A Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure

Heart Failure Clinical Trial

Official title:

A Multicentre, Randomised, Double-blind, 90-day Superiority Trial to Evaluate the Effect on Clinical Benefit, Safety and Tolerability of Once Daily Oral EMPagliflozin 10 mg Compared to Placebo, Initiated in Patients Hospitalised for acUte Heart faiLure (de Novo or Decompensated Chronic HF) Who Have Been StabilisEd (EMPULSE)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04157751
• Other study ID #: 1245-0204
• Secondary ID: 2019-002946-19
• Status: Completed
• Phase: Phase 3
• Start date: May 18, 2020
• Est. completion date: June 2, 2021

Study information

• Verified date: June 2022
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a study in adults who are in hospital for acute heart failure. The purpose of this study is to find out whether starting to take a medicine called empagliflozin soon after first being treated in hospital helps people with acute heart failure.

Participants are in the study for about 3 months. At the beginning, participants are still in hospital. Later, they visit the hospital about 3 times and get 1 phone call. Participants are put into 2 groups by chance. One group takes 1 empagliflozin tablet a day. The other group takes

1 placebo tablet a day. Placebo tablets look like empagliflozin tablets but do not contain any medicine. Empagliflozin belongs to a class of medicines known as SGLT-2 inhibitors. It is used to treat type 2 diabetes.

During the study, the doctors check whether participants have additional heart failure events like needing to go to the hospital again because of heart failure. The participants answer questions about how their heart failure affects their life. We then compare the results between the empagliflozin and placebo groups. The doctors also regularly check the general health of the participants.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 530
• Est. completion date: June 2, 2021
• Est. primary completion date: May 28, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Currently hospitalised for the primary diagnosis of acute heart failure (de novo or decompensated chronic HF), regardless of ejection fraction (EF). Patients with a diagnosis of hospitalized heart failure must have HF symptoms at the time of hospital admission

• Evidence of left ventricular ejection fraction (LVEF, either reduced or preserved EF) as per local reading preferably measured during current hospitalisation or in the 12 months prior to randomisation

• Patients must be randomised after at least 24 hours and no later than 5 days after admission, as early as possible after stabilization and while still in hospital

• Patients must fulfil the following stabilisation criteria (while in the hospital):

• SBP =100mm Hg and no symptoms of hypotension in the preceding 6 hours,

• no increase in i.v. diuretic dose for 6 hours prior to randomisation,

• no i.v. vasodilators including nitrates within the last 6 hours prior to randomisation

• no i.v. inotropic drugs for 24 hours prior to randomisation.

• Elevated NT-proBNP = 1600pg/mL or BNP =400 pg/mL according to the local lab, for patients without atrial fibrillation (AF); or elevated NT-proBNP = 2400pg/mL or BNP =600 pg/mL for patients with AF, measured during the current hospitalization or in the 72 hours prior to hospital admission,. For patients treated with an angiotensin receptor neprilysin inhibitor (ARNI) in the previous 4 weeks prior to randomisation, only NT-proBNP values should be used

• HF episode leading to hospitalisation must have been treated with a minimum single dose of 40 mg of i.v. furosemide (or equivalent i.v. loop diuretic defined as 20 mg of torasemide or 1 mg of bumetanide)

• Further Inclusion Criteria Apply

Exclusion Criteria:

• Cardiogenic shock

• Current hospitalisation for acute heart failure primarily triggered by pulmonary embolism, cerebrovascular accident, or acute myocardial infarction (AMI)

• Current hospitalisation for acute heart failure not caused primarily by intravascular volume overload;

• Below interventions in the past 30 days prior to randomisation or planned during the study:

• Major cardiac surgery, or TAVI (Transcatheter Aortic Valve Implantation), or PCI, or Mitraclip

• All other surgeries that are considered major according to investigator judgement

• Implantation of cardiac resynchronisation therapy (CRT) device

• cardiac mechanical support implantation

• Carotid artery disease revascularisation (stent or surgery)

• Acute coronary syndrome / myocardial infarction, stroke or transient ischemic attack (TIA) in the past 90 days prior to randomisation

• Heart transplant recipient, or listed for heart transplant with expectation to receive a transplant during the course of this trial (according to investigator judgement), or planned for palliative care for HF, or currently using left ventricular assist device (LVAD) or intra-aortic balloon pump (IABP) or any other type of mechanical circulatory support, or patients on mechanical ventilation, or patients with planned inotropic support in an outpatient setting

• Haemodynamically significant (severe) uncorrected primary cardiac valvular disease planned for surgery or intervention during the course of the study (note: secondary mitral regurgitation or tricuspid regurgitation due to dilated cardiomyopathy is not excluded unless planned for surgery or intervention during the course of the study)

• Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2 as measured during hospitalization (latest local lab measurement before randomisation) or requiring dialysis

• Type 1 Diabetes Mellitus (T1DM)

• History of ketoacidosis, including diabetic ketoacidosis (DKA)

• Further Exclusion Criteria Apply

Related Conditions & MeSH terms

• Heart Failure

Intervention

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

Locations

Country	Name	City	State
Belgium	Aalst - HOSP Onze-Lieve-Vrouw	Aalst
Belgium	Brussels - UNIV UZ Brussel	Brussel
Belgium	AZ Sint-Blasius	Dendermonde
Belgium	Ziekenhuis Oost-Limburg - Campus Sint-Jan	Genk
Belgium	UZ Leuven	Leuven
Belgium	Liège - HOSP CHR de la Citadelle	Liège
Belgium	UNIV Ambroise Paré	Mons
Canada	Toronto General Hospital	Toronto	Ontario
Canada	Royal Jubilee Hospital	Victoria	British Columbia
Canada	St. Boniface General Hospital	Winnipeg	Manitoba
China	Beijing AnZhen Hospital	Beijing
China	Beijing Chao-Yang Hospital	Beijing
China	The First Hospital of Jilin University	Changchun
China	West China Hospital	Chengdu
China	Xiamen Cardiovascular Hospital Xiamen University	Xiamen
China	First Affiliated Hospital of Xi'an JiaoTong University	Xian
Czechia	Univ.Hosp U Svate Anny, I.Internal Clinic-Cardiology,Brno	Brno
Czechia	University Hospital Brno	Brno
Czechia	University Hospital Motol	Prag
Czechia	District Hospital, Tabor	Tabor
Denmark	Aalborg Universitetsshospital	Aalborg
Denmark	Frederiksberg Hospital	Frederiksberg
Denmark	Herlev and Gentofte Hospital	Herlev
Denmark	Hvidovre Hospital	Hvidovre
Denmark	Viborg Regionhospital	Viborg
Germany	Charité - Universitätsmedizin Berlin	Berlin
Germany	Bremer Institut für Herz- und Kreislaufforschung (BIHKF) am Klinikum Links der Weser	Bremen
Germany	Herzzentrum Dresden GmbH Universitätsklinik	Dresden
Germany	Universitäts-Herzzentrum Freiburg, Bad Krozingen GmbH	Freiburg
Germany	Universitätsklinikum Gießen und Marburg GmbH	Gießen
Germany	Universitätsklinikum Jena	Jena
Germany	Asklepios Klinik Langen-Seligenstadt GmbH	Langen
Germany	Klinikum Leverkusen gGmbH, Leverkusen	Leverkusen
Germany	Universitätsklinikum Schleswig-Holstein, Campus Lübeck	Lübeck
Germany	Klinikum der Stadt Ludwigshafen am Rhein gGmbH	Ludwigshafen
Germany	Universitätsklinikum Würzburg AÖR	Würzburg
Hungary	Semmelweis University	Budapest
Hungary	University Debrecen Hospital	Debrecen
Hungary	University of Pecs	Pecs
Hungary	Fejer County Saint George University Teaching Hospital	Szekesfehervar
Hungary	Csongrad Country Dr Bugyi Istvan Hosp.	Szentes
Italy	ASST degli Spedali Civili di Brescia	Brescia
Italy	Università degli Studi "Magna Grecia" - Campus "S. Venuta"	Catanzaro
Italy	Ospedale della Val di Chiana Santa Margherita	Cortona
Italy	Az.Osp. Universitaria "Ospedali Riuniti"	Foggia
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano
Italy	Centro Cardiologico Monzino-IRCCS	Milano
Italy	Osp. Guglielmo da Saliceto AUSL di Piacenza	Piacenza
Italy	IRCCS San Raffaele	Roma
Italy	AO Città della Salute e della	Torino
Italy	Azienda Sanitaria Universitaria Giuliano Isontina	Trieste
Japan	Japan Community Health Care Organization Kyushu Hospital	Fukuoka, Kitakyushu
Japan	Mito Medical Center	Ibaraki, Higashiibaraki-gun
Japan	Kanagawa Cardiovascular and Respiratory Center	Kanagawa, Yokohama
Japan	Shinshu University Hospital	Nagano, Matsumoto
Japan	The Sakakibara Heart Institute of Okayama	Okayama, Okayama
Japan	Osaka University Hospital	Osaka, Suita
Japan	Kawaguchi Cardiovascular and Respiratory Hospital	Saitama, Kawaguchi
Japan	Saitama Sekishikai Hospital	Saitama, Sayama
Japan	Nihon University Itabashi Hospital	Tokyo, Itabashi-ku
Netherlands	Jeroen Bosch Ziekenhuis-Hertogenbosch	's HERTOGENBOSCH
Netherlands	Gelre Ziekenhuizen Apeldoorn	Apeldoorn
Netherlands	HagaZiekenhuis	Den Haag
Netherlands	TREANT Zorggroep	Emmen
Netherlands	Groene Hart ziekenhuis	Gouda
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Sint Jansdal Ziekenhuis	Harderwijk
Netherlands	Alrijne Leiderdorp	Leiderdorp
Netherlands	Bravis ziekenhuis, locatie Roosendaal	Roosendaal
Netherlands	Diakonessenhuis Utrecht	Utrecht
Norway	Helse Førde HF, Førde Sentralsjukehus	Førde
Norway	Sykehuset Innlandet HF, Avd. Lillehammer	Lillehammer
Norway	Akershus Universitetssykehus HF	Lørenskog
Norway	Helse Stavanger, Stavanger Universitetssykehus	Stavanger
Norway	Universitetssykehuset Nord-Norge, Tromsø	Tromsø
Poland	Saint Wincenty a Paulo Hosp., Cardiology Dept., Gdynia	Gdynia
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
Spain	Hospital Universitario Virgen de la Arrixaca	El Palmar
Spain	Hospital de Bellvitge	L'Hospitalet de Llobregat
Spain	Hospital Puerta de Hierro	Majadahonda
Spain	Hospital Virgen de la Victoria	Malaga
Spain	Hospital Moises Broggi	Sant Joan Despi
Spain	Hospital Nuestra Señora de Valme	Sevilla
Spain	Hospital Clínico de Valencia	Valencia
Sweden	Sahlgrenska Universitetssjukhuset, Östra	Göteborg
Sweden	Sahlgrenska US, Göteborg	Göteborg
United States	Pharmatex Research	Amarillo	Texas
United States	Grady Memorial Hospital	Atlanta	Georgia
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	Erie County Medical Center	Buffalo	New York
United States	The University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Ralph H. Johnson VA Medical Center	Charleston	South Carolina
United States	Cardiology Associates Research Co.	Daytona Beach	Florida
United States	Cardiovascular Associates of the Delaware Valley	Elmer	New Jersey
United States	Inova Fairfax Medical Campus	Falls Church	Virginia
United States	The DeMatteis Center for Cardiac Research and Education	Greenvale	New York
United States	University Of Mississippi Medical Center	Jackson	Mississippi
United States	University of Florida Health Jacksonville	Jacksonville	Florida
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	University of Wisconsin	Madison	Wisconsin
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Sentara Norfolk General Hospital	Norfolk	Virginia
United States	South Oklahoma Heart Research Group	Oklahoma City	Oklahoma
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of California Irvine	Orange	California
United States	Methodist Medical Center	Peoria	Illinois
United States	Center for Advanced Cardiac Care - Heart Failure Clinic	Plano	Texas
United States	North Carolina Heart and Vascular	Raleigh	North Carolina
United States	United Hospital	Saint Paul	Minnesota
United States	Stony Brook Medicine	Stony Brook	New York
United States	The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center	Torrance	California
United States	Jefferson Washington Township Hospital	Washington Township	New Jersey

Sponsors (2)

Lead Sponsor	Collaborator
Boehringer Ingelheim	Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  China,  Czechia,  Denmark,  Germany,  Hungary,  Italy,  Japan,  Netherlands,  Norway,  Poland,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Pairwise Comparisons With Wins of Clinical Benefit, a Composite of Death, Number of Heart Failure Events (HFEs), Time to the First HFE and =5-point Difference in CfB in KCCQ-TSS After 90 Days of Treatment	Clinical benefit, a composite of death, number of HFEs, time to first HFE and change from baseline (CfB) in Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) after 90 days of treatment. All patients randomised to empagliflozin are compared to all patients randomised to placebo within strata. For any two patients, a patient will win, i.e. achieve a better clinical outcome, as determined by assessing the following criteria sequentially, stopping when an advantage for either patient is shown: Death: death is worse than no death; earlier death is worse; tied if not possible to determine.; Number of HFEs: more HFEs is worse; tied, if same number of HFEs.; Time to first HFE: earlier HFE is worse; tied, if not possible to determine.; KCCQ-TSS CfB at Day 90: more positive CfB is better; the threshold for the difference is >= 5 for a win; tied, if difference < 5.; The KCCQ-TSS ranges from 0 to 100, where a higher score reflects a better outcome.; pct. = percentage	Up to 90 days. For KCCQ-TSS: at baseline and at day 90.
Secondary	Number of Participants With Improvement of at Least 10 Points in KCCQ-TSS After 90 Days of Treatment	Number of participants with improvement of at least 10 points in Kansas City Cardiomyopathy Questionnaire - Total Symptom Score (KCCQ-TSS) from baseline after 90 days of treatment.; The Kansas City Cardiomyopathy Questionnaire is a self-administered questionnaire that includes 23 items that map to 7 domains: symptom frequency, symptom burden, symptom stability, physical limitations, social limitations, quality of life and self-efficacy. The symptom frequency and symptom burden domains are merged into the total symptom score. Scores are represented on a 0-to-100-point scale, where a higher score reflects a better health status.	At baseline and at day 90.
Secondary	Change From Baseline in KCCQ-TSS After 90 Days of Treatment	Change from baseline in Kansas City Cardiomyopathy Questionnaire - Total Symptom Score (KCCQ-TSS).; The Kansas City Cardiomyopathy Questionnaire is a self-administered questionnaire that includes 23 items that map to 7 domains: symptom frequency, symptom burden, symptom stability, physical limitations, social limitations, quality of life and self-efficacy. The symptom frequency and symptom burden domains are merged into the total symptom score. The score is represented on a 0-to-100-point scale, where a higher score reflects a better health status.; Change from baseline in KCCQ-TSS at day 90 was modeled using a MMRM with visit (day 15 and day 30) as repeated measures, adjusted mean (standard error) after 90 days of treatment is reported.	At baseline, at day 15, 30 and at day 90.
Secondary	Change From Baseline in Log-transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) Area Under the Curve (AUC) Over 30 Days of Treatment	Change from baseline in log-transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) Area under the curve (AUC) over 30 days of treatment is reported.	From baseline to day 30.
Secondary	Percentage of Days Alive and Out of Hospital (DAOH) From Study Drug Initiation Until 30 Days After Initial Hospital Discharge	The follow-up time for DAOH analyses was defined as 30 days after initial hospital discharge, or time between initial hospital discharge and date of censoring for non-fatal events except for patients who died within the first 30 days, where 30 days was considered as the DAOH follow-up time.; DAOH for each patient was calculated as follow-up time subtracted by the number of days in hospital during the 30 days after initial hospital discharge as well as the number of days being dead within the 30 days. Percentage DAOH was defined as DAOH divided by the DAOH follow-up time of each patient multiplied by 100.	Up to 30 days after initial hospital discharge.
Secondary	Percentage of Days Alive and Out of Hospital (DAOH) From Study Drug Initiation Until 90 Days After Randomisation	The follow-up time for DAOH analyses was defined as 90 days after randomisation, or time between randomisation and date of censoring for non-fatal events except for patients who died within the first 90 days, where 90 days was considered as the DAOH follow-up time. DAOH for each patient was calculated as follow-up time subtracted by the number of days in hospital during the 90 days after randomisation as well as the number of days being dead within the first 90 days.; Percentage DAOH was defined as DAOH divided by the DAOH follow-up time of each patient multiplied by 100.	Up to 90 days after randomisation.
Secondary	Incidence Rate of First Occurrence of Cardiovascular (CV) Death or Heart Failure Event (HFE) Until End of Trial Visit	Incidence rate of first occurrence of CV death or HFE until end of trial visit per 100 patient-year (pt-yrs) at risk is reported.; Incidence rate per 100 pt-yrs = 100* number of patients with event / time at risk [years].	Up to 127 days.
Secondary	Number of Participants With Hospitalization for Heart Failure (HHF) Until 30 Days After Initial Hospital Discharge	Number of participants with hospitalization for heart failure (HHF) until 30 days after initial hospital discharge.	Up to 30 days after initial hospital discharge.
Secondary	Composite Renal Endpoint: Number of Participants With Chronic Dialysis, Renal Transplant, Sustained Reduction in eGFR(CKD-EPI)cr	The occurrence of the composite renal endpoint: chronic dialysis (with a frequency of twice per week or more for at least 90 days), or; renal transplant, or; sustained reduction in Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr) from baseline of =40%, or; sustained eGFR [mL/min/1.73 m2] <15 and baseline value =30, or; sustained eGFR <10 and baseline value <30; is reported by number of participants with component events. (These events may have occurred after the endpoint was already met. Combinations may not have occurred on the same day).; Sustained was determined by 2 or more consecutive post-baseline central laboratory measurements separated by at least 30 days.	Up to 90 days.
Secondary	Weight Change Per Mean Daily Loop Diuretic Dose After 15 Days of Treatment	Diuretic effect as assessed by weight change per mean daily loop diuretic dose after 15 days of treatment.; Diuretic dose = 40 mg intravenous furosemide or 80 mg oral furosemide.; Abbreviation: Kg: Kilogram	At baseline and at day 15.
Secondary	Weight Change Per Mean Daily Loop Diuretic Dose After 30 Days of Treatment	Diuretic effect as assessed by weight change per mean daily loop diuretic dose after 30 days of treatment.; Diuretic dose = 40 mg intravenous furosemide or 80 mg oral furosemide; Abbreviation: Kg: Kilogram	At baseline and at day 30.

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