Dapagliflozin After Transcatheter Aortic Valve Implantation
Phase: PHASE4
Conditions: Aortic Stenosis, Transcatether Aortic Valve Implantation
Sponsor: Spanish Society of Cardiology

 
 
 
 
 
 
 
Dapagliflozin after Transcatheter Aortic 
Valve Implantation  
 
▪ Identification number: EudraCT number 2020-003930-18 
▪ Promotor: Sección de Cardiología Geriátrica, Sociedad Española de 
Cardiología (SEC-DAPATAVI-2020) 
▪ Principal Investigators: PI: Sergio Raposeiras Roubín. Co-PI: Ignacio J. Amat 
Santos. 
▪ Scientific Coordinator: Andrés Íñiguez Romo. 
▪ Executive Coordinator: Emad Abu Assi. 
▪ Steering Committee: Andrés Íñiguez Romo, Josep Rodés Cabau, Luis 
Nombela-Franco, Borja Ibáñez, José María De la Torre, Ignacio Cruz González, 
Clara Bonanad Lozano, Ignacio Amat Santos, Sergio Raposeiras Roubín. 
▪ Executive committee: Emad Abu Assi, Andrés Íñiguez Romo, Ignacio Amat 
Santos, Sergio Raposeiras Roubín.  
▪ Local coordinators: Antonio Muñoz García, Sergio García Blas, Ángel Sánchez 
Recalde, Rafael Romaguera. 
 
DECLARATION OF CONFIDENTIALITY: The information in this document contains information 
that is privileged or confidential and must not be disclosed unless disclosure is required by law. In any 
case, the persons to whom this information is disclosed are informed that it is privileged or confidential 
and should not disclose it. These restrictions on disclosure will also apply to all future information that is 
provided to you, indicated as privileged or confidential. 
 
Draft or Version Number: V1.4.3 (14 de octubre de 2020) 

 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ....................................................................................................... 3 
STATEMENT OF COMPLIANCE .............................................................................................. 5 
PROTOCOL SYNOPSIS .............................................................................................................. 6 
SCHEMATIC OF STUDY DESIGN ............................................................................................ 9 
KEY ROLES ............................................................................................................................... 12 
INTRODUCTION ....................................................................................................................... 15 
BACKGROUND ..................................................................................................................... 15 
SCIENTIFIC RATIONALE ................................................................................................... 17 
OBJECTIVES AND PURPOSE ................................................................................................. 20 
HYPOTHESES ....................................................................................................................... 20 
STUDY DESIGN AND ENDPOINTS ....................................................................................... 21 
DESCRIPTION OF THE STUDY DESIGN .......................................................................... 21 
STUDY ENDPOINTS ............................................................................................................ 21 
STUDY ENROLLMENT AND WITHDRAWAL ..................................................................... 23 
PARTICIPANT INCLUSION CRITERIA ............................................................................. 24 
PARTICIPANT EXCLUSION CRITERIA ............................................................................ 24 
DEFINITIONS AND EVENT ADJUDICATION ...................................................................... 25 
DEFINITION FOR EVALUATIONS OF EVENTS DURING FOLLOW-UP ..................... 25 
EVENT ADJUDICATION ..................................................................................................... 31 
CENTERS SELECTION ............................................................................................................ 33 
RANDOMIZATION AND STRATEGIES FOR RECRUITMENT .......................................... 34 
FOLLOW-UP STRATEGIES ..................................................................................................... 35 
PATIENT ENGAGEMENT / RETENTION STRATEGIES ................................................. 35 
PARTICIPANT WITHDRAWAL .............................................................................................. 36 
CROSSOVERS ........................................................................................................................... 37 
PREMATURE TERMINATION OF STUDY ........................................................................... 38 
DAPAGLIFLOZIN THERAPY STRATEGY ............................................................................ 39 
TREATMENT DURING TAVI HOSPITALIZATION (i.e. before randomization) ............. 39 
SGLT-2 THERAPY BEFORE RANDOMIZATION ............................................................. 39 
DAPAGLIFLOZIN THERAPY AFTER DISCHARGE (i.e. after randomization) ............... 39 
MANAGEMENT OF PATIENTS AFTER A THE OCCURRENCE OF AN EVENT ............. 40 
DATA COLLECTION, STUDY PROCEDURES AND SCHEDULE ...................................... 41 
STUDY EVALUATIONS / TESTS ....................................................................................... 41 
DATA RECORDING ............................................................................................................. 41 
WEBSITE AND MOBILE APP: RANDOMIZATION AND ELECTRONIC CASE REPORT 
FORM (eCRF) ............................................................................................................................ 43 
DapaTAVI Website ................................................................................................................. 43 
DapaTAVI MOBILE APP ...................................................................................................... 43 
RANDOMIZATION SYSTEM .................................................................................................. 44 
eCRF SYSTEM ........................................................................................................................... 45 
CENTRAL eCRF COMPLETENESS: UPLOAD DISCHARGE REPORTS ........................ 45 
FOLLOW-UP PROCEDURES ................................................................................................... 46 
DATA SAFETY MONITORING BOARD (DSMB) ............................................................. 47 

 
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STUDY SCHEDULE .............................................................................................................. 47 
PRAGMATIC TRIAL JUSTIFICATION .................................................................................. 49 
STUDY DESIGN .................................................................................................................... 49 
PRAGMATIC DESIGN JUSTIFICATION ............................................................................ 49 
DATA ANALYSIS SET ............................................................................................................. 52 
RANDOMIZATION ................................................................................................................... 53 
STATISTICAL PLAN: SAMPLE SIZE CALCULATION, ADAPTIVE DESIGN, INTERIM 
ANALYSES ................................................................................................................................ 54 
SAMPLE SIZE ........................................................................................................................ 54 
INTERIM ANALYSIS ........................................................................................................... 55 
REDUCING BIAS .................................................................................................................. 55 
DESCRIPTIVE ANALYSIS................................................................................................... 56 
PRIMARY ANALYSIS .......................................................................................................... 56 
SECONDARY ANALYSIS .................................................................................................... 57 
SUBGROUP ANALYSIS ....................................................................................................... 57 
PRE-SPECIFIED SUB-GROUP ANALYSES ....................................................................... 57 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................... 59 
ETHICAL STANDARD ......................................................................................................... 59 
INSTITUTIONAL REVIEW BOARD ................................................................................... 59 
INFORMED CONSENT PROCESS ...................................................................................... 59 
PARTICIPANT AND DATA CONFIDENTIALITY ............................................................ 60 
DATA HANDLING AND RECORD KEEPING ....................................................................... 62 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ................................ 62 
STUDY RECORDS RETENTION ......................................................................................... 62 
PROTOCOL DEVIATIONS................................................................................................... 63 
PUBLICATION AND DATA SHARING POLICY .............................................................. 63 
STUDY ADMINISTRATION .................................................................................................... 64 
STEERING COMMITTEE ..................................................................................................... 64 
EXECUTIVE COMMITTEE .................................................................................................. 64 
DATA SAFETY MONITORING BOARD (DSMB) ............................................................. 64 
CLINICAL EVENTS COMMITTEE ..................................................................................... 64 
CONFLICT OF INTEREST POLICY ........................................................................................ 65 
REFERENCES ............................................................................................................................ 66 
 
 
   
 
 
 

 
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LIST OF ABBREVIATIONS 
 
ACC 
American College of Cardiology  
AE  
Adverse Event 
AF 
Atrial Fibrillation 
AHA 
American Heart Association 
AS 
Aortic Stenosis 
AVR 
Aortic Valve Replacement 
BNP 
B-type natriuretic peptide 
CEAC 
Clinical Events Adjudication Committee 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CMP  
Clinical Monitoring Plan 
CRF  
Case Report Form 
CRO 
Contract Research Organization 
CV 
Cardiovascular 
DCC  
Data Coordinating Center 
DM 
Diabetes Mellitus 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ESC 
European Society of Cardiology 
FDA 
Food and Drug Administration 
GCP  
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HF 
Heart Failure 
HFrEF 
Heart Failure with Reduced Ejection Fraction 
HR 
Hazard Ratio 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors  
IRB 
Investigational Review Board  
ISO 
International Organization for Standardization  
ITT 
Intention-to-treat 
LVEF 
Left Ventricular Ejection Fraction 

 
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LVH 
Left Ventricle Hypertrophy  
MI 
Myocardial infarction 
NIH 
National Institutes of Health 
NT-proBNP 
N-terminal pro-B-type natriuretic peptide 
NYHA 
New York Heart Association  
PI  
Principal Investigator 
PROBE 
Prospective, Randomized, Open-label Blinded Endpoint 
QC  
Quality Control 
SAE 
Serious Adverse Event 
SAP  
Statistical Analysis Plan 
SAVR 
Surgical Aortic Valve Replacement 
SGLT-2 
Sodium-Glucose coTransporter type 2 
SMC  
Safety Monitoring Committee 
TAVI 
Transcatheter Aortic Valve Implantation 

 
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STATEMENT OF COMPLIANCE 
 
The “Dapagliflozin after Transcatheter Aortic Valve Implantation” (DapaTAVI) trial 
will be carried out in accordance with Good Clinical Practice (GCP), in accordance with 
the International Conference on Harmonisation (ICH E6) and the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46).  
The Principal Investigator will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the sponsor and documented approval 
from the Institutional Review Board (IRB), except where necessary to eliminate an 
immediate hazard to the trial participants.  
 The Principal Investigator will assure that all staff members involved in the conduct of 
this study are informed about their obligations in meeting the above commitments.  
 
 
 
 
 
 
 
Principal Investigator: Sergio Raposeiras Roubín  
 
 
 

 
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PROTOCOL SYNOPSIS 
 
Title 
Dapagliflozin after Transcatheter Aortic Valve Implantation (Dapa-TAVI) 
Précis 
Pragmatic, controlled, prospective, randomized, open-label (open-label), 
evaluator-blind clinical trial (PROBE design) that will analyze the benefits of 
dapagliflozin treatment in patients with severe aortic stenosis discharged after 
implantation of an aortic valve prosthesis transcatheter (TAVI). 
Patients discharged after TAVI, with a history of heart failure (HF) plus 
depressed left ventricular ejection fraction (LVEF) (LVEF ≤ 40%) or diabetes 
mellitus (DM) or glomerular filtration rate (GFR) between 25 and 75 
ml/min/1.73 m2, will be randomized (1:1) before hospital discharge to receive 
treatment with dapagliflozin 10 mg/day or no dapagliflozin (no placebo). Only 
variables available during routine clinical practice will be collected and there 
will be no additional tests. The incidence of clinical events and adherence to 
the dapagliflozin arm will be documented at 2 timepoints (3 ± 1 months and 
12 months) by phone calls and review of medical records. 
Level of 
intervention / 
pragmatism of the 
trial 
Patients who undergo TAVI for severe aortic stenosis have a non-negligible 
probability of readmission in the first year for HF, which ranges between 15% 
and 20%. This rate tends to double in patients with a previous history of HF. 
Likewise, in patients with moderate-high surgical risk (which are most of 
patients who undergo TAVI in Spain), post-TAVI mortality in the first year is 
around 10%. 
In the last 2 years, dapagliflozin, a Sodium-Glucose Co-Transporter type 2 
(SGLT-2) inhibitor, has been shown to significantly reduce cardiovascular 
mortality and HF admission rate by 17% in 17,160 patients with DM [Study 
DECLARE-TIMI 38, NEJM 2019], in 26% in 4,744 patients with LVEF ≤ 
40% [DAPA-HF Study, NEJM 2019] and in 29% in 4,304 patients with GFR 
between 25 and 75 ml / min / 1.73 m2 [DAPA-CKD study, presented in 
August 2020 at the European congress of cardiology, pending publication]. 
The 3 clinical trials also showed a reduction in total mortality (17% and 31% 
in DAPA-HF and DAPA-CKD, both significant, and 7% in DECLARE-TIMI-
38, not significant), and in none of them an increased rate of adverse events 
has been seen compared to placebo. Thus, the 3 studies are consistent in 
reducing CV mortality and readmissions for HF, as well as in terms of drug 
safety. 
In post-TAVI patients, there is no standard medical treatment beyond 
antithrombotic therapy. Based on the 3 previously discussed clinical trials, it is 
proposed to analyze the possible benefit of prescribing dapagliflozin in post-

 
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TAVI patients, with a previous history of HF, who have any of these 3 
conditions in which dapagliflozin has shown prognostic benefit: ventricular 
dysfunction (LVEF ≤ 40%), renal dysfunction (GFR 25-75 ml / min / 1.73 m2) 
or DM. 
On the basis that dapagliflozin is a licensed drug, the use of dapagliflozin in 
the present study is supported by 3 published clinical trials with evidence of its 
efficacy (reduction in mortality and HF) and safety (adverse event rate equal 
to placebo) , and that the DapaTAVI trial does not require the performance of 
any additional diagnostic or therapeutic test beyond randomization to 
dapagliflozin (yes / no), without any additional risk or burden for patients, 
being a clinical trial independent of the pharmaceutical industry, without no 
commercial interest, it is considered as a low level of intervention. 
Study Duration 
 
 
3 years. 
• 
Recruitment: 2 years 
• 
Follow-up: 1 year.  
Endpoints 
Primary endpoint: Incidence rate of the composite of death or worsening 
heart failure (HF; including hospitalization for HF or an urgent visit resulting 
in intravenous therapy for HF) 
Secondary endpoints: 1) Incidence rate of individual components of the 
primary outcome. 2) Incidence rate of cardiovascular (CV) mortality. 3) 
Incidence rate of atrial fibrillation (AF) 
Tertiary endpoints: 1) Change in functional class (NYHA). 2) Safety 
endpoints (incidence rate of Major hypoglycemia, Symptomatic hypotension, 
Genito-urinary infections, Ketoacidosis, Amputation, and Necrotizing Fasciitis 
of the Perineum (Fournier’s Gangrene). 3) Crossovers. 
Population 
Patients with aortic stenosis and prior history of HF or reduced LVEF 
discharged after TAVI. 
Inclusion criteria 
• 
≥18 years old. 
• 
Severe aortic stenosis underwent TAVI. 
• 
Prior heart failure admission and one of the following criteria: 
➢ Left ventricular ejection fraction ≤ 40% or 
➢ Diabetes mellitus or 
➢ Estimated glomerular filtrate rate 25-75 ml/min/1.73 m2 
Exclusion criteria 
• 
Known allergy or intolerance to SGLT2 inhibitors. 
• 
Concomitant therapy with sulfonylurea or SGLT2 inhibitors. 
• 
Systolic blood pressure < 100 mmHg or diastolic blood pressure < 50 
mmHg. 
• 
An estimated glomerular filtration rate (GFR) below 25 ml per 

 
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minute per 1.73 m2. 
• 
Chronic cystitis and/or recurrent urinary tract infections (2 or more in 
the last year) 
• 
Poor control of diabetes mellitus that requires SGLT-2 inhibitor 
prescription on discharge according to treating physician judge. 
• 
Any medical condition that, in the investigator´s judgment, would 
seriously limit life expectancy (less than one year). 
• 
Pregnant or breast-feeding patients 
• 
Patients participating in other clinical trials. 
Phase 
IV. 
Number of Sites 
26. 
Study Drug 
Dapagliflozin 10-mg daily dose. 
Comparator 
Control (no dapagliflozin). 
Power calculation 
- Anticipated effect size: dapagliflozin treatment will be associated with a 30% 
reduction in the incidence rate of the primary composite endpoint 
• 
Anticipated incidence control arm: 30% 
• 
Anticipated incidence in dapagliflozin arm: 21% 
- Power: 0.8 
- Anticipated incidence of withdrawals/losses in follow-up: 5% 
- Sample size (including withdrawals): 1,020 (510 per treatment arm) 
Events 
adjudication 
Events will be adjudicated by a blinded committee after reviewing information 
sent by local investigators 
Interim analyses 
Two interim analyses will be performed on primary endpoint and secondary 
safety endpoints when 33% and 66% of events have been adjudicated (81 and 
172 events respectively).  
Chronogram 
2021-2024 
Q1 2021: Start of inclusion 
Q1 2022: Half way with inclusion (510 patients) 
Q1 2023: Anticipated end of inclusion (1,020 patients) 
Q1 2024: End of follow-up 
Q2 2024: Reporting primary, secondary, and tertiary outcomes 
Q3 2024: Subgroups analysis 

 
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SCHEMATIC OF STUDY DESIGN 
 
a) Flow Diagram  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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b) Process Diagram  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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c) Timeline Diagram  
 
 
 
 
 
 
 
 
 
 
 
 

 
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KEY ROLES 
 
• PRINCIPAL INVESTIGATORS  
➢ PI: Sergio Raposeiras Roubín, MD PhD  
Institution Name: Hospital Universitario Álvaro Cunqueiro & Instituto de 
Investigación Sanitaria Galicia Sur. 
Address: Estrada de Clara Campoamor, 341, 36213 Vigo, Pontevedra, Spain. 
Phone Number: +34 986 81 11 11  
Email: sergio.raposeiras.roubin@sergas.es 
➢ Co-PI: Ignacio J. Amat Santos, MD PhD 
Institution Name: Hospital Clínico Universitario de Valladolid. 
Phone number: +34 983 42 00 26 
Address: Avenidad Ramón y Cajal, 3, 47003 Valladolid, Spain. 
Email: ijamat@gmail.com 
 
• DATA COORDINATING CENTER:  
➢ Hospital Universitario Álvaro Cunqueiro (Servicio de Cardiología) 
➢ Centro Nacional de Investigaciones Cardiovasculares (CNIC) 
 
• MONITOR and DATA MANAGER 
➢ Monitor: Dra. María Melendo Viu. 
➢ Data manager: Sonia Blanco Prieto, Cristina Barreiro Pardal, María Cespón 
Fernández. 
 
• CLINICAL EVENTS ADJUDICATION COMMITTEE (CEAC): 
➢ Clinical Events Adjudication Committee (CEAC): Rodrigo Estévez Loureiro 
(director), Iván Núñez Gil, Rocío González Ferreiro, Javier López Pais, 
María Cespón Fernández. 
 
• DATA SAFETY MONITORING BOARD (DSMB):  

 
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➢ It will be assigned later, including at least one expert in biostatistics and 2 
experts in cardiology with experience in research / clinical trials. 
 
• METHODOLOGY LEADERS, STUDY DESIGN & BIOSTATISTICS:  
➢ Emad Abu Assi 
➢ Sergio Raposeiras Roubín 
 
• SITE INVESTIGATORS and INVESTIGATORS 
• Hospital Universitario Álvaro Cunqueiro, Vigo. IP: Dr. José Antonio Baz 
Alonso. 
• Hospital Clínico Universitario de Santiago, Santiago de Compostela. IP: Dr. 
Diego López Otero. 
• Hospital Juan Canalejo, La Coruña. IP: Dr. Jorge Salgado Fernández. 
• Hospital Universitario Marqués de Valdecilla, Santander. IP: Dr. José María De 
la Torre Hernández. 
• Hospital Universitario de Navarra, Pamplona. IP: Dr. Valeriano Ruiz Quevedo. 
• Hospital Universitario Miguel Servet, Zaragoza. IP:  Dr. Juan Sánchez-Rubio 
Lezcano. 
• Hospital Universitario Germans Trias i Pujol, Barcelona. Dr. Victoria Vilalta del 
Olmo. 
• Hospital Universitario Vall d'Hebron, Barcelona. Bruno García del Blanco. 
• Hospital Universitario Son Espases, Mallorca. IP: Dr. Vicente Peral Disdier. 
• Hospital Clínico Universitario de Valencia, Valencia. IP: Dr. Sergio García Blas. 
• Hospital Universitario y Politécnico La Fe, Valencia. IP: Dr. Francisco Ten 
Morro. 
• Complejo Hospitalario Universitario de Albacete, Albacete. IP: Dr. Juan G 
Córdoba Soriano. 
• Hospital Universitario Virgen de las Nieves, Granada. IP: Dr. Eduardo Molina 
Navarro. 
• Hospital Universitario Virgen de la Victoria, Málaga. IP: Dr. Antonio Muñoz 
García. 
• Hospital Puerta del Mar de Cádiz, Cádiz. IP: Dr. Livia Gheorge. 
• Hospital Juan Ramón Jiménez, Huelva. IP: Dr. José F Díaz Fernández. 
• Hospital Virgen del Rocío, Sevilla. IP: Dr. Manuel Villa Gil-Ortega. 
• Hospital Universitario Reina Sofía, Córdoba. IP: Dr. Manuel Pan Álvarez. 
• Hospital Clínico San Carlos, Madrid. IP: Dr. Luis Nombela-Franco. 

 
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• Hospital Universitario Ramón y Cajal, Madrid. IP: Dr Ángel Sánchez Recalde. 
• Hospital Puerta de Hierro, Madrid. IP: Dr. José A Fernández Díaz. 
• Hospital Universitario de La Princesa, Madrid. IP: Dr.  Fernando Alfonso. 
• Hospital General Universitario Gregorio Marañón, Madrid. IP: Dr. Enrique 
Gutiérrez Ibañes. 
• Hospital Fundación Jiménez Díaz, Madrid. IP: Dr. Borja Ibáñez. 
• Hospital Clínico Universitario, Salamanca. IP: Dr. Ignacio Cruz González. 
• Hospital Clínico Universitario de Valladolid. IP: Dr.  Ignacio J Amat-Santos. 
 
 
 
 
 

 
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INTRODUCTION 
 
BACKGROUND  
 
Epidemiology and prognosis of aortic stenosis 
Aortic valve stenosis (AS) is a progressive disease in which the end stage is 
characterized by obstruction of left ventricular outf low, resulting in inadequate cardiac 
output, decreased exercise capacity,  heart  failure (HF),  and  death from CV causes. 
The prevalence of AS is only about 0.2% among adults between the ages of 50 and 59 
years but increases to 9.8% in octogenarians, with an overall prevalence of 2.8% in 
adults older than 75 years of age (1). Although mortality is not increased when aortic 
stenosis is asymptomatic, the rate of death is more than 50% at 2 years for patients with 
symptomatic disease unless aortic-valve replacement is performed promptly (2). 
The left ventricle in aortic stenosis 
AS is associated with left ventricular hypertrophy (LVH), diastolic dysfunction, and 
decreased longitudinal shortening, although the ejection fraction remains normal in 
most patients (3). Left atrial enlargement is common owing to elevated left ventricular 
filling pressures. Pressure overload causes left ventricular remodelling and ultimately 
LVH. This is often seen as a means of limiting wall stress in order to maintain systolic 
function (4). Wall stress, by the law of Laplace, is related directly to intracavitary 
pressure and cavity size, but inversely to wall thickness. The ventricular hypertrophic 
adaptation follows four well-recognised mechanistic patterns: normal ventricular 
geometry, concentric remodelling, concentric hypertrophy and eccentric hypertrophy 
(5). Concentric remodelling is defined by a normal left ventricular mass and an 
increased relative wall thickness and concentric hypertrophy by a combination of LVH 
and increased relative wall thickness. There is evidence to suggest that adaptive 
remodelling becomes maladaptive with increasing LVH and consequent myocardial 
fibrosis. A study by Cioffi et al. showed that over 10 % of patients with asymptomatic 
severe AS exhibited inappropriate LVH and these patients had a 4.5-fold higher risk of 
death or hospital admission (6). LVH is associated with myofibrillar hypertrophy, but  
also  fibrosis,  which  is  the deposition   of   collagen   and   fibronectin.   

 
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Echocardiographic studies, however, have also demonstrated that 10–20 % of patients 
with AS do not have LVH (6).  
Interventions in aortic stenosis: TAVI 
AS  is  a  slowly  progressive  disease  but  is  associated  with  dismal  outcomes  
within  a  few  years  after  symptom  emergence  if  not  treated  with  aortic  valve  
replacement  (AVR) (7). Surgical aortic valve replacement (SAVR) had been the only 
effective treatment for  severe  AS    for  many  years. However,  transcatheter  aortic  
valve  implantation  (TAVI)  has  emerged  as  an  effective  alternative  to  SAVR,   
demonstrating   short-term   and   mid-term   outcomes  comparable  or  even  superior  
to  SAVR  regardless of the surgical risk of the patients (8). 
Clinical outcomes after TAVI  
TAVI has transformed the treatment of severe AS. However, questions remain 
regarding the long-term outcomes of this procedure.  
• Mortality: Although TAVI is associated with a significant reduction in 
mortality compared to conservative management, the incidence of death is not 
negligible at one year. In the 3 cohorts of PARTNER (Placement of AoRTic 
traNscathetER valve) trial, 1-year mortality was 1.1%, 11.8% and 30.7% in low, 
moderate, and high risk patients (9-11), respectively. In real world patients, the 
1-year mortality  ranges from 10 to 20% (11, 12), depending on the patient's 
risk.  
• Heart Failure (HF): HF is responsible of 15% of mortality in TAVI patients. 
The group of Alain Cribier reported a rate of 1-year HF admission of 24.1% 
after TAVI (13) , being significantly lower in other studies (± 15%) (12, 14). 
The HF admission rate is twice in patients with prior HF admissions before 
TAVI (13), and it is also increased in patients with high levels of NTproBNP 
(14) . 
 

 
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SCIENTIFIC RATIONALE 
 
Impact of Dapagliflozin in reduction of HF readmissions 
Accumulating mechanistic insights suggest that sodium–glucose co-transporter 2 
(SGLT‐2) inhibitors ─especially dapagliflozin and empagliflozin─ may be valuable in 
the treatment of HF regardless of diabetes mellitus (DM) status and LVEF. SGLT‐2 
inhibitors may exert cardioprotective effects through several distinct mechanisms, 
including:  
➢ Improvement in ventricular loading conditions secondary to reductions in 
preload ─mediated by osmotic diuresis and natriuresis─ (15) and afterload 
(potentially occurring via lowering of arterial pressure and stiffness) (16). 
➢ Provision of an alternative cardiac energy supply in the form of cardiac ketones 
─specifically β‐hydroxybutyrate─ (17). 
➢ Direct inhibition of the sodium/hydrogen (Na+/H) exchanger in the 
myocardium, leading to reduction in or reversing of cardiac injury, hypertrophy, 
fibrosis, remodeling, and systolic dysfunction (18). 
➢ Reduction in left ventricular mass and improvement in diastolic function through 
inhibition of cardiac fibrosis ─a feature of HF─ (19).  
➢ Improvement in endothelial dysfunction (20).  
➢ Stimulation of increased glucagon secretion, potentially improving cardiac 
performance by either increasing cardiac index and fuel availability or 
decreasing peripheral vascular resistance (21). 
Patients with HF, regardless of LVEF, have sodium and fluid retention as well as 
coronary, myocardial, and systemic endothelial dysfunction, even in the absence of 
overt DM (22). As the natriuretic ─most notably─, glucosuric, and metabolic effects of 
SGLT‐2 inhibitors have been demonstrated in patients with and without DM, it has been 
postulated that SGLT‐2 inhibitors may benefit patients with HF regardless of DM status 
(23). This has been demonstrated in several preclinical studies (24, 25). In a preclinical 
model of HF, empagliflozin treatment (or gene knockout simulation of SGLT‐2 
inhibition) improved cardiac function (17). In preclinical models of myocardial 

 
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infarction, dapagliflozin has demonstrated attenuation of cardiac fibrosis, and 
empagliflozin has been shown to improve cardiac function and remodeling (24). In 
other experimental models of HF without diabetes mellitus, empagliflozin prevented 
worsening of cardiac function (17). 
Two clinical trials with SGLT-2 inhibitors have shown benefit in patients with HF with 
HF and reduced ejection fraction (HFrEF) ─regardless of DM status─. The DAPA-HF 
trail, with dapagliflozin, was presented in European Society of Cardiology (ESC) 
Congress 2019, with 30% reduction of HF readmission and 17% reduction of all-cause 
death (26).  The EMPEROR reduced HF will be presented soon, but it has already been 
advanced that empagliflozin reduced the primary end-point of death and HF. After a 
fast-track designation and priority review, the US FDA approved dapagliflozin on 
5/5/2020 to reduce the risk of cardiovascular death or hospitalization in patients with 
HFrEF with or without Type 2 diabetes. 
Recently, the results of DAPA-CKD trial were presented in ESC Congress 2020 (Paris, 
September 2020), showing a benefit of dapagliflozin in reducing mortality and 
worsening HF in patients with an estimated glomerular filtrate rate (eGFR) 25-75 
ml/min/1.73 m2. 
Possible benefit of Dapagliflozin in TAVI patients 
Almost 1 out of 3 of the patients with severe aortic stenosis and prior admissions by HF 
who underwent TAVI are readmitted in the first year after TAVI due to HF (13, 14). 
Furthermore, 1 out of 10 patients dies in the first year after TAVI (12). A recent study 
showed that the regression of left ventricular mass after TAVI was associated with with 
lower death and hospitalization rates (27).  
Dapagliflozin demonstrated a nearly 30% reduction in readmissions for HF in the 
DECLARE and DAPA-HF clinical trials (26, 28), for patients with reduced LVEF or 
DM and high CV risk. Recently, another clinical trial (DAPA-LVH) showed that 
dapagliflozin treatment significantly reduced left ventricular mass in patients with LVH 
(29). The regression of left ventricular mass suggests dapagliflozin can initiate reverse 

 
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remodelling and changes in left ventricular structure that may partly contribute to the 
cardio-protective effects of dapagliflozin.  
The DapaTAVI trial is a controlled randomized clinical trial that will address whether 
dapagliflozin therapy after TAVI reduces the incidence of major clinical events 
(mortality and HF readmission) in patients with aortic stenosis and history of prior HF, 
and one of the following conditions: DM, or LVEF ≤ 40%, or eGFR 25-75 ml/min/1.73 
m2. The justification for undertaking a trial like DapaTAVI is based on the comments 
above. We propose a clinical trial with dapagliflozin ─drug that reduces HF and CV 
death, in addition to causing ventricular mass regression─ in TAVI patients 
─population at high risk of death and HF readmission─.  
Currently there is no study about medical therapy with SGLT-2 inhibitors in patients 
with TAVI. DapaTAVI trial will fill this gap and will contribute refining the treatment 
of TAVI patients across the world. 
 
 
 
 
 
 

 
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OBJECTIVES AND PURPOSE 
 
The objective of the DapaTAVI trial is to investigate the effects dapagliflozin therapy 
on mortality and CV morbidity in patients with severe aortic stenosis and previous 
admission for HF undergoing TAVI with any of these 3 medical conditions: DM, LVEF 
≤ 40% or renal dysfunction (GFR 25-75 ml / min / 1.73 m2) 
 
HYPOTHESES 
 
Main hypotheses: 
1) Dapagliflozin therapy in TAVI patients with prior history of HF and diabetes 
mellitus, reduced LVEF (LVEF ≤ 40%) or renal dysfunction (eGFR 25-75 
ml/min/1.73 m2), is associated with reduced 1-year mortality or worsening of 
HF. 
Secondary hypotheses: 
1) Dapagliflozin therapy in TAVI patients with prior history of HF and diabetes 
mellitus, reduced LVEF (LVEF ≤ 40%) or renal dysfunction (eGFR 25-75 
ml/min/1.73 m2), is associated with reduced 1-year CV mortality 
2) Dapagliflozin therapy in TAVI patients with prior history of HF and diabetes 
mellitus, reduced LVEF (LVEF ≤ 40%) or renal dysfunction (eGFR 25-75 
ml/min/1.73 m2),  is associated with reduced 1-year incidence of AF. 
3) Dapagliflozin therapy in TAVI patients with prior history of HF and diabetes 
mellitus, reduced LVEF (LVEF ≤ 40%) or renal dysfunction (eGFR 25-75 
ml/min/1.73 m2), is associated with improvement in functional class. 
 
 
 
 

 
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STUDY DESIGN AND ENDPOINTS 
 
DESCRIPTION OF THE STUDY DESIGN 
 
Dapa-TAVI is a pragmatic, controlled, prospective, randomized, open-label blinded 
endpoint (PROBE design) clinical trial. Patients being discharged after TAVI who meet 
all inclusion criteria, and none of the exclusion criteria, will be eligible for the 
enrollment. Patients will be 1:1 randomized to 1 of these 2 arms: 
▪ Intervention group: Sodium-glucose cotransporter-2 (SGLT-2) inhibitor 
therapy with daily oral dose of dapagliflozin 10 mg. 
▪ Control group: no SGLT-2 inhibitor therapy with dapagliflozin. 
Apart from dapagliflozin therapy (or control), patients will be treated according to 
current standards (per managing physician prescription). 
STUDY ENDPOINTS 
 
➢ PRIMARY ENDPOINT  
▪ Incidence rate of the composite of all-cause mortality or worsening HF 
(including hospitalization for HF or an urgent visit resulting in intravenous 
therapy for HF). 
➢ SECONDARY ENDPOINTS  
▪ Indicence rate of individual components of primary endpoint. 
▪ Incidence rate of CV death. 
▪ Incidence rate of atrial fibrillation (AF). 
➢ TERTIARY ENDPOINTS  
▪ Improvement in NYHA class. 
▪ Safety endpoints: 
- 
Symptomatic hypotension. Symptomatic hypotension includes postural 
dizziness with systolic blood pressure < 100 mmHg, and orthostatic 
hypotension (defined as a decrease of >20 mmHg in systolic blood 

 
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pressure or >10 mmHg in diastolic blood pressure from a supine to a 
standing position). 
- 
Major hypoglycemia. Major hypoglucemia is defined as an event where 
all the following criteria were confirmed by the investigator: (1) the 
patient experienced symptoms of severe impairment in consciousness or 
behaviour; (2) the patient needed external assistance; (3) intervention 
was needed to treat the hypoglycaemia; and (4) there was prompt 
recovery of acute symptoms following the intervention. 
- 
Ketoacidosis. 
- 
Genital or Urinary Infections 
- 
Amputation 
- 
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) 
▪ Crossovers (incidence rate and reasons). 

 
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STUDY ENROLLMENT AND WITHDRAWAL 
 
Estimated date to initiate enrollment is Q1 2021. It is anticipated that enrollment will be 
performed in a 2 years time frame.  Screening of patient candidates will be done during 
index hospital admission (i.e. admission for TAVI). Individuals meeting inclusion 
criteria (and not meeting any exclusion criterion) will be invited to participate 
immediately before hospital discharge. Patients may be recruited after hospital 
discharge as long as randomization is one within two following weeks after TAVI.  
Women and members of minority groups and their subpopulations will be included in 
accordance with the NIH (National Institutes of Health) Policy on Inclusion of Women 
and Minorities as Participants In Research Involving Human Subjects.  
Anticipated recruitment rate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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PARTICIPANT INCLUSION CRITERIA 
 
➢ Patients (≥18 years, both genders) with severe aortic stenosis (aortic valve area ≤ 
1.0 cm2, or indexed aortic valve area ≤ 0.6 cm2/m2, or jet velocity ≥ 4.0 m/s, or 
mean gradient ≥ 40 mmHg) underwent TAVI. 
➢ Prior heart failure admission and one of the following criteria: 
o Left ventricular ejection fraction ≤ 40% or 
o Diabetes mellitus or 
o Estimated glomerular filtrate rate 25-75 ml/min/1.73 m2 
 
PARTICIPANT EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from 
participation in this study: 
1) Known allergy or intolerance to SGLT2 inhibitors. 
2) Concomitant therapy with sulfonylurea or SGLT2 inhibitors. 
3) Systolic blood pressure < 100 mmHg or diastolic blood pressure < 50 mmHg. 
4) An estimated glomerular filtration rate (GFR) below 25 ml per minute per 1.73 
m2. 
5) Chronic cystitis and/or recurrent urinary tract infections (2 or more in the last 
year) 
6) Poor control of diabetes mellitus that requires SGLT-2 inhibitor prescription on 
discharge according to treating physician judge. 
7) Any medical condition that, in the investigator´s judgment, would seriously limit 
life expectancy (less than one year). 
8) Pregnant or breast-feeding patients 
9) Patients participating in other clinical trials. 
 

 
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DEFINITIONS AND EVENT ADJUDICATION 
 
DEFINITION FOR EVALUATIONS OF EVENTS DURING FOLLOW-UP   
 
• Worsening HF: including hospitalization for HF or an urgent visit resulting in 
intravenous therapy for HF, similar as was previously defined in DAPA-HF 
trial. 
• HF admission: the definition of HF admission is adapted from the 2016 
European Society Guidelines (ESC) Guidelines (30) and from the document 
published by the American College of Cardiology (ACC) and American Heart 
Association (AHA) working group to standardize clinical data (31). A 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 HF. 
 
2) The patient’s length-of-stay in hospital extends for at least 24 hours (or a 
change in calendar date if the hospital admission and discharge times are 
unavailable). 
 
3) The patient exhibits documented new or worsening symptoms due to HF on 
presentation, including at least ONE of the following:  
a. Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, 
paroxysmal nocturnal dyspnea). 
b. Decreased exercise tolerance. 
c. Fatigue. 
d. Other symptoms of worsened end-organ perfusion or volume 
overload (as determined by the medical judgement of the 
investigator). 
 
4)  The patient has objective evidence of new or worsening HF, consisting of at 
least TWO physical examination findings OR one physical examination 
finding and at least ONE laboratory criterion, including:  

 
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a.  Physical examination findings considered to be due to heart failure, 
including new or worsened:  
o Peripheral edema.  
o Increasing abdominal distention or ascites (in the absence of 
primary hepatic disease).  
o Pulmonary rales/crackles/crepitations.  
o Increased jugular venous pressure and/or hepatojugular 
reflux.  
o S3 gallop.  
o Clinically significant or rapid weight gain thought to be 
related to fluid retention. 
b. Laboratory evidence of new or worsening HF, if obtained within 24 
hours of presentation, including:  
o Increased B-type natriuretic peptide (BNP)/ N-terminal pro-
BNP 
(NT-proBNP) 
concentrations 
consistent 
with 
decompensation of heart failure (such as BNP > 500 pg/mL 
or NT-proBNP > 2,000 pg/mL). In patients with chronically 
elevated natriuretic peptides, a significant increase should be 
noted above baseline.  
o Radiological evidence of pulmonary congestion.  
o Non-invasive diagnostic evidence of clinically significant 
elevated left- or rightsided ventricular filling pressure or low 
cardiac output. For example echocardiographic criteria could 
include: E/e’ > 15 or D-dominant pulmonary venous inflow 
pattern, plethoric inferior vena cava with minimal collapse 
on inspiration, or decreased left ventricular outflow tract 
minute stroke distance (time velocity integral). 
o Invasive diagnostic evidence with right heart catheterization 
showing a pulmonary capillary wedge pressure (pulmonary 
artery occlusion pressure) ≥ 18 mmHg, central venous 
pressure ≥ 12 mmHg, or a cardiac index < 2.2 L/min/m2  
 

 
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5) The patient receives initiation or intensification of treatment specifically for 
HF, including at least ONE of the following:  
a. Augmentation in oral diuretic therapy. 
b. Intravenous diuretic or vasoactive agent (e.g., inotrope, vasopressor, 
or vasodilator). 
c. Mechanical or surgical intervention, including:  
o Mechanical circulatory support (e.g. intra-aortic balloon 
pump, ventricular assist device, extracorporeal membrane 
oxygenation, total artificial heart). 
o Mechanical 
fluid 
removal 
(e.g., 
ultrafiltration, 
hemofiltration, dialysis). 
• Urgent visit for HF: any unplanned visits for HF decompensation resulting in 
intravenous therapy for HF, including diuretic or inotropic drugs.  
• Death: All deaths reported post-randomization, except for patients who have 
withdrawn their consent, should be adjudicated. Deaths will be sub-classified by 
CV, non-CV primary cause or undetermined cause of death. Classification of 
deaths as CV or non-CV is aimed at capturing the primary cause of death. The 
primary cause as defined here is the underlying disease or injury that initiated 
the train of events resulting in death. 
• Cardiovascular (CV) death: CV deaths include deaths that result from an 
myocardial infarction, sudden cardiac death, death due to HF, death due to 
stroke, death due to CV procedures, death due to CV hemorrhage, and death due 
to other CV causes (31).  
1. Death due to Acute Myocardial Infarction (MI): refers to a death within 30 
days after a myocardial infarction (MI) related to consequences seen 
immediately after the myocardial infarction, such as progressive congestive 
HF, inadequate cardiac output, or refractory arrhythmia. If these events 
occur after a “break” (e.g., a HF and arrhythmia free period), they should be 
designated by the immediate cause. The acute MI should be verified by the 
diagnostic criteria outlined for acute MI (including autopsy findings showing 
recent MI or recent coronary thrombus) and there should be no conclusive 

 
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evidence of another cause of death. Sudden, unexpected cardiac death, 
involving cardiac arrest, often with symptoms suggestive of myocardial 
ischemia, and accompanied by presumably new ST elevation, or new left left 
bundle branch block and/or evidence of fresh thrombus by coronary 
angiography and/or at autopsy, but death occurring before blood samples 
could be obtained, or at a time before the appearance of cardiac biomarkers 
in the blood should be considered death due to acute MI. Death resulting 
from a procedure to treat myocardial ischemia or to treat a complication 
resulting from myocardial infarction should also be considered death due to 
acute MI. If death occurs before biochemical confirmation of myocardial 
necrosis can be obtained, adjudication should be based on clinical 
presentation and electrocardiographic (ECG) evidence. Death due to a 
myocardial infarction that occurs as a direct consequence of a cardiovascular 
investigation/procedure/operation will be classified as death due to other 
cardiovascular cause. 
2. Sudden Cardiac Death: refers to death that occurs unexpectedly and includes 
the following deaths: 
a. Death witnessed and instantaneous without new or worsening 
symptoms. 
b. Death witnessed within 60 minutes of the onset of new or worsening 
cardiac symptoms. 
c. Death witnessed and attributed to an identified arrhythmia (e.g., 
captured on an ECG recording or witnessed on a monitor by either a 
medic or paramedic, or unwitnessed but found on implantable 
cardioverter-defibrillator review). 
d. Death after unsuccessful resuscitation from cardiac arrest or 
successfully resuscitated from cardiac arrest but who die within 24 
hours without identification of a non-cardiac etiology. 
e. Death > 24hrs after a patient has been successfully resuscitated from 
cardiac arrest and without identification of a non-CV etiology. 
f. Unwitnessed death in a subject seen alive and clinically stable ≤ 24 
hours prior to being found dead without any evidence supporting a 

 
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specific non-cardiovascular cause of death (information regarding the 
patient’s clinical status preceding death should be provided, if 
available. 
3. Death due to HF or Cardiogenic Shock: refers to death occurring in the 
context of clinically worsening symptoms and/or signs of HF not in the 
context of an acute MI and without evidence of another cause of death. New 
or worsening signs and/or symptoms of congestive HF include any of the 
following: 
a. New or increasing symptoms and/or signs of HF requiring the 
initiation of, or an increase in, treatment directed at HF or occurring 
in a patient already receiving maximal therapy for HF. 
b. Heart failure symptoms or signs requiring continuous intravenous 
drug therapy or oxygen administration.  
c. Confinement to bed predominantly due to heart failure symptoms. 
d. Pulmonary edema sufficient to cause tachypnea and distress not 
occurring in the context of an acute MI or as the consequence of an 
arrhythmia occurring in the absence of worsening HF. 
e. Cardiogenic shock not occurring in the context of an acute MI or as 
the consequence of an arrhythmia occurring in the absence of 
worsening HF. Cardiogenic shock is defined as systolic blood 
pressure (SBP) < 90 mm Hg for greater than 1 hour, not responsive to 
fluid resuscitation and/or heart rate correction, and felt to be 
secondary to cardiac dysfunction and associated with at least one of 
the following signs of hypoperfusion:  Cool, clammy skin; or oliguria 
(urine output < 30 mL/hour); or cardiac index < 2.2 L/min/m2. 
Cardiogenic shock can also be defined as systolic blood pressure ≥ 90 
mm Hg as a result of positive inotropic or vasopressor agents alone 
and/or with mechanical support in less than 1 hour. This category will 
include sudden death occurring during an admission for worsening 
HF. 

 
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4. Death due to Stroke: refers to cerebrovascular event the sequelae of which 
lead to death, generally within 30 days. The cerebrovascular event should be 
verified by the diagnostic criteria outlined for cerebrovascular events 
(including autopsy findings) and there should be no conclusive evidence of 
another cause of death. 
5. Death due to CV Procedures: refers to death caused by the immediate 
complications of a cardiac procedure. 
6. Death due to CV Haemorrhage: refers to death related to haemorrhage such 
as a non-stroke intracranial haemorrhage, non-procedural or non-traumatic 
vascular rupture (e.g., aortic aneurysm), or haemorrhage causing cardiac 
tamponade. 
7. Death due to Other CV Causes: refers to a CV death not included in the 
above categories but with a specific, known cause (e.g., pulmonary 
embolism or peripheral arteria disease). 
• Non-CV Death: Non-CV death is defined as any death not covered by CV death 
and falling into one of the following categories:  
1. Pulmonary failure  
2. Renal 
3. Gastrointestinal causes 
4. Hepatobiliary 
5. Pancreatic 
6. Infection (includes sepsis) 
7. Inflammatory (e.g., Systemic Inflammatory Response Syndrome / Immune 
(including autoimmune, may include anaphylaxis from environmental (e.g., 
food allergies) 
8. Haemorrhage that is neither CV bleeding or stroke 
9. Non-CV procedure or surgery 
10. Trauma 
11. Suicide  
12. Non-prescription drug reaction or overdose  

 
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13. Prescription drug reaction or overdose  
14. Neurological (non-cardiovascular)  
15. Malignancy  
16. Other, please specify.  
• Undetermined Cause of Death: Undetermined Cause of Death refers to a death 
not attributable to one of the above categories of CV death or to a non-CV 
cause. Inability to classify the cause of death may be due to lack of information 
(e.g., the only available information is “patient died”) or when there is 
insufficient supporting information or detail to assign the cause of death. In 
general, most deaths should be classifiable as CV or non-CV, and the use of this 
category of death, therefore, should be discouraged and should apply to few 
patients in well-run clinical trials. 
• Atrial fibrillation (AF): The diagnosis of AF is based on the physical finding of 
an irregular supraventricular heart rhythm and is confirmed with an ECG or 
rhythm strip. 
• Functional status: Functional status will be measured as New York Heart 
Association (NYHA) functional classification of heart failure for dyspnea.  
 
EVENT ADJUDICATION 
 
Once a potential event is detected either by a local investigator or during a follow-up, a 
report from the hospital in which the patient is admitted will be requested (with any 
personal identification of the patient blinded). All events need to be adjudicated by the 
Clinical Events Adjudication Committee (CEAC). For the evaluation of the events, the 
local investigator should prepare anonymous copies of the original source of data 
(clinical reports, complementary tests [catheterizations, ECG, X-ray, etc], lab tests and 
all relevant information). The regional PI will be responsible for sending the 
information confidential to the scientific project manager, who will prepare 
documentation for the CEAC. The CEAC will have a chairman and 3 additional 

 
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members. All events will be evaluated by at least 2 members of the CEAC. In the case 
of controversies, the opinion of the chairman will prevail. 
Patients will be followed up for the entire duration of the study regardless of having an 
adjudicated event. For the composite primary endpoint, the first event will be included 
in analysis, but for secondary endpoints, different events in the same patients will be 
individually evaluated.  
 
 

 
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CENTERS SELECTION 
 
Any center with TAVI program is eligible to participate. During hospital selection, the 
number of patients discharged with a TAVI during the past 12 months will be evaluated. 
A minimum number of patients per year (n=12) will be agreed with the hospital. 
Hospitals not fulfilling the agreed number will eventually be disqualified from 
recruitment. Hospital with electronic medical records will be prioritized.  

 
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RANDOMIZATION AND STRATEGIES FOR RECRUITMENT 
Patients will be screened during index hospitalization for TAVI. At discharge (or after 
discharge provided randomization takes place within 14 days after TAVI), and after 
informed consent is signed, patients will be randomized to receive or not dapagliflozin. 
After discharge, patients will be included in each center's TAVI follow-up program (as 
per local practice).  
Randomization will be done via web or via a dedicated mobile application. Each 
investigator participating in the trial will have a log-in username and password that links 
her/him to a specific hospital. During randomization, ten fields will be needed to 
complete:  
1. Full name of patient 
2. Telephones (personal and that from relatives) 
3. Date of TAVI 
4. DM status. 
5. Age 
6. Sex 
7. Creatinine (mg/dL) 
8. LVEF (%).  
9. Does the patient meet all the inclusion criteria and none of the exclusion criteria? 
(Yes / No, they can only be randomized if yes is selected). 
10. Has the patient signed informed consent? (Yes / No, they can only be 
randomized if yes is selected) 
Data will be stored in a secure server located at the Coordinator Center (Hospital Álvaro 
Cunqueiro, Vigo) and will be kept confidential according to legal regulations for data 
protection. 
 

 
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FOLLOW-UP STRATEGIES 
 
Follow-up will consist on telephone calls and review of patients' medical records. 
Once a local investigator identifies that a patient has been admitted for something 
potentially relevant to the study, he/she will be responsible for collecting the 
information (admission report, tests, etc..) and send it blinded to the central site for 
blinded event adjudication.  
Follow ups will be done at 2 timepoints: 3±1, 12 months. 
 
PATIENT ENGAGEMENT / RETENTION STRATEGIES 
 
After randomization, each patient will receive a card identifying the clinical trial that 
will contain a brief explanation of the aims of it. In the trial card, the arm in which the 
patient was included (dapagliflozin yes or no) will be stated, together with a central 
telephone number and email. The patient will be encouraged to contact (phone 
call/email) for any question related to the trial (either from the patients or from any 
physician seeing the patient). Any change related to dapagliflozin therapy (stop or 
initiate dapagliflozin) will be ideally communicated before implementation so the 
research team can annotate the reasons for the change. Moreover, any change in clinical 
status (admissions, symptoms, etc..) related to the study may be reported using this 
telephone number or email. Patients will be asked to carry the study card always with 
them to facilitate interaction.  
No incentives will be established for participating in the study.  
 

 
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PARTICIPANT WITHDRAWAL 
 
Given that this is an open label study with an approved medication and crossovers are 
not a criterium for withdrawal from the study (see below), the only reason for patient 
withdrawal from the study is the willingness of the patient to be excluded from the trial. 
 

 
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CROSSOVERS 
 
Crossovers (stop dapagliflozin therapy in the dapagliflozin treatment arm or initiate 
dapagliflozin in the control arm) will be indicated clinically by treating physicians. 
Patients and any treating physician will be asked to call the central coordinating center 
to discuss any crossover before taking the decision. Any decision will always be made 
by treating physician, but these will be encouraged to do so only if there is a clear 
clinical indication for it. 
Crossovers will be annotated along with the main reason driving the change. Patients 
with crossover will remain in the trial and follow ups will be done as per protocol. Since 
the main endpoint of the study is in an intention-to-treat basis, patients will be analyzed 
according to randomization regardless crossovers. Post-hoc analysis will take into 
consideration crossovers and patients adhering to original randomization arm during the 
entire follow-up of the study will be analyzed (see pre-specified groups). 
 

 
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PREMATURE TERMINATION OF STUDY 
 
This study may be suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, 
will be provided by the IP to the IRB.  
Circumstances that may warrant termination or suspension include, but are not limited 
to:  
▪ Determination of unexpected, significant, or unacceptable risk to participants. 
▪ Demonstration of efficacy that would warrant stopping. 
▪ Insufficient compliance to protocol requirements.  
▪ Data that are not sufficiently complete and/or evaluable.  
 
  

 
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DAPAGLIFLOZIN THERAPY STRATEGY 
 
TREATMENT DURING TAVI HOSPITALIZATION (i.e. before randomization) 
 
During the inhospital phase, patients will be treated based on the clinical judgment of 
their responsible physician, strongly suggesting adherence to the recommendations of 
Clinical Practice Guidelines.  
 
SGLT-2 THERAPY BEFORE RANDOMIZATION  
 
Randomization for DapaTAVI is at the time of discharge or after hospital discharge (in 
this case always within 14 first days after TAVI), thus treatment during index 
hospitalization (i.e. before randomization) is completely at the discretion of the treating 
physician. Patients receiving SGLT-2 inhibitors before randomization will not included 
in the trial. 
 
DAPAGLIFLOZIN THERAPY AFTER DISCHARGE (i.e. after randomization) 
 
▪ DAPAGLIFLOZIN DOSING: Dapagliflozin 10 mg once a day.  
▪ ROUTE OF ADMINISTRATION: oral. 
▪ ACQUISITION OF STUDY MEDICATION: This is a pragmatic trial and 
dapagliflozin therapy is included in the clinical practice armamemtarium. Thus, 
prescription of dapagliflozin agent will be done by physicians according to 
randomization arm. The study will not provide with any medication to the study. 
▪ DURATION OF THERAPY: The patient will be maintained with / without 
dapagliflozin throughout the study period (1 year) if no crossover occurs (see 
specific section).    

 
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MANAGEMENT OF PATIENTS AFTER A THE OCCURRENCE OF AN 
EVENT 
 
When a patient suffers a clinical event (included or not in the list of clinical endpoints), 
treating physicians are encouraged to contact the coordinating center and local PI. 
Patients suffering a clinical endpoint (including those included in the primary 
composite) will remain in the study and should undergo the scheduled follow-ups.  
In the case that a patient suffers any clinical endpoint, it is strongly recommended to 
manage the patients according to Clincal Practice Guidelines. If the physician feels 
appropriate to initiate or to stop SGLT-2 inhibitor therapy, this will always prevail. 
Crossover will be annotated and patients followed-up according to original plan. 
In all cases, cardiologists from the research team will be available anytime for 
discussion about the management of patients.  
 
 
 
 
 
 

 
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DATA COLLECTION and STUDY PROCEDURES 
STUDY EVALUATIONS 
STUDY EVALUATIONS / TESTS 
 
DapaTAVI is a pragmatic open label randomized clinical trial. There are no medical 
specific procedures apart from telephone follow ups and registries consultation. No 
medical exams or tests will be performed for the study matter. All exams and actions are 
those clinically indicated and the study investigators will collect data from clinical 
records.  
 
DATA RECORDING 
 
The following variables will be collected and included in the web-based eCRD.  
BASELINE VARIABLES TO COLLECT 
Number 
Variable 
Demographic and antropometric data 
1 
Age 
2 
Sex 
3 
Weight 
4 
Height 
Cardiovascular risk factors 
5 
Hypertension 
6 
Diabetes mellitus 
Cardiovascular history 
8 
Peripheral artery disease 
9 
Ischemic heart disease 
10 
Prior myocardial infarction 
11 
Prior stroke 
12 
Atrial fibrillation 
13 
Bundle branch block prior to TAVI 
14 
Prior pacemaker 
15 
Prior aortic bioprothesis 
16 
Prior valvuloplasthy 
Comorbidity 
17 
Chronic obstructive pulmonary disease 
18 
Chronic kidney disease 
Echocardiographic data (prior to TAVI) 
19 
Left ventricular ejection fraction 

 
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20 
Aortic valve area 
21 
Mean gradient 
22 
Left ventricular hypertrophy 
23 
Moderate-severe mitral regurgitation 
Laboratory data (prior to randomization) 
24 
Hemoglobin 
25 
Creatinine 
26 
NTproBNP 
Complications post TAVI (prior to randomization) 
27 
Bundle branch block 
28 
Moderate-severe aortic regurgitation 
29 
Left ventricular ejection fraction 
30 
Need of pacemaker 
Medical therapy at discharge 
 
 

 
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WEBSITE AND MOBILE APP: RANDOMIZATION AND ELECTRONIC 
CASE REPORT FORM (eCRF) 
STUDY EVALUATIONS 
DapaTAVI Website 
 
There will be a wesite with a general information of the trial available to the general 
public (pre-loggin). Each investigator will have a username and password allowing 
her/him to enter the post-loggin site. The username/password identifies the center of the 
investigator (information used for randomization). 
After loggin there will be several options, including download protocol, download 
inform consent forms, download participant identification cards, and check mach of the 
trial.  
 
DapaTAVI MOBILE APP 
 
There will be a mobile phone application containing most of the information in the 
website. The main purpose of the mobile app is to facilitate recruitment.  

 
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RANDOMIZATION SYSTEM 
 
Once a patient is ready to be included in the trial, and after informed consent has been 
signed, researchers will click the “Randomize a new patient” button. Eight fields will be 
requested (see specific section above) and then the patient Study Number and treatment 
allocation will be displayed.   
1. Full name of patient 
2. Telephones (personal and that from relatives) 
3. Date of TAVI 
4. DM status. 
5. Age 
6. Sex 
7. Creatinine (mg/dL) 
8. LVEF (%).  
9. Does the patient meet all the inclusion criteria and none of the exclusion criteria? 
(Yes / No, they can only be randomized if yes is selected). 
10. Has the patient signed informed consent? (Yes / No, they can only be 
randomized if yes is selected) 
 
When accesing via mobile app, randomization will be done after entering the eight 
fields. 
 

 
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eCRF SYSTEM 
 
To complete baseline and follow-up data, another button will bring researcher to the 
electronic case report form (eCRF). There will be a web-based eCRF to upload the 
information required for this trial (see section Data collection). 
 
CENTRAL eCRF COMPLETENESS: UPLOAD DISCHARGE REPORTS 
 
Researchers will be offered with the possibility of completing baseline variables by the 
coordinating center (University Hospital Álvaro Cunqueiro, Vigo, Spain). For this 
purpose, a copy of the admission report will be requested. To comply with the 
protection data law, the admission reports should be sent in a secure system.  
When accesing via website, there will an option for “upload admission report”. The file 
containing the report (.pdf or .doc) will be selected and uploaded in the system. Since 
the variables collected in DapaTAVI are those clinically available, it is expected that 
most of the information will be contained in the admission report.  
When accesing via mobile app, there will a possibility of taking a photograph of the 
admission report with the mobile camera. To avoid retention of photos of the admission 
report in the mobile phones, the app will not allow selection of previously done photos, 
only a direct access to the camera via app.   

 
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FOLLOW-UP PROCEDURES 
 
• Specific study follow-up. All patients will be monitored by telephone and 
through their medical records at 3±1 and 12 months, to know their vital status, 
development of an end-point event or any adverse effect. Whenever a patient 
presents a clinical event, the medical history will be requested to the local PI. 
For the DapaTAVI trial, no specific ECG, echocardiogram, or laboratory 
monitoring are need, only clinical data.  
Local researchers will be offered with the possibility of doing telephone calls 
from the national coordinating center (Hospital Álvaro Cunqueiro, Vigo, Spain). 
This will be agreed at the beginning of the study or anytime during the march of 
the trial (i.e. if a center initially is willing to do telephone follow-ups but later 
thinks this is not possible, the coordinating center will take over this 
responsibility anytime).  
On phone calls, the following fields will be completed after interacting with the 
patient/family:  
1. Vital status (alive/death). If death, cause of death (cardiovascular, non-
cardiovascular). 
2. Any HF hospital readmissions or visit to the emergency department  
(yes/no).  
When the patient died or was admitted to a hospital for any cause 
which may be related to any of the study endpoints, medical 
reports will be requested to the local investigator.  
3. Adherence to randomization arm (yes/no). If no, date (month/year) of 
crossover, and reason for crossover (free text field). 
4. Functional health status by the NYHA scale. 
• General monitoring. All patients will receive the usual follow-up performed at 
their center for patients after TAVI. Once a potential event is detected either by a 

 
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local investigator, a report from the local investigator should be sent to the 
coordinating center for the evaluation by the adjucation committee.  
• Specific data: Al investigators will be encouraged to report information about 
ECG, analytical, and echocardiographic data throughout the first year.TUD 
EVALUATIONS 
DATA SAFETY MONITORING BOARD (DSMB)  
 
A Data Safety Monitoring Board (DSMB) will be established to formally review the 
accumulating data from this trial to ensure there is no avoidable increased risk for harm to 
subjects. Two interim analyses will be performed on primary endpoint and secondary 
safety endpoints when 33% (81) and 66% (172) of events have been adjudicated (see 
interim analysis section below). The DSMB will be chaired by an academic cardiologist 
who is an expert in TAVI care and statistical analyses in clinical trials. 
 
STUDY SCHEDULE 
 
• SCREENING: During hospitalization for TAVI. 
• ENROLLMENT/BASELINE.  At discharge, randomization will take place and 
baseline patient data will be recorded.   The investigator must ensure that the 
patient signs the informed consent, meets the inclusion criteria and has no 
exclusion criteria. 
• OPEN-LABEL TREATMENT PHASE: 2 years. 
o FOLLOW-UP. At 3±1 and 12 months. Clinical follow-up (telephone and 
medical history revision) will be performed to detect any potential event 
(end-points and adverse events). To report data about echocardiography 
and laboratory tests during the first year will be optional  
o FINAL FOLLOW-UP. 1 year after last patient enrolment. All patients 
underwent 12 months follow-up.  
o EARLY TERMINATION VISIT. In case the patient leaves the study 
ahead of time (due to personal decision), a clinical follow-up (telephone 
and medical history) will be performed at the time of leaving the study. 

 
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SCREENING 
ENROLLMENT 
OPEN LABEL TREATMENT 
STRATEGY 
During admission 
At discharge 
After discharge 
Month 3±1 
Month 12 
Administrative data 
Inclusion/exclusion criteria 
X 
 
 
 
Informed consent 
 
X 
 
 
Demographic 
 
X 
 
 
Clinical data 
Medical history 
 
X 
 
 
Data about TAVI 
 
X 
 
 
Physical examination 
 
X 
 
 
Medication history 
 
X 
 
 
ECG 
 
X 
X* 
Echocardiography 
 
X 
X* 
Laboratory data 
 
X 
X* 
Medication at discharge 
 
X 
 
 
Drug (dapagliflozin yes/no) 
Randomization  
 
X 
 
 
Follow-up 
Vital status 
 
 
X 
X 
Events of end-point 
 
 
X 
X 
Adverse events 
 
 
X 
X 
Addition of SGLT-2 inhibitor 
 
 
X 
X 
Discontinuation of dapafliflozin 
 
 
X 
X 
Functional class 
 
 
X 
X 
 
 
* Although not mandatory, researchers will be encouraged to attach ECG, 
echocardiograms reports, and laboratory tests data performed in the first year 
after TAVI. 
 
 
 
 

 
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PRAGMATIC TRIAL JUSTIFICATION 
 
STUDY DESIGN 
 
The Dapagliflozin after Transcatheter Aortic Valve Implantation (DapaTAVI) study is a 
multinational, pragmatic, parallel-controlled, prospective, randomized, open-label 
blinded endpoint phase IV parallel- clinical trial (32). 
 
PRAGMATIC DESIGN JUSTIFICATION 
 
Pragmatic clinical trials are performed under normal conditions with the intention of 
providing results that are more applicable to clinical practice and decision making. The 
adequacy of the intended purpose of the DapaTAVI trial to a pragmatic design was 
evaluated through the nine PRECIS-2 domains (33): 
 
 
 
 

 
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1. Eligibility - to what extent are the participants in the trial similar to those who 
would receive this intervention if it was part of usual care?  
• Exclusion criteria are limited to formal contraindications for SGT2-
inhibitors. No specific restrictions are present and inclusion criteria is 
extremely flexible: every patient with aortic stenosis and any degree of 
LVH being discharged after TAVI with prior historiy of HF or LVEF ≤ 
40%  is eligible (Score 5) 
2. Recruitment - how much extra effort is made to recruit participants over and 
above what that would be used in the usual care setting to engage with patients?  
• Participant recruitments are performed in tertiary referral hospitals at 
hospital discharge. No additional resources or publicity are used to 
recruitment. (Score 5) 
3. Setting - how different is the setting of the trial and the usual care setting?  
• Identical setting to usual care setting. (Score 5) 
4. Organization - how different are the resources, provider expertise and the 
organization of care delivery in the intervention arm of the trial and those 
available in usual care?  
• Information cards are given to the participants. A telephone information 
system is available for participant questions. (Score 4) 
5. Flexibility (delivery) - how different is the flexibility in how the intervention is 
delivered and the flexibility likely in usual care?  
• Full flexibility, dapagliflozin 10 mg once a day (Score 5) 
6. Flexibility (adherence) - how different is the flexibility in how participants 
must adhere to the intervention and the flexibility likely in usual care?  
• Patients receive usual encouragement to adhere to the intervention. 
Medical care providers are encouraged to maintain treatment unless a 
new clear clinical indication is present. No other measures to improve 
compliance. (Score 4) 
7. Follow-up - how different is the intensity of measurement and follow-up of 
participants in the trial and the likely follow-up in usual care?  
• Participants are followed as usual care except for 3 additional phone 
contacts during the follow-up period. (Score 4) 

 
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8. Primary outcome - to what extent is the trial's primary outcome relevant to 
participants?  
• The primary outcome is a composite of hard clinically meaningful 
endpoints: mortality or HF admission. (Score 5) 
9. Primary analysis - to what extent are all data included in the analysis of the 
primary outcome?  
• Primary analysis is performed applying the intention-to-treat principle in 
the full dataset, no matter whether compliance. (Score 5)  
 
 

 
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DATA ANALYSIS SET 
 
➢ Full Analysis Set: 
In this document, the term full analysis set is used to describe the analysis set 
which is as complete as possible and as close as possible to the intention-to-treat 
ideal of including all randomized subjects. Participants who fail to satisfy an 
entry criterion (eligibility violations) will be excluded from this dataset.  In order 
not to introduce bias, the following circumstances have to apply: 
o The entry criterion will be measured prior to randomization. 
o The detection of the relevant eligibility violations will be made 
completely objectively.  
o All detected violations of the particular entry criterion will be excluded. 
 
➢ Per Protocol Set: 
The per protocol set is the subset of the subjects in the full analysis set without 
treatment crossovers. In this data set, participants who switch from their 
randomized treatment will be therefore censored at the time of their switch. 
 
 

 
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RANDOMIZATION 
 
Randomization will be performed centrally via a web or dedicated mobile application. 
Randomization will follow a permuted-block design with varying block sizes to ensure 
the continued equivalence of each group size and will be estratified according to center. 

 
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STATISTICAL PLAN: SAMPLE SIZE CALCULATION, ADAPTIVE DESIGN, 
INTERIM ANALYSES 
 
SAMPLE SIZE 
 
The number of subjects was determined for the primary endpoint of the trial. 
➢ Assumptions: 
• Overall alpha value: 0.05 
o Haybittle-Peto approach for interim monitoring 
▪ 1st interim analysis: alpha value of 0.001 
▪ 2nd interim analysis: alpha value of 0.001 
▪ Final analysis: alpha value of 0.05  
• Power: 0.80. 
• Test: log-rank (superiority – two-sided) 
• Minimal treatment effect: HR 0.70. 
• 1-year incidence of primary endpoint (controls): 30% 
• Accrual period: 2 years 
• Follow-up period: 1 year for all patients.  
• Percentage of subjects anticipated to withdraw: 5% 
➢ Number of expected primary endpoints: 260. 
➢ Sample size: 1,020 participants 
 
ADAPTIVE SAMPLE SIZE:  The sample size for this study was based on the 
anticipated incidence of the composite endpoint. It is anticipated that the 1-year 
incidence of the primary endpoint will be 30% in the control arm and 21% in the 
dapagliflozin arm (thus, 25.5% in the overall population). To reduce the chances of 
having an underpowered study secondary to an event rate lower than predicted, a 
blinded examination of the study overall event rate will be done 3 months before 
closing the recruitment. At that moment, it is anticipated that >400 patients already 
underwent 12 months follow-up. In the case that the overall event rate is below 25%, 
the DSMB will discuss the possibility to doing a re-calculation of sample size according 
to actual event rate, and the chair will decide if it is needed to increase sample size (thus 

 
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extend recruitment period). As this analysis will be performed in a blinded fashion, 
adjustment for multiplicity is not required and will not be applied. 
 
INTERIM ANALYSIS 
 
Two interim analyses will be performed on primary endpoint and secondary safety 
endpoints when 33% (86) and 66% (172) of events have been adjudicated. Efficacy and 
safety interim analyses will be performed following the same methodological guidelines 
described in this document for the final analysis. Stopping rules for efficacy analysis 
will be based on the statistical Haybittle-Peto approach, with an overall alpha value 
0.05. Safety analyses will be addressed by applying descriptive statistical methods to 
the data, supplemented by calculation of confidence intervals. No formal statistical 
stopping rules for safety data will be predefined.  
 
 
REDUCING BIAS 
 
• Randomization:  
Randomization introduces a deliberate element of chance into the assignment of 
treatments to subjects in a clinical trial. In this trial, randomization procedure is 
organized centrally, and it is characterized by being stratified by center and 
follows a permuted-block design with varying block sizes to reduce 
predictability of the random sequence. 
• Blinding: 
As this trial follows a PROBE design, open-label and blinded endpoint 
adjudication are intrinsic characteristics. Masking is no implemented for patient 
and care provider. Therefore, to reduce potential bias, the endpoint adjudication 
panel remains blinded to treatment allocation and hard clinical meaningful 
endpoints have been selected as primary endpoint. 
• Multiplicity: 

 
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Multiplicity can raise concerns regarding type I error. To address multiplicity 
problems, two strategies are implemented. First, a composite endpoint is selected 
as primary endpoint. Second, Haybittle-Peto approach is applied to account for 
interim analyses. 
• External validity: 
The pragmatic design of this trial, as evaluated through PRECIS-2 guidelines, 
increases the generalizability of its conclusions to real daily clinical practice.  
 
DESCRIPTIVE ANALYSIS 
 
The distribution of continuous variables will be analyzed with graphical methods. For 
normally distributed variables, results will be expressed as mean ± SD; otherwise they 
will be represented as median (first quartile to third quartile). Categorical variables will 
be expressed as absolute frequency (%). Significance testing of baseline differences 
between treatment groups will be not performed. 
 
PRIMARY ANALYSIS 
 
Primary analyses will be performed in the “full data set” in an intention-to-treat fashion. 
The intervention arm will be compared against the control arm for the composite 
primary endpoint.  Time-to-event will be evaluated using the Kaplan-Meier survival 
analysis followed by multivariable Cox proportional hazards model. Hazard ratios (HR) 
with corresponding 95% confidence intervals will be calculated for treatment effect 
estimation. All patients without an event will be censored at last day of follow-up. 
Patients that withdraw from follow-up will be considered censored on the day of 
withdrawal. Due to the randomization process and the large sample size of the trial, it 
will be not expected the presence of covariate relevant imbalances between treatment 
groups. However, for exploratory purpose, standardized differences will be calculated. 
Those known prognostic factor presenting an imbalance higher than 0.1 standardized 
difference will be included in the multivariable Cox model. For all tests, we will use 2-
sided p-values with alpha ≤0.05 level of significance. 

 
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SECONDARY ANALYSIS 
 
The secondary endpoints will be the individual components of the primary composite 
endpoint, besides CV mortality and the development of new atrial fibrillation. Analyses 
will be performed following the same guidelines described for primary analysis. 
Multiplicity adjustment will be not implemented because the hierarchical structure 
between primary and secondary endponits. 
To better explore the treatment effect under ideal circumstances (explanatory approach), 
primary and secondary endpoint analyses will be replicated in the “per protocol data 
set” using same methods described above. 
 
SUBGROUP ANALYSIS 
 
All subgroup analyses will be performed using interaction models based on the primary 
analysis model, also including the subgroup in question and the treatment-subgroup 
interaction as factors, and presented as treatment hazard ratios for each subgroup and 
the interaction p-value. Subgroups will be specified in the endpoints section below.  
 
PRE-SPECIFIED SUB-GROUP ANALYSES  
 
➢ Diabetic vs non-diabetic patients.  
➢ LVEF ≤ vs > 40%.  
➢ ≥ 80 years vs < 80 years of age on recruitment 
➢ Males vs females 
➢ Atrial fibrillation versus sinus rhythm 
➢ Hypertensive vs normotensive patients 
➢ Moderate-severe vs mild LVH. 
➢ Treatment with beta-blockers vs. no beta-blockers 

 
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➢ Treatment with renin-angiotensin system blocking drugs vs no renin-angiotensin 
system blocking drugs. 

 
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ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
 
ETHICAL STANDARD 
 
The investigator will ensure that this study is conducted in full conformity with 
Regulations for the Protection of Human Subjects of Research codified in 45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, and/or the ICH E6. 
 
INSTITUTIONAL REVIEW BOARD 
 
The protocol, informed consent form, recruitment materials, and all participant 
materials will be submitted to the Institutinal Review Board (IRB) for review and 
approval. Approval of both the protocol and the consent form must be obtained before 
any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  
 
INFORMED CONSENT PROCESS 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of participation will be provided to 
the participants and their families. Consent forms will be IRB-approved and the 
participant will be asked to read and review the document. The investigator will explain 
the research study to the participant and answer any questions that may arise. All 
participants will receive a verbal explanation in terms suited to their comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research 
participants. Participants will have the opportunity to carefully review the written 
consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their surrogates or think about it prior to agreeing 
to participate. The participant will sign the informed consent document prior to any 

 
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procedures being done specifically for the study. The participants may withdraw 
consent at any time throughout the course of the trial. A copy of the informed consent 
document will be given to the participants for their records. The rights and welfare of 
the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study 
 
PARTICIPANT AND DATA CONFIDENTIALITY 
 
Participant confidentiality is strictly held in trust by the participating investigators and 
the sponsor. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the 
study or the data will be released to any unauthorized third party without prior written 
approval of the sponsor. The study monitor, other authorized representatives of the 
sponsor, or representatives of the IRB, may inspect all documents and records required 
to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.  
The study data entry and study management systems used by clinical sites, by the 
coordinating center, and research staff, will be secured and password protected. The 
study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all study databases will be de-
identified and archived at the Instituto de Investigacion Sanitaria Galicia Sur, for as 
long a period as dictated by local IRB and Institutional regulations.  Individual 
participants and their research data will be identified by a unique study identification 
number. 
To further protect the privacy of study participants, a Certificate of Confidentiality will 
be obtained. This certificate protects identifiable research information from forced 
disclosure. It allows the investigator and others who have access to research records to 
refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 

 
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information that would identify research participants, Certificates of Confidentiality 
help achieve the research objectives and promote participation in studies by helping 
assure confidentiality and privacy to participants. 
 
 
 
 

 
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DATA HANDLING AND RECORD KEEPING 
 
 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported.  
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. When making changes or corrections, cross out the original entry 
with a single line, and initial and date the change.  
Copies of the electronic CRF (eCRF) will be provided for use as source documents and 
maintained for recording data for each participant enrolled in the study. Data reported in 
the eCRF derived from source documents should be consistent with the source 
documents or the discrepancies should be explained and captured in a progress note and 
maintained in the participant’s official electronic study record.  
Clinical data (including AEs, concomitant medications, and expected adverse reactions 
data) will be entered into the data capture system. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data 
that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly 
from the source documents. 
 
STUDY RECORDS RETENTION 
 
Study documents should be retained for a minimum of 2 years after completing the 
study. These documents should be retained for a longer period, however, if required by 
local regulations. No records will be destroyed without the consent of the sponsor. It is 
the responsibility of the sponsor to inform the investigator when these documents no 
longer need to be retained 
 

 
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PROTOCOL DEVIATIONS 
 
It is the responsibility of the site to use continuous vigilance to identify and report 
protocol deviations, defined as any noncompliance with the clinical trial protocol. 
Protocol deviations must be sent to the local IRB. The site PI/study staff is responsible 
for knowing and adhering to their IRB requirements.  
 
PUBLICATION AND DATA SHARING POLICY 
 
According to the clinical trials registration policy of the International Committee of 
Medical Journal Editors (ICMJE) member journals, the DapaTAVI trial will be 
registered in a public trials registry such as EUDRA and ClinicalTrials.gob, which is 
sponsored by the National Library of Medicine.  
Study design will be presented in a scientific publication. 
The results will be submitted to peer-reviewed journal fulfilling the ICMJE guidelines, 
ensuring that the public has access to the published results. 
 

 
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STUDY ADMINISTRATION 
 
STEERING COMMITTEE 
 
The Steering Committee will govern the conduct of the study. The Steering Committee 
is responsible for making decisions, endorsing executive committee actions, and 
providing advice.  
 
EXECUTIVE COMMITTEE 
 
The executive committee is responsible to implement the actions of the trial and to 
assure the trial is conducted according to its design. The executive committee is 
responsible for the daily operations of the trial. 
 
DATA SAFETY MONITORING BOARD (DSMB) 
 
The DSMB is a group of experts who monitor patient safety and treatment efficacy data 
while a clinical trial is ongoing. The primary mandate of the DSMB is to protect patient 
safety. If adverse events of a particularly serious type are more common in the 
experimental arm compared to the control arm, then the DSMB would have to strongly 
consider termination of the study. 
 
CLINICAL EVENTS COMMITTEE 
 
The clinical events committee is responsible for evaluating the information provided 
regarding a potential event and adjudicate events according to the trial protocol. This 
committee is blinded to treatment allocation. Information collected will be blinded and 
any comment related to treatment allocation will be eliminated before the committee has 
access to this information. 

 
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CONFLICT OF INTEREST POLICY 
 
The DapaTAVI trial is an independent, investigator-initiated and investigator-led, 
multicentre, randomised trial. Any actual conflict of interest of persons who have a role 
in the design conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed.  
 
 
 

 
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