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EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced)

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ClinicalTrials.gov Identifier: NCT03057977
Recruitment Status : Completed
First Posted : February 20, 2017
Results First Posted : May 18, 2021
Last Update Posted : May 18, 2021
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief Summary:
The aim of the study is to investigate the safety and efficacy of empagliflozin versus placebo on top of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction.

Condition or disease Intervention/treatment Phase
Heart Failure Drug: Empagliflozin Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3730 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III Randomised, Double-blind Trial to Evaluate Efficacy and Safety of Once Daily Empagliflozin 10 mg Compared to Placebo, in Patients With Chronic Heart Failure With Reduced Ejection Fraction (HFrEF)
Actual Study Start Date : March 6, 2017
Actual Primary Completion Date : May 1, 2020
Actual Study Completion Date : May 28, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Experimental: Empagliflozin Drug: Empagliflozin
once daily
Other Name: JARDIANCE, JARDIANZ, GIBTULIO

Placebo Comparator: Placebo Drug: Placebo
once daily




Primary Outcome Measures :
  1. Time to the First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF) [ Time Frame: From randomisation until completion of the planned treatment period, up to 1040 days. ]

    Time to the first event of adjudicated cardiovascular (CV) death or adjudicated hospitalisation for heart failure (HHF). The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25.

    Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier.

    Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.



Secondary Outcome Measures :
  1. Occurrence of Adjudicated Hospitalisation for Heart Failure (HHF) (First and Recurrent) [ Time Frame: From randomisation until completion of the planned treatment phase, up to 1040 days. ]

    Reported is the total number of HHF events (first and recurrent) which occurred.

    All data up to the end of the planned treatment period (including the data after the end of treatment for patients not completing the treatment period as planned) from all randomised patients was used.


  2. eGFR (CKD-EPI) cr Slope of Change From Baseline [ Time Frame: Assessed at baseline, week 4, 12, 32, 52, 76, 100, 124, 148 and at end of treatment (EOT), up to 1040 days. ]

    Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr) [mL/min/1.73m2] slope of change from baseline.

    Available on-treatment change-from-baseline data were to be used. Patients without on-treatment data after randomisation were not to be included in this analysis. Slope represents the long term effect on eGFR.

    Timepoints after baseline were included in calculation of slope of change from baseline. Descriptive statistic (mean(standard error)) is reported.


  3. Time to First Event in Composite Renal Endpoint: Chronic Dialysis, Renal Transplant or Sustained Reduction of eGFR(CKD-EPI)cr [ Time Frame: From randomisation until completion of the planned treatment period, up to 1040 days. ]

    Time to the first event in the composite renal endpoint: chronic dialysis (with a frequency of twice per week or more for at least 90 days), 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).

    The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25.

    Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier.

    Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.


  4. Time to First Adjudicated Hospitalisation for Heart Failure (HHF) [ Time Frame: From randomisation until completion of the planned treatment period, up to 1040 days. ]

    Time to first adjudicated Hospitalisation for Heart Failure (HHF). The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier.

    Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.


  5. Time to Adjudicated Cardiovascular (CV) Death [ Time Frame: From randomisation until completion of the planned treatment period, up to 1040 days. ]

    Time to adjudicated CV (Cardiovascular) death. The incidence rate (patients with events per 100 person years at risk) is reported.

    The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25.

    Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier.

    Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.


  6. Time to All-cause Mortality [ Time Frame: From randomisation until completion of the planned treatment period, up to 1040 days. ]

    Time to all-cause mortality. The incidence rate (patients with events per 100 person years at risk) is reported.

    The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25.

    Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier.

    Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.


  7. Time to Onset of Diabetes Mellitus (DM) [ Time Frame: From randomisation until completion of the planned treatment period, up to 1040 days. ]

    Time to onset of DM (Glycated haemoglobin (HbA1c) ≥6.5% or as diagnosed by the investigator) in patients with pre-DM (no history of DM and no HbA1c ≥6.5% before treatment, and a pre-treatment HbA1c value of 5.7 to <6.5%). The incidence rate (patients with events per 100 person years at risk) is reported.

    The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25.

    Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier.

    Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.


  8. Change From Baseline in KCCQ (Kansas City Cardiomyopathy Questionnaire) Clinical Summary Score at Week 52 [ Time Frame: Assessed at baseline, week 12, week 32 and week 52. ]

    Change from baseline in KCCQ (Kansas City cardiomyopathy questionnaire) clinical summary score at Week 52. The KCCQ is a 23-item self-administered questionnaire designed to evaluate physical limitations, symptoms (frequency, severity, and changes over time), social limitations, selfefficacy, and quality of life in patients with Heart Failure. The KCCQ-clinical summary score comprises the following domains: Symptom frequency, symptom burden and physical limitation. The score is calculated by summing domain responses and then transforming scores to a 0-100 unit scale with higher scores indicating better health status.

    For patients who died, a worst score (score of 0) is imputed at all subsequent scheduled visits after the date of death.

    Standard error is adjusted standard error. Change from baseline in KCCQ-score at week 52 was modeled using a MMRM with visit (week 12, 32 and 52) as repeated measures, adjusted mean (standard error) at week 52 is reported.


  9. Number of All-cause Hospitalizations (First and Recurrent) [ Time Frame: From randomisation until completion of the planned treatment phase, up to 1040 days. ]
    Number of all-cause hospitalizations (first and recurrent).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Male or female patient age >= 18 years at screening. For Japan only: Age >= 20 years at screening
  • Patients with chronic HF (Chronic Heart Failure) NYHA (New York Heart Association Classification) class II-IV and reduced EF (Ejection Fraction) (LVEF (Left Ventricular Ejection Fraction) <=40%) and elevated NT-proBNP (N-terminal of the prohormone brain natriuretic peptide)

    • If EF >= 36% to <= 40%: NT-proBNP >= 2500 pg/ml or patients without AF (atrial fibrillation/atrial flutter) and NT-proBNP >= 5000 pg/ml for patients with AF
    • If EF >= 31% to <= 35%: NT-proBNP >= 1000 pg/ml for patients without AF and NT-proBNP >=2000 pg/ml for patients with AF
    • If EF<= 30%: NT-proBNP >= 600 pg/ml for patients without AF and NT-proBNP >=1200 pg/ml for patients with AF
    • EF ≤ 40% and hospitalization for heart failure in the past 12 months: NTproBNP ≥ 600 pg/ml for patients without AF and NT-proBNP >= 1200 pg/ml for patients with AF
  • Appropriate dose of medical therapy for HF consistent with prevailing local and international CV (Cardiovascular) guidelines, stable for at least 1 week prior to Visit 1
  • Appropriate use of medical devices such as cardioverter defibrillator (ICD) or a cardiac resynchronization therapy (CRT) consistent with prevailing local or international CV guidelines
  • Signed and dated written ICF (Informed Consent Form)
  • Further inclusion criteria apply

Exclusion criteria:

  • Myocardial infarction, coronary artery bypass graft surgery, or other major cardiovascular surgery, stroke or TIA (Transient Ischaemic Attack) in past 90 days prior to Visit 1
  • Heart transplant recipient, or listed for heart transplant
  • Acute decompensated HF
  • Systolic blood pressure (SBP) >= 180 mmHg at Visit 2.
  • Symptomatic hypotension and/or a SBP < 100 mmHg
  • Indication of liver disease
  • Impaired renal function, defined as eGFR (Estimated Glomerular Filtration Rate) < 20 mL/min/1.73 m2 (CKD-EPI (Chronic Kidney Disease - Epidemiology Collaboration Equation)) or requiring dialysis
  • History of ketoacidosis
  • Current use or prior use of a SGLT (Sodium-glucose co-transporter)-2 inhibitor or combined SGLT-1 and 2 inhibitor
  • Currently enrolled in another investigational device or drug study
  • Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors
  • Women who are pregnant, nursing, or who plan to become pregnant while in the trial
  • Further exclusion criteria apply

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03057977


Locations
Show Show 520 study locations
Sponsors and Collaborators
Boehringer Ingelheim
Eli Lilly and Company
Investigators
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Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  Study Documents (Full-Text)

Documents provided by Boehringer Ingelheim:
Study Protocol  [PDF] November 20, 2019
Statistical Analysis Plan  [PDF] June 19, 2020

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT03057977    
Other Study ID Numbers: 1245.121
2016-002280-34 ( EudraCT Number )
First Posted: February 20, 2017    Key Record Dates
Results First Posted: May 18, 2021
Last Update Posted: May 18, 2021
Last Verified: April 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Empagliflozin
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs