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.

Heart Failure Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03448406
• Other study ID #: 1245-0167
• Secondary ID: 2017-004072-59
• Status: Completed
• Phase: Phase 3
• Start date: March 20, 2018
• Est. completion date: October 9, 2019

Study information

• Verified date: November 2020
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 315
• Est. completion date: October 9, 2019
• Est. primary completion date: October 4, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• Empagliflozin
Film-coated tablet
• Placebo
Film-coated tablet

Locations

Country	Name	City	State
Australia	University of the Sunshine Coast	Birtinya	Queensland
Australia	Peninsular Health CV Research Unit	Frankston	Victoria
Australia	Canberra Hospital	Garran	Australian Capital Territory
Canada	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
Germany	CIMS Studienzentrum Bamberg GmbH	Bamberg
Germany	Charité - Universitätsmedizin Berlin	Berlin
Germany	Klinische Forschung Berlin GbR	Berlin
Germany	Cardiologicum Dresden und Pirna	Dresden
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	IKF Pneumologie GmbH & Co. KG	Frankfurt
Germany	Universitäts-Herzzentrum Freiburg, Bad Krozingen GmbH	Freiburg
Germany	Universitätsklinikum Köln (AöR)	Köln
Germany	Universitätsklinikum Leipzig	Leipzig
Germany	Universitätsklinikum Magdeburg AöR	Magdeburg
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz
Germany	Universitätsklinikum Ulm	Ulm
Germany	Universitätsklinikum Würzburg	Würzburg
Greece	General Hospital of Athens "G. Gennimatas"	Athens
Greece	General Hospital of Athens Konstantopoulio-Agia Olga	Athens
Greece	General Hospital of Chalkida	Chalkida
Greece	University General Hospital of Heraklion	Herakleion, Crete
Greece	Univ. Gen. Hosp. of Ioannina	Ioannina
Greece	University Hospital of Thessaloniki AHEPA	Thessaloniki
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano
Italy	Asst Santi Paolo E Carlo	Milano
Italy	Centro Cardiologico Monzino-IRCCS	Milano
Italy	Ospedale Regina Montis Regalis	Mondovì (CN)
Italy	Università Federico II	Napoli
Italy	Università degli studi di Palermo	Palermo
Italy	IRCCS San Raffaele	Roma
Norway	Sykehuset Østfold Kalnes	Grålum
Norway	Oslo Universitetssykehus HF, Rikshospitalet	Oslo
Norway	Helse Stavanger, Stavanger Universitetssykehus	Stavanger
Norway	St. Olavs Hospital, Universitetssykehuset i Trondheim	Trondheim
Poland	10.Military Clin.Hospital&Polyclinic	Bydgoszcz
Poland	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	Pulawy
Poland	Central Hospital of Medical Academy, Warsaw	Warsaw
Poland	4. Military Clinical Hospital with Polyclinic SP ZOZ	Wroclaw
Portugal	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	Lisboa
Portugal	CHLO, EPE - Hospital S. Francisco Xavier	Lisboa
Portugal	CHULN, EPE - Hospital de Santa Maria	Lisboa
Portugal	Centro Hospitalar Universitário São João,EPE	Porto
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Germans Trias i Pujol	Badalona
Spain	Hospital de la Inmaculada Concepción	Granada
Spain	Hospital San Rafael	Granada
Spain	Hospital Universitario Virgen de las Nieves	Granada
Spain	Hospital La Princesa	Madrid
Spain	Hospital Ramón y Cajal	Madrid
Spain	Hospital Clínico de Valencia	Valencia
Sweden	Sahlgrenska Universitetssjukhuset, Östra	Göteborg
Sweden	Sahlgrenska US, Göteborg	Göteborg
Sweden	Skånes universitetssjukhus, Lund	Lund
Sweden	Akardo Med Site	Stockholm
United States	Albany Stratton VA Medical Center Albany, NY	Albany	New York
United States	Northwest Heart Clinical Research, LLC	Arlington Heights	Illinois
United States	Grady Memorial Hospital	Atlanta	Georgia
United States	University of Colorado Denver	Aurora	Colorado
United States	DiscoveResearch, Inc.	Beaumont	Texas
United States	St Luke's Clinic - Idaho Cardiology Associates	Boise	Idaho
United States	Grace Research, LLC	Bossier City	Louisiana
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Columbia Heart Clinic	Columbia	South Carolina
United States	Western Connecticut Health Network	Danbury	Connecticut
United States	John D. Dingell VA Medical Center	Detroit	Michigan
United States	Med Research One	Florissant	Missouri
United States	Mary Washington Hospital Research Department	Fredericksburg	Virginia
United States	Clinical Investigation Specialists, Inc	Gurnee	Illinois
United States	Chicago Medical Research	Hazel Crest	Illinois
United States	Angiocardiac Care of Texas	Houston	Texas
United States	California Heart Specialists	Huntington Beach	California
United States	The Jackson Clinic, PA	Jackson	Tennessee
United States	The DOCS	Las Vegas	Nevada
United States	Rama Research LLC	Marion	Ohio
United States	Advance Medical Research Center	Miami	Florida
United States	Infinite Clinical Research	Miami	Florida
United States	Bio1 Clinical Research	Miami Beach	Florida
United States	Mobile Heart Specialists, PC	Mobile	Alabama
United States	Rutgers Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	York Clinical Research, LLC	Norfolk	Virginia
United States	Pharmacology Research, LLC	North Miami Beach	Florida
United States	Midwest Heart and Vascular Specialists	Overland Park	Kansas
United States	Palm Beach Gardens Research Center, LLC	Palm Beach Gardens	Florida
United States	UNC REX Healthcare	Raleigh	North Carolina
United States	Black Hills Cardiovascular Research	Rapid City	South Dakota
United States	PMG Research of Rocky Mount, LLC	Rocky Mount	North Carolina
United States	East Coast Institute for Research, LLC	Saint Augustine	Florida
United States	The Center for Clinical Trials, Inc.	Saraland	Alabama
United States	Grace Research, LLC	Shreveport	Louisiana
United States	Cox Medical Center South	Springfield	Missouri
United States	Manshadi Heart Institute, Inc	Stockton	California
United States	Acacia Medical Research Institute,LLC	Sugar Land	Texas
United States	University of California Los Angeles	Torrance	California
United States	Georgia Arrhythmia Consultants and Research Institute	Warner Robins	Georgia
United States	Clinical Trials of America LA, LLC	West Monroe	Louisiana
United States	PMG Research of Wilmington, LLC	Wilmington	North Carolina
United States	Cozy Research LLC	Zephyrhills	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Boehringer Ingelheim	Eli Lilly and Company

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline to Week 12 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes in Standardised Conditions (6MWTD)	Change from baseline to week 12 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions (6MWTD). If repeated 6-minutes walk test (6MWT) measurements were available for the same day, the longest distance was used for analysis. Change from baseline was defined as the distance walked in 6 minutes at Week 12 minus the baseline value.; Baseline value was defined as the last available measurement before start of treatment with randomised study medication. If a participant was present at the visit at Week 12 but did not perform the 6MWT, the participant was evaluated as having walked a distance of 0 meter. If no value was available for Week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above.	At baseline and at Week 12
Secondary	Change From Baseline to Week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS)	Change from baseline in KCCQ-TSS was defined as the endpoint value at week 12 minus the last available measurement before start of treatment with randomised study medication. The KCCQ is 23 item self-administered questionnaire and comprises 7 domains: physical limitation, symptom frequency, symptom burden, symptom stability, social limitation, self-efficacy and quality of life. Additionally 3 summary scores exist: TSS, clinical summary score, and overall summary score. The scores of the KCCQ domains and summary scores range from 0 to 100, with higher score indicating better outcome. If no questionnaire was available at week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. If no questionnaire was available at baseline, change from baseline was not imputed.	At baseline and at Week 12
Secondary	Change From Baseline to Week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized Format (CHQ-SAS) Dyspnea Score	Change from baseline in CHQ-SAS was defined as the endpoint value at week 12 minus the last available endpoint value before start of treatment with randomised study medication. The CHQ-SAS evaluates 3 domains: dyspnoea, fatigue, and emotional function. Scores of the domains range from 1 to 7, with higher score indicating better quality of life. If no questionnaire was available at week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. If no questionnaire was available at baseline, change from baseline was not imputed.	At baseline and at Week 12
Secondary	Change From Baseline to Week 6 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes	Change from baseline to week 6 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions. Change from baseline was defined as the distance walked in 6 minutes at Week 6 minus the baseline value. Baseline value was defined as the last available measurement before start of treatment with randomised study medication.; If a participant was present at the visit at Week 6 but did not perform the 6-Minuted Walking Test, the participant was evaluated as having walked a distance of 0 meter. If no value was available for Week 6, an imputed value was used.	At baseline and at Week 6
Secondary	Change From Baseline in Clinical Congestion Score at Week 12	Change from baseline to week 12 in Clinical Congestion score is defined as the score-value at week 12 minus the score-value at baseline. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. The Clinical Congestion Score (summary score) is based on 3 items: orthopnoea, jugular venous distention (JVD) and oedema. Each item was assessed through a 4-measure questionnaire, which was further converted to a standardised 4-point scale ranging from 0 to 3, with 0 indicating no or fewer symptoms and 3 indicating continous or more symptoms. If at least 2 of the 3 items are not missing, the summary score is calculated as: (average over items JVD, orthopnea and oedema actually answered)*3. The summary score ranges from 0 to 9, with lower value indicating better health, and higher value indicating worse health. Mean is adjusted mean.	At baseline and at Week 12
Secondary	Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12	Change from baseline to week 12 in PGI-S of Heart Failure Symptoms. The Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms is a 1-item questionnaire to assess the patient's impression of symptoms severity, specifically: shortness of breath, fatigue and swelling. The PGI-S asks the Patient to choose one response that best describes how his/her heart failure symptoms, specifically: shortness of breath, fatigue and swelling are now on a 5-category scale, ranging from 'Not at all' (1) to 'Very severe' (5). Number of participants by change in score are reported. Change in score was defined as the number of categories improved/deteriorated from baseline to week 12.	At baseline and at Week 12
Secondary	Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12	Change from baseline to week 12 in Patient Global Impression of Severity (PGI-S) of dyspnoea. The PGI-S of Dyspnoea is a 1-item questionnaire designed to assess the participant´s impression of symptom severity, specifically dyspnoea. The PGI-S item asks the participant to choose one response that best describes how his/her dyspnoea is now on a 5-category scale, ranging from 'Not at all' (1) to 'Very severe' (5). Number of participants by change in score are reported. Change in score was defined as the number of categories improved/deteriorated from baseline to week 12.	At baseline and at Week 12
Secondary	Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12	The Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms is a 1-item questionnaire to assess the patient's impression of change in heart failure symptoms, specifically: shortness of breath, fatigue, and swelling. The PGI-C asks the patient to choose one Response that best describes the overall change (if any) in his/her heart failure symptoms, specifically: shortness of breath, fatigue, and swelling since he/she started taking the study medication on a 7- category scale ranging from 'Very much better' (+3) to 'Very much worse' (-3).	Week 12
Secondary	Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12	The PGI-C in Dyspnoea is a 1-item questionnaire designed to assess the patient's Impression of change in dyspnoea. The PGI-C asks the patient to choose one response that best describes the change (if any) in his/her shortness of breath when performing usual activities since he/she started taking the study medication on a 7-category scale ranging from 'Very much better' (+3) to 'Very much worse' (-3).	Week 12
Secondary	Relative Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NTproBNP) at Week 12	Relative change from baseline to week 12 in N-terminal pro-brain natriuretic peptide (NTproBNP). Relative change from baseline is expressed as ratio of week 12 to baseline. Baseline value was defined as the mean of all available measurements from the screening visit until start of treatment with randomised study medication. Mean is adjusted mean.	Within 3 weeks prior to treatment start and at Week 12.

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