Clinical trial NCT04792190
Conditions: Atrial Fibrillation
Keywords: Atrial Fibrillation
Sponsor: University of Rochester
Start date: 2021-07-27; Completion date: 2023-06-30
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter trial to evaluate the impact of treatment with dapagliflozin versus placebo following catheter ablation of atrial fibrillation (AF) on the burden of AF during 6-12 months of follow-up. This prospective, randomized, multicenter, placebo-controlled trial aims to enroll 25 subjects with AF (paroxysmal or persistent) who are scheduled to undergo catheter ablation of patients.

Detailed description:
This is a multicenter trial to evaluate the impact of treatment with dapagliflozin versus placebo following catheter ablation of AF on the burden of AF during 6-12 months of follow-up. This prospective, randomized, multicenter, placebo-controlled trial aims to enroll 25 subjects with AF (paroxysmal or persistent) who are scheduled to undergo catheter ablation of patients. All enrolled subjects will be required to have a cardiac implantable electronic device (CIED) capable of assessing the burden of AF. Following catheter ablation for AF and functional CIED subjects will be randomized to treatment with dapagliflozin 10 mg once daily versus placebo. The primary endpoint for the trial will be AF burden assessed at 6-12 months following catheter ablation of AF. The Investigational Drug Services at the University of Rochester will be in charge of dispensing all study related drugs to subject.

Arms: arm 1: A block randomization method will be use to randomize subjects to treatment with dapagliflozin 10 mg once daily. Subjects will take 1 blinded tablet of study drug (dapagliflozin) dosed once daily, per the randomization scheme, for 12 months. Each subject will be dispensed 35 blinded doses per month, during each month of participation in the trial. Quarterly pill counts will be performed to track compliance. arm 2: Subjects will take 1 blinded tablet of placebo drug dosed once daily, per the randomization scheme, for 12 months. Each subject will be dispensed 35 blinded doses per month, during each month of participation in the trial. Quarterly pill counts will be performed to track compliance.
Interventions: intervention 1: dapagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects will take 1 blinded tablet of study drug (dapagliflozin 10 mg) dosed once daily, for 12 months. intervention 2: Subjects will take 1 blinded capsule of placebo drug dosed once daily

Protocol documents:
Prot_SAP_000.pdf: 
DAPA-AF Protocol
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Use of Dapagliflozin to Reduce Burden of Atrial Fibrillation in Patients Undergoing 
Catheter Ablation of Symptomatic Atrial Fibrillation
(DAPA-AF)
Prospective, Randomized, Multicenter, Placebo-Controlled Trial
Principal Investigator: Mehmet K. Aktas, MD
Co-Principal Investigator: Ilan Goldenberg, MD
Co-Principal Investigator: Steven Wittlin, MD
1. PURPOSE OF STUDY 
To investigate the effect of dapagliflozin vs. placebo on the burden of atrial fibrillation (AF) in 
subjects undergoing catheter ablation of AF.
2. BACKGROUND AND RATIONALE 
Atrial fibrillation (AF) is a major public health concern in the United States, affecting an 
estimated 2.3 million Americans.1 The prevalence of AF in the U.S. is projected to reach 12.1 
million by the year 2030.2 AF is the most common sustained arrhythmia seen in clinical practice 
and accounts for approximately one-third of hospitalizations for cardiac dysrhythmias. AF is 
associated with significant mortality, morbidity, and healthcare costs.3, 4 In total, the 
management of AF and its complications costs the U.S. healthcare system approximately $26 
billion each year.5 These costs are expected to increase dramatically unless AF is prevented and 
treated in a timely and effective manner. Antiarrhythmic drug therapy and catheter ablation (in 
select patients) has been the primary treatment for AF,6 but these respective approaches may be 
associated with toxic sides effects7 and procedural complications.8-10 Furthermore, current 
approaches have limited efficacy and most patients require multiple interventions in order to 
achieve control, albeit often inadequate.11, 12  Catheter ablation of AF is performed at many 
medical centers in the United States and throughout much of the developed world and the 
number of patients undergoing ablation of AF continues to rise (Figure 1 below).13 
There are 
myriad of 


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pathophysiologic processes, both at the cellular and structural level, that have been shown to 
lead to the onset and maintenance of AF (Figure 2).6 A commonly observed structural change in 
patients with AF is left atrial enlargement and dilatation. At the cellular level inflammation and 
fibrosis have been identified in patients with AF, even in the absence of structural heart 
disease.14 Left atrial stretch secondary to HF results in neurohormonal activation, which in turn 
can activate multiple downstream profibrotic factors.15 Oxidative stress has been linked to the 
onset and maintenance of AF.16 It is recognized that the onset of AF begets adverse structural 
and electrophysiologic alterations which further begets AF.17  
 
The sodium-glucose cotransporter-2 (SGLT2) is expressed in the proximal convoluted tubules 
of the glomerulus and is responsible for reabsorption of the majority of filtered glucose.18 
Treatment with dapagliflozin, a selective SGLT2 inhibitor (SGLT2i), results in glucosuria and 
its use was initially approved in the treatment of hyperglycemia in patients with type 2 diabetes 
mellitus (T2DM).19-21 Patients with T2DM treated with SGLT2i were shown to experience 
significant reductions in cardiovascular (CV) mortality,22, 23 and more recent studies have shown 
that the CV and heart failure (HF) benefit of treatment with SGLT2i are independent of the 
presence of T2DM.24, 25 Numerous pleotropic effects of SGLT2i treatment have been 
postulated,26 including a reduction in preload by way of osmotic diuresis and natriuresis,27 
reduction in afterload via vascular effects that results in vasodilation,28 inhibition of cardiac 
fibrosis,29 reduction in atrial dilatation30 as well reductions in inflammation31 and oxidative 
stress.32 
In a retrospective sub-analysis of the DECLARE-TIMI 58 trial, dapagliflozin treatment in 
patients with T2DM was associated with a significant 19% reduction in the risk of AF and atrial 
flutter events.25 There are several putative mechanisms as to how dapagliflozin therapy may be 
Figure 2: Mechanisms Predisposing to AF


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effective in controlling AF.  First, natriuresis and diuresis caused by dapagliflozin may decrease 
LA volume and stretch,27, 30 which is known to trigger AF. Second, dapagliflozin has been 
shown to attenuate the release of inflammatory cytokines such as TNF-α which induces 
apoptosis, chamber dilatation and scar formation.31 Third dapagliflozin has been shown to 
reduce fibrosis and oxidative stress possibly rendering the atrial substrate less able to promote 
and maintain AF.29, 32 Finally, SGLT2i have been shown to reduce epicardial fat,33 which is 
closely interconnected with AF.  Thus, it is possible that the pleotropic effects of SGLT2i on 
atrial function, inflammation, fibrosis, and oxidative stress may translate into a corresponding 
reduction in AF burden following catheter ablation of AF. 
The DAPA-HF trial enrolled over 4,700 patients with heart failure with reduced ejection 
fraction (HFrEF) who were randomized to treatment with the SGLT2i dapagliflozin versus 
placebo which were given on top of usual treatment for HF.34 After a median follow-up time of 
18 months, a significant 26% reduction in the composite endpoint of worsening HF or CV death 
was observed in the dapagliflozin treated group. The beneficial effects of dapagliflozin on CV 
morbidity and mortality were observed regardless of the presence of T2DM. Based on the 
results of the DAPA-HF trial, the Food and Drug Administration (FDA) expanded and approved 
the use of dapagliflozin in patients with HFrEF (with and without T2DM) as an oral agent to 
reduce the risk of CV death and hospitalization for worsening HF.
The DAPA-CKD trial enrolled 4304 patients with an estimated glomerular filtration rate (GFR) 
of 25 to 75 ml per minute per 1.73 m2 of body-surface area and urinary albumin-to-creatinine 
ratio of 200 to 5000 to receive dapagliflozin or placebo. After a median of 2.4 years, the 
independent data monitoring committee stopped the trial because of significant efficacy with 
dapagliflozin treatment. The primary outcome, which was a composite of sustained decline in 
the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or 
cardiovascular causes, was 39% lower among dapagliflozin treated patients when compared to 
placebo. Based on the results of the DAPA-CKD trial, the FDA further expanded and approved 
use of dapagliflozin to reduce the risk of sustained eGFR decline, end-stage kidney disease, CV 
death, and hospitalization for HF in adults with chronic kidney disease at risk of progression.
Dapagliflozin is an FDA approved oral agent used 1) to reduce the risk of cardiovascular death 
and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with 
reduced ejection fraction, 2) to reduce the risk of hospitalization for heart failure in adults with 
type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple CV risk factors 
and 3) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 
diabetes mellitus, 4) to reduce the risk of sustained eGFR decline, end-stage kidney disease, CV 
death, and hospitalization for HF in adults with chronic kidney disease at risk of progression.
Our understanding of the risk factors and complications of AF is based mostly on studies that 
have evaluated AF in a binary fashion (present or absent) and have not investigated AF burden 
(quantity or amount of AF that a person has). AF burden was shown to be associated with 
increased risk of cardioembolic stroke, and other cardiac and noncardiac outcomes, including 
HF progression, hospitalizations, and mortality.35-38 A reproducible definition of AF burden is 
the amount of time spent in AF divided by the total amount of time a patient is monitored. 
Cardiac implantable electronic devices (CIED) consisting of either a permanent pacemaker 


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(PPM), implantable cardioverter defibrillator (ICD), cardiac resynchronization therapy with 
defibrillator (CRT-D) or an implantable cardiac monitor (ICM) are capable of tracking the 
amount of AF during specified time periods. Numerous studies have analyzed the diagnostic 
accuracy of AF detection by CIEDs and have found very high sensitivity and specificity as well 
as a strong positive predictive value.39-41
In this study we propose to evaluate the impact of treatment with dapagliflozin versus placebo 
following catheter ablation of AF on the burden of AF during 6-12 months of follow-up using 
CIEDs. We hypothesize that a treatment regimen that includes dapagliflozin in AF patients who 
undergo catheter ablation will decrease the subsequent burden of CIED detected AF when 
compared to placebo.
3. ADMINISTRATIVE ORGANIZATION  
The University of Rochester is the Coordination and Data Center (CDC) for the multisite study.  
The University of Rochester Medical Center and 6 additional sites (7 total enrolling sites) will be 
participating in this trial.  The University of Rochester CDC will provide each site with the study 
protocol and a model consent form, along other relevant subject study materials.    As the 
Coordination and Data Center (CDC), the University of Rochester will provide comprehensive 
training on the study protocol, study operations, and the electronic data capture system 
(TrialMaster).  All training will be documented for each enrolling site.
The Principal Investigator will oversee in conjunction with the CDC all research activities at the 
collaborating sites which will be conducted per the protocol, study operations instructions and 
study training. Research activities will include: subject screening, consenting, enrollment, 
conduct of baseline study procedures, conduct of follow-up study procedures, and drug 
dispensing via the UR Investigational Drug Services (IDS). The CDC is responsible for data 
management, analysis, and coordination of logistics. The enrolling sites will manage all subject 
recruitment activity and data collection per protocol as well as interact with the CDC and 
enrolling site study team regarding study operations.  The CDC will be responsible for overall 
study management, data management, data reporting, and site communications for the study. The 
CDC will act as liaison between the UR Research Subject Review Board (RSRB) which will be 
the reviewing IRB for the study, and the UR-unaffiliated collaborating sites. The CDC will 
coordinate with these sites all reviewing IRB communications regarding initial and amendment 
protocol and consent reviews and approvals, as well as ongoing continuing reviews to ensure 
study and regulatory compliance. The PI in conjunction with the CDC will be responsible for 
overseeing notification to the UR-unaffiliated site investigators and delegated site personnel in 
writing of the RSRB review determinations. Additionally, the PI will conduct quarterly or ad hoc 
conference calls with site PIs and primary coordinators. Weekly internal team meetings will be 
held with the CDC and UR study team; these may be reduced to bi-weekly or monthly as the 
study progresses.
The University of Rochester is the Study Sponsor and is receiving funding from Astra-Zeneca for 
conducting this research study.


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4. STUDY DESIGN
The study is a randomized placebo-controlled prospective multicenter clinical trial of 
symptomatic AF potential subjects who are scheduled to undergo catheter ablation of AF. Prior 
to undergoing ablation, potential subjects will be enrolled (consented) into the study. Following 
successful ablation, study subjects will be randomized in a 1:1 ratio to treatment with 
dapagliflozin (10 mg daily) versus placebo. Prior to randomization the subject must have had 
the AF catheter ablation and an implanted functional CIED in place as described below.
AF burden will be monitored by a CIED) either, 1) ICM, used as standard of care (SOC) for AF 
management or 2) existing PPM, ICD, or CRT-D that has remote monitoring capabilities. 
Enrolled subjects will be followed for a minimum duration of 6 months and a maximum 
duration of 12 months following randomization in both the dapagliflozin and placebo arms as 
follows:

CIED interrogation to quantitate AF burden will be performed during in office visits 
and during remote device interrogations. Interrogation results (PHI redacted by 
enrolling site) will be shared with the study coordination and database center (CDC) at 
the University of Rochester where it will be further reviewed by an independent study 
arrhythmia adjudication committee. AF burden will be quantified.

Clinical data on medication, cardiovascular events, quality of life, and subject reported 
outcomes, will be collected at standard clinical visits.
Primary Endpoint
AF burden assessed at the final follow-up visit following catheter ablation of AF, defined as 
percentage of time spent in AF (i.e. amount of time spent in AF divided by the total 
amount of time a subject was monitored).
Secondary Endpoints 
1. Rate of health care utilization (recurrent hospitalizations, unplanned office visits, 
unplanned remote visits, need for emergency room visits)
2. Post-ablation HF hospitalization
3. AF burden and impact on quality of life measured using the AFEQT score.
Tertiary (exploratory) Endpoints
We will acquire data on the effect of dapagliflozin treatment on clinical outcomes in diabetic 
and non-diabetic subjects with AF. Accordingly, the following exploratory outcomes will be 
compared between the two groups:
1. Other cardiovascular events such as stroke and myocardial infarction
2. Association of AF burden and AF type (paroxysmal vs persistent) with clinical 
decompensation defined as CV hospitalization, unplanned office visits, unplanned 
remote visits, emergency room visits or death.
3. Death


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Figure 3: Study Design
Baseline Testing
AFEQT Score
Placebo
(n=12)
Primary Endpoint
AF Burden at final 
follow-up visit 6-12 
months post 
randomization
Secondary Endpoints
Healthcare Utilization
AFEQT Score
HF Hospitalization
 Dapagliflozin 10 mg
 (n=13)
Primary Endpoint 
AF Burden at final 
follow-up visit 6-12 
months post 
randomization
Secondary Endpoints
Healthcare Utilization
AFEQT Score
HF Hospitalization
AF Ablation + CIED 
(n=25)
Randomize 1:1
Double Blind
4.1.
SUBJECT POPULATION
The study population will include subjects undergoing catheter ablation of AF with an implanted 
CIED or indication for CIED that can be implanted prior to randomization per Figure 3.
Consented eligible subjects will be randomized in a 1:1 ratio to either intervention (dapagliflozin 10 
mg once daily) or control (placebo); About 13 or 12 subjects enrolled to each group for a total of 25 
subjects across all enrolling sites. After enrollment (consent), QoL assessment will be obtained 
using the AFEQT questionnaire.  The subjects will then undergo the index catheter ablation of atrial 
fibrillation.  If CIED does not exist prior to consent then CIED implant will occur prior to, during or 
within 24 hours of the ablation procedure. Following catheter ablation and successful CIED 


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implant, the subject will be randomized, baseline data collected and the subject will be followed 
over a minimum duration of 6 months and up to 12 months duration depending on date of 
randomization. Subsequent study visits visit will be virtual (through phone contact and/or 
videoconferencing) in which: a) remote de-identified CIED interrogations will be transmitted to the 
CDC by the site research coordinator; b) follow-up data on subject status, study drug 
accountability/compliance, and healthcare utilization/adverse events will be obtained. QoL testing 
will be repeated at the 12-month follow-up visit. We believe that the virtual approach to study visits 
and data collection will contribute to significantly higher acceptance and enrollment than in 
previous studies.
Follow-up visits will be done at 3, 6, 9 and 12 months following randomization. 
The study duration is 3 years including a planned study startup period of 6 months, an enrollment 
period of 18 months, a follow-up period of 6 months, and 6 months for closeout and analysis. 
4.2.
STUDY INTERVENTIONS
Please see section 8 entitled study procedures that includes further study interventions.
This study is not studying CIEDs nor the AF ablation procedure but will utilize data already 
clinically used and available from the CIED. Subjects without a CIED in situ will undergo CIED 
implant at the time of, or within 24 hours following the ablation procedure. All consented subjects 
will be implanted with a CIED using standard of care procedures and indication and then undergo 
randomization.  All CIEDs including future upgrades that are utilized in this study will be FDA 
approved and used per the current FDA indications as standard of care to monitor arrhythmias 
following catheter ablation. Subjects are consented as it is required that the QOL questionnaire be 
obtained prior to the AF ablation. Subjects will be screen failures and not undergo randomization if 
catheter ablation is not performed or if there is no existing functional CIED within 24 hours 
following the ablation procedure.  
There are risks associated with the use of any medication. It is important to note that in this 
study, dapagliflozin will be administered in the intervention according to currently approved 
FDA indications for it use. Medications inherently may be associated with side effects. The 
clinical research team is experienced in cardiovascular trials and the clinical management of 
subjects with heart disease/heart failure and will be monitoring for any adverse effects. This is a 
Phase 4 study, and we are comparing two management strategies that are currently employed in 
clinical practice.
5. INCLUSION AND EXCLUSION CRITERIA
Inclusion Criteria

Eligible for treatment with dapagliflozin per current FDA-approved indications, 
including: 1) heart failure (NYHA class II-IV) with reduced left ventricular ejection 
fraction (<50%), or 2) type 2 diabetes mellitus and established cardiovascular (CV) 
disease or multiple CV risk factors, or 3) as an adjunct to diet and exercise to improve 
glycemic control in adults with type 2 diabetes mellitus, 4) adults with chronic kidney 
disease at risk of progression as defined by the National Kidney Foundation as estimated 
GFR <60 ml/minute/1.73 m2.


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
Scheduled to undergo ablation of symptomatic paroxysmal or persistent AF prior to date 
of randomization per current guideline indications.

A glycated hemoglobin level < 10.5% during the past 6 calendar months prior to consent 
only in patients with type 2 diabetes mellitus

Age > 18 years

Existing functional CIED or planned to undergo CIED implant as SOC before or within 
24 hours following the AF ablation procedure and prior to randomization date.
Exclusion Criteria

Type 1 diabetes mellitus

History of diabetic keto-acidosis

Child Pugh Class C liver disease

Last measured estimated GFR < 25  ml/minute/1.73 m2 

Pregnancy, plan to become pregnant <1 year after consent or breast feeding 

Current therapy with an SGLT2 inhibitor

Hypersensitivity to dapagliflozin

On heart transplant list or likely to undergo heart transplant 

Unwilling or unable to cooperate with the protocol

Participation in other clinical trials (observational registries are allowed with approval). 

Unwilling to sign the consent for participation

Life expectancy <1 year after consent date for any medical condition
6. RECRUITMENT METHODS
Each site participating in the study will develop and implement recruitment methods that are 
appropriate to their institutional policies and guidelines, along with consideration to the rights 
and welfare of human subject research. An overall Recruitment Plan describing the use of 
recruitment materials and processes will be required as an addendum to the individual site’s 
customized protocol for RSRB review and approval.  Sites will utilize the IRB approved Study-
related Documents customized with their individual site information which will be submitted for 
approval to the RSRB under their local site submission documents. Any additional site-specific 
recruitment materials the site develops outside of the approved Study-related Documents will be 
submitted to the RSRB for local site approval.
If the potential subject meets inclusion/exclusion criteria at time of consent, the study team will 
approach potential subjects for participation in the study based on the policies of the enrolling 
site.  Enrolling site study staff will use a recruitment phone script and phone number obtained 
from a potential subject’s records to contact a potential subject by phone. If during a clinic visit, 
the enrolling site staff will approach the potential subject with the same information as in the 
phone script to assess a potential subject’s willingness to participate in the study. 
7. CONSENT PROCESS
A model consent document as well as the study protocol will be provided to each site to obtain 
reviewing IRB approval specific to the enrolling site.  Revisions to the model consent require 
approval from the Coordination and Data Center prior to submission of the consent to the 
reviewing IRB.  Only the current site-specific reviewing IRB-approved consent form will be 


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provided to the potential subject for all consenting process options described below.
The informed consent process will be conducted by the Principal Investigator or individual 
authorized to conduct the process and will follow the local applicable laws, rules, regulations and 
guidelines.  The informed consent process may be conducted in person or remotely using either a 
paper consent form or an electronic eConsent depending on the option that the potential subject 
prefers as indicated in the initial study recruitment contact with a study team member.  
If using a paper consent form to remotely consent a potential subject, 2 copies of the consent 
should be mailed or e-mailed to the potential subject approximately 1 week prior to the 
telemedicine visit to allow the potential subject time to review the consent.  A telemedicine 
appointment will be set up to discuss questions regarding the study with the potential subject and 
confirm the potential subject fully understands the study requirements.  If the potential subject 
agrees to participate in the study, the potential subject will sign both consent forms and mail one 
back to the site team using the self-addressed envelope including postage that was provided by 
the site team.  If the potential subject receives the consent via email, the potential subject will be 
asked to print 2 copies of the consent form and mail one back to the site team or bring the signed 
paper consent to the initial study visit.
The consent document will also be created using an electronic consent form that may be 
electronically signed by the potential subject. The site may consent a potential subject using a 
secure, web-based, HIPAA-compliant, TrialMaster data collection platform with a user 
management system allowing project owners to grant and control varying levels of access to data 
collection instruments and data (e.g. read only, de-identified-only data views) for other users.  The 
study team member(s) delegated by the enrolling site PI for e-consenting would need to utilize 
uniquely assigned access website credentials to enter the potential subject’s email address to 
enable the email to be sent by the website to the potential subject per the initial recruitment call.  
The website instructions, secured link, access credentials and unique signing code as identity 
verification assigned by the website system will be emailed to the potential subject.  The 
potential subject may review the consent on the website and send questions to the study team via 
the website.  
A telemedicine visit will be set up to discuss questions regarding the study with the potential 
subject and to confirm the potential subject fully understands the study requirements.   If the 
potential subject decides to participate in the study, then the potential subject will be provided 
with a unique subject-assigned signing code to electronically sign the consent during the 
telemedicine visit.  The website will indicate to the potential subject that this electronic signature 
is equivalent to a handwritten signature on a hard copy of the consent. The study coordinator will 
be able to print a final signed consent after completion of the e-signing process. The potential 
subject’s access to the website will be restricted to only the consent and be disabled following 
consent signature. 
The consent document will be used as a guide for discussion with the potential subject.  The 
potential subject will be given sufficient time to ask questions and to consider participation.  The 
study team provides contact information (email and phone) for potential subjects to contact a study 
team member with questions either in person, email or through the website that has a link for 
questions with a message sent to the PI and other delegated members of the study team.  The study 


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team may respond to questions by email, phone or sending a message to the patient with a response 
to any questions in addition to the telemedicine visit specifically set up to discuss the study with the 
potential subject prior to consent signing.  The potential subject’s email will only be entered in the 
electronic system if the potential subject chooses to electronically sign the consent. 
The potential subject’s refusal to participate or subject’s withdrawal from the study will not 
interfere with future medical treatment.  All subjects will receive a copy of their signed informed 
consent and the original will be maintained at the enrolling site.  Subject recruitment at an 
enrolling site may not begin until the reviewing IRB approval is obtained related to the enrolling 
site study protocol and consent. 
Consent to Re-Contact: 
Data collected may be used for the development of future research studies. The enrolling sites 
will maintain the confidentiality of the data throughout the process. Only authorized research 
personnel at the enrolling site working on the project will have access to the data. Consent for 
this purpose will be asked of subjects and response noted via checkboxes for subjects to indicate 
consent to future use of information and for “Consent to Re-Contact.”  
Subjects will be asked to consent to re-contact by the study physician, or someone from the study 
team, in the future about using information for research that is not described in the consent form. 
Additionally, they will be given the option to consent to future contact from the study team about 
participation in other research.  
8. STUDY PROCEDURES
After signing consent, all subjects will undergo randomization and study related procedures, as 
well as standard of care procedures, per Table 1 and as indicated below. 
All subjects will either have a functional CIED already implanted prior to AF ablation, at time 
of AF ablation or within 24 hours following AF ablation as standard of care.
All subjects enrolled in the study will remain on SOC medications and participation in the study 
will not require discontinuation of any SOC medications. 
Intervention Management Arm (Dapagliflozin)
A block randomization method will be use to randomize subjects to treatment with 
dapagliflozin 10 mg once daily versus placebo. Subjects will take 1 blinded tablet of study drug 
(dapagliflozin) dosed once daily, per the randomization scheme, for a 6-12 month duration 
depending on date of randomization. All active and placebo tablets will be identical in 
appearance (same size, shape and color). Subjects will be encouraged to start study drug within 
2 weeks of the date of randomization. Study subjects will be instructed to ingest all tablets 
whole and not to open them. Each subject will be dispensed 35 blinded doses per month, during 
each month of participation in the trial. Quarterly pill counts will be performed to track 
compliance.  All drug dispensing (dapagliflozin and matching placebo) will be managed by the 
Investigational Drug Services (IDS) in the Department of Pharmacy at the University of 
Rochester Medical Center. The unit manages drug dispensing for numerous clinical trials and 


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has vast experience in this field. Any study related side effects will be reported to the 
independent Data and Safety Monitoring Board (DSMB) for review (details below). The cost of 
study drug will be covered by the study. 
Patients with diabetes who are started on dapagliflozin will continue to undergo standard of 
care glucose monitoring as directed by the primary treating physician. The initiation of 
dapagliflozin does not require any incremental testing/monitoring beyond what is performed as 
standard of care.
IDS is in full compliance with federal, state, Joint Commission on Accreditation of Healthcare 
Organizations (JCAHO), and American Society of Health-System Pharmacists (ASHP) 
requirements regarding control of investigational drugs. Investigational drugs will be stored in 
both the IDS and the Department of Pharmacy to ensure appropriate access, security, stability, 
and compliance with FDA guidelines. Drug order, receipt, and return forms will be maintained 
for all medications used in the clinical trial. Drug accountability records will be maintained for 
all study drug received, stored, dispensed and destroyed by the IDS. Study drug supplies will be 
inventoried on a regular basis for quality assurance purposes. IDS will maintain records after 
study completion according to FDA requirements, or as specified per protocol. JCAHO 
requires that anyone administering an investigational drug have a working knowledge of the 
drug, such as its purpose, side effects, precautions, and procedures for administration. All IDS 
personnel involved in the trial will receive the necessary training to ensure full compliance with 
good clinical practice guidelines.
Control Arm (Placebo)
Subjects will take 1 blinded tablet of placebo drug dosed once daily, per the randomization 
scheme, for a minimum duration of 6 months and maximum duration of 12 months.
Procedures for Both Groups – Regardless of Randomization:  
Post-randomization, follow-up of subjects in each arm will include SOC visits at 3, 6, 9 and 12 
months. When feasible these will be virtual (TeleHome) visits in order to minimize study 
related burden on enrolled subjects. Study related adverse events and protocol deviations will 
be recorded during each of these SOC visits.  CIED interrogation data will be obtained either 
via remote CIED downloads or during in-office visits. The interrogation data will be acquired 
in a standardized PDF format. The interrogation report will de-identified. All protected health 
information will be removed and subject ID will be entered for tracking. The de-identified PDF 
file will be uploaded to the study web-based data management system in a HIPAA compliant 
manner. CIED interrogation reports will be reviewed by an independent Events Adjudication 
Committee, blinded to treatment assignment. The final SOC visit will take place in-office, 
during which time all study related procedures and assessments will be completed.
Standard of Care Procedures 

In-office or TeleHome follow up visits as scheduled will occur at 3, 6, 9 and 12 
months.   These visits will include a medical assessment, drug 
accountability/compliance, device interrogation, and subjects will be questioned 
about clinical and medical (adverse) events. 


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
12 lead ECGs if performed as SOC at Baseline, 3 months, 6 months, 9 months and 12 
months.

Remote interrogation data from CIED will be collected. 

Echocardiographic data if performed as SOC.

Blood sugar monitoring in diabetics per SOC.
Research Activities:  

Chart reviews will be performed by the study team at each time point and include data 
about clinical history, medications, ablation procedure, device implantation, and 
follow-up data will be collected from the medical record.  

Assessment of healthcare utilization (comprising the total of unplanned in-office 
visits, hospitalizations, repeat ablations, or death).

AFEQT questionnaires will be completed by the subject at baseline and the final 
follow-up visit. The questionnaire should take the subject approximately ten minutes 
to complete. We will utilize an instrument specifically designed for patients with AF, 
the Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT), a questionnaire focusing 
on symptoms, daily activities, treatment concerns and treatment satisfaction.
Method of Assigning Subjects to Treatment 
Subjects will be randomized 1:1 to Dapagliflozin versus placebo. Randomization will occur 
electronically using the electronic data collection system, TrialMaster that is available 24/7 to all 
study personnel.
Follow-up 3, 6, 9, 12 months (See Table 1)
Following enrollment and randomization all subjects will have SOC follow-up in-office or 
TeleHome visits at 3, 6, 9 and 12 months. TeleHome videoconferencing visits may be replaced 
with in-office visits as needed. 
All subjects will be followed for a time-period of a minimum of 6 months and maximum of 12 
months.  
The following study related data will be collected during SOC visits after ablation.

3 Months ± 1 calendar months from study drug initiation date
o
Review of medical history including adverse events, hospitalization, 
unplanned office visits, and emergency room visits
o
Study drug accountability and compliance
o
Current cardiac medication
o
Blood sugar values in diabetic patients 
o
Assessment of symptoms
o
12-Lead ECG (if done per standard of care)
o
CIED Interrogation 

6 Months ± 1 calendar months from study drug initiation date
o
Review of medical history including adverse events, hospitalization, 
unplanned office visits, and emergency room visits


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o
Study drug accountability and compliance
o
Current cardiac medication
o
Blood sugar values in diabetic patients
o
Assessment of symptoms
o
12-Lead ECG (if done per standard of care)
o
CIED Interrogation 
o
AFEQT Questionnaire (if final follow-up visit)

9 Months ± 1 calendar months from study drug initiation date
o
Review of medical history including adverse events, hospitalization, 
unplanned office visits, and emergency room visits
o
Study drug accountability and compliance
o
Current cardiac medication
o
Blood sugar values in diabetic patients 
o
Assessment of symptoms
o
12-Lead ECG (if done per standard of care)
o
CIED Interrogation
o
AFEQT Questionnaire (if final follow-up visit)

12 Months ± 1 calendar months from study drug initiation date
o
Review of medical history including adverse events, hospitalization, 
unplanned office visits, and emergency room visits
o
Study drug accountability and compliance
o
Current cardiac medication
o
Blood sugar values in diabetic patients 
o
Assessment of symptoms, NYHA functional class
o
12-Lead ECG and Echocardiogram data (if done per standard of care)
o
CIED Interrogation 
o
AFEQT Questionnaire
Communication at Randomization and the Conclusion of the Final Follow-up Visit
In order to maintain oversight and continued clinical management, the site PI will communicate 
by letter with the subject’s treating physician that the subject is randomized and participating in 
the study. Also, at the conclusion of the final treatment visit, if the patient tolerated the study 
drug (Dapagliflozin or placebo), the site PI will communicate by letter with the subject’s treating 
physician that it is recommended that the subject be treated with an SGLT2 inhibitor per FDA-
approved indication.


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Table 1:  Schedule of Activities
Reportable
Data Items
Screen/
Consent/
Randomization
Baseline 
In-Office or 
TeleHome 
Visit
3 months 
In-Office or 
TeleHome Visit
6 months 
In-Office or 
TeleHome Visit
9 months 
In-Office or 
TeleHome Visit
12 months 
Timeframe
Confirm 
eligibility,
consent,
randomize
Following 
randomization
3 months  (+/-1 
calendar month) 
after date of 
study drug 
initiation
6 months  (+/-1 
calendar month) 
after date of 
study drug 
initiation
9 months  (+/-1 
calendar month) 
after date of 
study drug 
initiation
12 months  (+/-
1 calendar 
month) after 
date of study 
drug initiation
Inclusion/Exclusion
√
Informed Consent 
√
Demographics 
√
Medical/Cardiac 
History
√
Limited Physical 
Exam/NYHA
√
√
AF Ablation*
√
CIED Device*
√
AFEQT 
Questionnaire
√
√***
√***
√
CV and Diabetes  
Medication Log*
√
√
√
√
√
ECG*
√
√
√
√
√
LVEF 
(Echocardiogram)*
√
√
HbA1c**  (per SOC)
√
√
√
Study Drug 
Initiation/
Accountability
√
√
√
√
√
CIED Interrogation 
and Activity Data* 
√
√
√
√
Follow-up 
Contact/Cardiac 
Events/Procedures/
Glucose**
√
√
√
√
√
Adverse Events, HF 
hospitalization, 
Unplanned 
hospitalization, 
office, remote or ER 
visit, death
√
√
√
√
√
Protocol Deviations
√
√
√
√
√
* Standard of care procedures ** Diabetic subjects only   ***If final follow-up visit
Plans for return of research results:
Research results will not be provided directly to subjects, but will be presented in national 
conferences and published in peer-reviewed papers after study completion. If requested by 
subjects we will send the published research results to subjects.  Subjects will be notified if 
anything of medical importance is found.


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9. RISKS TO SUBJECTS
The optimal treatment of patients undergoing ablation of AF remains an area of intense research. 
Patients undergoing ablation of AF experience a high rate of recurrent AF.  There is evidence 
that dapagliflozin therapy may reduce the burden of AF.  All patients enrolled in this study will 
have an FDA approved indication for dapagliflozin therapy. If a patient becomes pregnant during 
the course of the study, study drug should be discontinued immediately and CDC notified. 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 medication.
The study is designed to prospectively evaluate whether dapagliflozin can reduce the burden of 
AF after ablation when compared to placebo. 
Confidentiality Risk(s)
The risk to participating in this study may include a potential risk of a breach in confidentiality.  
Every effort will be made to keep the data confidential.  To protect against this risk the 
information collected at each enrolling site will be entered by site personnel into a password 
protected electronic data capture (EDC) system.   Subjects will be assigned a unique subject 
identification number at the time of registration, which is completed in the EDC system. The 
subject identification number is not connected with any PHI, such as date of birth or medical 
record.
Dapagliflozin Treatment Risks
Dapagliflozin has been studied in multiple clinical trials and has been found to be very well 
tolerated and has a high safety profile. However, the following serious risks have been associated 
with dapagliflozin treatment.
1.
Volume Depletion: Dapagliflozin can cause intravascular volume depletion which may 
manifest as symptomatic hypotension or acute transient changes in creatinine. Acute 
kidney injury requiring hospitalization and dialysis has been reported in patients 
with type 2 diabetes receiving SGLT dapagliflozin. Patients with impaired renal function 
(eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may 
be at increased risk for volume depletion or hypotension. Diuretic dosing may be titrated 
according to symptoms, signs, weight and other information per standard clinical 
practice. Temporary interruption of study drug may also be considered in subjects at 
potential risk of volume contraction.
2.
Ketoacidosis in Diabetes Mellitus has been reported in patients with type 1 and type 2 
diabetes receiving dapagliflozin. Some cases can be fatal. If ketoacidosis is suspected, the 
study drug will be discontinued. Patients on dapagliflozin may require monitoring and 
temporary discontinuation in situations known to predispose to ketoacidosis
3.
Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the risk for urinary tract 
infections (UTIs) and serious UTIs have been reported with dapagliflozin. Patients on 
study drug will be evaluated for signs and symptoms of UTIs and will be treated 
promptly.
4.
Hypoglycemia: dapagliflozin can increase the risk of hypoglycemia when co-
administered with insulin and insulin secretagogues. Patients with type 2 diabetes at 
randomization will continue to take their glucose-lowering therapies but dose adjustments 


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may be required at the discretion of the treating primary care physician as per standard of 
care glucose monitoring in diabetic patients. The dose of insulin and/or sulfonylurea 
therapy may be reduced to minimize the risk of hypoglycemia at the discretion of the 
primary treating physician per standard clinical practice.
5.
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Rare but serious, life-
threatening cases have been reported in patients with diabetes mellitus receiving SGLT2 
inhibitors including dapagliflozin. Cases have been reported in females and males. 
Serious outcomes have included hospitalization, surgeries, and death. Patients will be 
assessed for pain or tenderness, erythema, swelling in the genital or perineal area, along 
with fever or malaise. If suspected, prompt treatment will be instituted and study drug 
will be discontinued.
6.
Genital Mycotic Infections: dapagliflozin increases the risk of genital mycotic 
infections, particularly in patients with prior genital mycotic infections. Patients will be 
monitored and treat appropriately
The DAPA-HF trial enrolled 4,744 patients with heart failure with reduced ejection fraction 
(HFrEF) and randomized patients to treatment with dapagliflozin 10 mg once daily versus 
matching placebo. Dapagliflozin was stopped in 249 patients and placebo was stopped in 258 
patients (10.5 vs 10.9%, P=0.71). Table below lists common adverse reactions associated with 
dapagliflozin therapy compiled from 12 placebo-controlled clinical trials. Standard of care 
monitoring of blood sugar values will be recommended for all diabetic patients enrolled in the 
study regardless of treatment allocation.  Of note, treatment with an SGLT2 inhibitor was not 
shown to be associated with increased risk of hypoglycemia, and in the DAPA-HF study the rate 
of hypoglycemia was 1/2368 in the Dapagliflozin treatment arm vs. 4/2368 in the placebo arm. 
All adverse events during the trial will be prospectively collected and reviewed (detailed below 
in Table 2).
Mitigation of risk associated with the Study Drug will follow drug labelling 
Table 2:


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recommendations per standard of care and procedures performed in the DAPA-HF clinical 
trial. These will include:
1.
Glucose and HgBA1c monitoring in diabetic subjects will be performed as per standard 
of care. Patients with type 2 diabetes at randomization will continue to take their glucose-
lowering therapies but these can be adjusted at the discretion of their diabetes health care 
provider. The dose of insulin and/or sulfonylurea therapy may be reduced to minimize the 
risk of hypoglycemia at the discretion of the primary treating physician per standard 
clinical practice.
2.
Study drug will permanently be discontinued if pregnancy or diabetic ketoacidosis occur. 
Dose reduction (to dapagliflozin 5 mg daily or matching placebo) or temporary 
discontinuation may be considered in cases of acute, unexpected declines eGFR (while 
investigating other causes such as nephrotoxic drugs, urinary traction infection, or 
obstruction.  Similarly, in cases of volume depletion and/or hypotension, alternative 
causes should be considered (e.g. gastrointestinal fluid loss, use of non-essential blood 
pressure-lowering drugs) and the dose of concomitant diuretic therapy re-assessed and 
reduced, if appropriate. Temporary interruption of study drug may also be considered, 
prophylactically, in subjects at potential risk of volume contraction/hypotension, such as 
subjects with an acute medical illness potentially causing volume depletion because of 
inadequate fluid intake or fluid/blood losses (e.g. gastroenteritis, gastrointestinal 
hemorrhage), or subjects undergoing major surgery.
3.
Subject notification of possible adverse events at enrollment.
4.
Adverse event data collection and independent DSMB monitoring.
Placebo Arm Treatment Risks
Subjects randomized to the placebo arm will undergo standard of care management following 
AF ablation. With regard to AF outcomes there are no known risks associated with not treating 
with dapagliflozin in the placebo arm.  
10. POTENTIAL BENEFITS TO SUBJECTS
Subjects randomized to dapagliflozin may experience a lower burden of AF following ablation. 
11. COSTS FOR PARTICIPATION
There are no additional costs to the subject. All office visit/procedures will follow standard of 
care guidelines and are covered by subject’s medical insurance. The randomization process will 
not add to subject costs.
12. PAYMENT FOR PARTICIPATION 
There will be no compensation for participation in this study.
13. SUBJECT WITHDRAWALS
Randomized subjects may be withdrawn prior to the study completion for a variety of reasons 
including:
a) Subject withdraws consent for any reason and will not be replaced.
b) Subject is lost to follow up despite best efforts to locate the subject and will not be replaced.
c) Subject withdrawn by physician.


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Subjects may be considered lost to follow up after missing two consecutive follow-up visits with 
documented efforts to contact the subject. 
These subjects will not undergo any additional study activities after withdrawal. Data collection 
will occur until the date of withdrawal and utilized in the study analysis. Withdrawn subjects 
who have been randomized will not be replaced.  Withdrawn subjects will be requested to return 
all study drug at the time of withdrawal if contact is made with the subject.  Subjects will not be 
required to withdraw from the study if the study drug is discontinued or unblinded. Subjects will 
not be required to be withdrawn from study if the subject decides not to take the study drug.
14. PRIVACY AND CONFIDENTIALITY OF SUBJECTS AND RESEARCH DATA
Data collected during this study will be obtained for research purposes and derived from study 
procedures, CIED interrogation data, subject records and subject visits. All study data will be 
stored in perpetuity in a password-protected database located at the CCRC per Section 15 and 
de-identified. Data will be accessible to the research sites and people who work with the 
University of Rochester which may use the results of the study for other research purposes. To 
protect confidentiality and privacy, subject data will be assigned a code using a unique subject 
ID number at the time of randomization and linked to subject identifiers that are stored 
separately in a study log solely maintained by the enrolling site study coordinator. The electronic 
data will be directly entered and extracted from computer system for data collection using 
encryption and physical controls. There is no plan to share, transmit or transfer the data. The 
subject’s email address will not be stored nor transmitted with the study data if the subject opts 
for electronic consent signature via the study website.  
15. DATA / SAMPLE STORAGE FOR FUTURE USE
Study coordination, database management and statistical analysis will be performed by the 
Clinical Cardiovascular Research Center (CCRC) at the University of Rochester Medical Center 
(U of R) acting as the Coordination and Data Center for the study.  
Data will be captured using TrialMaster, a HIPAA compliant secure web-based electronic data 
capture (EDC) system that is used to support the clinical research process.  Data that are entered 
are validated against a set of rules to ensure the accuracy of the clinical data.  The TrialMaster 
system is housed on CCRC servers that are housed behind the U of R firewall in the U of R 
Primary Data Center, where physical access and environmental controls are in place to protect 
the data.  All access to the data is through an authentication process provided by the system and 
over the encrypted, secured U of R network, which both provide the necessary controls to 
prohibit unauthorized access to the clinical data.  Continuous availability of the data is provided 
by mirroring the databases to servers located in a physically separate Secondary Data Center. 
Additional details are in the Data Safety Monitoring section below. Only authorized research 
personnel working on the project will have access to the data.
Only enrolling site personnel authorized by the site Principal Investigator will have access to the 
EDC system.  Study personnel at each site delegated with EDC permission will be required to 
complete EDC training before receiving access to the system.  Site personnel with EDC 
permission will have access to the system 24/7 for data entry.  Study personnel will initially enter 


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all data related to the randomization and baseline data collection and will then complete data 
entry after each identified data collection timeframe per Table 1.  
Data collected may be used for the development of future research studies. We will maintain the 
confidentiality of the data throughout the process. The subject will be given the option to agree 
or decline to be re-contacted in the future by the study doctor, or someone from the study team, 
about using the subject’s information for research that is not described in the DAPA-AF study 
consent form; or to participate in other research. Re-contacting the subject may be made in 
person, by phone or by mail.
16. DATA AND SAFETY MONITORING PLAN
Adverse Event (AE) Data
An AE is the development of an undesirable medical condition or the deterioration of a 
preexisting medical condition following or during exposure to study drug, whether or not 
considered causally related to the product. An undesirable medical condition can be symptoms 
(e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the abnormal results of an 
investigation (e.g. laboratory findings, electrocardiogram). In clinical studies, an AE can include 
an undesirable medical condition occurring at any time, including run-in or washout periods, 
even if no study drug has been administered. The term AE is used to include both serious and 
non-serious AEs. 
All adverse events will be collected after subject randomization at all subject contacts as 
indicated in Table 1. Adverse event data will be captured in the electronic data capture system 
and enrolling site investigators are responsible for reporting to and following reviewing 
Institutional Review Board (IRB) guidelines and reported to the DSMB.  De-identified adverse 
event safety data will be provided to Astra-Zeneca, the study drug manufacturer as reported in a 
password-protected file per post-market FDA regulations.
Adverse Event Reporting 
Enrolling site investigators shall report in the CDC electronic data collection system within five 
business days of PI awareness non-serious adverse events that are only related or suspected to be 
related to study activities and/or study medication, and all serious adverse events regardless of 
the relationship to the study activities and/or study medication per the serious event definitions 
below. Events leading to death or death (if event leading to death) of a subject must be reported 
as an adverse event, per the serious adverse event definition below. The enrolling site PI is aware 
that investigators are responsible for reporting to and following the guidance of any other 
applicable oversight bodies, including the reviewing Institutional Review Broad (IRB). 
The CDC will be forwarding relevant documents to the Chair of DSMB for review and the Chair will 
determine whether individual case will require immediate assessment by the full DSMB committee 
or it could be assessed during electively scheduled DSMB meeting. Any SAEs meeting criteria for 
expedited reporting, the PI will be responsible for reporting to FDA and will notify AZ concurrently. 
We will also inform Astra Zeneca, the study drug manufacturer, about reported adverse events per 
FDA post-marketing regulation requirements.
Serious Adverse Event Definition 


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This population is at increased risk of heart failure, death, and poor clinical outcomes. A serious 
adverse event (SAE) is defined as any adverse medical experience that results in any of the 
following outcomes regardless of causal relationship with the study drug: 
Results in death

Is immediately life-threatening or results in death

Requires in-patient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity or substantial disruption of the

ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the subject or may require medical

Intervention to prevent one of the outcomes listed above. 
Unanticipated Problem Definition
An Unanticipated problem is any event, experience, issue, instance, problem or outcome that meets 
all 3 of the following criteria:

Is unexpected in terms of the nature, severity or frequency given the research procedures 
that are described in the protocol–related documents AND in the characteristics of the 
population under study or if cause is study drug an adverse event or suspected adverse 
reaction is considered unanticipated if it is not listed in the study drug package insert or is 
not listed at the specificity or severity that has been observed per the study drug package 
insert.

Is related or possibly related to participation in research.  This means that there is a 
reasonable possibility that the incident may have been caused by the procedures and/or study 
drug involved in the research study.

The incident suggests that the research places the subject or others at greater risk of harm 
(physical, psychological, economic or social) than was previously known or recognized OR 
results in actual harm of the subject or others.  An unanticipated problem generally required 
a change in policy or procedure, warrants consideration of substantive changes to the 
protocol/consent or other immediate corrective actions in order to reduce the risk or 
eliminate immediate hazard.
Data and Safety Monitoring Board 
A data and safety monitoring board (DSMB) will be appointed to independently monitor the 
conduct and the outcome of the trial. The DSMB will be responsible for monitoring the safety 
and well-being of the subjects participating in this study and ensuring the ethical conduct of the 
trial. The DSMB will be responsible for safeguarding the interests of study participants, 
assessing the safety and efficacy of study procedures and study drug, and for monitoring the 
overall conduct of the study.
The main focus of DSMB activity will be to monitor complications after randomization. For all 
randomized subjects, data on clinical events including adverse events, cardiovascular 
hospitalizations, and death will be collected and provided to the DSMB for evaluation of risks 
associated with participation in the trial.
The DSMB will be an independent group advisory to the Coordination and Data Center study 
principal investigator and asked to provide recommendations about starting, continuing, and 


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stopping the study. In addition, the DSMB asked to make recommendations, as appropriate, 
about:

Efficacy of the study intervention

Benefit/risk ratio of procedures and participant burden

Selection, recruitment, and retention of participants

Adherence to protocol requirements

Completeness, quality, and analysis of measurements

Amendments to the study protocol and consent forms

Performance of individual sites 

Participant safety
The board will be comprised of 4 independent members: (1) 1 statistician with experience in 
clinical trials; (2) 1 cardiologist with expertise in clinical trials; (3) 1 electrophysiologist with 
expertise in ablation and arrhythmia treatment; and (4) 1 endocrinologist with expertise in 
diabetic monitoring and treatment. The DSMB will meet before trial commencement, after 25 
subjects are enrolled and when the 6 month follow-up visit is completed on the last randomized 
subject. It is anticipated that these meetings will take place via conference call. One of the 
clinicians will be selected to chair the committee and will serve as the principal representative of 
the group. The Chair of the committee will be informed monthly about adverse events and will 
monitor safety of the subjects during interim time between formal meetings of DSMB.
Reports will be sent by the CDC to the DSMB chair, to report data on expected and unexpected 
adverse events as they are reported by the enrolling site. The Chair of the DSMB will have the 
right to convene additional meetings with all DSMB members when needed.  The DSMB will 
carefully consider if these events are consistent with anticipated clinical outcome, i.e. unrelated, 
or a consequence of the study activity and/or study drug, i.e. related. Information on all these 
events will be sent to DSMB Chair as they occur and in addition, a full DSMB report including 
an adverse event summary will be prepared before every elective DSMB meeting.
17. DATA ANALYSIS PLAN
Descriptive statistics will be used to evaluate the rates related to the primary endpoint and 
health care utilization and HF hospitalization secondary endpoints for each group in the study 
population. Further, mean quality of life AFEQT scores will also be reported. General linear 
models will be used to identify factors associated with the risk of both AF burden and recurrent 
endpoints during follow-up. 
For the primary endpoint of AF burden, defined as percentage of time spent in AF (i.e. amount 
of time spent in AF divided by the total amount of time a patient was monitored), the 
student’s t-test will be used to statistically compare the placebo group vs. the active treatment 
group. This approach is subject to an examination of the distribution of the percent time in AF. 
Currently, patients with persistent AF account for >60% of the AF ablation volume in each of the 
enrolling sites and therefore we anticipate a higher burden of AF than what has been reported in 
patients with paroxysmal AF, including CAPTAF (in which patients with paroxysmal AF 


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comprised 70% of the study population).42 
Our preliminary data on 125 patients implanted with an ICM at URMC of whom 65% had 
persistent AF, show an overall AF burden of 25%. Other published studies have shown a higher 
burden of AF in persistent AF populations.43 In the present study, enrollment will use a stratified 
proportionate allocation in a 2:1 ratio by type of AF (persistent vs. paroxysmal, respectively) to 
ensure a sufficient proportion of subjects with persistent AF.
 
Sample size
Our re-estimated power calculations are based on the following parameters:
1. 25 subjects randomized
2. Minimum follow-up of 6 months, average follow-up of 9 months.
3. Our preliminary interrogations suggest that we may have underestimated AF burden 
(possibly due to the higher risk characteristics of enrolled patients with heart failure, 
diabetes, and renal dysfunction). The revised AF burden estimate takes a conservative 
measure of at least 40%. 
The Table below provides power calculations for a treatment effect in the range of 40% to 50%.
SD
sample
total
Reduce
Average 
AF 
burden: 
placebo
Average AF 
burden: 
Intervention
deviation
power 
size
dropout
sample
50%
40%
20.0%
15%
85%
23
10%
25
45%
40%
22.0%
15%
76%
23
10%
25
43%
40%
22.8%
15%
73%
23
10%
25
40%
40%
24.0%
15%
66%
23
10%
25
Based on our preliminary interrogation data above, the primary outcome of AF burden over an 
average follow-up of 9 months is assumed to be 40% in the placebo group and 20-24% in the 
intervention (dapagliflozin) group, with a standard deviation of 15% (a conservative estimate 
which allows for 10% drop-out).  With a sample of 25 subjects randomized, a reduction from 
40% to 20%-22% would provide 85%-76% power, respectively. Other possible scenarios are 
provided in the Table above.
We therefore, believe that the study may be the first to provide pilot prospective data on the 
possible antiarrhythmic properties of dapagliflozin following AF ablation.
The study power should not be affected by the association of diabetic status and cardiovascular 
medications with the study drug, Dapagliflozin, or AF burden, the primary outcome of the study. 
Further, prior publications have not shown differential effects of this drug within diabetic status 
or medication subgroups. Also, because the study drug and placebo groups will be randomly 


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assigned the distribution of diabetic patients and use of cardiovascular medications should be 
similar in the two. We will perform a sensitivity analysis where we adjust for diabetics and heart 
failure both parametrically and non-parametrically. Finally, the study was not designed to be 
powered to look for affects in subgroups of the study population, only in the overall enrolled 
study group.
18. COORDINATING CENTER TRACKING
Acting as Coordinating Center for the study, in order to ensure all required information is 
provided to the reviewing IRB, a Coordinating Center Tracking Spreadsheet will be submitted at 
the time of each annual progress review.  


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References:
1.
Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV and Singer DE. 
Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm 
management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation 
(ATRIA) Study. Jama. 2001;285:2370-5.
2.
Colilla S, Crow A, Petkun W, Singer DE, Simon T and Liu X. Estimates of current and 
future incidence and prevalence of atrial fibrillation in the U.S. adult population. The American 
journal of cardiology. 2013;112:1142-7.
3.
Jackson SL, Tong X, Yin X, George MG and Ritchey MD. Emergency Department, 
Hospital Inpatient, and Mortality Burden of Atrial Fibrillation in the United States, 2006 to 2014. 
The American journal of cardiology. 2017;120:1966-1973.
4.
Patel NJ, Deshmukh A, Pant S, Singh V, Patel N, Arora S, Shah N, Chothani A, Savani 
GT, Mehta K, Parikh V, Rathod A, Badheka AO, Lafferty J, Kowalski M, Mehta JL, Mitrani 
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