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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

Tracking Information
First Submitted Date  ICMJE March 26, 2018
First Posted Date  ICMJE April 2, 2018
Last Update Posted Date June 17, 2019
Actual Study Start Date  ICMJE May 21, 2018
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 26, 2018)
  • 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).
  • 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03485222 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 26, 2018)
  • LV-Ejection Fraction index [ Time Frame: 6 months ]
    The volumetric fraction of blood ejected from the left ventricle of the heart with each heartbeat
  • 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
  • 6 min walk test [ Time Frame: 6 months ]
    The distance covered over a time of 6 minutes
  • 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).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity? (ATRU-4).
Official Title  ICMJE EMPA-TROPISM Trial: Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity?
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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Cardiovascular Diseases
Intervention  ICMJE
  • Drug: Empagliflozin
    6 months
  • Drug: Placebos
    placebo equivalent for 6 months
Study Arms  ICMJE
  • Experimental: Empagliflozin
    10mg once a day
    Intervention: Drug: Empagliflozin
  • Placebo Comparator: Placebos
    placebo once a day
    Intervention: Drug: Placebos
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 26, 2018)
80
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Juan Badimon, PhD 212-241-8484 Juan.Badimon@mssm.edu
Contact: Carlos Santos-Gallego, MD 212-241-8484 Carlos.santos-gallego@mssm.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03485222
Other Study ID Numbers  ICMJE GCO 17-2457
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party Juan Badimon, Icahn School of Medicine at Mount Sinai
Study Sponsor  ICMJE Icahn School of Medicine at Mount Sinai
Collaborators  ICMJE
  • Boehringer Ingelheim
  • Eli Lilly and Company
Investigators  ICMJE
Principal Investigator: Juan J Badimon, PhD Icahn School of Medicine at Mount Sinai
PRS Account Icahn School of Medicine at Mount Sinai
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP