Clinical trial NCT03485222
Conditions: Cardiovascular Diseases
Keywords: Cardiovascular diseases Heart Failure LV remodeling SGLT-2 Inhibitors Empagliflozin Cardiac MRI
Sponsor: Icahn School of Medicine at Mount Sinai
Start date: 2018-05-21; Completion date: 2020-02-13
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Purpose:

The overall hypothesis of the study is that the benefits attained in the EMPA-OUTCOME were, at least in part, mediated by a glucose-independent mechanism. Thus, to demonstrate the existence of the postulated non-glucose dependent effects, the researchers will investigate the safety and efficacy of empagliflozin versus placebo on top of guideline-directed medical therapy in heart failure patients with reduced ejection fraction without diabetes.

Detailed description:
Heart failure (HF) is a frequent co-morbid condition associated with poor prognosis in diabetes, particularly among older patients. HF accounts for more than 1 Million hospitalizations annually in USA. In addition, HF hospitalizations are associated with significant high risk of post-discharge mortality and recurrent hospitalizations. Almost one-half of patients will be re-hospitalized within 6 months and one-third will die within 12 months of discharge. Median survival after HF diagnosis is about 5 years and is similar for HFpEF and heart failure with reduced ejection fraction (HFrEF) patients. Diabetes as co-morbidity multiplies risk of hospital admissions in HF patients.

Type 2 Diabetes Mellitus (T2DM) is a pathological condition characterized by elevated glucose levels and it is associated with high incidence of cardiovascular (CV) events. Several hypoglycemic agents have successfully managed the elevated glucose levels but with little or no impact on CV events. Management of concomitant HF in T2DM is particularly challenging, as some glucose-lowering agents, such as TZDs, are contraindicated in the treatment of HF patients. Thus, there was a need for an oral agent that improved glycemia as well as provided CV benefits. Empagliflozin is the first glucose-lowering agent showing that not only improves glycemic control but also has cardiovascular benefits. The recent EMPA-OUTCOME trial has shown significant reductions in major adverse cardiac events (MACE), cardiovascular mortality, and hospitalization for Heart Failure (HF) by Empagliflozin given on top of standard-of-care therapy for T2DM patients with Cardiovascular disease (CVD). The dramatic change driving the superiority of the primary composite outcome was a significantly lower CV death rate (38% relative risk reduction). In addition, there were also an impressive 35% and 38% relative risk reductions in hospitalization for heart failure (HF) and death from any cause, respectively.

Empagliflozin is a member of a new class of hypoglycemic agents, the SGLT-2 inhibitors. There are a couple of characteristics that single out the SGLT2 inhibitors from other hypoglycemic drugs. One is their low hypoglycemic risk since they act on the urinary excretion of glucose without interfering with the physiologic response to hypoglycemia. And the other is their "positive" cardiovascular effects such as lowering blood pressure, arterial stiffness, urinary microalbuminuria and triglycerides while increasing HDL-Cholesterol levels. Therefore, the combination of the above-mentioned observations led to some investigators to suggest that these benefits may be, at least in part, independent of its hypoglycemic activity and thus, Empagliflozin could be considered a "cardiac" drug.

Arms: arm 1: 10mg once a day arm 2: placebo once a day
Interventions: intervention 1: Empagliflozin intervention 2: Placebos
Intervention descriptions: intervention 1: 6 months intervention 2: placebo equivalent for 6 months

Protocol documents:
Prot_SAP_001.pdf: 
EMPA-TROPISM Trial: Are the "cardiac benefits" of Empagliflozin independent of its hypoglycemic
activity? 
PI: Juan Badimon, MD 
NCT03485222 
Document Date: Nov 28, 2017


Icahn School of Medicine at Mount 
Sinai Mount Sinai Beth Israel 
Mount Sinai Brooklyn 
The Mount Sinai Hospital Mount 
Sinai Queens 
New York Eye and Ear Infirmary of 
Mount Sinai 
Mount Sinai St. Luke's Mount Sinai 
West 
Program for the Protection of Human 
Subjects  
Institutional Review Boards 
Mount Sinai Health System 
One Gustave L. Levy Place, Box 1081 
New York, NY 10029-6574 T 212-824-
8200 
F 212-876-6789 
irb@mssm.edu icahn.mssm.edu/pphs 
 
 
 
Table of Contents 
 
 
 
1. Title ................................................................................................................................................. 1 
2. Background ..................................................................................................................................... 2 
3. Research Personnel ........................................................................................................................ 4 
4. Subjects - Enrollment ...................................................................................................................... 5 
5. Subjects - Setting and Resources ................................................................................................... 5 
6. Subjects - Populations .................................................................................................................... 5 
7. Subjects - Participation ................................................................................................................... 6 
8. Subjects - Risk and Benefits ........................................................................................................... 7 
9. Procedures - Narrative .................................................................................................................. 10 
10. Procedures - Details ...................................................................................................................... 12 
11. Consent - Obtaining Consent ........................................................................................................ 13 
12. Data – Collection, HIPAA and Storage .......................................................................................... 14 
13. Data - Safety Monitoring ............................................................................................................... 15 
14. Drugs / Biologics ........................................................................................................................... 18 
 


1 
 
 
1. Title 
 
Protocol Title 
EMPA-TROPISM Trial: Are the "cardiac benefits" of Empagliflozin independent of its hypoglycemic activity? 
 
 
 
Principal Investigator 
 
Juan Badimon 
 
Primary Department 
 
Medicine - Cardiology 
 
Application Initiated By 
 
Juan Badimon 
 
 
Lay Summary 
Empagliflozin is the first drug that improves glucose control and has cardiovascular benefits. A recent trial has 
shown significant reductions in adverse events. Cardiovascular mortality and hospitalization were reduced by 
empagliflozin given on top of standard-of-care therapy in diabetics.  Some investigators have suggested that 
these benefits are independent of its glucose lowering effect and thus, Empagliflozin could be considered a 
"cardiac" drug. 
 
Our overall hypothesis is that the benefits attained from empagliflozin were at least in part, mediated by a 
glucose- independent mechanism. Thus, we are proposing to conduct a study to investigate the postulated 
benefits of empagliflozin vs placebo involving non-diabetic patients with heart failure. 


 
2 
 
 
2. Background 
 
Objectives 
Our overall hypothesis is that the benefits attained in the EMPA-OUTCOME were at least in part, mediated by 
a glucose-independent mechanism. Thus, to demonstrate the existence of pleiotropic (non-glucose dependent) 
effects associated with empagliflozin administration, we are proposing to conduct a pilot randomized, double 
blind, placebo- control, single-center study to investigate the postulated "cardiovascular" benefits of 
empagliflozin 10mg/day vs placebo involving non-diabetic HF patients with reduced ejection fraction. 
 
Background 
Empagliflozin is the first glucose-lowering agent that not only improves glycemic control but also has 
cardiovascular benefits. The recent EMPA-OUTCOME trial has shown significant reductions in major adverse 
cardiac events (MACE), cardiovascular mortality, and hospitalization for Heart Failure (HF) with empagliflozin 
given on top of standard-of-care therapy for T2DM patients with cardiovascular disease (CVD). Some 
investigators have suggested that these benefits may be independent of its hypoglycemic activity and thus, 
Empagliflozin could be considered a "cardiac" drug. This hypothesis has emanated from the data of the EMPA 
OUTCOME clinical trial. 
 
Empagliflozin treatment did not have any effects on the rate of the traditional atherothrombotic events. The 
dramatic change driving the superiority of the primary composite outcome (major adverse CV events) was a 
significantly lower CV death rate (38% relative risk reduction). In addition, there were also an impressive 35% 
and 38% relative risk reductions in hospitalization for heart failure (HF) and death from any cause. Of the major 
interest is that these benefits occurred in the absence of any major differences in glycemic, lipid, or blood 
pressure (BP) control. Management of concomitant HF in T2DM is particularly challenging, as some glucose-
lowering agents, such as TZDs, are contraindicated in patients with HF. Until recently, there was an unmet 
need for an oral agent that improved glycemia as well as provided CV benefits, including decreasing HF in 
patients with, or at risk of, CVD. 
 
Type 2 diabetes mellitus (T2DM) is one of the most common chronic health conditions in the United States; it 
affects approximately 10% of adults with up to one-quarter being undiagnosed. T2DM is associated with 
substantial cardiovascular (CV) morbidity and mortality. Heart failure (HF) is a frequent co-morbid condition 
associated with poor prognosis in diabetes, particularly among older patients. HF accounts for more than 1 
Million hospitalizations annually in USA. In addition, HF hospitalizations are associated with significant high risk 
of post-discharge mortality and recurrent hospitalizations. Almost one-half of patients will be re-hospitalized 
within 6 months and one-third will die within 12 months of discharge. Median survival after HF diagnosis is 
about 5 years, and is similar for HFpEF and HFrEF patients. Diabetes as co-morbidity multiplies risk of hospital 
admissions in HF patients. 
 
Management of concomitant HF in T2DM patients is particularly challenging. Some glucose-lowering agents, 
such as TZDs, are contraindicated in patients with HF. Until recently, there was an unmet need for an oral 
agent capable of improving glycaemia as well as providing CV benefits, including mitigating HF in patients with 
or at risk of CVD. There are a couple of characteristics that single out the SGLT2 inhibitors from other 
hypoglycemic drugs. One is their low hypoglycemic risk since their act on the urinary excretion of glucose 
without interfering with the physiologic response to hypoglycemia, and the other is their "positive" 
cardiovascular effects such as lowering blood pressure, arterial stiffness, urinary microalbuminuria and 
triglycerides while increasing HDL-cholesterol levels. The recent EMPA-OUTCOME trial showed significant 
reductions in major adverse cardiac events (MACE), CV mortality, and hospitalization for HF with Empagliflozin 
when given on top of standard-of-care therapy for T2DM and CVD. Therefore, the combination of the above-
mentioned observations led to some investigators to suggest that these benefits may be, at least in part, 
independent of its hypoglycemic activity and thus, Empagliflozin could be considered a "cardiac" drug. 
 
Our overall hypothesis is that the benefits attained in the EMPA-OUTCOME were at least in part, mediated by 
a glucose-independent mechanism. Thus, to demonstrate the existence of pleiotropic (non-glucose dependent) 


 
3 
 
effects associated with empagliflozin administration, we are proposing to conduct a pilot randomized, double 
blind, placebo- control, single-center study to investigate the postulated "cardiovascular" benefits of 
empagliflozin 10mg/day vs placebo involving non-diabetic HF patients with reduced ejection fraction. 
 
Primary Endpoints 
The primary end-point will be to determine whether empagliflozin mitigates changes in LV end systolic volume 
(ESV) or LV end diastolic volume (EDV) in HF patients without diabetes when compared to placebo. We have 
chosen LV volume because it is the strongest predictor of adverse cardiovascular outcomes even after 
adjusting for LVEF and MI size (White HD Circulation. 1987;76:44–51 and Migrino RQ Circulation. 
1997;96:116–121). 
 
Secondary End-points 
1. To determine changes in LV mass, LV-EF and remodeling index (LV mass/LV-EDV) with empagliflozin 
compared with placebo. 
2. To determine if there is a change in left atrial volume (an accurate indicator of chronic increase in LV filling 
pressures) with empagliflozin compared with placebo. 
3. To determine if there is a change in right ventricular (RV) EDV, RV-ESV and, RV-EF with empagliflozin 
compared with placebo. 
4. To determine if there is a change in cardiac interstitial fibrosis as assessed by T1 mapping with 
empagliflozin compared with placebo. 
5. To determine if there is a change in VO2 Oxygen consumption with empagliflozin compared with placebo. 
6. To determine if there is a change in Visceral and epicardial fat as measured by CMRI with empagliflozin 
compared with placebo. 
7. To determine if there is a change in arterial stiffness measured by CMRI with empagliflozin compared with 
placebo. 
8. To determine if there is a change in body composition analysis (BCA anthropromorphic measurements) 
with empagliflozin compared with placebo. 
9. Effect of the treatment on several cardiovascular and inflammatory biomarkers with empagliflozin 
compared with placebo. 
10. To determine if there is a change in exercise tolerance by the 6 min walk test with empagliflozin compared 
with placebo. 
11. To determine if there is a change in the patient-reported quality of life by the Minnesota Living with HF and 
SF-36 questionnaires. 
 
Safety and Tolerability 
Patients will be monitored for signs of hypoglycemia, urinary tract infections, bone fractures, diabetic 
ketoacidosis and thromboembolic during the follow-up period. We will also assess survival, hospitalizations 
and HF worsening (more visits, increase in prescription of diuretics, etc).  


 
4 
 
 
3. Research Personnel 
 
Name/Department 
Role/Status 
Juan Badimon / Medicine - Cardiology 
Principal Investigator 
Alvaro Garcia Ropero / Cardiology 
Co-Investigator 
Johanna Contreras / Medicine - Cardiology 
Co-Investigator 
Valentin Fuster / Medicine - Cardiology 
Co-Investigator 
Donna Mancini / Medicine - Cardiology 
Co-Investigator 
Sean Pinney / Medicine - Cardiology 
Co-Investigator 
Ronald Tamler / Medicine - Endocrinology 
Co-Investigator 
Javier Sanz / Medicine - Cardiology 
Co-Investigator 
Mohammad Zafar / Medicine - Cardiology 
Co-Investigator 
Carlos Santos- Gallego / Medicine - Cardiology 
Co-Investigator 
Arianna Patricia Vargas Delgado / Cardiology 
Co-Investigator 
 
 
 
 
 


 
5 
 
 
 
4. Subjects - Enrollment 
 
Site Name 
 
 
 
 
 
 
 
Icahn School of Medicine at Mount Sinai 
 
Subjects To Be Enrolled  
 
 
 
 
 
100 
 
Total Number of Subjects Needed To Complete Study  
80 
 
 
5. Subjects - Setting and Resources 
 
Feasibility of Meeting Recruitment Goals 
HF patients will be identified from the HF clinic at Mount Sinai and the Mount Sinai Consortium database for 
patients with chronic heart failure. The MSSM consortium includes the Mount Sinai Medical center of 
Manhattan, Elmhurst Hospital in Queen, the VA Bronx and the Mount Sinai Saint Luke's Hospital in Harlem 
and the Mount Sinai-West Hospital (former Roosevelt Hospital). 
 
The Consortium's database contains more than 10,000 HF patients. This proposal involves non-diabetic HF 
patients and given the common co-existence of diabetes affecting to 40-50% of HF patients; the database still 
offers us a potential 5,000 HF patients that could be candidates for enrollment in our study. 
 
Facilities to be Used for Conducting Research 
Consent Form and blood collection: Atran Bldg 6th Room 20 CMRI - Lauder Imaging facilities 
O2 consumption and Vo2 consumption: Cardiopulmonary Exercise laboratory on Guggenheim 6. 
 
 
6. Subjects - Populations 
Inclusion Criteria 
Patients should meet the following inclusion criteria: 
1. Ambulatory patients age more than 18 years 
2. Diagnosis of Heart failure (NYHA II to III) 
3. LVEF<50% on echocardiography or CMRI 
4. Have stable symptoms and therapy for HF more than 1 week. 
 
Exclusion Criteria 
1. Pregnant or lactating women. 
2. Any history of diabetes by medical history or by any of the established criteria by the American Diabetes 
Association. It also includes patients with history of diabetes in remission. 
3. ACS or cardiac surgery within the last 3 months. 
4. Cancer or any other life-threating condition. 


 
6 
 
5. Glomerular Filtration Rate < 30 ml/Kg/min. 
6. Use of continuous parental inotropic agents. 
7. Systolic BP < 90 mm Hg. 
8. Recreational drugs and /or excessive alcohol. 
9. Psychiatric disease incompatible with being in study. 
10. Any contraindication to MRI procedures. 
11. Any other medical or physical condition precluding the subject's participation. 
 
 
7. Subjects - Participation 
 
Duration of an Individual Subjects Participation in the Study  
 
6 months 
 
Duration Anticipated to Enroll All Study Subjects 
 
 
 
20 months 
 
Estimated Date for the Investigators to Complete This Study  
 
3-5 years 
 
Procedures for Subjects to Request Withdrawal 
You may stop taking part in this research study at any time without any penalty. This will not affect your ability 
to receive medical care at any of the Mount Sinai Health System hospitals or to receive any benefits to which 
you are otherwise entitled.  
If you decide to withdraw your consent, we ask that you contact Dr. Juan J Badimon, and let him know that you 
are withdrawing from the study. His mailing address is the Icahn School of Medicine at Mount Sinai, One 
Gustave L. Levy Place, Box 1030, New York, NY 10029. If you wish to withdraw your authorization as well you 
must contact Dr. Badimon in writing at the Icahn School of Medicine at Mount Sinai, One Gustave L. Levy 
Place, Box 1030, New York, NY 10029. 
You may also withdraw your permission for the use and disclosure of any of your information for research, but 
you must do so in writing to the Principal Investigator at the address on the first page. Even if you withdraw 
your permission, we may still use the already collected information if it is necessary to complete the study. 
Your health information may still be used or shared after you withdraw your authorization if you should have an 
adverse event from participating in the study. 
 
Procedures for Investigator to Withdraw Subjects 
The study doctor, the sponsor or the institution may stop your involvement in this research study at any time 
without your consent. This may be because the research study is being stopped, the instructions of the study 
team have not been followed, the investigator believes it is in your best interest, or for any other reason. If 
specimens or data have been stored as part of the research study, they too can be destroyed without your 
consent. 
 
Participants Will Be Recruited 
 
Yes 
 
Recruitment Method(s) 
 
Clinical Practice, Registry/Bank, Records  


 
7 
 
 
How Participants Will Be Identified 
In all disclosures outside of Mount Sinai, you will not be identified by name, social security number, address, 
telephone number, or any other direct personal identifier unless disclosure of the direct identifier is required by 
law. Some records and information disclosed may be identified with a unique code number. The Principal 
Investigator will ensure that the key to the code will be kept in a locked file, or will be securely stored 
electronically. The code will not be used to link the information back to you without your permission, unless the 
law requires it, or rarely if the Institutional Review Board allows it after determining that there would be minimal 
risk to your privacy. 
 
 
Who Will Initially Approach Potential Participants 
 
Treating Physician, Clinic Personnel 
 
How Research Will Be Introduced to Participants 
Research will be introduced by the primary physician or physicians from the Heart Failure Program at ISMMS. 
They will be informed of the significant cardiac benefits obtained in heart failure and diabetic patients. In 
addition, we will tell the participants that the objective of the study is to investigate whether the benefits seen 
in the HF and diabetic population could be extrapolated to HF patients independently of their diabetic status. 
 
How Participants Will Be Screened 
All approached participants will have a diagnosis of HF. Upon signing of the informed consent form, a blood 
sample will be collected and analyzed to assure that participants fulfill ALL the inclusion criteria but NONE of 
the exclusion criteria. We will ask questions about their medical history and perform a physical exam that 
includes weight, height, body temperature, blood pressure, pulse rate, and EKG. In addition, we will collect 
blood and urine to check for routine lab tests, hepatitis B and C, use of recreational drugs and HIV test. The 
results of the drug testing will NOT be placed in the participant's medical record. 
 
 
8. Subjects - Risk and Benefits 
 
Risks to Subjects 
Empagliflozin is approved by the FDA for the treatment of high levels of glucose in diabetic subjects. This drug 
has been studied in tens of thousands of patients and, despite its well-established benefits, the adverse effects 
observed and that could very rarely affect you are: 
 
Low sugar levels manifested as blurry vision, accelerated cardiac pulse, irritability, nervousness, 
headaches, shivers, sweating, tireless, tingles and/or appetite loss. 
 
Blood pressure lowering manifested as headache, dizziness, confusion, irritability, sweat and irregular 
cardiac pulse. 
 
Dehydration manifested as headache, dizziness, confusion, weakness specially when standing up. 
 
Ketoacidosis manifested as headache, fatigue, nausea/vomiting, stomach ache, breathing difficulties, 
abdominal pain, urinating urges, appetite loss. 
 
Urinary infections (penis in men and vagina in women) manifested as frequent urination urges, irritation 
while urinating, blood and/or bad smell of the urine, pain in the stomach and/or pelvis. 
 
Allergies manifested as cutaneous rushes, inflammation and/or itching in the face, tongue and throat as 
well as dizziness and breathing difficulties. 
 
In case you experience any of these symptoms, stop taking the study drug and immediately contact the 
investigators at the phone number provided below in this document. 


 
8 
 
 
There are no reports of any psychological or social risks associated with the treatment. 
 
The risks of a blood draw include pain, bruising, and the slight possibility of infection at the place where 
the needle goes in. Some people feel dizzy or may faint during or after a blood draw. 
 
Description of Procedures Taken to Lessen the Probability or Magnitude of Risks 
Upon randomization, all participants will be invited to come to the MSMC at 1- and 3-months post-therapy 
initiation to assure the safety of the assigned treatment. 
They will be instructed on the symptoms typical of the potential risks associated with the treatment. In case of 
any doubt, they should stop taking the drug and call the investigators. In conditions of significant discomfort or 
pain, they should go to the closest Emergency Room and notify the investigators. 
 
Provisions for Research Related Harm / Injury 
If you believe that you have suffered an injury related to this research as a participant in this study, you should 
contact the Principal Investigator, Dr. Juan J Badimon or Dr. Carlos Santos-Gallego, at 212-241-8484. If you 
are injured or made sick from taking part in this research study, medical care will be provided. Generally, this 
care will be billed to you or your insurance in the ordinary manner and you will be responsible for all treatment 
costs not covered by your insurance, including deductibles, co-payments and coinsurance. This does not 
prevent you from seeking payment for injury related to malpractice or negligence. Contact the investigator for 
more information. 
 
Expected Direct Benefit to Subjects 
It is important to know that you may not get any benefit from taking part in this research. However, possible 
benefits may be a reduction in the frequency of hospitalization and an improvement of the symptoms 
associated with heart failure in the group receiving the study treatment. 
 
Benefit to Society 
It is hoped the knowledge gained from this study will be of benefit to others in the future. 
 
Provisions to Protect the Privacy Interests of Subjects 
As part of this research project, it will be necessary for the research team and others to use and share some of 
the private protected health information. Consistent with the federal Health Insurance Portability and 
Accountability Act (HIPAA), we are asking your permission to receive, use and share that information. 
 
The research team and other authorized members of The Mount Sinai Hospital and Mount Sinai School of 
Medicine (together, "Mount Sinai") workforce may use and share your information to ensure that the research 
meets legal, institutional or accreditation requirements. For example, the School's Program for the Protection 
of Human Subjects is responsible for overseeing research on human subjects, and may need to see your 
information. If you receive any payments for taking part in this study, the Mount Sinai Medical Center Finance 
Department may need your name, address, social security number, payment amount, and related information 
for tax reporting purposes. If the research team uncovers abuse, neglect, or reportable diseases, this 
information may be disclosed to appropriate authorities. 
 
Outside of Mt Sinai, the following agencies may receive some of your protected information: 
- The sponsoring government agency and/or their representative who need to confirm the accuracy of the 
results submitted to the government or the use of government funds. 
- National Institutes of Allergies and Infectious Disease National Institutes of Health Department of Health 
and Human Services (NAID/NIH/DHHS). 
- A Data Safety Monitoring Board or other committee that will monitor the study on an ongoing basis for 
safety. 


 
9 
 
- The United States Food and Drug Administration. 
- The United States Department of Health and Human Services and the Office of Human Research 
Protection. 
In all disclosures outside of Mount Sinai, you will not be identified by name, social security number, address, 
telephone number, or any other direct personal identifier unless disclosure of the direct identifier is required by 
law. 
 
Economic Impact on Subjects 
You will not be charged for the clinic visits or laboratory tests that are required by this study. 
If you agree to comply with all the visits, you will be given up to $400 for your time and inconvenience. The 
payment will be pro-rated between all the visits as follow: 
V1 - $20; V2 - $150; V3 - $40; V4 - $40; V5 - $150. 
Payment will be provided in the form of a check generated by the Mount Sinai Finance depart. Checks require 
some time to be prepared and will be given to you as available. 
Tax laws may require the Mount Sinai Finance Department to report the amount of payment you receive from 
Mount Sinai to the Internal Revenue Service (IRS) or other agencies as applicable. Generally, this reporting 
would take place if receiving payments that equal $600 or more from Mount Sinai in a calendar year. You 
would be responsible for the payment of any tax that may be due. 
 
 
 
 
 


 
10 
 
9. Procedures - Narrative 
 
Description of the Study Design 
If you agree to participate in this research study, the following information describes what may be involved. All 
the research activities will take place at the MSMC. 
The first step will be that the study nurse or doctor will explain you the basis for the study and all the research 
activities involved in your participation. Thereafter, you will be asked to sign this consent form. Before signing 
it, ask your study nurse or doctor anything that you do not fully understand. After you have signed this form, 
you will be asked some questions and will undergo some tests at the screening visit to see if you qualify and if 
it is safe for you to join the study. 
All the procedures done during the study are solely for research purposes. The total volume blood collected 
during the 6-months of the study duration will be 75 mls. (5 table spoons). This amount is much less than one 
blood donation and, therefore, should not affect your health. 
The procedures included in each one of the visits are described below: 
 
Visit 1 Screening: This visit with last approx. 1 hour and it will take place at the 6th Floor of the Atran Building 
at the MSMC. We will ask you some questions about your medical history (about your health) and perform a 
physical exam that includes your weight, height, body temperature, blood pressure, pulse rate, and one EKG 
(checks the electrical activity of the heart). In addition, we will collect one sample of blood (1 table spoon) and 
urine to check for routine lab tests, hepatitis B and C, use of recreational drugs use (amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, etc.) and HIV test. The results of the drug testing will NOT be 
placed in your medical record. 
If you qualify and are willing to participate in the study, we will ask you to return for the 2nd visit within the next 
30 days. In case you do not qualify, your participation will end in this visit. 
 
Visit 2 Randomization: This visit will be approx. 4 hours long. You will be asked to report to the 6th Floor, 
Room 20 of the Atran Building at the MSMC in fasting state. This visit will serve to perform all the baseline 
(pre-treatment) procedures. The procedures to be performed during this visit will be: 
- Magnetic Resonance Imaging to study cardiac parameters of your cardiac function. You will be introduced 
inside of a magnet where you should stay as quiet as possible for about 45-60 minutes. As routinely done in 
clinical you will receive Gadolinium that is a contrast that facilitate the visualization of your heart. This 
procedure does not involve the exposure to any ionizing radiation and thus, does not present any important 
risk to your health. 
- Oxygen consumption. You will be asked to walk on a treadmill while being EKG-monitored. Your blood 
pressure will be monitored before and after the procedure. You will also wear a mask that will allow to 
measure the Oxygen consumption. This procedure will take approx. 20-30 minutes 
- 6-minute walking test. - We will ask you to walk for a total of 6-minutes and then walked distance will be 
recorded. If necessary you will be allowed to stop and rest during the 6-minutes period. This walk will be 
repeated at the end of the 6-months of the study duration and the difference between the distance walked in 
the two procedures will tell us about the effects of the treatment. 
- Heart Failure Questionnaire. - we will ask you some questions about the quality of life. The questioner will 
be repeated at the end of the 6-months of study. 
- We will collect one blood sample (15ml 1 stable spoon) to study some blood parameters 
Following baseline testing procedures, you will be randomized to one of two possible treatment groups 
(Empagliflozin or Placebo). Randomization is a process used in clinical studies to make sure that the observed 
effects of study treatment are real. The study treatment you get will be chosen by chance, like flipping a coin. 


 
11 
 
Neither you nor the study doctor will choose what study treatment you get. You will have an equal chance of 
being assigned to either study treatment group. One group will receive a pill of empagliflozin (10mg/day) while 
the other (placebo-control) group will receive a sugar pill without active medicine. The study pills will be taken 
orally and preferable at the same time every day. The study pill will be taken in addition to all the drugs 
prescribed by your physician. You will be provided detailed instructions on how to take your study pills in 
person during this visit. 
The treatments in this study will be 'blinded', meaning neither you nor the study investigators will know which 
study treatment you are getting. This information could be obtained in an emergency however, you will not be 
told which study treatment you are getting, but your study doctor will know. 
At the end of this visit, we will provide you with a supply of the assigned pills and you will be allowed to go 
home. We will schedule your next visit within 1-2 weeks of visit 2. 
 
Visit 3 Safety: This visit will last approx. 1 hour. You will be asked to report to the 6th Floor of the Atran 
Building at the MSMC in a fasting state. During this visit, we will perform the same procedures at per the visit1. 
The most important reason for this visit is to monitor the safety and efficacy of the medicine that you are taking. 
During this visit, we will record your vital signs (weight, height, body temperature, blood pressure, pulse) and 
collect one blood sample (15mls or 1 table spoon) for routine lab test (lipids, glucose, liver enzymes, etc.). We 
will ask you questions about your health since your last visit. Thereafter, we will provide you with a supply of 
the assigned pills and your visit will end. 
 
Visit 4 Maintenance: This visit will last approx.1 hour. Within 12-14 weeks of the previous visit, you will be 
asked to report to the 6th Floor of the MSMC in a fasting state. The reason for this visit is to continue 
monitoring the safety and efficacy of the medicine that you are taking. We will repeat the procedures done 
during your previous visit (i.e. record your vital signs and collect one blood sample for routine lab test) and ask 
you questions about your health status since your last visit. Thereafter, we will provide you with a supply of the 
assigned pills and your visit will end. 
 
Visit 5 Final: This will be the last visit and will have an approx. duration of approx. 4 hours. You will be asked to 
report to the 6th Floor of the Atran Building at the MSMC in a fasting state. During this visit, we will repeat the 
procedures performed during visit 2. The procedures will be: Magnetic resonance imaging, Oxygen 
consumption, 6-minute walking test, the Minnesota questioner and collect one blood sample (15 mls or 1 table 
spoon). We will record your vital signs (body weight, height, body temperature, blood pressure, pulse) and 
EKG to check your health status. The comparison of the results obtained during visit 2 and visit 5 will allow us 
to delineate the effects of the study drug. At the end of this visit, your participation in the study will end. 
 
Description of Procedures Being Performed 
Cardiac Magnetic Resonance Imaging (CMR): CMR studies will be performed at the Cardiac Imaging Facilities 
of the Mount Sinai Heart under the direction of Dr. Javier Sanz (Investigator of the proposal). Images will be 
acquired with a 3.0 Tesla magnet (Achieva, Philips Medical Systems, Netherlands). Steady-state free 
precession short axis images (TR 3.6 ms, TE 1.6 ms, flip angle 45º, field of view 250 x 250 mm, SENSE factor 
3, voxel size 1 x 1 x 5 mm, no gap, number of averages 3, bandwidth 1286 Hz, 12 lines per segment) from the 
LV base through LV apex will be used for the quantification of LV volumes, ejection fraction and mass. Late 
gadolinium enhancement (LGE) will be performed 15 minutes after the administration of gadolinium 
(Magnevist, 0.2 mmol/kg) using an inversion- recovery fast gradient echo sequence (TR 9 ms, TE 5.4 ms, TI 
optimized to null normal myocardium, gating factor 3, field-of-view 250 x 250 mm, pixel size 1 x 1 x 5 mm, 
SENSE factor 3, number of averages 3, bandwidth 232 Hz, TFE factor 16). A Look-Locker sequence will be 
performed before and 10 minutes after gadolinium administration to evaluate interstitial myocardial fibrosis 
using the T1 mapping technique. All CMR images will be blindly analyzed using commercially available 
software (Extended MR Workspace, Philips Medical Systems, Netherlands). Epicardial and endocardial 


 
12 
 
contours will be traced in each SSFP cine image to obtain LV end-diastolic volume (LVEDV), LV end-systolic 
volume (LVESV), LV ejection fraction (LVEF) and LV mass; by convention, papillary muscles will be included in 
the LV cavity. LV scar size will be measured by LGE and expressed as a percentage of the LV mass; the 
absolute MI size also was quantified in grams (calculated as volume multiplied by myocardial density [1.05 
g/cm3]). Infarct was defined as myocardium with signal intensity was higher than 3 standard deviations of that 
in remote, normal. Longitudinal relaxation times for T1 mapping quantification will be measured using cvi42 
software (already present in our clinical facility). 
 
Peak Oxygen Consumption: Cardiopulmonary exercise testing will be done prior to randomization and at 6 
months of therapy. Patients will report in the fasting state to the Mount Sinai Research Cardiopulmonary 
Exercise laboratory on Guggenheim 6. This facility is under the direction of Dr. Donna Mancini (investigator of 
this proposal). Patients will perform a treadmill exercise using the modified Naughton protocol with continuous 
EKG monitoring. Blood pressure will be measured prior to exercise, at the end of each exercise stage and at 
peak exercise. The patient will be connected using a mouthpiece to a metabolic cart (Medical Graphics Ultima 
Cardio 2, St Paul, Minn) for continuous measurement of oxygen consumption, carbon dioxide production and 
minute ventilation. Symptom limited exercise will be performed. Perceived levels of dyspnea and fatigue will be 
measured using the Borg scale. Peak VO2, VE/ VCO2 ratio and the aerobic threshold will be recorded. 
 
6 minute walk test: Patients will perform a 6 min walk test prior to and 6 months post randomization. In a quiet 
100 ft hall the patients will be instructed to walk as fast and perform as many laps as possible between the 
distance markers over a period of 6 minutes. The walk test will be supervised but unencouraged. Blood 
pressure and heart rate are measured at the start and end of the 6 min. Patients will be allowed to stop and 
rest if needed. The total distance walk will be recorded. 
 
Heart Failure Questionnaire: We will ask you some questions about the quality of life. The questionnaire will 
be repeated at the end of the 6-months of study. 
 
Inflammatory and cardiovascular biomarkers: will be assessed two times throughout the study: at the time of 
randomization and at the end of the study using the Human Cytokine/Chemokine Panel I kit (Luminex; Cat # 
HCYTMAG-60K-PX41) that allows to measure 41 inflammatory cytokines and chemokines with well-
established predictive value for CV risk and mortality. The effect of the treatment will be assessed by changes 
in the value of the selected biomarkers between the randomization and the end of study time–points. 
Description of the Source Records that Will Be Used to Collect Data About Subjects 
All the data will be recorded in a specifically prepared Case Report Form (CRF) that includes all the 
parameters mentioned in the next section 
 
Description of Data that Will Be Collected Including Long-Term Follow-Up 
The major end-points are the effect of the treatment on cardiac function assessed by CMRI. Vital signs and 
routine blood parameters will be assessed at each visit. In addition at the screening and at the end of the 6-
months of follow-up we will monitor the effect of the treatments on systemic cytokines and chemokines with 
well-established predictive value for CV risk and mortality by using the Human Cytokine/Chemokine Panel I kit 
(Luminex; Cat # HCYTMAG-60K-PX41). 
 
10. 
Procedures - Details 
Surveys or Interviews 
 
Yes 
 
Names of Standardized Instruments 
To determine if there is a change in the patient-reported quality of life by the Minnesota Living with HF and SF-
36 questionnaires. We will also ask for any adverse event at each of the visits. 
 


 
13 
 
 
11. 
Consent - Obtaining Consent 
 
Consent Process 
 
Adult Consent 
 
Where and When Consent Will Be Obtained 
Informed consent form will be obtained at the Heart Failure Unit and/or Atran 6th Floor Room 20 
 
Waiting Period for Obtaining Consent 
A maximum 4 weeks 
 
SOP HRP-090 Informed Consent Process for Research Is Being Used 
Yes 
Process to Document Consent in Writing  
Will Use Standard Template 
 
 
Non-English Speaking Participants Will Be Enrolled  
Yes 
 
What Languages Other Than English Will Be Used 
Spanish speaking participants will be also approached. They will be offered a consent form in Spanish. 
 
 
What Process Will Be Used  
Long Form 
 


 
14 
 
12. 
Data – Collection, HIPAA and Storage 
 
Description of Health Information That Will Be Viewed, Recorded, or Generated 
- Clinical History 
- Vital signs 
- Routine clinical lab tests 
- Cardiac function assessed by CMRI 
- Oxygen consumption 
- Systemic biomarkers 
 
HIV / AIDS Related Information Will Be Viewed or Recorded 
No 
 
Obtaining HIPAA Authorization  
Yes 
 
How PHI Will Be Protected from Improper Use or Disclosure 
Participants will be identified by a study code. Only the PI will have access to the subject identification. The 
code will be under lock at the PI's office. 
 
PHI Will Be Destroyed at the Earliest Opportunity Consistent with the Research 
No 
 
Justification for Retaining PHI Indefinitely 
It will be retained for a maximum of 3 years 
 
PHI Will Be Shared  
No 
 
Location Where Data Will Be Stored 
At the PI's office (Atran Building 6th Floor Room20) in a locked cabinet 
 
How will the data be stored? 
 
Coded and de-identified. 
 
Duration Data Will Be Stored 
3 years after the end of the study 
 
Steps That Will Be Taken to Secure the Data During Storage, Use, and Transmission 
Only the PI will have access to the identifying code 
 
Power Analysis/Data Analysis Plan (Including Any Statistical Procedures) 
At the end of the study, the data analysis will performed. All data will be presented as mean±SD. For statistical 
comparison, data will be initially tested for Normality by using the Kolmogorov-Smirnov's test. In case the data 
follow a normal distribution, they will be compared between groups using a Student-t test. If the data do not 
follow a normal distribution, data will be presented as median ± interquartilic range. Medians will be compared 
between groups with the nonparametric Mann-Whitney's U (as 2 groups will be compared); when variances 
look different (ratio >2), the Welch t test will be used instead. Two-way repeated-measures ANOVA will be 
used to compare values between 2 groups at different time-points. All statistical calculations will be performed 
with SPSS 18.0. Differences will be considered statistically significant at values of P<0.05. 
 
 
 
 


 
15 
 
 
13. 
Data - Safety Monitoring 
 
More Than the Minimum Data Safety Monitoring Will Be Done 
Yes 
 
Principal Monitor 
Donna Mancini 
 
Additional Monitors 
Name 
Ronald Tamler 
Department 
Medicine - Endocrinology 
 
Name 
Sean Pinney 
Department 
Medicine - Cardiology 
 
Name 
Usman Baber 
Department 
Medicine - Cardiology 
 
Name 
Samantha Sartori 
Department 
Cardiovascular Institute 
 
Specific Items That Will Be Monitored for Safety 
Effect of the treatment on routine lab test. Safety and tolerability of the treatments is the major reason for visits 
3 and 4. Major items to be monitored are: hypoglycemia, urinary tract infections, bone fractures, diabetic 
ketoacidosis and thromboembolic events will be monitored during the follow-up period. 
We will also assess survival, re-hospitalizations and heart failure worsening (as more visits, increase in 
prescription of diuretics, etc) 
 
Frequency of Data Review 
Each 6-months or more frequently as needed during the study development. 
 
Rules for Alteration of Study Design 
Patients showing any adverse effect (as mentioned before) to the treatments will be advised to stop taking the 
drug and removed from the trial. 
 
Selection Procedures to Minimize Toxicity 
Potential candidates will be screened for eligibility prior randomization. Upon treatment initiation, they will be 
monitored at 1- and 3- months for presence of adverse effects. 
We will also performe a test for safety at study termination. 
 
Grading System to Evaluate Adverse Events 
The intensity of clinical AEs will be graded on a 3-point scale (mild, moderate, severe) and will be reported on 
specific AE pages of the CRF. The three categories of intensity are defined as follows: 
 
Mild. - The event may be noticeable to the subject. It does not usually influence daily activities, and 
normally does not require intervention. 
 
Moderate. - The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
 
Severe. - The event may cause noticeable discomfort, and usually interferes with daily activities. The 
subject may not be able to continue in the study, and treatment or intervention is usually needed. 
A mild, moderate, or severe AE may or may not be serious. These terms are used to describe the intensity of a 


 
16 
 
specific event. Medical judgment should be used on a case-by-case basis. Seriousness, rather than intensity 
assessment, determines the regulatory reporting obligations. 
Each AE must be assessed by the investigator as to whether or not there is a reasonable possibility of causal 
relationship to the study treatment, and reported as either related or unrelated. The determination of the 
likelihood that the study treatment caused the AE will be provided by the investigator. 
 
Procedures to Assure Data Accuracy 
The PI will serve as Investigator of Records (IoR). He will appoint a senior member of his clinical research staff 
to serve as Study Coordinator, who will work closely with the Regulatory Manager of the Mount Sinai Heart, to 
monitor case report forms (CRFs) on a weekly basis, and the SMC will meet every 6 months, or more 
frequently is needed, during the study to review CRFs. 
The Study Coordinator will verify data collected on case report forms against source documents. Source 
documents can include any of the following: hospital records, research records, laboratory values, subject 
diaries, checklists, pharmacy records, data recorded from automated instruments (such as ECG), medical 
transcriptions, magnetic media images, and x-rays. 
The Study Coordinator will work closely with the Mount Sinai Heart Regulatory Manager to compare the 
procedures defined in the protocol as well as regulatory requirements to ensure data integrity. Internal auditing 
includes the review of all the regulatory documents; (IRB, regulatory agency correspondence) and clinical 
records. The IoR and the Study Coordinator will ensure the following regulatory requirements are met: 
- Verify investigator qualifications. 
- Review PI and sub-investigator CV's and registrations and verify documentation was current at time of study 
visit. 
- Verify current certifications and lab normal ranges protocol-required procedures. 
- Verify equipment not covered under CLIA or CAP certifications are adequately maintained and review 
certifications. 
- Verify facilities remain adequate throughout the trial. 
- Ensure drug dispensation and storage complies with regulatory requirements. 
- Verify documentation in the master file of receipt of disposition/use and return of product. 
- Verify the master file contains guidelines for handling product. 
- Verify the site maintains records that indicate product has been supplied only to eligible subjects at protocol 
specified doses. 
- The investigator's records for study drug shipping receipts including lot number and quantity (if applicable). 
- Shipping receipts to other sites (if applicable). 
- Review of dispensing logs including the subject initials, number, dose or quantity and person dispensing. 
- Temperature log. 
- Return receipts. 
- Verify that the protocol or the master file documents provides the necessary instruction s to the patients on 
how to use, handle, store, and return drug. 
- Verify the site is following the approved IRB protocol. 
- Ensure protocol deviations and violations are reported. 
- Verify Informed Consent process. 
- Informed Consent review. 
- Review of the signed informed consent documents for the correct version, completeness of the subject's or 
legally authorized representative signature and date, signature and date of person obtaining the consent, 
investigator signature and date, and witness name, signature and date when required. 
- Documentation of the informed consent process or enrollment note. The staff member should evaluate for 
documentation of the informed consent discussion, a question and answer period, the subject had adequate 
time to reflect, make an informed decision, signed the informed consent prior to the initiation of any study 
procedures and received a copy of the signed informed consent. 
- Verify correct version of IRB-approved consent form was used. 
- Verify the subject completed a HIPAA form prior to enrollment. 
- Verify staff has adequate training and responsibilities have not been delegated to unauthorized individuals. 
- Report subject recruiting and enrollment rate. 
- Compare the number of subjects who signed informed consent to the limit approved by the IRB. 


 
17 
 
- Check subject screening log to document subjects who entered screening but did not participate in the trial. 
- Verify accuracy of records and completeness of CRF entries and ensure corrections are made when 
necessary. 
 
Suspension Reported to 
Study suspension would be immediately reported to the IRB and the funding agency (Boehringer-Ingelheim) by 
the PI. 
 
Anticipated Circumstances of Subject Withdrawal 
The anticipated circumstances for a subject withdrawal are: 
- presence of an adverse event. 
- poor adherence to the study. 
- any other circumstances based on the opinion of the treating physician. 
 
Primary or Secondary Safety Endpoints 
Primary end-point: hypoglycemia, urinary tract infections, diabetic ketoacidosis and thromboembolic events 
during the follow-up period. Secondary end-points: bone fractures, re-hospitalizations and heart failure 
worsening (assessed as more visits, increase in prescription of diuretics, etc) 


 
18 
 
 
 
14. 
Drugs / Biologics 
Generic Name 
Empagliflozin 
 
Brand Name 
 
Jardiance 
Icahn School of Medicine at Mount Sinai (ISMMS) Is the Coordinating Center 
Yes 
 
Role of the Investigational Drug Service (IDS) 
None 
 
Controlled Substance  
No 
 
Drug / Biologic Will Be Supplied By 
Sponsor 
 
Using Placebo 
Yes 
 
Placebo Will Be Supplied By 
Sponsor 
 
Where Drug / Biologic Will Be Administered 
Outpatient Faculty Practice Associates (FPA) 
 
Storage Requirements of Drug / Biologic 
Controlled Room Temperature (15 - 30°C) 
 
Where Drug / Biologic Will Be Stored 
By Research Personnel at a Site Outside of Hospital Areas 
 
ALL of the Following Storage Criteria Are Met 
The storage area is well maintained, provides adequate lighting, ventilation, sanitation, space and security. * 
The temperature in the storage area is controlled and monitored using calibrated monitoring devices. * The 
temperature monitoring system has sensors for continuous monitoring and alarms set at the points 
representing the temperature extremes. * Records of temperatures and alarms are maintained and all 
excursions outside the labeled storage conditions are appropriately investigated and reported to the sponsor.