Clinical trial NCT03448419: 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
Official title: A Phase III Randomised, Double-blind Trial to Evaluate the Effect of 12 Weeks Treatment of Once Daily EMPagliflozin 10 mg Compared With Placebo on ExeRcise Ability and Heart Failure Symptoms, In Patients With Chronic HeArt FaiLure With Reduced Ejection Fraction (HFrEF) (EMPERIAL-reduced)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Failure
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
Collaborators: name: Eli Lilly and Company
First posted: 2018-02-28
Enrollment: 312
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)


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
* Further exclusion criteria applies

Primary outcomes:
measure: Change From Baseline to Week 12 in Exercise Capacity as Measured by the 6-Minutes-Walking-Test (6MWT) Distance
timeFrame: At baseline and at week 12
Secondary outcomes:
measure: Change From Baseline to Week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS)
timeFrame: At baseline and at week 12
measure: Change From Baseline to Week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized Format (CHQ-SAS) Dyspnea Score
timeFrame: At baseline and at week 12
measure: Change From Baseline to Week 6 in Exercise Capacity as Measured by the 6-Minutes-Walking-Test (6MWT) Distance
timeFrame: At baseline and at week 6
measure: Change From Baseline to Week 12 in Clinical Congestion Score
timeFrame: At baseline and at week 12
measure: Change From Baseline to Week 12 in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms
timeFrame: At baseline and at week 12
measure: Change From Baseline to Week 12 in Patient Global Impression of Severity (PGI-S) of Dyspnoea
timeFrame: At baseline and at week 12
measure: Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12
timeFrame: At week 12
measure: Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12
timeFrame: At week 12
measure: Relative Change From Baseline to Week 12 in N-terminal Pro-brain Natriuretic Peptide (NTproBNP)
timeFrame: Within 3 weeks prior to treatment start and at Week 12
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Mobile Heart Specialists, PC
state: Alabama
city: Saraland
country: United States
facility: The Center for Clinical Trials, Inc.
state: Alabama
city: Huntington Beach
country: United States
facility: California Heart Specialists
state: California
city: Stockton
country: United States
facility: Manshadi Heart Institute, Inc
state: California
city: Torrance
country: United States
facility: University of California Los Angeles
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Danbury
country: United States
facility: Western Connecticut Health Network
state: Connecticut
city: Miami Beach
country: United States
facility: Bio1 Clinical Research
state: Florida
city: Miami
country: United States
facility: Infinite Clinical Research
state: Florida
city: Miami
country: United States
facility: Advance Medical Research Center
state: Florida
city: North Miami Beach
country: United States
facility: Pharmacology Research, LLC
state: Florida
city: Palm Beach Gardens
country: United States
facility: Palm Beach Gardens Research Center, LLC
state: Florida
city: Saint Augustine
country: United States
facility: East Coast Institute for Research, LLC
state: Florida
city: Zephyrhills
country: United States
facility: Cozy Research LLC
state: Florida
city: Atlanta
country: United States
facility: Grady Memorial Hospital
state: Georgia
city: Warner Robins
country: United States
facility: Georgia Arrhythmia Consultants and Research Institute
state: Georgia
city: Boise
country: United States
facility: St Luke's Clinic - Idaho Cardiology Associates
state: Idaho
city: Arlington Heights
country: United States
facility: Northwest Heart Clinical Research, LLC
state: Illinois
city: Gurnee
country: United States
facility: Clinical Investigation Specialists, Inc
state: Illinois
city: Hazel Crest
country: United States
facility: Chicago Medical Research
state: Illinois
city: Overland Park
country: United States
facility: Midwest Heart and Vascular Specialists
state: Kansas
city: Bossier City
country: United States
facility: Grace Research, LLC
state: Louisiana
city: Shreveport
country: United States
facility: Grace Research, LLC
state: Louisiana
city: West Monroe
country: United States
facility: Clinical Trials of America LA, LLC
state: Louisiana
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Jackson
country: United States
facility: University Of Mississippi Medical Center
state: Mississippi
city: Florissant
country: United States
facility: Med Research One
state: Missouri
city: Las Vegas
country: United States
facility: The DOCS
state: Nevada
city: New Brunswick
country: United States
facility: Rutgers Robert Wood Johnson Medical School
state: New Jersey
city: Mineola
country: United States
facility: New York Heart Research Foundation, Inc.
state: New York
city: Rocky Mount
country: United States
facility: PMG Research of Rocky Mount, LLC
state: North Carolina
city: Wilmington
country: United States
facility: PMG Research of Wilmington, LLC
state: North Carolina
city: Marion
country: United States
facility: Rama Research LLC
state: Ohio
city: Columbia
country: United States
facility: Columbia Heart Clinic
state: South Carolina
city: Rapid City
country: United States
facility: Black Hills Cardiovascular Research
state: South Dakota
city: Jackson
country: United States
facility: The Jackson Clinic, PA
state: Tennessee
city: Beaumont
country: United States
facility: DiscoveResearch, Inc.
state: Texas
city: Houston
country: United States
facility: Angiocardiac Care of Texas
state: Texas
city: Fredericksburg
country: United States
facility: Mary Washington Hospital Research Department
state: Virginia
city: Norfolk
country: United States
facility: York Clinical Research, LLC
state: Virginia
city: Wausau
country: United States
facility: Aspirus Research Institute
state: Wisconsin
city: Garran
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Birtinya
country: Australia
facility: University of the Sunshine Coast
state: Queensland
city: Cairns
country: Australia
facility: Cairns Base Hospital
state: Queensland
city: Frankston
country: Australia
facility: Peninsular Health CV Research Unit
state: Victoria
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Mississauga
country: Canada
facility: KMH Cardiology Centres Inc.
state: Ontario
city: Toronto
country: Canada
facility: Toronto Heart Centre
state: Ontario
city: Waterloo
country: Canada
facility: Sameh Fikry Medicine Professional Corporation
state: Ontario
city: Bamberg
country: Germany
facility: CIMS Studienzentrum Bamberg GmbH
city: Berlin
country: Germany
facility: Klinische Forschung Berlin GbR
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Bremen
country: Germany
facility: Bremer Institut für Herz- und Kreislaufforschung (BIHKF) am Klinikum Links der Weser
city: Dresden
country: Germany
facility: Cardiologicum Dresden und Pirna
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Esslingen
country: Germany
facility: Klinikum Esslingen GmbH
city: Frankfurt
country: Germany
facility: IKF Pneumologie GmbH & Co. KG
city: Freiburg
country: Germany
facility: Universitäts-Herzzentrum Freiburg, Bad Krozingen GmbH
city: Köln
country: Germany
facility: Universitätsklinikum Köln (AöR)
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Athens
country: Greece
facility: General Hospital of Athens Konstantopoulio-Agia Olga
city: Athens
country: Greece
facility: General Hospital of Athens "G. Gennimatas"
city: Haidari, Athens
country: Greece
facility: General University Hospital "Attikon"
city: Herakleion, Crete
country: Greece
facility: University General Hospital of Heraklion
city: Ioannina
country: Greece
facility: Univ. Gen. Hosp. of Ioannina
city: Thessaloniki
country: Greece
facility: University Hospital of Thessaloniki AHEPA
city: Milano
country: Italy
facility: Centro Cardiologico Monzino-IRCCS
city: Milano
country: Italy
facility: Asst Santi Paolo E Carlo
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Napoli
country: Italy
facility: Università Federico II
city: Palermo
country: Italy
facility: Università degli studi di Palermo
city: Roma
country: Italy
facility: IRCCS San Raffaele
city: Grålum
country: Norway
facility: Sykehuset Østfold Kalnes
city: Hønefoss
country: Norway
facility: Vestre Viken, Ringerike Sykehus HF
city: Oslo
country: Norway
facility: Oslo Universitetssykehus HF, Rikshospitalet
city: Stavanger
country: Norway
facility: Helse Stavanger, Stavanger Universitetssykehus
city: Trondheim
country: Norway
facility: St. Olavs Hospital, Universitetssykehuset i Trondheim
city: Bydgoszcz
country: Poland
facility: INTERCORE Medical Center
city: Krakow
country: Poland
facility: Leszek Bryniarski Specialized Medical Cabinet
city: Lodz
country: Poland
facility: Card.Cli.Mil.Med.Ac.Uni.Cli.Hosp. Cent.Vetera.Hosp.Lodz
city: Lodz
country: Poland
facility: Cent.Clin.Hosp.Med.Univ.Lodz,Electrocard
city: Lodz
country: Poland
facility: Provincial Specialist M. Kopernik Hospital
city: Pulawy
country: Poland
facility: Independent Public Healthcare, Dept. of Cardiology, Pulawy
city: Torun
country: Poland
facility: The Provincial Polyclinical Hospital in Torun
city: Warsaw
country: Poland
facility: Central Hospital of Medical Academy, Warsaw
city: Wroclaw
country: Poland
facility: 4. Military Clinical Hospital with Polyclinic SP ZOZ
city: Carnaxide
country: Portugal
facility: CHLO, EPE - Hospital de Santa Cruz
city: Coimbra
country: Portugal
facility: CHUC - Centro Hospitalar e Universitário de Coimbra, EPE
city: Leiria
country: Portugal
facility: Centro Hosp. de Leiria-Pombal
city: Lisboa
country: Portugal
facility: CHLC, EPE - Hospital de Santa Marta
city: Lisboa
country: Portugal
facility: CHLO, EPE - Hospital S. Francisco Xavier
city: Lisboa
country: Portugal
facility: CHULN, EPE - Hospital de Santa Maria
city: Penafiel
country: Portugal
facility: CHTS, EPE - Hospital Padre Américo
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário São João,EPE
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Granada
country: Spain
facility: Hospital San Rafael
city: Granada
country: Spain
facility: Hospital de la Inmaculada Concepción
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: L'Hospitalet de Llobregat
country: Spain
facility: Hospital de Bellvitge
city: Madrid
country: Spain
facility: Hospital La Princesa
city: Valencia
country: Spain
facility: Hospital Clínico de Valencia
city: Göteborg
country: Sweden
facility: Sahlgrenska US, Göteborg
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset, Östra
city: Stockholm
country: Sweden
facility: Akardo Med Site
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.