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Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects (EMPA)

Primary Purpose

Heart Failure, Type II; Diabetes

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Empagliflozin
Placebo Oral Capsule
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring cardio-renal

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Stable HF as defined by:
  • No hospitalization for >60 days
  • Stable HF medications for >=2 weeks, and stable diuretics for 4 weeks
  • Opinion of HF cardiologist that the patient is at their optimal volume status
  • Chronic daily oral loop diuretic dose >=20mg furosemide equivalents
  • Diagnosis of type II diabetes
  • Patient monitors blood glucose regularly at home
  • eGFR >=45 mL/min/1.73 m2
  • >=18 years old

Exclusion Criteria:

  • Active titration of chronic HF medications expected during the study period
  • Use of a non-loop diuretic, aside from an aldosterone antagonist (<=25mg spironolactone or <=50mg eplerenone)
  • Critical stenotic valvular disease, complex congenital heart disease, or prior heart transplant
  • History of diabetic ketoacidosis, "brittle" diabetes, and/or frequent hypoglycemia or severe hypoglycemic episodes requiring emergent intervention (ER visit or EMS response, glucagon administration or forced oral carbs) in the last 6 months
  • History of bladder dysfunction, incontinence, pyelonephritis, urosepsis, or frequent urinary tract infections
  • Anemia (defined as hemoglobin <8g/dL)
  • Pregnancy or breastfeeding
  • History of serious hypersensitivity
  • Participation in another trial with an investigational drug within the 30 days prior to informed consent
  • Use of another SGLT-2 inhibitor
  • Appears unlikely, or unable to participate in the required study procedures, as assessed by the study PI or research RN (ex: clinically-significant psychiatric, addictive, or neurological disease)
  • Inability to give written informed consent or follow study protocol

Sites / Locations

  • Yale New Haven Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Placebo, then empagliflozin

Empagliflozin, then Placebo

Arm Description

Patients are randomized upon enrollment to determine whether they take empagliflozin or the matched placebo during the first 2-week treatment phase of the study. All patients then undergo a 2-week "washout period" before crossing over to the alternate therapy.

Patients are randomized upon enrollment to determine whether they take empagliflozin or the matched placebo during the first 2-week treatment phase of the study. All patients then undergo a 2-week "washout period" before crossing over to the alternate therapy.

Outcomes

Primary Outcome Measures

urine sodium concentrations via ion selective electrodes
Determine if acute SGLT2 inhibition will improve the natriuretic effect of a loop diuretic compared to placebo. Measuring the natriuretic effect of a loop diuretic (placebo v acute SGLT2 inhibition) via urine sodium output.

Secondary Outcome Measures

blood volume
Determine the effect of 14 days of SGLT2 inhibition on blood volume. Daxor Blood Volume Sample Collection Volumex Injection: The Volumex tracer (radiolabeled albumin) is injected as an intravenous bolus (IV-push). (As soon as the tracer injection begins, a stopwatch is started and never zeroed out. Running times are used for the entire procedure). Serial Blood Collection A series of 5 post-Volumex blood samples is collected, after tracer injection, allowing for complete mixing in the bloodstream. Sample Timing: Samples are ideally spaced ~6 minutes apart, and are collected approximately 12, 18, 24, 30 and 36 minutes after Volumex administration.

Full Information

First Posted
January 17, 2017
Last Updated
June 24, 2020
Sponsor
Yale University
Collaborators
Boehringer Ingelheim
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1. Study Identification

Unique Protocol Identification Number
NCT03027960
Brief Title
Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects
Acronym
EMPA
Official Title
Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects
Study Type
Interventional

2. Study Status

Record Verification Date
June 2020
Overall Recruitment Status
Completed
Study Start Date
June 27, 2017 (Actual)
Primary Completion Date
May 14, 2019 (Actual)
Study Completion Date
June 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University
Collaborators
Boehringer Ingelheim

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The investigators propose a small pilot proof of concept study to not only prove the existence of, but also probe the mechanisms underlying cardio-renal effects of empagliflozin in patients with heart failure. The investigators propose a 50 patient randomized, double-blind, placebo-controlled crossover study with patients with stable HF, type II diabetes and an eGFR >45ml/min/1.73 m2 who are chronically receiving loop diuretics.
Detailed Description
Study Objectives Study the acute/short term effect and cardio-renal mechanisms of sodium-glucose cotransporter 2 (SGLT2) inhibition in patients with heart failure. Determine the effect of chronic combined SLLGT2 and loop diuretic exposure in patients with heart failure. Primary Outcomes Aim 1 (Acute): Determine if acute SGLT2 inhibition will improve the natriuretic effect of a loop diuretic compared to placebo. Aim 2 (Chronic): Determine the effect of 14 days of SGLT2 inhibition on blood volume.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure, Type II; Diabetes
Keywords
cardio-renal

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare Provider
Allocation
Randomized
Enrollment
21 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo, then empagliflozin
Arm Type
Experimental
Arm Description
Patients are randomized upon enrollment to determine whether they take empagliflozin or the matched placebo during the first 2-week treatment phase of the study. All patients then undergo a 2-week "washout period" before crossing over to the alternate therapy.
Arm Title
Empagliflozin, then Placebo
Arm Type
Experimental
Arm Description
Patients are randomized upon enrollment to determine whether they take empagliflozin or the matched placebo during the first 2-week treatment phase of the study. All patients then undergo a 2-week "washout period" before crossing over to the alternate therapy.
Intervention Type
Drug
Intervention Name(s)
Empagliflozin
Intervention Description
10mg empagliflozin for a 2-week period
Intervention Type
Drug
Intervention Name(s)
Placebo Oral Capsule
Intervention Description
10 mg placebo for a 2-week period
Primary Outcome Measure Information:
Title
urine sodium concentrations via ion selective electrodes
Description
Determine if acute SGLT2 inhibition will improve the natriuretic effect of a loop diuretic compared to placebo. Measuring the natriuretic effect of a loop diuretic (placebo v acute SGLT2 inhibition) via urine sodium output.
Time Frame
36 days
Secondary Outcome Measure Information:
Title
blood volume
Description
Determine the effect of 14 days of SGLT2 inhibition on blood volume. Daxor Blood Volume Sample Collection Volumex Injection: The Volumex tracer (radiolabeled albumin) is injected as an intravenous bolus (IV-push). (As soon as the tracer injection begins, a stopwatch is started and never zeroed out. Running times are used for the entire procedure). Serial Blood Collection A series of 5 post-Volumex blood samples is collected, after tracer injection, allowing for complete mixing in the bloodstream. Sample Timing: Samples are ideally spaced ~6 minutes apart, and are collected approximately 12, 18, 24, 30 and 36 minutes after Volumex administration.
Time Frame
14 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Stable HF as defined by: No hospitalization for >60 days Stable HF medications for >=2 weeks, and stable diuretics for 4 weeks Opinion of HF cardiologist that the patient is at their optimal volume status Chronic daily oral loop diuretic dose >=20mg furosemide equivalents Diagnosis of type II diabetes Patient monitors blood glucose regularly at home eGFR >=45 mL/min/1.73 m2 >=18 years old Exclusion Criteria: Active titration of chronic HF medications expected during the study period Use of a non-loop diuretic, aside from an aldosterone antagonist (<=25mg spironolactone or <=50mg eplerenone) Critical stenotic valvular disease, complex congenital heart disease, or prior heart transplant History of diabetic ketoacidosis, "brittle" diabetes, and/or frequent hypoglycemia or severe hypoglycemic episodes requiring emergent intervention (ER visit or EMS response, glucagon administration or forced oral carbs) in the last 6 months History of bladder dysfunction, incontinence, pyelonephritis, urosepsis, or frequent urinary tract infections Anemia (defined as hemoglobin <8g/dL) Pregnancy or breastfeeding History of serious hypersensitivity Participation in another trial with an investigational drug within the 30 days prior to informed consent Use of another SGLT-2 inhibitor Appears unlikely, or unable to participate in the required study procedures, as assessed by the study PI or research RN (ex: clinically-significant psychiatric, addictive, or neurological disease) Inability to give written informed consent or follow study protocol
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey Testani, MD
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale New Haven Hospital
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06511
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32410463
Citation
Griffin M, Rao VS, Ivey-Miranda J, Fleming J, Mahoney D, Maulion C, Suda N, Siwakoti K, Ahmad T, Jacoby D, Riello R, Bellumkonda L, Cox Z, Collins S, Jeon S, Turner JM, Wilson FP, Butler J, Inzucchi SE, Testani JM. Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects. Circulation. 2020 Sep 15;142(11):1028-1039. doi: 10.1161/CIRCULATIONAHA.120.045691. Epub 2020 May 15.
Results Reference
derived

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Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects

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