Clinical trial NCT03448406: This Study Tests Empagliflozin in Patients With Chronic Heart Failure With Preserved Ejection Fraction (HFpEF). 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 Preserved Ejection Fraction (HFpEF) (EMPERIAL - Preserved)
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: 315
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 (6MWT) in patients with chronic heart failure (CHF) with preserved 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 child bearing potential (WOCBP) 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
* Six minute walk test (6MWT) distance ≤350 m at screening and at baseline.
* Patients with CHF diagnosed for at least 3 months before Visit 1, and currently in NYHA class II-IV
* Chronic heart failure (CHF) with preserved Ejection fraction (EF) defined as left ventricle ejection fraction(LVEF) \> 40 % as per echocardiography at Visit 1 per local reading and no prior measurement of LVEF ≤ 40% under stable conditions.
* Elevated N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) \> 300 pg/ml for patients without atrial fibrillation (AF), OR \> 600 pg/ml for patients with AF, as analysed at the Central laboratory at Visit 1
* Patients must have at least one of the following evidence of heart failure (HF):

  * Structural heart disease (left atrial enlargement and/or left ventricular hypertrophy) documented by echocardiogram at Visit 1, OR
  * Documented Hospitalization for Heart Failure (HHF) within 12 months prior to Visit 1
* Consistent with prevailing CV guidelines, if oral diuretics are prescribed to control symptoms, patients must be on an appropriate and stable dose of oral diuretics for at least 2 weeks prior to Visit 1 to control symptoms.
* Clinically stable at randomization with no signs of heart failure decompensation (as per investigator judgement).

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 transient ischemic attack in past 90 days prior to Visit 1
* Acute decompensated HF (exacerbation of CHF) 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, 1245-0168)
* 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 systolic blood pressure (SBP) \< 100 mmHg at Visit 1 or 2
* 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.
* ICD implantation within 1 month prior to Visit 1 or planned during the course of the trial
* Implanted cardiac resynchronisation therapy (CRT)
* Treatment with i.v. iron therapy or erythropoietin (EPO) 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 Distance Walked in 6 Minutes in Standardised Conditions (6MWTD)
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 Distance Walked in 6 Minutes
timeFrame: At baseline and at Week 6
measure: Change From Baseline in Clinical Congestion Score at Week 12
timeFrame: At baseline and at Week 12
measure: Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12
timeFrame: At baseline and at Week 12
measure: Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12
timeFrame: At baseline and at Week 12
measure: Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12
timeFrame: Week 12
measure: Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12
timeFrame: Week 12
measure: Relative Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NTproBNP) at Week 12
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: Detroit
country: United States
facility: John D. Dingell VA Medical Center
state: Michigan
city: Florissant
country: United States
facility: Med Research One
state: Missouri
city: Springfield
country: United States
facility: Cox Medical Center South
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: Albany
country: United States
facility: Albany Stratton VA Medical Center Albany, NY
state: New York
city: Raleigh
country: United States
facility: UNC REX Healthcare
state: North Carolina
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: Sugar Land
country: United States
facility: Acacia Medical Research Institute,LLC
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: Garran
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Birtinya
country: Australia
facility: University of the Sunshine Coast
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: Dresden
country: Germany
facility: Cardiologicum Dresden und Pirna
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
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: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg AöR
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: Chalkida
country: Greece
facility: General Hospital of Chalkida
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: Mondovì (CN)
country: Italy
facility: Ospedale Regina Montis Regalis
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: 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: Bydgoszcz
country: Poland
facility: 10.Military Clin.Hospital&Polyclinic
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: 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: 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: Madrid
country: Spain
facility: Hospital La Princesa
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
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: Lund
country: Sweden
facility: Skånes universitetssjukhus, Lund
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.