This Study Tests Empagliflozin in Patients With Chronic Heart Failure With Reduced Ejection Fraction (HFrEF). The Study Looks at How Far Patients Can Walk in 6 Minutes and at Their Heart Failure Symptoms

NCT ID: NCT03448419

Last Updated: 2020-11-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 312 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-20
• Study Completion Date: 2019-10-07

Brief Summary

The primary objective of the study is to evaluate the effect of empagliflozin 10 mg versus placebo on exercise ability using the 6 minute walk test in patients with chronic HF with reduced ejection fraction (LVEF ≤ 40%) Secondary objectives are to assess Patient-Reported Outcome (PRO)

Conditions

Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Empagliflozin

Group Type: EXPERIMENTAL

Empagliflozin

Intervention Type: DRUG

Film-coated tablet

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Film-coated tablet

Interventions

Empagliflozin

Film-coated tablet

Intervention Type: DRUG

Placebo

Film-coated tablet

Intervention Type: DRUG

Other Intervention Names

JARDIANCE, JARDIANZ, GIBTULIO

Eligibility Criteria

Inclusion Criteria

• Of full age of consent (according to local legislation, usually ≥ 18 years) at screening.
• Male or female patients. Women of childbearing potential (WOCBP)1 must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information.
• Signed and dated written informed consent in accordance with ICHGCP and local legislation prior to admission to the trial
• 6MWT distance ≤350 m at screening and at baseline.
• Patients with chronic HF diagnosed for at least 3 months before Visit 1 and currently in NYHA class II-IV
• Chronic HF with reduced EF defined as LVEF ≤ 40 % as per echocardiography at Visit 1 as per local reading (obtained under stable condition).
• Elevated NT-proBNP > 450 pg/ml for patients without atrial fibrillation (AF) OR NTproBNP > 600 pg/ml for patients with AF as analysed at the Central laboratory at Visit 1
• Patients must be clinically stable and on appropriate and stable dose of medical therapy for HF (such as ACEi, ARB, β-blocker, oral diuretics, MRA, ARNI, ivabradine), consistent with prevailing CV guidelines, stable for at least 4 weeks prior to Visit 1(screening) with the exception of diuretics which must have been stable for at least two weeks prior to Visit 1. The investigator must document the reason in case the patient is not on such medication or if not on target dose of any heart failure medication as per local guidelines.
• Clinically stable at randomization with no signs of heart failure decompensation (as per investigator judgement).
• Appropriate use of medical devices such as cardioverter defibrillator (ICD) or a cardiac resynchronization therapy (CRT) consistent with prevailing local or international CV guidelines, and if a device is required, it must have been implanted for at least 3 months prior to visit 1 for CRT and 1 month prior to visit 1 for ICD.

Exclusion Criteria

• Myocardial infarction (increase in cardiac enzymes in combination with symptoms of ischaemia or newly developed ischaemic ECG changes), coronary artery bypass graft surgery or other major cardiovascular surgery, stroke or TIA in past 90 days prior to Visit 1
• Acute decompensated HF (exacerbation of chronic HF) requiring intravenous (i.v.) diuretics, i.v. inotropes or i.v. vasodilators, or left ventricular assist device within 4 weeks prior to Visit 1, and/or during screening period until Visit 2
• Previous or current randomisation in another Empagliflozin Heart Failure trial (i.e. studies 1245.110, 1245.121, 1245-0167)
• Type 1 Diabetes Mellitus (T1DM)
• Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2 (CKD-EPIcr) or requiring dialysis, as determined at Visit 1
• Symptomatic hypotension or a SBP < 100 mmHg at Visit 1 or 2
• Systolic blood pressure (SBP) ≥ 180 mmHg at Visit 1 or 2, or SBP >160mmHg at both Visit 1 and 2
• Atrial fibrillation or atrial flutter with a resting heart rate >110 bpm documented by ECG at Visit 1 (Screening)
• Unstable angina pectoris in past 30 days prior to Visit 1
• Largest distance walked in 6 minutes (6MWTD) at baseline <100m.
• Any presence of condition that precludes exercise testing such as:

• claudication,
• uncontrolled (according to investigator judgement) bradyarrhythmia or tachyarrhythmia,
• significant musculoskeletal disease,
• primary pulmonary hypertension,
• severe obesity (body mass index ≥40.0 kg/m2),
• orthopedic conditions that limit the ability to walk (such as arthritis in the leg, knee or hip injuries)
• amputation with artificial limb without stable prosthesis function for the past 3 months
• Any condition that, in the opinion of the investigator, would contraindicate the assessment of 6MWT
• Patients in a structured (according to Investigator judgement) exercise training program in the 1 month prior to screening or planned to start one during the course of this trial.
• Planned implantation of ICD or CRT during the course of the trial.
• Treatment with i.v. iron therapy or erythropoietin within 3 months prior to screening
• Treatment with i.v. iron therapy or erythropoietin within 3 months prior to screening

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eli Lilly and Company

INDUSTRY

Sponsor Role: collaborator

Boehringer Ingelheim

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Mobile Heart Specialists, PC

Mobile, Alabama, United States

The Center for Clinical Trials, Inc.

Saraland, Alabama, United States

California Heart Specialists

Huntington Beach, California, United States

Manshadi Heart Institute, Inc

Stockton, California, United States

University of California Los Angeles

Torrance, California, United States

University of Colorado Denver

Aurora, Colorado, United States

Western Connecticut Health Network

Danbury, Connecticut, United States

Infinite Clinical Research

Miami, Florida, United States

Advance Medical Research Center

Miami, Florida, United States

Bio1 Clinical Research

Miami Beach, Florida, United States

Pharmacology Research, LLC

North Miami Beach, Florida, United States

Palm Beach Gardens Research Center, LLC

Palm Beach Gardens, Florida, United States

East Coast Institute for Research, LLC

Saint Augustine, Florida, United States

Cozy Research LLC

Zephyrhills, Florida, United States

Grady Memorial Hospital

Atlanta, Georgia, United States

Georgia Arrhythmia Consultants and Research Institute

Warner Robins, Georgia, United States

St Luke's Clinic - Idaho Cardiology Associates

Boise, Idaho, United States

Northwest Heart Clinical Research, LLC

Arlington Heights, Illinois, United States

Clinical Investigation Specialists, Inc

Gurnee, Illinois, United States

Chicago Medical Research

Hazel Crest, Illinois, United States

Midwest Heart and Vascular Specialists

Overland Park, Kansas, United States

Grace Research, LLC

Bossier City, Louisiana, United States

Grace Research, LLC

Shreveport, Louisiana, United States

Clinical Trials of America LA, LLC

West Monroe, Louisiana, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

University Of Mississippi Medical Center

Jackson, Mississippi, United States

Med Research One

Florissant, Missouri, United States

The DOCS

Las Vegas, Nevada, United States

Rutgers Robert Wood Johnson Medical School

New Brunswick, New Jersey, United States

New York Heart Research Foundation, Inc.

Mineola, New York, United States

PMG Research of Rocky Mount, LLC

Rocky Mount, North Carolina, United States

PMG Research of Wilmington, LLC

Wilmington, North Carolina, United States

Rama Research LLC

Marion, Ohio, United States

Columbia Heart Clinic

Columbia, South Carolina, United States

Black Hills Cardiovascular Research

Rapid City, South Dakota, United States

The Jackson Clinic, PA

Jackson, Tennessee, United States

DiscoveResearch, Inc.

Beaumont, Texas, United States

Angiocardiac Care of Texas

Houston, Texas, United States

Mary Washington Hospital Research Department

Fredericksburg, Virginia, United States

York Clinical Research, LLC

Norfolk, Virginia, United States

Aspirus Research Institute

Wausau, Wisconsin, United States

Canberra Hospital

Garran, Australian Capital Territory, Australia

St Vincent's Hospital Sydney

Darlinghurst, New South Wales, Australia

University of the Sunshine Coast

Birtinya, Queensland, Australia

Cairns Base Hospital

Cairns, Queensland, Australia

Peninsular Health CV Research Unit

Frankston, Victoria, Australia

University of Calgary

Calgary, Alberta, Canada

KMH Cardiology Centres Inc.

Mississauga, Ontario, Canada

Toronto Heart Centre

Toronto, Ontario, Canada

Sameh Fikry Medicine Professional Corporation

Waterloo, Ontario, Canada

CIMS Studienzentrum Bamberg GmbH

Bamberg, , Germany

Klinische Forschung Berlin GbR

Berlin, , Germany

Charité - Universitätsmedizin Berlin

Berlin, , Germany

Bremer Institut für Herz- und Kreislaufforschung (BIHKF) am Klinikum Links der Weser

Bremen, , Germany

Universitätsklinikum Köln (AöR)

Cologne, , Germany

Cardiologicum Dresden und Pirna

Dresden, , Germany

Universitätsklinikum Düsseldorf

Düsseldorf, , Germany

Klinikum Esslingen GmbH

Esslingen am Neckar, , Germany

IKF Pneumologie GmbH & Co. KG

Frankfurt, , Germany

Universitäts-Herzzentrum Freiburg, Bad Krozingen GmbH

Freiburg im Breisgau, , Germany

Universitätsklinikum Leipzig

Leipzig, , Germany

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, , Germany

Universitätsklinikum Ulm

Ulm, , Germany

Universitätsklinikum Würzburg

Würzburg, , Germany

General Hospital of Athens Konstantopoulio-Agia Olga

Athens, , Greece

General Hospital of Athens "G. Gennimatas"

Athens, , Greece

General University Hospital "Attikon"

Haidari, Athens, , Greece

University General Hospital of Heraklion

Herakleion, Crete, , Greece

Univ. Gen. Hosp. of Ioannina

Ioannina, , Greece

University Hospital of Thessaloniki AHEPA

Thessaloniki, , Greece

Centro Cardiologico Monzino-IRCCS

Milan, , Italy

Asst Santi Paolo E Carlo

Milan, , Italy

ASST Grande Ospedale Metropolitano Niguarda

Milan, , Italy

Università Federico II

Napoli, , Italy

Università degli studi di Palermo

Palermo, , Italy

IRCCS San Raffaele

Roma, , Italy

Sykehuset Østfold Kalnes

Grålum, , Norway

Vestre Viken, Ringerike Sykehus HF

Hønefoss, , Norway

Oslo Universitetssykehus HF, Rikshospitalet

Oslo, , Norway

Helse Stavanger, Stavanger Universitetssykehus

Stavanger, , Norway

St. Olavs Hospital, Universitetssykehuset i Trondheim

Trondheim, , Norway

INTERCORE Medical Center

Bydgoszcz, , Poland

Leszek Bryniarski Specialized Medical Cabinet

Krakow, , Poland

Card.Cli.Mil.Med.Ac.Uni.Cli.Hosp. Cent.Vetera.Hosp.Lodz

Lodz, , Poland

Cent.Clin.Hosp.Med.Univ.Lodz,Electrocard

Lodz, , Poland

Provincial Specialist M. Kopernik Hospital

Lodz, , Poland

Independent Public Healthcare, Dept. of Cardiology, Pulawy

Puławy, , Poland

The Provincial Polyclinical Hospital in Torun

Torun, , Poland

Central Hospital of Medical Academy, Warsaw

Warsaw, , Poland

4. Military Clinical Hospital with Polyclinic SP ZOZ

Wroclaw, , Poland

CHLO, EPE - Hospital de Santa Cruz

Carnaxide, , Portugal

CHUC - Centro Hospitalar e Universitário de Coimbra, EPE

Coimbra, , Portugal

Centro Hosp. de Leiria-Pombal

Leiria, , Portugal

CHLC, EPE - Hospital de Santa Marta

Lisbon, , Portugal

CHLO, EPE - Hospital S. Francisco Xavier

Lisbon, , Portugal

CHULN, EPE - Hospital de Santa Maria

Lisbon, , Portugal

CHTS, EPE - Hospital Padre Américo

Penafiel, , Portugal

Centro Hospitalar Universitário São João,EPE

Porto, , Portugal

Hospital General Universitario de Alicante

Alicante, , Spain

Hospital Germans Trias i Pujol

Badalona, , Spain

Hospital San Rafael

Granada, , Spain

Hospital de la Inmaculada Concepción

Granada, , Spain

Hospital Universitario Virgen de las Nieves

Granada, , Spain

Hospital de Bellvitge

L'Hospitalet de Llobregat, , Spain

Hospital La Princesa

Madrid, , Spain

Hospital Clínico de Valencia

Valencia, , Spain

Sahlgrenska US, Göteborg

Gothenburg, , Sweden

Sahlgrenska Universitetssjukhuset, Östra

Gothenburg, , Sweden

Akardo Med Site

Stockholm, , Sweden

Countries

United States; Australia; Canada; Germany; Greece; Italy; Norway; Poland; Portugal; Spain; Sweden

References

Anker SD, Ponikowski P, Wanner C, Pfarr E, Hauske S, Peil B, Salsali A, Ritter I, Koitka-Weber A, Brueckmann M, Lindenfeld J, Abraham WT; EMPERIAL Investigators and National Coordinators. Kidney Function After Initiation and Discontinuation of Empagliflozin in Patients With Heart Failure With and Without Type 2 Diabetes: Insights From the EMPERIAL Trials. Circulation. 2021 Oct 12;144(15):1265-1267. doi: 10.1161/CIRCULATIONAHA.121.054669. Epub 2021 Aug 16. No abstract available.

Reference Type: DERIVED

PMID: 34397263 (View on PubMed)

Abraham WT, Ponikowski P, Brueckmann M, Zeller C, Macesic H, Peil B, Brun M, Ustyugova A, Jamal W, Salsali A, Lindenfeld J, Anker SD; EMPERIAL Investigators and National Coordinators. Rationale and design of the EMPERIAL-Preserved and EMPERIAL-Reduced trials of empagliflozin in patients with chronic heart failure. Eur J Heart Fail. 2019 Jul;21(7):932-942. doi: 10.1002/ejhf.1486. Epub 2019 Jun 19.

Reference Type: DERIVED

PMID: 31218819 (View on PubMed)

Nassif ME, Kosiborod M. Effects of sodium glucose cotransporter type 2 inhibitors on heart failure. Diabetes Obes Metab. 2019 Apr;21 Suppl 2:19-23. doi: 10.1111/dom.13678.

Reference Type: DERIVED

PMID: 31081589 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Other Identifiers

2017-004073-14

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1245-0168

Identifier Type: -

Identifier Source: org_study_id