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Empagliflozin and Cardiac Remodelling in People Without Diabetes (EMPA-HEART 2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04461041
Recruitment Status : Not yet recruiting
First Posted : July 8, 2020
Last Update Posted : July 8, 2020
Sponsor:
Collaborators:
Canadian Medical and Surgical Knowledge Translation Research Group
Boehringer Ingelheim
Applied Health Research Centre
Information provided by (Responsible Party):
St. Michael's Hospital, Toronto

Brief Summary:
The purpose of this study is to evaluate the effects of empagliflozin on cardiac structure, function and circulating biomarkers in patients with cardiovascular risk factors, but without diabetes. Empagliflozin is an antihyperglycemic agent approved by Health Canada and the FDA for the treatment of type 2 diabetes. Previous post-marketing clinical trials demonstrated a reduction in cardiovascular deaths and heart failure in patients with type 2 diabetes treated with empagliflozin. In the first EMPA-HEART trial, we demonstrated that empagliflozin reduces cardiac mass in patients with type 2 diabetes, as seen through cardiac magnetic resonance imaging (cMRI). Therefore, the aim of this study, EMPA-HEART 2, is to determine whether empagliflozin can similarly impact cardiac structure in patients without diabetes, but with various cardiovascular risk factors.

Condition or disease Intervention/treatment Phase
Cardiovascular Diseases Left Ventricular Hypertrophy Drug: Empagliflozin Drug: Placebo Phase 4

Detailed Description:

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (empagliflozin, canagliflozin and dapagliflozin) are approved medications to improve glycemic control in adult patients with type 2 diabetes. When added to current standard-of-care diabetes treatment, SGLT2 inhibitors are associated with clinically meaningful reductions in major adverse cardiovascular events, reduced rates of hospitalization for heart failure and a decrease in major adverse kidney outcomes. Importantly, these benefits were observed consistently in people with and without type 2 diabetes and across all levels of baseline glycemic control. These data point towards a glucose-independent, cardioprotective effect of SGLT2 inhibition. How SGLT2 inhibition might reduce cardiac outcomes in people without diabetes remains unclear, and this is the specific objective of EMPA-HEART 2.

The study drug, empagliflozin (marketed as Jardiance), belongs to a class of medications that lowers blood glucose (sugar) by preventing glucose from entering back into blood circulation and ensures it is eliminated in urine. Empagliflozin is approved by the FDA and Health Canada for the treatment of type 2 diabetes.

This is a double-blind, randomized, placebo-controlled, parallel-group study of empagliflozin vs. placebo in patients without diabetes but with various cardiovascular risk factors. The purpose is to determine the effects of empagliflozin on cardiac structure by using cMRI. Patients who have given informed consent will undergo a baseline cMRI and will then be randomly assigned in a 1:1 basis to either empagliflozin 10 mg once daily or matching placebo. An end of study cMRI will be performed at 26 weeks (6 months after starting the study drug).

The study subjects will be followed for 6 months. The patients will be assessed using cMRI, which is considered the "gold standard" for measuring left ventricular (LV) volume, mass, and ejection fraction. The investigators will assess changes from baseline in LV mass, LV end-diastolic volume, end-systolic volume, LV ejection fraction, LV diastolic and systolic function, and LV wall stress via cMRI in enrolled patients treated with empagliflozin compared to those who receive placebo. Additionally, changes from baseline in blood pressure, hematocrit, and biomarkers involved in the pathophysiology of heart failure, namely NT-proBNP, will be evaluated at 6 months.

Study assessments and potential adverse events reporting will be undertaken at each study visit.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 164 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Empagliflozin and Cardiac Remodelling in People Without Diabetes
Estimated Study Start Date : July 2020
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Empagliflozin
Single 10 mg tablet, administered orally once daily for 6 months
Drug: Empagliflozin
Single oral tablet
Other Name: Jardiance

Placebo Comparator: Placebo
Single 10 mg tablet, administered orally once daily for 6 months
Drug: Placebo
Placebo tablet manufactured to mimic empagliflozin 10 mg tablet




Primary Outcome Measures :
  1. Left Ventricular (LV) mass [ Time Frame: 6 months ]
    Change in Left Ventricular (LV) mass (indexed to body surface area (BSA)) at 6 months. This will be measured using CMRI.


Secondary Outcome Measures :
  1. LV end-diastolic volume [ Time Frame: 6 months ]
    Change in LV end-diastolic volume (indexed to BSA) at 6 months. This will be measured using CMRI.

  2. LV end-systolic volume [ Time Frame: 6 months ]
    Change in LV end-systolic volume (indexed to BSA) at 6 months. This will be measured using CMRI.

  3. Left Ventricular Ejection Fraction (LVEF) [ Time Frame: 6 months ]
    Change in LVEF at 6 months. This will be measured using CMRI.

  4. LV wall stress [ Time Frame: 6 months ]
    Change in LV wall stress at 6 months. This will be measured using CMRI.

  5. LV systolic function [ Time Frame: 6 months ]
    Change in LV systolic function at 6 months. This will be measured using CMRI.

  6. LV diastolic function [ Time Frame: 6 months ]
    Change in LV diastolic function at 6 months. This will be measured using CMRI.

  7. NT-proBNP [ Time Frame: 6 months ]
    Change in circulating NT-proBNP at 6 months.

  8. Systolic and diastolic blood pressure [ Time Frame: 6 months ]
    Change in systolic and diastolic blood pressure at 6 months.

  9. Hematocrit [ Time Frame: 6 months ]
    Change in hematocrit at 6 months in patients.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Female Not of childbearing potential and male subjects ≥40 and ≤ 80 years of age (Women Not of childbearing potential are females who are permanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause or ≥6 weeks post-surgical bilateral oophorectomy prior to Screening.)
  2. ≥1 of the major criteria or ≥2 of the minor criteria below:

    Major criteria:

    • Increased LVMi of ≥96 g/m2 for women and ≥116 g/m2 for men (as calculated by echocardiogram); or LVMi ≥81 g/m2 for women and ≥85 g/m2 for men (as calculated by cMRI)
    • ECG evidence of LV hypertrophy (as per the Sokolow-Lyon criteria)
    • Structural heart disease defined as interventricular septal thickness or posterior wall thickness at end-diastole of ≥11 mm (as measured by 2D echocardiography or cMRI)
    • Persistent hypertension (defined as office blood pressure ≥140/90 mmHg) despite being on ≥3 antihypertensive medications

    Minor criteria:

    • Prior history of a myocardial infarction (≥3 months ago)
    • eGFR ≥30 and ≤60 mL/min/1.73 m2 (as measured by the CKD-EPI formula)
    • Body mass index (BMI) ≥27 and ≤40 kg/m2
  3. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures

Exclusion Criteria:

  1. Female subjects who are pregnant, lactating or of childbearing potential, or are pre- menopausal
  2. Known type 1 or type 2 diabetes
  3. Hemoglobin A1C (A1C) ≥6.5%
  4. eGFR <30 mL/min/1.73m2
  5. Indication of liver disease, defined by serum levels of either alanine-aminotransferase (ALT or SGPT), aspartate-aminotransaminase (AST or SGOT), or alkaline phosphatase (ALP) above 3 x upper limit of normal (ULN) as determined at Visit 1
  6. Hemoglobin < 90 g/L at Visit 1
  7. History of ketoacidosis, or increased chance of developing diabetic ketoacidosis (DKA) e.g. patients who suffer from excessive vomiting, diarrhea, or sweating; subjects who are on a very low carbohydrate diet; or subjects who drink a lot of alcohol.
  8. Systolic blood pressure <95mmHg (as measured at the office/clinic visit)
  9. Subjects in whom further coronary revascularization by either percutaneous coronary intervention or bypass surgery is being contemplated within 6 months, or who have undergone coronary revascularization in the prior 3 months
  10. Significant allergy or known intolerance to SGLT2is or any ingredient in the formulations
  11. Subjects currently experiencing any clinically significant or unstable medical condition that in the opinion of the investigator might limit their ability to complete the study, or to comply with the requirements of the protocol, including: dermatologic disease, hematological disease, pulmonary disease, hepatic disease, gastrointestinal disease, genitourinary disease, endocrine disease, neurological disease, and psychiatric disease
  12. Any malignancy not considered cured (except basal cell carcinoma of the skin). A subject is considered cured if there has been no evidence of cancer recurrence for the 5 years prior to screening
  13. Subjects who have participated in other interventional studies which may affect any of the primary or secondary outcomes of the study within 30 days of the screening visit
  14. BMI >40 kg/m2
  15. Contraindications or inability to undergo magnetic resonance imaging such as the presence of metallic fragments, clips, or devices
  16. Known history of infiltrative cardiomyopathy such as cardiac amyloidosis or cardiac sarcoidosis
  17. Severe aortic stenosis
  18. Severe aortic regurgitation
  19. Severe mitral stenosis
  20. Severe mitral regurgitation
  21. Low voltage on ECG limb leads defined by the amplitude of the QRS complex in each limb lead ≤0.5 mV

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): NCT04461041


Contacts
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Contact: Subodh Verma, MD PhD 416 864 5997 Subodh.Verma@unityhealth.to
Contact: Val Panzov, MD 416 360 4000 ext 47125 Val.Panzov@unityhealth.to

Locations
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Canada, Ontario
St. Michael's Hospital
Toronto, Ontario, Canada, M5B 1W8
Contact: David Mazer, MD    416 864 5825    David.Mazer@unityhealth.to   
Contact: Sanjay Yagnik    416 864 6060 ext 2920    Sanjay.Yagnik@unityhealth.to   
Sponsors and Collaborators
St. Michael's Hospital, Toronto
Canadian Medical and Surgical Knowledge Translation Research Group
Boehringer Ingelheim
Applied Health Research Centre
Investigators
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Principal Investigator: Subodh Verma, MD PhD St. Michael's Hospital, Toronto
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Responsible Party: St. Michael's Hospital, Toronto
ClinicalTrials.gov Identifier: NCT04461041    
Other Study ID Numbers: 1245-0206
First Posted: July 8, 2020    Key Record Dates
Last Update Posted: July 8, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by St. Michael's Hospital, Toronto:
Cardiovascular disease
Cardiac Magnetic Resonance Imaging
Sodium-Glucose Transporter 2 Inhibitors
Additional relevant MeSH terms:
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Cardiovascular Diseases
Pathological Conditions, Anatomical
Heart Diseases
Hypertrophy, Left Ventricular
Hypertrophy
Cardiomegaly
Empagliflozin
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs