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Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity? (ATRU-4). (EMPA-TROPISM)

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ClinicalTrials.gov Identifier: NCT03485222
Recruitment Status : Recruiting
First Posted : April 2, 2018
Last Update Posted : June 17, 2019
Sponsor:
Collaborators:
Boehringer Ingelheim
Eli Lilly and Company
Information provided by (Responsible Party):
Juan Badimon, Icahn School of Medicine at Mount Sinai

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.


Condition or disease Intervention/treatment Phase
Cardiovascular Diseases Drug: Empagliflozin Drug: Placebos Phase 4

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 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: EMPA-TROPISM Trial: Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity?
Actual Study Start Date : May 21, 2018
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Empagliflozin
10mg once a day
Drug: Empagliflozin
6 months

Placebo Comparator: Placebos
placebo once a day
Drug: Placebos
placebo equivalent for 6 months




Primary Outcome Measures :
  1. Left Ventricle-end systolic volume (ESV) [ Time Frame: 6 months ]
    End-systolic volume (ESV) is the volume of blood in a ventricle at the end of contraction of the left ventricle (LV).

  2. LV-end diastolic volume (EDV) [ Time Frame: 6 months ]
    End-diastolic volume (EDV) is the volume of blood in the left ventricle at end load or filling in (diastole) or the amount of blood in the ventricles just before systole.


Secondary Outcome Measures :
  1. LV-Ejection Fraction index [ Time Frame: 6 months ]
    The volumetric fraction of blood ejected from the left ventricle of the heart with each heartbeat

  2. VO2 Consumption [ Time Frame: 6 months ]
    Oxygen consumption - the amount of oxygen consumed by the tissues of the body, usually measured as the oxygen uptake in the lung, also called the V02max measure

  3. 6 min walk test [ Time Frame: 6 months ]
    The distance covered over a time of 6 minutes

  4. Kansas Cardiomyopathy questionnaire (KCCQ-12) [ Time Frame: 6 months ]
    The KCCQ-12 is an instrument most widely used to evaluate QoL in Heart Failure (HF) patients. It is a questionnaire containing 12 questions with full scores ranging from 12 (poor quality of life) to 70 (good quality of life).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients should meet the following inclusion criteria:
  • Ambulatory patients age 18-85 years
  • Diagnosis of Heart failure (NYHA II to III)
  • LVEF<50% on echocardiography or CMRI in the previous 6 months
  • Have stable symptoms and therapy for HF within the last 3 months.

Exclusion Criteria:

  • Pregnant or lactating women.
  • 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.
  • ACS or cardiac surgery within the last 3 months.
  • Cancer or any other life-threatening condition.
  • Pancreatitis.
  • Glomerular Filtration Rate < 45 ml/Kg/min.
  • Use of continuous parental inotropic agents.
  • Systolic BP < 90 mm Hg.
  • Psychiatric disease incompatible with being in study.
  • Any contraindication to MRI procedures.
  • Any other medical or physical condition considered to be inappropriate by a study physician.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03485222


Contacts
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Contact: Juan Badimon, PhD 212-241-8484 Juan.Badimon@mssm.edu
Contact: Carlos Santos-Gallego, MD 212-241-8484 Carlos.santos-gallego@mssm.edu

Locations
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United States, New York
Mount Sinai Heart - Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Principal Investigator: Juan J Badimon, PhD         
Sponsors and Collaborators
Icahn School of Medicine at Mount Sinai
Boehringer Ingelheim
Eli Lilly and Company
Investigators
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Principal Investigator: Juan J Badimon, PhD Icahn School of Medicine at Mount Sinai

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Responsible Party: Juan Badimon, Professor, Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT03485222     History of Changes
Other Study ID Numbers: GCO 17-2457
First Posted: April 2, 2018    Key Record Dates
Last Update Posted: June 17, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Juan Badimon, Icahn School of Medicine at Mount Sinai:
Cardiovascular diseases
Heart Failure
LV remodeling
SGLT-2 Inhibitors
Empagliflozin
Cardiac MRI

Additional relevant MeSH terms:
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Cardiovascular Diseases
Empagliflozin
Hypoglycemic Agents
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs