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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

Tracking Information
First Submitted Date  ICMJE February 16, 2017
First Posted Date  ICMJE February 20, 2017
Results First Submitted Date  ICMJE April 26, 2021
Results First Posted Date  ICMJE May 18, 2021
Last Update Posted Date May 18, 2021
Actual Study Start Date  ICMJE March 6, 2017
Actual Primary Completion Date May 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 26, 2021)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 16, 2017)
Composite primary endpoint - Time to first event of adjudicated CV (Cardiovascular) death or adjudicated HHF (Hospitalisation for Heart Failure) in patients with Heart Failure with reduced Ejection Fraction (HFrEF) [ Time Frame: up to 38 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 26, 2021)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: February 16, 2017)
  • Occurrence of adjudicated HHF (Hospitalisation for Heart Failure) (first and recurrent) [ Time Frame: up to 38 months ]
  • eGFR (Estimated Glomerular Filtration Rate) (CKD-EPI (Chronic Kidney Disease - Epidemiology Collaboration Equation))cr slope of change from baseline [ Time Frame: up to 38 months ]
  • Time to first occurrence of sustained reduction of eGFR [ Time Frame: up to 38 months ]
    Time to first occurrence of sustained reduction of >= 40% eGFR (CKD-EPI)cr or
    • sustained eGFR (CKD-EPI)cr <15 mL/min/1.73 m2 for patients with baseline eGFR >=30 mL/min/1.73 m2
    • sustained eGFR (CKD-EPI)cr <10 mL/min/1.73 m2 for patients with baseline eGFR <30 mL/min/1.73 m2
  • Time to first adjudicated HHF (Hospitalisation for Heart Failure) [ Time Frame: up to 38 months ]
  • Time to adjudicated CV (Cardiovascular) death [ Time Frame: up to 38 months ]
  • Time to All-cause Mortality [ Time Frame: up to 38 months ]
  • Time to onset of DM (Diabetes Mellitus) [ Time Frame: up to 38 months ]
  • Change from baseline in clinical summary score (HF (Chronic Heart Failure) symptoms and physical limitations domains) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) at week 52 [ Time Frame: Baseline and Week 52 ]
  • Occurrence of all-cause hospitalisation (first and recurrent) [ Time Frame: up to 38 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced)
Official Title  ICMJE 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)
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Heart Failure
Intervention  ICMJE
  • Drug: Empagliflozin
    once daily
    Other Name: JARDIANCE, JARDIANZ, GIBTULIO
  • Drug: Placebo
    once daily
Study Arms  ICMJE
  • Experimental: Empagliflozin
    Intervention: Drug: Empagliflozin
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 28, 2020)
3730
Original Estimated Enrollment  ICMJE
 (submitted: February 16, 2017)
2850
Actual Study Completion Date  ICMJE May 28, 2020
Actual Primary Completion Date May 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Belgium,   Brazil,   Canada,   China,   Czechia,   France,   Germany,   Hungary,   India,   Italy,   Japan,   Korea, Republic of,   Mexico,   Netherlands,   Poland,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03057977
Other Study ID Numbers  ICMJE 1245.121
2016-002280-34 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Boehringer Ingelheim
Study Sponsor  ICMJE Boehringer Ingelheim
Collaborators  ICMJE Eli Lilly and Company
Investigators  ICMJE
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
PRS Account Boehringer Ingelheim
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP