They will provide comprehensive education on HF, diet, symptoms, and 
medications.   
Hospital T2D Education.  Prior to discharge, all patients with T2D will receive information on: 
1. Diabetes education, if not received within 1 year of admission.   
2. Blood glucose target between 80 and 180 mg/d before meals. 
3. Use of glucose meters for home glucose self-monitoring.   
4. Measurement of urinary ketones. 
5. Keeping BG records. Participants will receive a logbook to record glucose tests results. 
6. Hypoglycemia recognition and management.  
7. Insulin administration (if needed). 
8. Education about signs and symptoms of diabetic ketoacidosis, use of glucose monitoring and 
urinary ketone testing. 
 
Treatment recommendations at discharge in patients with diabetes  
 
Study Medications:  Study subjects will be randomized 1:1 to receive either dapagliflozin 10 mg or 
matching placebo at the time of discharge.  
 
 
Admission HbA1c between 6.5% and 8%:  
• Start study medication (dapagliflozin or 
placebo) once daily 
• If no contraindications, re-start OADs 
(metformin, DPP4-i) at the same dose 
prior to admission  
• Hold sulfonylureas or insulin 
secretagogues if HbA1c < 7.0%. If 
HbA1c >7%, reduce dose of 
sulfonylurea and insulin secretagogues 
by 50% or stopped according to 
physician discretion. 
• In patients receiving insulin prior to 
admission, reduce TDD of hospital dose 
by 50% 42,43.  
 
Admission HbA1c between 8% and 10%:  
 
• Patients receiving OAD treatment prior to admission: 
• Start study medication (dapagliflozin or placebo) once daily 
• If no contraindications, re-start OADs prior to admission (metformin, DPP-4 inhibitors) 
• Hold sulfonylureas or insulin secretagogues if HbA1c < 8.0%. If HbA1c >8%, reduce dose of 
sulfonylurea and insulin secretagogues by 50% or stopped according to physician discretion. 
 
• Patients receiving OAD and insulin combination prior to admission: 
• Start study medication (dapagliflozin or placebo) once daily 
• If no contraindications, re-start OADs prior to admission, except for sulfonylureas, insulin 
secretagogues or thiazolidinedione (as described above).    
• Discharge patient on basal insulin at 50% of daily hospital dose.  
 
• Patients receiving basal bolus insulin treatment prior to admission: 


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• Start study medication (dapagliflozin or placebo) once daily 
• Discharge on basal insulin at 50% of hospital dose or 75% of pre-admission daily insulin dose. 
 
Admission HbA1c > 10%:   
 
• Patients receiving OAD treatment prior to admission: 
• Start study medication (dapagliflozin or placebo) once daily 
• If no contraindications, re-start OADs prior to admission (metformin, DPP-4 inhibitors) 
• If HbA1c >10%, reduce dose of sulfonylurea and insulin secretagogues by 50%. 
• Insulin naïve patients prior to admission, reduce TDD of hospital insulin dose by 25%.  
• Patients receiving OAD and insulin combination prior to admission: 
• Start study medication (dapagliflozin or placebo) once daily 
• If no contraindications, re-start OADs prior to admission, except for sulfonylureas, insulin 
secretagogues or thiazolidinedione.    
• In patients receiving insulin prior to admission, reduce TDD of hospital dose by 25%.  
 
• Patients receiving basal bolus insulin treatment prior to admission: 
• Start study medication (dapagliflozin or placebo) once daily 
• Discharge on basal insulin at 50% of hospital dose or 75% of pre-admission daily insulin dose. 
 
Algorithm for basal insulin dose adjustment after hospital discharge: 
 
Basal Insulin  
If mean FBG > 180 mg/dL for the last 
2 consecutive days and no episodes of 
hypoglycemia (BG <70 mg/dL) 
Increase TDD by 4 IU 
If mean FBG > 140 mg/dL for the last 
2 consecutive days and no episodes of 
hypoglycemia (BG <70 mg/dL) 
Increase TDD by 2 IU 
If mean FBG between 100 to 140 mg/dL for 
the last 2 days and no hypoglycemia  
No Change 
If any FBG between 70 – 99 mg/dl 
Decrease by 4 IU or 10% of TDD 
If any FBG or RBG < 70 mg/dl 
Decrease by 8 IU or 20% of TDD 
If any FBG or RBG < 40 mg/dl 
Decrease TDD by 30% 
 
Schedule of Clinic and Phone Visits: 
The study will include 10 study contacts: 1 screening visit and 1 randomization visit while subjects are 
still in the hospital. After discharge, patients will have a total of 5 in-person clinic visits and 3 phone 
contacts over a 26-week period.  
At the Screening Visit, patients will be evaluated for participation using inclusion and exclusion criteria.   
At Visit 1 - Randomization, subjects will be randomized to receive the study drug that will commence 
after discharge and will be added to the ongoing therapy.  The study treatment period will end at Visit 9 
(week 26). The following table provides information as to the study procedures to be completed at each 
visit. 
 
 
 
 
 
 


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Schedule of Assessments: 
Visit 
Screening 
Randomization 
(Discharge)e 
2 
3 
4 
5 
6 
7 
8 
9 
Week 
0 
0 
2 
6 
8 
12 
16 
20 
24 
26 
Clinic / CTSA Visit 
 
X 
X 
X 
 
X 
 
X 
 
X 
Phone Visit 
 
 
 
 
X 
 
X 
 
X 
 
Sign Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Weight, BMI 
 X 
X 
 
X 
 
X 
 
X 
 
X 
Physical Exam 
X 
X 
 
X 
 
X 
 
X 
 
X 
Vital Signs 
X 
X 
 
X 
 
X 
 
X 
 
X 
Blood & Urine Sampling a 
X 
X 
 
X^ 
 
X 
 
X^ 
 
X 
Urine Pregnancy Test b  
X 
 
 
X 
 
X 
 
X 
 
X 
6-minute Walk Distance 
 
 
X 
 
 
X 
 
 
 
X 
KCCQ Questionnaire 
 
X 
 
 
 
X 
 
 
 
X 
CHQ-SAS Questionnaire 
 
X 
 
 
 
X 
 
 
 
X 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
 
Xd 
 
 
 
 
 
 
 
 
Echocardiogram c 
 
X 
 
 
 
X 
 
 
 
 
Review Home BG Testing Results in T2D 
 
 
X 
X 
X 
X 
 
X 
X 
X 
Home Urine Ketone Testing, if Indicated 
 
 
X 
X 
X 
X 
 
X 
X 
X 
Study Drug Dispensing 
 
X 
 
 
 
X 
 
 
 
 
Study Drug Returned 
 
 
 
 
 
X 
 
 
 
X 
T2D Education 
X 
 
 
 
 
 
 
 
 
 
Heart Failure Education 
X 
 
 
 
 
 
 
 
 
 
aAdmission tests: For screening purposes we will use available laboratory results during current admission 
(chemistry including eGFR, HbA1c, urine studies), additional testing will be necessary to meet all the baseline lab 
requirements such as serum magnesium, NT-proBNP, ketones (patients with T2D at investigator’s discretion), 
albumin/creatinine ratio,  random urine sodium , at baseline (prior to discharge). Follow up testing at 12 and 26 
weeks; other ^blood tests at 6 and 20 weeks and urine culture will be performed at investigator’s discretion. b 
Urine pregnancy test for women with childbearing potential at investigator’s discretion c Echocardiogram during 
hospital admission (or within 6 months prior to index hospitalization) and at 12 weeks follow up visit. All visits 
have a +/-7-day visit window. d the most current ECG during admission. e Randomization can be performed prior 
to discharge or up to 7 days after discharge  (if discharge planning over the weekend. **COVID-19: For 
modified study visit options applicable during the time period of the COVID-19 emergency, please see appendix 
B. 
 
 


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Drug Dispensing Scheme 
Three bottles of dapagliflozin 10 mg or matching placebo will be dispensed by investigational pharmacy 
at randomization and at the 12-week clinic visit. Each bottle containing 35 tablets.  
 
 
Rescue therapy 
Patients with T2D will be discharge on pre-admission oral agents and or insulin therapy except for 
sulfonylureas or TZDs. Dose of OADs and/or insulin will be adjusted as an outpatient to achieve and 
maintain a fasting BG between 80-140 mg/dl and a random BG < 180 mg/dl.   
 
Duration of treatment 
26 weeks. 
 
Measurements During follow-up:   
 
1. Clinical Outcomes: 
a. Hospital readmissions, emergency department / urgent clinic visits for HF management 
and death (See appendix A: Heart Failure Hospitalization, ER visit and urgent outpatient 
clinic visit) 
2. Glycemic control: 
a. Mean daily fasting and pre-meal blood glucose levels.  
b. HbA1c concentration at 12 and 26 weeks (T2D patients) 
c. Number of hypoglycemic events  
i. Clinically significant hypoglycemia defined as a BG < 54 mg/dl 
ii. Symptomatic hypoglycemia defined as an event with typical symptoms (i.e., sweating, 
palpitation, and feeling of hunger) with or without confirmation by plasma glucose <70 
mg/dl (3.9 mmol/L).   
iii. Severe hypoglycemia defined as episodes necessitating assistance and associated with 
measured plasma glucose < 40 mg/dl (2.2 mmol/L) or with prompt recovery after 
administration of carbohydrates, glucagon, or other resuscitative actions. These 
episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. 
Blood glucose measurements may not be available during such an event, but 
neurological recovery attributable to the restoration of BG to normal is considered 
sufficient evidence that the event was induced by low plasma glucose. 
 
3. T2D treatment: 
a. Number of patients receiving insulin therapy, dosage, and compliance. 
b. Use of other oral agents, dosage, and compliance. 
 
4. Blood pressure and heart rate 
a. The most recent documented blood pressure (BP) of the day of screen can be used to 
determine enrollment eligibility.  At randomization, the seated BP will be recorded in 
both the left and the right arms. Blood pressure (BP) and heart rate (HR) will be 
measured after the patient has been sitting and resting for at least 5 minutes. The arm 
with the highest seated systolic BP readings will be the one used for all subsequent 
readings (preferred arm).  
 
 
5. Orthostatic blood pressure 
 
 
a. Supine BP and pulse- The supine BP and pulse must be measured prior to the standing 
BP and pulse. After the patient rests in the supine position for at least 5 minutes, supine 
BP and pulse will be determined in the preferred arm 


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b. Standing BP and pulse - After the supine BP and pulse measurements are obtained, the 
patient will stand for 2 to 3 minutes. Standing BP and pulse will be determined from the 
preferred arm.  
                    All readings must be recorded. For study analyses, the average of the BP and pulse readings 
will be used. 
 
6. Anthropomorphic measurements 
a. Weight, height, waist, and hip circumference.  
b. Weight: Body weight will be measured without shoes and wearing light clothing. 
c. Height: Height (without shoes) will be measured in centimeters. 
d. Body Mass Index (BMI): BMI will be calculated by the formula: body weight (Kg)/m2. 
 
7. Six-minute walk distance (6MWD) 
a. The six-minute walk test requires a 100-ft hallway. This test measures the distance that a 
patient can quickly walk on a flat, hard surface in a period of 6 minutes. The six-minute 
walk test serves as a standardized test for functional capacity quantification of HF 
patients and is predictive of adverse cardiovascular outcomes 44.  Most patients do not 
achieve maximal exercise capacity during the 6-minute walk test 45; instead, they choose 
their own intensity of exercise and can stop and rest during the test.  
 
9. Kansas City Cardiomyopathy Questionnaire (KCCQ)46 is a disease-specific health status 
instrument composed of 23 items that quantify the domains of physical limitation, symptoms, 
self-efficacy, social limitation, and quality of life limitation due to HF. Scores range from 0 to 
100. For the KCCQ overall summary score, a small but clinically meaningful change is ≥ 5 
points.  
 
10. The Chronic Heart Failure Questionnaire (CHQ-SAS) is a validated questionnaire that assesses 
patients’ perception of their HF and measures the impact of HF symptoms 47,48. The CHQ-SAS 
contains16 standardized questions that assess dyspnea during daily activities, fatigue and 
emotional function. Items are rated on a 7-point Likert scale ranging from 1 to 7.  
 
11. Echocardiogram 
Echocardiograms will be performed at baseline (standard of care) and during follow-
up. Echocardiographic measurements will include measurements of LV end-diastolic dimension 
(LVEDD), LV end-systolic dimension (LVESD), LV end-diastolic volume (LVEDV), LV end-
systolic volume (LVESV), left atrial dimension (LAD), interventricular septal (IVS) and LV 
posterior wall (LVPW) thickness by 2D echocardiography or M-mode. LVEF assessment based 
on 2D echocardiography using the quantitative 2D biplane volumetric Simpson method from 4- 
and 2-chamber views. Patients with repeated echocardiography during the hospitalization or 
during follow-up, we will use the data from the examination performed closest to discharge.  
 
12. Cost-effectiveness evaluation of resource utilization overall healthcare costs after hospital 
discharge in patients with ADHF.  We propose to conduct an accompanying within-trial cost-
effectiveness analysis using observed trial data. We will adopt a healthcare payer perspective for 
this analysis. The primary outcomes include total costs of trial participants. Per the 
recommendations of the Second Panel on Cost-Effectiveness in Health and Medicine49 and of the 
Consolidated Health Economic Reporting Standards (CHEERS)50, we will provide an impact 
inventory table and reporting checklist in our reports. 
Data for cost outcomes will be derived from observed trial data based on abstraction of 
electronic medical record systems.  


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Costs: All costs will be expressed in uniform currency such as 2020 U.S. dollars. Total costs will 
include all direct costs associated with clinical care provided, and external health care service 
utilization (ER visits and hospitalizations). External healthcare service utilization will include 
routine office visits, after-hour clinic visits, after-hour clinic visits (urgent care), ambulance use, 
emergency room visits, and hospitalizations.  To calculate the total costs of utilization at 6 
months, the median prices of each healthcare service51 will be multiplied by the number of each 
service use during the trial.   
 
13. Laboratory assessments.  Blood and urine samples for determination of clinical chemistry, and 
NT proBNP levels will be obtained as per Study Plan.  Serum magnesium and random urine 
sodium will be measured at baseline and repeated at 12 and 26 weeks. 
14. Treatment Compliance/Adherence 
e. The administration of study medication will be recorded. All stops of study medication 
prescribed by the investigator will be recorded. Study personnel will collect/record any 
decrease in oral agents and insulin dosage, and if the investigator determined to stop any 
previously used OADs or insulin during the study.   
f. Missed doses of dapagliflozin or placebo blinded study medication will not be taken. If a 
dose is missed, the next regularly scheduled dose will be taken and will not be doubled. 
 
15. Drug Accountability 
g. The study personnel will account for all study medication dispensed to and returned from 
the patient. 
h. Patients will be asked to bring all unused study medication and empty packages to the 
site at each office visit. Any discrepancy between dispensed and returned study 
medication will be explained. 
i. Any patient found to be noncompliant would be counseled on the importance of taking 
their study medication as prescribed. 
 
Randomization and Blinding 
This is a double blinded, randomized, placebo-controlled trial in patients with heart failure.  Computer-
generated randomization tables will be provided by Dr. Limin Peng at the Emory School of Public 
Health. Block randomization based on diabetes (with or without) status. The randomization tables will 
be mailed to each institution where a member of the research team will oversee the randomization 
process and group assignment.  
 
Procedures for unblinding the study: 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment. The Emory University of 
Atlanta physician (Guillermo Umpierrez or delegate) should be consulted whenever possible prior 
to the investigator breaking the blind. 
 
Recruitment and Retention: Potential study subjects will be identified and pre-screened among 
patients admitted with ADHF. For each center, a research coordinator will screen all admission daily to 
identify patients with a diagnosis of ADHF. Once a potential participant is identified, the research 
coordinator will first contact the primary care team/provider to discuss protocol (if needed) and request 
permission to approach patient and relatives. Then the research coordinator will approach the potential 
participant/and or family members to explain the purpose, intervention, and potential benefits/risks of 
participating in this study.  A study coordinator will conduct informed consent in eligible subjects prior 
to any study procedures. Screening and recruitment reports will be generated weekly that include actual 


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and expected recruitment statistics.  Strategies to address potential problems with recruitment will 
include weekly communications with Drs. Umpierrez and research team.  
Subject retention and study adherence are the two most important barriers in research trials in 
hospital and post-discharge trials. Our team has applied problem-solving approach to promote 
continued adherence in previous intervention studies, with adherence to previous inpatient/discharge 
trials exceeding 85%. During screening, participants and family members will be informed about which 
clinically intervention, treatment and relevant test and when these tests will be performed during the 
study. Only subjects who fully understand these commitments and appear likely to follow the study 
protocol will be enrolled. We will have dedicated study coordinators who will conduct screening and 
obtain consent for participation.   
Withdrawal Criteria 
1. The subject may withdraw at will at any time. 
2. The subject may be withdrawn from the trial at the discretion of the investigator due to a safety 
concern or if judged non-compliant with trial procedures or included in contravention to the 
inclusion and/or exclusion criteria. 
3. Adverse events (AE), i.e., any clinical, laboratory abnormality or concurrent illness which, in 
the opinion of the investigator, indicates that continued participation in the study is not in 
the best interest of the patient. 
4. Doubling of serum creatinine above the baseline value confirmed by a repeated measurement 
within one week (study medication can be discontinued and continue study visits as described in the   
premature treatment discontinuation). 
5. Pregnancy or intention to become pregnant. 
 
Subject Replacement 
There will be no replacement of subjects in this trial. 
 
Unscheduled Visits 
Additional unscheduled phone and/or clinic visits may also be performed at any time during the study at 
investigator’s discretion (abnormal results, etc.). 
 
Premature Treatment Discontinuation: 
Patient agrees to undergo the Premature Treatment Discontinuation Visit and then continue 
in-person study visits 
The patient agrees to undergo the Premature Treatment Discontinuation Visit (PTDV) as visit 9 and then 
continue in-person study visits according to plan. This is the preferred option and patients who 
discontinue study medication will always be asked if they agree to this approach. If agreed, as 
above, the patient will undergo their PTDV at the next scheduled office visit after the study 
medication is stopped. The patient will continue attending subsequent study visits according to 
schedule,  
 
Patient refuses to continue in-person study visits but agrees to undergo modified follow-up 
If the patient refuses to continue in-person study visits, but agrees to undergo modified follow up, 
the in-person PTDV visit (as visit 9) should be performed as soon as possible after the study medication 
is stopped. All subsequent visits until the end of study date will be done as modified follow-ups (e.g., 
regular telephone contacts, a contact at study closure, or other means) in order to ascertain 
whether any endpoints or safety events had occurred. Such a patient has not withdrawn his/her 
consent or withdrawn from the study. 
 


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Patient refuses any form of follow-up 
If the patient refuses any form of follow-up, he/she officially withdraws from the study and 
withdraws consent. This decision must be documented. At the end of the study, vital status on all 
such patients will be collected from publicly available sources, in accordance with local regulations. 
 
Lost to follow up patients  
To prevent patients being lost to follow-up, patient’s contact details, including next of kin contacts will 
be collected initially and updated regularly by the research team. The research coordinators will educate 
the patient on the importance of contact with the research team throughout the study. Repeated attempts 
will be made to locate and obtain pertinent medical information for patients who are initially lost to 
follow-up. A patient will be classified as lost to follow up only if he/she has failed to return for the 
required study visits and his/her vital status remains unknown despite multiple attempts to contact 
him/her via telephone, fax, e-mail, certified letter or through patient locator agencies (if allowed by 
national regulation). The informed consent forms will include language to grant the option to employ 
outside companies to assist in obtaining updated contact information or ascertainment of vital status of 
lost patients using publicly available source.  
 
Study Sites: This study will be performed at 4 academic institutions: 
Grady M. Hospital: Endocrinology section:  Guillermo Umpierrez, MD, CDE (Principal investigator), 
Francisco Pasquel, MD, MPH, Georgia Davis, MD, Maya Fayfman, MD, Saumeth Cardona, MD, MPH 
-Cardiology section:  Modele O. Ogunniyi, MD, MPH, Nanette K. Wenger, MD 
Emory University Hospital:  
- Endocrinology section:  Alexandra Migdal, MD (Co-PI), Rodolfo Galindo, MD 
- Cardiology section:  Alanna Morris, MD, Arshed A. Quyyumi, MD 
Emory Saint Joseph’s Hospital:  
-Cardiology Section: David Markham, MD, Ryan Martin, MD 
 
 
Non-Emory/Grady Centers for consideration:  Two centers will be selected among Tulane 
University, Temple University and University of Michigan, which have collaborated with Emory in 
conducting clinical research studies in hospitalized patients and hospital discharge studies.   
 
Tulane University:  Dragana Lovre, MD (Site PI) 
Temple University: Daniel Rubin, MD (Site PI) 
 
 
Statistical Methods  
This study is randomized placebo-controlled trial. The overall hypothesis is that dapagliflozin will 
reduce the rates of the combined outcomes of hospital readmissions, ER visits, clinic visits for HF and 
death (primary endpoint) and improve symptoms, quality of life and results in a reduction in NT 
proBNP and resource utilization/costs as compared with placebo in patients with ADHF.  
Sample Size and Power Calculations: The sample size calculation is based on the primary endpoint 
measured as the proportion of patients who have hospital readmission, emergency department (ER) 
visits, and urgent unplanned clinic visit for HF and death during the 26-weeks follow-up period. 
Approximately 5.7 million people have been diagnosed with HF ion the US 52. Patients hospitalized for 
HF are at high risk for readmission, with a 1 and 3-month readmission rate between 20-30% 53-56 and a 
6-month readmission rate as high as 50% to 60%  57,5859. An analysis of Medicare data from the Centers 
for Medicare and Medicaid Services among 28,919 patients with HF hospitalizations, the 6—9 month 
following the initial HF admission, 60% of patients had 1 or more readmissions for any cause 58. 
Similarly, the national registry of heart failure in Spain with 45.3% of patients with diabetes, a known 
diagnosis of diabetes was associated with increased all-cause mortality (HR 1.54; 95%CI 1.20–1.97, p = 
0.001) and readmissions (HR 1.46; 95%CI 1.18–1.80, p < 0.001). In that study, 40.9% of patients with 


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diabetes were readmitted within 6-12 months after discharge 60. An additional study of 462 hospitalized 
patients with T2D, 44% of the HF events were readmitted to the hospital within 6-month of the primary 
admission 61.  Thus, our review of the literature indicates that about ~ 40-60% of patients with diabetes 
with heart failure will be readmitted within 6-month of follow-up. 
 
SGLT2-is have been shown to markedly reduced HF hospital admissions in patients with and without 
diabetes.  In the CVD-Real Study, which included 961 HF cases, SGLT2-i reduced the rates of HF 
hospitalizations hazard ratio, 0.61; 95% confidence interval, 0.51-0.73; P<0.001. 62 The CVD-Real 2 
multinational study of 235,064 patients with T2D, initiation of an SGLT-2i was also associated with a 
lower risk of all-cause death and hospitalization for heart failure, as compared to other glucose lowering 
drugs 24. The use of SGLT-2i vs. other glucose lowering drugs was associated with lower risk of death 
and heart failure 24. Recent RCT examining cardiovascular outcome using SGLT2-i reported a 
significant reduction in hospitalization for HF 20,21. In the DECLARE trial, dapagliflozin resulted in 
lower rate of hospitalization for heart failure compared to placebo (HR, 0.73; 95% CI, 0.61 to 0.88)23. 
The EMPA-REG OUTCOME study showed a 35% reduction in HF hospitalizations 20.  In addition, in 
the CANVAS Program the benefits were greater in patients with a previous history of HF compared 
with those without HF at baseline (HR, 0.87; 95% CI, 0.72–1.06; P interaction = 0.021) 11. In the 
Canvas Program, the rate of HF was reduced in patients with history of HF from 28.1% to 14.1% 
between patients treated with canagliflozin and placebo.   
Based on data summarized above, we assume the composite event rate in the placebo group is between 
40-60%, which would be reduced by 30% in the dapagliflozin group.  Based on two-sided Chi-square 
test, with preserved alpha=0.05, with 176 subjects, we would achieve over 80% power to detect a 30% 
reduction in proportion of patients with readmission, ER visits, urgent unplanned clinic visit for HF or 
death if the composite event rate in the placebo group is 50%. Accounting for 10% attrition, we propose 
to recruit 392 patients (196 per group).  
In the table below, we provide estimated power based on the same method, corresponding to different 
placebo composite event rates that are between 40-60%: 
Composite event rate 
in the placebo group 
40% 
45% 
50% 
55% 
60% 
 
Estimated Power  
 
62% 
 
 
72% 
 
82% 
 
88% 
 
93% 
 
The results in the above table suggest promising power for the proposed study. 
We will implement an adaptive design63-65 with conditional power calculation and potential for re-
estimation of the sample size, if necessary, after the interim analysis scheduled to be performed after 
50% of the patients were enrolled and completed the 26 weeks of study period (196 patients) and 
undergone adjudication of the primary composite endpoint. Sample size re-estimation will be performed 
based on the observed composite event rate per group at the time of the interim analysis.  See below 
“interim efficacy analysis”.   
Analysis of Primary Endpoint: 
We will first compare the proportion of patients with at least 1 readmission, ER visit or unplanned 
urgent clinic visit for HF or death between the two study groups, using Chi-squares test or Fisher’s 
Exact tests. Logistic regression will be conducted to adjust for the effects of other potential confounders 
(e.g. age, gender). Stepwise, backward, or forward model selection strategy will be adopted to determine 
the variables to be included in the final model. Standard diagnostic and model checking procedures, 


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such as deviance residual plot and Hosmer- Lemeshow test, will be applied to examine the fit of the 
developed models.  
Analysis of Secondary Endpoints:  The secondary endpoints include continuous longitudinal outcomes 
(e.g. change in KCCQ score from baseline at 6, 12, and 26 weeks), and discrete outcomes (e.g. whether 
patients with a ≥ 5pts increase in KCCQ score). To analyze continuous longitudinal outcomes, we will 
first conduct cross-sectional analyses based on nonparametric Wilcoxon tests (or t-tests), followed by 
multivariate linear regression, where responses may be transformed to better meet the normality 
assumption.  Then we will apply repeated measures ANOVA or repeated measures linear regression 
model to assess the outcome differences between the two study groups, simultaneously evaluating the 
outcomes measured at different time points while appropriately accommodating the within-subject 
correlations. For discrete outcomes, we will conduct univariate analyses based on Chi-square tests (or 
Fisher’s Exact tests). For binary discrete outcomes, we will use logistic regression models to account for 
the effects of other potential confounders. For other types of discrete outcome (e.g. counts), we will 
apply Poisson regression models or Negative Binomial regression models to address the confounding 
effects of other variables. Standard model selection and checking procedures will be applied to ensure 
the adequacy of the adopted models.  
 
Cost-Effectiveness Analyses: The endpoints include healthcare charges, and numbers and incidences of 
emergency room visits, urgent clinic visits for HF, and hospitalizations. For continuous outcomes (e.g. 
charges), we will use Wilcoxon rank-sum test to compare them between the two groups. Linear 
regression or quantile regression will be performed to assess the group difference adjusting for other 
potential confounders such as baseline utility scores.  The Chi-square test will be used to compare 
categorical outcomes (e.g. categorized frequency of emergence room visits), followed by generalized 
linear models (e.g. logistic regression model) which adjusts for other potential confounders. . To model 
repeatedly measured cost-related outcomes (e.g. utility scores) over time, repeated measures analyses 
via linear mixed models or generalized linear mixed model will also be performed to estimate the effect 
of dapagliflozin, time, and their interaction. Potential covariates such as age, gender, race, insurance, 
and duration of T2D, along with baseline utility score, will be adjusted. Standard model selection and 
checking procedures will be applied to ensure the adequacy of the adopted models.   
 
DATA AND SAFETY MONITORING BOARD  
An independent Data and Safety Monitoring Board (DSMB) is established and responsible for 
monitoring the trial according to the protocol to ensure the safety of patients in the trial. During the 
course of the study, the DSMB will review the cumulative data collected, evaluate the risk/benefit 
profile.  The DSMB plans to meet after every 6 months or after 150 patients are enrolled.  
The DSMB would recommend one of the following actions:  
1. Continue the study without modification  
2. Modify protocol - based on the safety findings may include frequency of safety monitoring, 
alterations in study procedures. A recommendation on sample size increase/decrease will be 
considered after the 50% interim efficacy analysis review.  
3. Stop the study - because there is overwhelming efficacy or safety concern, i.e., the risks to 
patients exceed the benefits to be obtained.  
 
Interim Efficacy Analysis  
For this study, one interim efficacy analysis is planned for the purpose of sample size re-estimation after 
50% of the enrolled patients (n=196) have completed the 26 weeks of study period and undergone 
adjudication of the primary composite endpoint. The process of performing this interim efficacy analysis 
would, by definition, lead to unblinding of patient treatment to the DSMB. The efficacy analysis and 
sample size re-estimation will be performed by DSMB members and Dr. Limin Peng from the School of 
Public Health. 


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Stopping Due to Overwhelming Evidence of Efficacy  
Group sequential tests would be performed when 70% of randomized patients have a completed follow-
up assessment and have their events adjudicated, using the Gamma family alpha spending function (with 
gamma = -5)63-65.  
 
Safety 
 
Potential risks associated with dapagliflozin use: 
Hypoglycemia.  It is possible that following the proposed protocol, T2D patients receiving basal insulin 
or dapagliflozin alone or in combination with antidiabetic treatment may develop hypoglycemia (< 54 
mg/dl). The frequency of hypoglycemia in patients with T2D treated with dapagliflozin is expected to be 
< 10%. The number of reports of hypoglycemia will be analyzed statistically.  For this analysis, 
hypoglycemia is defined as a capillary and/or laboratory BG <70 mg/dl, and clinically significant 
hypoglycemia a BG < 54 mg/dl.  Severe hypoglycemia is defined as an event with symptoms consistent 
with hypoglycemia in which the subject required the assistance of another person and blood glucose less 
than 40 mg/dl. 
Volume depletion.  SGLT2-is, including dapagliflozin may cause intravascular volume contraction. 
Treatment with SGLT2-i leads to increased diuresis, which may result in a modest reduction in blood 
pressure 66,67. The risk of volume depletion is enhanced when two diuretics are used in combination, 
especially with the use of loop diuretics.  Therefore, the drug should be given with caution in patients 
with volume depletion and hypotension. In this trial, we will exclude patients with hemodynamic shock 
with systolic blood pressure <100 mm Hg after initial fluid resuscitation.  
Hypotension.  SGLT2-is, including dapagliflozin may cause natriuresis and intravascular volume 
contraction that may lead a modest reduction in blood pressure 66,67. The risk of hypotension may be 
higher in elderly patients with renal impairment receiving two diuretics and the use of loop diuretics.  In 
this trial, we will exclude patients with systolic blood pressure <100 mm Hg and during therapy, diuretic 
and/or antihypertensive drugs may need to be adjusted in patients with blood pressure < 100 mmHg.  
Urinary tract infection.  Dapagliflozin as all of the SGLT2-i are associated with more frequent urinary 
tract infections compared with placebo. The percentage of diagnosed urinary tract infections in a recent 
safety analysis was 3.6% for dapagliflozin and 3.7% for placebo. Urinary tract infections were observed 
in a greater proportion in patients with a history of recurrent urinary tract infection compared with those 
without a history of recurrent infection. In this trial, patients with a diagnosis of pyelonephritis or 
recurrent urinary tract infections will be excluded, and symptoms/signs of UTI will be closely monitored 
during the clinical trial. 
Mycotic genital infection.  The use of SGLT2-i has been associated with increased susceptibility to 
genital mycotic infections 68,69. In the recent DECLARE study (REF), the rate of genital infections that led to 
discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001). This AE is 
usually mild in intensity, respond to local/systemic treatment, and rarely result in drug discontinuation. 
In this trial, patients with recurrent genital mycotic infections will be excluded, and symptoms/signs of 
mycotic genital infection will be closely monitored during the trial. 
 
Diabetic ketoacidosis is a rare complication in patients with T2D reported with the use of SGLT2-i. In 
the recent DECLARE study, diabetic ketoacidosis was more common with dapagliflozin than with 
placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the 
regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001). Patients treated 
with dapagliflozin who present with signs and symptoms consistent with severe metabolic acidosis will 
be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated 


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with dapagliflozin may be present even if blood glucose levels are less than 250 mg/dL 70-72. If 
ketoacidosis is suspected, the drug should be discontinued, patient should be evaluated, and prompt 
treatment should be instituted. Treatment of DKA may require insulin, fluid replacement 73,74.  
 
Acute kidney injury and impairment in renal function. There have been reports of acute kidney 
injury in patients receiving SGLT2-I 74-76. Dapagliflozin should be avoided during prolonged fasting or 
fluid losses (such as gastrointestinal illness). SGLT2-i may increase serum creatinine and decreases 
eGFR. Patients with moderate renal impairment (eGFR less than 25 mL/min/1.73 m2) should not be 
started on dapagliflozin.  
Lower limb amputation.  An increased risk for lower limb amputation (primarily of the toe) has been 
observed in clinical studies with SGLT2-I therapy 77,78.  In the recent DECLARE study, the rate of non-
traumatic lower limb amputations was not increased compared to placebo treatment. Patients at 
increased risk of amputations including such as a history of prior amputation and diabetic foot ulcers 
will not be enrolled in this trial. 
Changes in serum magnesium.  Recent reports and a meta-analysis of 18 RCTs involving 15,309 
patients provided evidence that SGLT2 inhibitors significantly increase serum magnesium levels in 
patients with T2D 79. On average, serum magnesium levels were raised by 0.04-0.06 mmol/l for all 
SGLT2-I agents indicating a drug class effect. The mechanisms are not completely understood, but 
likely relates to SGLT2 i- induced glucosuria and osmotic diuresis. The significant elevations in serum 
magnesium levels are not known, with some studies reporting an association between high magnesium 
levels and total mortality in individuals with heart failure 80 and those receiving hemodialysis 81. 
However, in the general population and in people with type 2 diabetes, high end of the normal range 
of serum magnesium has been associated with a lower risk of cardiovascular events 79, lower systolic 
BP by 2.00 mmHg and diastolic BP by 1.78 mmHg compared with placebo 79. It has been 
hypothesized that a modest increase in serum magnesium could have contributed to a reduction in 
cardiovascular mortality observed among participants with type 2 diabetes in the EMPA-REG 
OUTCOME trial 20,79.  
 
 
Definition of Adverse Events 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered an investigational product 
and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of investigational product, whether considered related to the 
investigational product. 
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
Not related: There is not a reasonable causal relationship between study drug administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, 
or evaluation of a subject. (To prevent reporting bias, subjects should not be questioned regarding the 
specific occurrence of one or more AEs.) 
Serious Adverse Events.  A Serious Adverse Event (SAE) is any untoward medical occurrence that at 
any dose:  


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• Results in death 
• Is life-threatening (defined as an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more 
severe) 
• Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect?  
• is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require intervention [e.g. medical, surgical] to prevent 
one of the other serious outcomes listed in the definition above.) Examples of such events include, 
but are not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.) Potential drug 
induced liver injury is also considered an important medical event.  
• Suspected transmission of an infectious agent (e.g. pathogenic or nonpathogenic) via the study drug 
is an SAE.  
NOTE: The following hospitalizations are not considered SAEs:  
− a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event) 
− elective surgery, planned prior to signing consent 
− admissions as per protocol for a planned medical/surgical procedure 
− routine health assessment requiring admission for baseline/trending of health status  
− medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study.  
− admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative reason). 
 
Serious Adverse Event Collection and Reporting 
• The collection of AEs will start after the signing of the informed consent.  All SAEs, whether related 
or not related to study drug, will be collected, including those thought to be associated with protocol-
specified procedures. An SAE report will be completed for any event where doubt exists regarding 
its seriousness.  
• If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship will be specified in the narrative section of the SAE Report Form. 
• SAEs, whether related or not related to study drug, and pregnancies must be reported to the IRB and 
sponsor within 24 hours. SAEs will be recorded on an SAE Report Form; If only limited information 
is initially available, follow-up reports are required. (Note: Follow-up SAE reports should include 
the same investigator term(s) initially reported.)  
• If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report will be sent within 24 hours to the Emory IRB and 
sponsor using the same procedure used for transmitting the initial SAE report.  
• All SAEs will be followed to resolution or stabilization. 
Non-serious Adverse Events 
• A non-serious adverse event is an AE not classified as serious. 


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• The collection of non-serious AE information should begin at initiation of study drug. Non-serious 
AE information will also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects.  
• Non-serious AEs will be followed to resolution or stabilization or reported as SAEs if they become 
serious. Follow-up will be performed for non-serious AEs that cause interruption or discontinuation 
of study drug and for those present at the end of study treatment as appropriate. All identified non-
serious AEs will be recorded and described on the non-serious AE page of the CRF.  
• Completion of supplemental CRFs will be performed for AEs and/or laboratory abnormalities that 
are reported/identified during the study. 
Overdose 
• An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose will be reported as 
an SAE. 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities will be captured on the non-serious AE CRF page or 
SAE Report Form as appropriate: 
• Any laboratory test result that is clinically significant or meets the definition of an SAE  
• Any laboratory test result abnormality that required the subject to have study drug discontinued or 
interrupted 
• Any laboratory test result abnormality that required the subject to receive specific corrective therapy. 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value). 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of investigational product exposure, including during at 
least 6 half-lives after product administration, the investigational product will be permanently 
discontinued in an appropriate manner (e.g., dose tapering if necessary, for subject safety).  
Protocol-required procedures for study discontinuation and follow-up will be performed on the subject 
unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy follow-up 
procedures will be considered if indicated. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational product 
under study may have interfered with the effectiveness of a contraceptive medication. 
 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the patient was 
discontinued from the study. 
 
The investigator will immediately notify the sponsor and IRB within 24 hours and in accordance with 
SAE reporting procedures.  All pregnancies and outcomes of pregnancy should be reported to 
AstraZeneca’s 
designated fax line: +1 302 886 4114 or email: AEMailboxClinicalTrialTCS@astrazeneca.com if a 
secure line is set up. 
 
Recording of adverse events  
Adverse Events will be collected throughout the study until and including the last visit/contact.  


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Variables  
The following variables will be collected for each AE:  
• 
AE (verbatim)  
• 
The date when the AE started and stopped  
• 
Maximum intensity  
• 
Whether the AE is serious or not  
• 
Investigator causality rating against the Investigational Product (yes or no)  
• 
Action taken with regard to investigational product  
• 
Whether this event is potentially a clinical endpoint /event of special interest  
• 
Outcome.  
In addition, the following variables will be collected for SAEs:  
• 
Date AE met criteria for serious AE  
• 
Date Investigator became aware of serious AE  
• 
AE is serious due to  
• 
Date of hospitalization  
• 
Date of discharge  
• 
Probable cause of death  
• 
Date of death  
• 
Autopsy performed  
• 
Causality assessment in relation to Study procedure(s)  
• 
Causality assessment in relation to Other medication  
• 
Description of AE.  
• 
It is important to distinguish between serious and severe AEs. An AE of severe intensity need 
not necessarily be considered serious. If the intensity of an AE changes, only the maximum 
intensity of the event will be recorded; however, the AE intensity will be recorded at the time of 
reporting.  
Maximum intensity will be graded according to the following rating scale:  
• 
Mild (awareness of event but easily tolerated)  
• 
Moderate (discomfort enough to cause some interference with usual activity)  
• 
Severe (inability to carry out usual activity)  
Causality collection  
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or ‘no’ to 
the question ‘Do you consider that there is a reasonable possibility that the event may have been 
caused by the investigational product?’  
For SAEs causal relationship will also be assessed for other medication and study procedures. Note 
that for SAEs that could be associated with any study procedure the causal relationship is implied as 
‘yes’.  
Adverse Events based on examinations and tests  
The results from protocol mandated laboratory tests and vital signs will be summarized in the 
clinical study report. Deterioration as compared to baseline in protocol-mandated laboratory values, 
vital signs and other safety variables will therefore only be reported as AEs if they fulfill any of the 
SAE criteria or are the reason for discontinuation of treatment with the investigational product.  


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If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, the 
sign or symptom will be reported as an AE and the associated laboratory result/vital sign will be 
considered as additional information. Wherever possible the reporting Investigator uses the clinical, 
rather than the laboratory term (e.g., anemia versus low hemoglobin value). In the absence of clinical 
signs or symptoms, clinically relevant deteriorations in non-mandated parameters will be reported as 
AE(s).  
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE if they fulfill any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product.  
Hepatic disorders  
All patients with a confirmed result of AST and/or ALT >3x ULN, will have additional central 
laboratory tests performed throughout the study. For patients who are discontinued from the study as a 
result of sustained elevated liver safety abnormalities, additional central laboratory tests will be 
performed at the time of end of Treatment Visit. 
Pre-defined liver enzyme elevations will undergo adjudication. The definitions of events to be 
adjudicated are provided in the Event Reporting Manual. For all events identified for adjudication, the 
Investigator will complete the appropriate eCRF pages and provide source documentation as detailed in 
the Event Reporting Manual.  
Hematuria  
All events of hematuria (confirmed by microscopy at the central laboratory) during the study will be 
worked up for a possible cause. If no immediate or benign cause is identified as judged by the 
Investigator (e.g., menstruation, kidney stone, urinary tract infection [UTI] where hematuria is 
subsequently resolved after successful treatment), patients will undergo further evaluation by the 
investigator or another qualified professional. The choice of tests will be per local standard of care. The 
patient will continue to receive IP treatment during these investigations (unless otherwise 
contraindicated). All confirmed events of bladder cancer will lead to the discontinuation of 
investigational product.  
Possible malignancies  
All possible malignancies (except for non-melanoma skin cancer) will be identified based on a pre-
specified list of Medical Dictionary for Regulatory Activities (MedDRA) preferred terms. The identified 
events will be independently adjudicated. For all events identified for adjudication, the Investigator will 
complete the appropriate eCRF pages and provide source documentation as detailed in the Event 
Reporting Manual. The Investigator will clearly describe the event as benign or malignant if known. All 
confirmed events of bladder cancer will lead to the discontinuation of investigational product.  
Renal disorders  
For patients with signs of deteriorating renal function additional monitoring needs to be conducted. Any 
patient with an increase ≥ 50% above baseline will be scheduled for a re-test within 1 week whenever 
possible.  
If the re-tested serum creatinine is < 50% above baseline the patient can resume normal visit schedule.  
If the re-tested increase in increase in serum creatinine ≥ 50% above baseline, the patient’s renal 
function will continue to be monitored according to the judgment of the Investigator. In this 
circumstance, the Investigator will consider evaluating the patient for potentially reversible causes of 


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renal dysfunction including: concurrent use of NSAIDS, antibiotics, or other medications known to 
affect measures of serum creatinine; volume depletion; urinary tract infection and obstructive uropathy. 
If the eGFR falls below 25 ml/min, continue current dose of 10mg to reduce the risk of further eGFR 
decline.  
Hypoglycemic events  
At each visit the Investigator will inquire about occurrence of major hypoglycemic events according to 
the below definition.  
Major hypoglycemic event defined as symptomatic events requiring external assistance due to severe 
impairment in consciousness or behavior, and prompt recovery after glucose or glucagon administration. 
Plasma glucose measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the 
event was induced by a low blood glucose concentration.  
Hypoglycemic episodes or symptoms of hypoglycemia will only be reported if the event fulfills the 
definition of a major hypoglycemic event, the protocol criteria for an SAE or leads to discontinuation of 
IP.  
Volume depletion  
Dapagliflozin has a modest diuretic effect. The risk of volume depletion is enhanced when two diuretics 
are used in combination and in patients that otherwise are at risk for volume depletion. Therefore, 
caution will be exercised when administering to patients at risk for volume depletion due to co-existing 
conditions or concomitant medications, such as loop diuretics. These patients will be carefully 
monitored for volume status, electrolytes, and renal function.  
UTI  
If the Investigator believes that a UTI may be present, a properly collected set of urine cultures will be 
obtained and sent to a local laboratory prior to initiation of antibiotic therapy to confirm a presumptive 
diagnosis of cystitis, urinary tract infection, pyelonephritis. Clinical judgment and local standards of care 
should apply to decisions concerning therapy.  
In patients with clinical evidence of upper UTI (e.g., pyelonephritis) or presumed urosepsis, the 
Investigator may consider temporarily stopping IP until the course of treatment of the infection has been 
completed and clinical recovery has occurred. It is recommended that a follow-up urine culture is 
obtained within 7 days of clinical recovery from a documented UTI.  
Asymptomatic bacteriuria  
During enrollment, randomized treatment and follow up of patients in this trial, the Investigator may 
discover a patient with asymptomatic bacteriuria. Asymptomatic bacteriuria is defined as the presence of 
≥ 105 colony forming units/mL of bacteria, in a properly collected voided urine specimen, without signs 
or symptoms typically attributed to urinary tract infection. Asymptomatic bacteriuria is prevalent among 
diabetic women, and is associated with pyuria in 70% of cases.  
Adjudication of suspected CV endpoints  
The primary outcome of the study is to compare the efficacy of dapagliflozin compared with placebo, on 
the composite rate of hospital admissions, emergency department visits, urgent clinic visits for HF and 
death after admission with ADHF.  
Definition of heart failure hospitalization, emergency department visit and urgent ambulatory heart 


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failure is included in Appendix A.  
Suspected CV outcome events in the study will be identified either by the Investigator and reported AEs. 
For all events identified for adjudication the Investigator will enter information in the eCRF and provide 
source documentation.  
Reporting of serious adverse events  
Investigators and other study site personnel will inform the Emory IRB, FDA and sponsor (AZ) of any 
SAE via a MedWatch/AdEERs form that occurs in the course of the study immediately or within 24 
hours of when he or she becomes aware of it. Follow-up information on SAEs will also be reported by 
the Investigator with the same time frame. It is the responsibility of the investigator to compile all 
necessary information and ensure that the Emory IRB, sponsor and FDA receives a report according to 
the FDA reporting requirement timelines and to ensure that these reports are also submitted to 
AstraZeneca at the same time.  
All SAEs have to be reported, whether or not considered causally related to the investigational product, 
or to the study procedure(s). All SAEs will be recorded.  All SAEs collected in the study are to be 
reported to AstraZeneca. 
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 and ethical committees, of any SAEs 
as per local requirements, and concurrently AstraZeneca.   
 
SAEs that do not require expedited reporting need to be reported to AstraZeneca at least quarterly, 
preferably as they occur, either as individual case reports or as line listings. 
 
When reporting to AstraZeneca, a cover page should accompany the SAE form indicating the following: 
• External Sponsored Research (ESR) 
• The investigator’s name and address 
• The trial name/title and AstraZeneca ESR reference number 
 
Investigative site must indicate, either in the SAE report or the cover page, the causality of events in 
relation to all study medications. 
 
Send SAE report and accompanying cover page 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 
Hypoglycemia risk protection: 
 
We will follow safeguards to minimize the risk to our subjects: a) we will carefully monitor response to 
medical treatment every 2 weeks by telephone contact and during clinic visits, b) women of reproductive 
age who are sexually active will undergo a urine pregnancy tests prior to participation in the study, c) 
patients with significant comorbidities such as chronic kidney disease greater than stage II, cirrhosis, 
gastroparesis, and pancreatic disease will be excluded from the study.  
Hypoglycemia:  We expect that less than 10% of dapagliflozin treated patients will experience 
hypoglycemia during follow-up; however, approximately 20% to 30% of subjects treated with basal 
insulin and study drug will experience one or more episodes of hypoglycemia.  Patients will receive 
diabetes education prior to discharge and will be instructed on hypoglycemia sign/symptoms and 


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treatment.  Patients will be asked to call the T2D center and/or PCP in the event of hypoglycemia. If a 
patient develops hypoglycemia, the daily dose of insulin will be reduced by 10% to 30%.     
Treatment of Hypoglycemia (BG <70 mg/dL) 
For BG < 70 mg/dL, follow hypoglycemic orders below: 
• If patient is alert and can tolerate oral intake, give 20 grams of fast-acting carbohydrate (6 oz. 
fruit juice or regular soda, crackers). 
• If patient is not alert and cannot tolerate oral intake, call 911, give 1 mg glucagon IM or SQ 
• Check finger stick BG q 15 minutes and repeat above treatment until BG > 100 mg/dL. 
• Once BG > 100 mg/dL, repeat finger stick BG 1 hour later and provide a meal or carbohydrate 
 
Potential Benefits to the Subject:  We believe that all subjects will benefit greatly from this study.  
Improved glycemic control after hospital discharge may significantly reduce complications and reduce 
readmissions as well as the risk of hyperglycemia and hypoglycemia.   
Potential Benefits to Society:  This study will provide important information on the benefits of 
dapagliflozin after discharge for the management of patients with T2D.  We will determine whether 
glycemic control is different among insulin and dapagliflozin after hospital discharge. 
Risk/Benefit Assessment:  There are no prospective, randomized studies to assess the efficacy and 
safety of dapagliflozin for the management of T2D after hospital discharge in patients with a recent HF 
admission. This study will test the efficacy of dapagliflozin in preventing hospital readmissions during 
the following 6-months after hospital discharge in patients with and without diabetes.  
Therapeutic Alternatives:  Patients can be treated with insulin regimen and oral agents (glyburide, 
glipizide, DPP4 inhibitors and GLP1 analogs) currently available for the treatment of T2D.  In addition, 
there are several well-established medications that have been proven effective in improving cardiac 
function in patients with a history of heart failure.  
Inclusion of women.  We anticipate that ~50% of the study subjects will be female.  No patients under 
the age of 18 and no pregnant women will be included in the study.  Absence of pregnancy will be 
demonstrated by blood or urine testing prior to randomization (in female of childbearing potential only).   
Inclusion of minorities.  Patients will not be excluded based on race or ethnic origin.  We anticipate 
that half of patients will be African Americans, 10% Hispanics, and the rest Caucasians.   
Inclusion of children. No patients under the age of 18 will be recruited in this study. 
Confidentiality.  Informed consent will follow the procedure of Emory University Institutional Review 
Board. Every potential participant will be informed in writing and verbally with the important and key 
points of the study.  The research team will obtain a witnessed informed consent prior to inclusion of a 
patient into the study.  Data collection records with personal identifiers will be stored in locked file 
cabinets.  Presentation of the study results at scientific meetings or in publications will not identify 
subjects. Access to research and confidential records will be limited to clinical investigators, 
coordinators and the IRB at Emory University. 
 
Payment for Participation.  Participation in this study is voluntary.  Patients will receive twenty-five 
dollars ($25.00) during the hospital stay and visit 2, and fifty dollars ($50.00) after each clinic visit after 
discharge. Total compensation up to three hundred dollars ($300).  
Financial Obligation.  No additional cost to patients or to the institution will be incurred for research 
purposes. Research studies will be performed at no cost to study subjects. Dapagliflozin and matching 
placebo will be provided by the sponsor at no cost to participants.   


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Research Injuries. If a patient is injured because of taking part in this study, Dr. Umpierrez and 
investigators, along with the medical facility will make medical care available to the patient at the 
patient’s own cost.  Financial compensation for such things as lost wages, disability or discomfort due to 
an injury related to the study is not available.   
Financial Conflict of Interests.  None of the investigators in this study have any outside activities that 
may represent a conflict of interest.  None of the investigators have an economic interest in an outside 
entity, or act as officers, directors, employees or consultants with such an entity, whose financial interest 
may be affected by this research study. 
Informed Consent. After identification of eligible patients these individuals will be provided basic 
information regarding the study and, if interested, they will then be screened by research staff using the 
inclusion/exclusion criteria delineated elsewhere in this protocol.  The consent form, potential risks and 
benefits, and the rights of research participants will be explained to the participant by the investigators 
or research coordinator.  Individuals will be asked if they have any questions, and research staff will 
answer these questions.  The principal investigator will also be available to answer questions that 
participants may have during the consent procedure or during the time a participant is enrolled in the 
study.  The consent form will be completed in accordance with the IRB guidelines of Emory University.  
A signed copy of the consent form will be provided to the participant and a copy will be placed in the 
file that is maintained for each participant in the study office.   
 
 


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Appendix A: Heart Failure Hospitalization, Emergency Room visit for heart failure and urgent 
outpatient clinic visit 
Heart Failure (HF) Hospitalization is defined as an event that meets ALL of the following criteria:  
1. The patient is admitted to the hospital with a primary diagnosis of heart failure  
2. The patient exhibits new or worsening HF symptoms, including at least ONE of the following:  
a) Dyspnea (dyspnea at rest, orthopnea, paroxysmal nocturnal dyspnea)  
b) Decreased exercise tolerance  
c) Fatigue  
d) Other symptoms of worsened end-organ perfusion or volume overload  
3. The patient has objective evidence worsening heart failure, consisting of at least TWO physical 
examination findings OR one physical examination finding and at least ONE laboratory 
criterion), including:  
1. Physical examination findings:  
a) Peripheral edema  
b) Increasing abdominal distention or ascites  
c) Pulmonary rales/crackles/crepitations  
d) Increased jugular venous pressure and/or hepatojugular reflux  
e) S3 gallop  
f) Clinically significant weight gain thought to be related to fluid retention  
2. Laboratory evidence of heart failure, including: 
a) Increased N-terminal pro-BNP (NT- proBNP) or B-type natriuretic peptide (BNP) 
concentrations consistent with decompensation of heart failure.  
b) Radiological evidence of pulmonary congestion  
c) Non-invasive or invasive diagnostic evidence of clinically significant elevated left- 
or right-sided ventricular filling pressure or low cardiac output by echocardiogram 
report.  
d) The patient receives initiation or intensification of treatment specifically for heart 
failure, including at least ONE of the following:  
a. Augmentation in oral diuretic therapy  
b. Intravenous diuretic, inotrope, or vasodilator therapy  
c. Mechanical or surgical intervention, including: Mechanical circulatory support 
(e.g., intra-aortic balloon pump, ventricular assist device) or Mechanical fluid 
removal (e.g., ultrafiltration, hemofiltration, dialysis)  
Emergency Room Visit for Heart Failure: defined as an event that meets all of the following: 
1. Unscheduled visit to the Emergency Department (ED) with worsening symptoms and with a 
primary diagnosis of heart failure, with intensified HF treatment but not requiring HF 
hospitalization.  
2. The patient exhibits new or worsening symptoms due to heart failure as described above, 
including at least ONE of the following:  
a) dyspnea (dyspnea at rest, orthopnea, paroxysmal nocturnal dyspnea),  
b) decreased exercise tolerance, increasing fatigue,  


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c) symptoms of worsened end-organ perfusion or volume overload  
3.  The patient has objective evidence worsening heart failure, with at least TWO physical 
examination findings OR one physical examination finding and ONE laboratory criterion):  
A) Physical examination findings:  
2. Peripheral edema  
3. Increasing abdominal distention or ascites  
4. Pulmonary rales/crackles/crepitations  
5. Increased jugular venous pressure and/or hepatojugular reflux  
6. S3 gallop  
7. Clinically significant weight gain thought to be related to fluid retention  
B) Laboratory evidence of heart failure, including: 
1. Increased N-terminal pro-BNP (NT- proBNP) or B-type natriuretic peptide (BNP) 
concentrations consistent with decompensation of heart failure.  
2. Radiological evidence of pulmonary congestion  
3. Non-invasive or invasive diagnostic evidence of clinically significant elevated 
left- or right-sided ventricular filling pressure or low cardiac output by 
echocardiogram report.  
4. The patient receives initiation or intensification of treatment specifically for heart 
failure, including at least ONE of the following:  
1. Augmentation in oral diuretic therapy  
2. Intravenous diuretic, inotrope, or vasodilator therapy  
3. Mechanical or surgical intervention, including: Mechanical circulatory support 
(e.g., intra-aortic balloon pump, ventricular assist device) or Mechanical fluid 
removal (e.g., ultrafiltration, hemofiltration, dialysis)  
 
Urgent Heart Failure Visit:  defined as an event that meets all of the following:  
1. 
The patient has an urgent, unscheduled office/practice or emergency department visit for a 
primary diagnosis of heart failure, but not meeting the criteria for a heart failure 
hospitalization.  
2. 
All signs and symptoms for heart failure hospitalization (i.e., a) symptoms; b) physical 
examination findings/laboratory evidence of new or worsening heart failure, as indicated 
above)  
3. 
The patient receives initiation or intensification of treatment specifically for heart failure, as 
detailed in the above section with the exception of oral diuretic therapy, which will not be 
sufficient.  
 
 


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Appendix B: COVID-19 
On March 11, 2020, the World Health Organization declared the 2019 novel coronavirus – and 
COVID-19, disease caused by the virus – a global pandemic. In response, efforts to contain the 
spread of COVID-19 have been implemented across the United States and have impacted the 
conduct of clinical research trials. In an effort to maintain, as much as possible, the integrity of 
the DAPA HF on Hospital Readmission trial so that the data can be used to answer the 
questions that the trial intended, certain adjustments in visit procedures may be considered on a 
case-by-case basis, as outlined below. Emory University should be notified before making 
these adjustments. 
• Screening/randomization Visit (Visit S/R) – hospital admission: 
o Screening/randomization activities may be suspended at sites until such time that it is 
considered appropriate by the site to resume activities 
• Visit 2 (Week 2) - office visit: 
o This visit can be conducted at 2 weeks or less. This visit is usually conducted at the 
same time participant has been scheduled for follow up with heart failure services after  
hospital discharge.  
 
• Visit 3 (Week 6), 7 (Week 20) - office visit: 
o an office visit is preferred 
o The visit could be delayed and the visit window extended to accommodate an office 
visit 
o Conducting the visit by phone could be considered 
o If conducted by phone, complete the phone visit procedures outlined in the 
Schedule of Assessments on page 9 
o If laboratory collection is needed at investigator’s discretion, please mail/email 
study laboratory requisition for participant to choose a convenient LabCorp location 
 
• Visit 4 (Week 8), 6 (Week 16), and  8 (Week 24)  - phone visits: 
• Conduct visits, as scheduled, by phone 
 
• Visit 5 (Week 12) - office visit: 
o An office visit is needed to collect study endpoints (echocardiogram, laboratories, 
questionnaires, 6-minute walk test, and dispensing IP)  
o The visit could be delayed and the visit window extended to accommodate an office 
visit  
o If needed, study drug could potentially be mailed by sites to a patient to keep them 
on study drug (depending upon local regulations) until such time that the Week 12 
visit can be conducted in the office 
 
• Visit 9 (Week 26) - office visit: 
o An office visit is needed to collect study endpoints (laboratories, questionnaires, and 
6-minute walk test). 
The visit could be delayed and the visit window extended to accommodate an office 
visit