Effects of Empagliflozin on Clinical Outcomes in Patients With Acute Decompensated Heart Failure (EMPA-RESPONSE)

Randomized, Double Blind, Placebo Controlled, Multicenter Pilot Study on the Effects of Empagliflozin on Clinical Outcomes in Patients With Acute Decompensated Heart Failure (EMPA-RESPONSE-AHF)

Acute decompensated heart failure is the fastest growing disease in the world and the leading cause of hospital admissions worldwide. Short term mortality and rehospitalization are extremely high (20-30% within 3-6 months) and there is no therapy available that improves clinical outcome in these patients. Empagliflozin is a selective inhibitor of sodium glucose co-transporter with diuretic and renal- protective properties. In patients with type 2 diabetes at high risk for cardiovascular events, empagliflozin reduced the risk of hospitalization for heart failure by 35%. Based on the promising pharmacological profile of empagliflozin in relation to the needs for treatment of acute decompensated heart failure, we hypothesize that empagliflozin exerts positive effects in acute decompensated heart failure, with or without diabetes,

This is a randomized, placebo-controlled, double-blind, parallel group, multicenter study in subjects admitted for acute decompensated heart failure. Eighty eligible subjects will be randomized in a 1:1 ratio to receive either empagliflozin 10 mg/day or matched placebo.

Study Overview

• Status: Completed
• Conditions: Heart Failure; With Decompensation; Heart Failure，Congestive; Heart Failure Acute
• Intervention / Treatment: Drug: Empagliflozin 10 MG; Drug: Placebo Oral Tablet

Detailed Description

This is a randomized, placebo-controlled, double-blind, parallel group, multicenter study in subjects admitted for acute decompensated heart failure. Eighty eligible subjects will be randomized in a 1:1 ratio to receive either empagliflozin 10 mg/day or matched placebo.

Treatment will be continued until 30 days after index event, and primary efficacy measurements will be carried out during hospitalization and safety events until 60 days after index hospitalisation.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9700RB
    • University Medical Center Groningen
  • Brabant
    • Den Bosch, Brabant, Netherlands
      • Jeroen Bosch Ziekenhuis
  • Drenthe
    • Emmen, Drenthe, Netherlands
      • Treant zorggroep
  • Friesland
    • Sneek, Friesland, Netherlands
      • Antonius Ziekenhuis
  • Overijssel
    • Zwolle, Overijssel, Netherlands
      • Isala Klinieken

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female >18 years of age; Women of non-child-bearing potential must have a documentation of surgical sterilization (hysterectomy and/or bilateral oophorectomy) OR must have experienced menopause (no menses for >12 months). Women of child bearing potential must have a negative pregnancy test, AND must use highly effective methods of contraception during treatment with IP plus 5 days after the end of study drug administration.

• Hospitalized for AHF; AHF is defined as including all of the followings measured at any time between presentation (including the emergency department) and the end of screening:

  1. Dyspnea at rest or with minimal exertion
  2. Signs of congestion, such as edema, rales, and/or congestion on chest radiograph
  3. BNP ≥350 pg/mL or NT-proBNP ≥1,400 pg/mL (for patients with AF: BNP≥500 pg/mL or NT-proBNP ≥2,000 pg/mL)
  4. Treated with loop diuretics at screening
• Able to be randomized within 24 hours from presentation to the hospital
• Able and willing to provide freely given written informed consent
• eGFR (CKD-EPI) ≥30 ml/min/1.73m2 between presentation and randomization

Exclusion Criteria:

• Diabetes Mellitus Type I
• Dyspnea primarily due to non-cardiac causes
• Cardiogenic shock
• Acute coronary syndrome within 30 days prior to randomization
• Planned or recent percutaneous or surgical coronary intervention within 30 days prior to randomization
• Signs of keto-acidosis and/or hyperosmolar hyperglaecemic syndrome (pH>7.30 and glucose >15 mmol/L and HCO3>18 mmol/L)
• Pregnant or nursing (lactating) women
• Current participation in any interventional study
• Inability to follow instructions or comply with follow-up procedures
• Any other medical conditions that may put the patient at risk or influence study results in the investigator's opinion, or that the investigator deems unsuitable for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Empagliflozin; Empagliflozin 10 mg daily, oral, 30 days	Drug: Empagliflozin 10 MG; 10 mg daily, oral, 30 days
PLACEBO_COMPARATOR: Placebo; Matching Placebo 10 mg daily, oral, 30 days	Drug: Placebo Oral Tablet; Matching Placebo, 10 mg daily, oral, 30 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dyspnea	Change in Dyspnea on VAS analogue scale (AUC) VAS Score is a measure/scale where patients on a scale from 0 to 100 can assign their current dyspnea score. 0 means there can be no worse dyspnea, 100 means it cannot get any better (perfect). The change in Dyspnea VAS means higher score is better outcomes. Individual changes in VAS score are be visualized (virtually) as a curve where the X-axis shows study day baseline to day 4, and y-axis shows VAS score. Using this approach, area under the curves for each study day (trapezoids) can be calculated, and added together, resulting in an overall VAS AUC score (mmxh) and change in VAS can be caculated	From baseline to Day 4
Diuretic Response	Weight change from baseline per 40 mg of Furosemide equivalent	Total weight change from baseline to Day 4
Length of Stay	Hospital stay of Index admission	within 60 days
Plasma NTproBNP	Change in NTproBNP	From baseline to Day 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death and/or Heart Failure Re-admission	Death and/or heart failure re-admission at day 30	Day 30
Inhospital Worsening Heart Failure, All Cause Mortality or Heart Failure Readmission at Day 60	Inhospital Worsening Heart Failure or All Cause mortality or Heart Failure Readmission at day 60	60 days
All Cause Mortality	All Cause Mortality at 60 days	60 day

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serious Adverse Events	SAE including all cause mortality. Per request Clintrials.gov different from Protocol definition	60 days

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Investigators: Principal Investigator: Adriaan Voors, Prof. Dr., University Medical Center Groningen

Publications and helpful links

General Publications

• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.
• Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):323-34. doi: 10.1056/NEJMoa1515920. Epub 2016 Jun 14.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 18, 2017
• Primary Completion (ACTUAL): September 18, 2019
• Study Completion (ACTUAL): September 18, 2019

Study Registration Dates

• First Submitted: June 23, 2017
• First Submitted That Met QC Criteria: June 26, 2017
• First Posted (ACTUAL): June 27, 2017

Study Record Updates

• Last Update Posted (ACTUAL): February 19, 2020
• Last Update Submitted That Met QC Criteria: February 9, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: heart failure; empagliflozin; diuretic response
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 2017-001679-22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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