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

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ClinicalTrials.gov Identifier: NCT03057951
Recruitment Status : Completed
First Posted : February 20, 2017
Results First Posted : June 6, 2022
Last Update Posted : June 6, 2022
Sponsor:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Description
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Brief Summary:

This is a study in adults with chronic heart failure. People with chronic heart failure may need to be hospitalised for their condition. Some people with chronic heart failure may eventually die from their condition. The purpose of the study is to find out whether a medicine called empagliflozin lowers the chances of patients having to go to hospital for heart failure and whether it improves their survival. The study is open to patients with a type of chronic heart failure called chronic heart failure with preserved ejection fraction.

Participants stay in the study until researchers have enough information about how effective empagliflozin is. It is expected that participants who enter at the very beginning of the enrolment period may be in the study for over 3 years, while participants who enter near the end of the enrolment period may be in the study for less than 2 years. The participants are put into 2 groups. It is decided by chance who gets into which group. One group gets empagliflozin tablets every day and the other group gets placebo tablets every day. Placebo tablets look like empagliflozin tablets but contain no medicine.

Participants visit the doctors regularly. During these visits, the doctors collect information about the participant's health. The doctors want to know how many patients had to go to hospital because of heart failure or who died from cardiovascular disease.


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

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5988 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 Preserved Ejection Fraction (HFpEF)
Actual Study Start Date : March 2, 2017
Actual Primary Completion Date : April 26, 2021
Actual Study Completion Date : April 26, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arms and Interventions
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Arm Intervention/treatment
Experimental: 10 mg Empagliflozin Drug: Empagliflozin
once daily
Other Name: JARDIANCE, JARDIANZ, GIBTULIO
Placebo Comparator: Placebo Drug: Placebo
once daily


Outcome Measures
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Primary Outcome Measures :
  1. Time to First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF) [ Time Frame: From randomization until completion of the planned treatment phase, up to 1403 days. ]

    Failure with preserved Ejection Fraction (HFpEF). The incidence rate per 100 patient years (pt-yrs) is presented and calculated as followed:

    Incidence rate per 100 pt-yrs = 100 * number of patients with event / time at risk [years].

    Time at risk [years] = 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.



Secondary Outcome Measures :
  1. Occurrence of Adjudicated Hospitalisation for Heart Failure (HHF) (First and Recurrent) [ Time Frame: From randomization until completion of the planned treatment phase, up to 1403 days. ]
    Reported is the total number of adjudicated HHF events (first and recurrent) which occurred.

  2. eGFR (CKD-EPI) cr Slope of Change From Baseline [ Time Frame: At baseline, week 4, 12, 32, 52, 76, 100, 124, 148, 172 and week 196, up to 1043 days. ]

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

    Available on-treatment change-from-baseline data were used. The slope represents the long term effect of eGFR change from baseline and provides the yearly rate of decline.

    Timepoints after baseline were included in calculation of slope of change from baseline.

    The slope per patient was calculated using a random coefficient model with terms for treatment, region, baseline status of diabetes, age, sex, left ventricular ejection fraction (LVEF) and glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula (eGFR (CKD-EPI)cr) at baseline and in addition the factors "time", "treatment-by-time interaction", and "baseline eGFR (CKD-EPI)cr-by-time interaction".


  3. Time to the First Event in the Composite Renal Endpoint: Chronic Dialysis, Renal Transplant, or Sustained Reduction in eGFR (CKD-EPI)cr [ Time Frame: From randomization until completion of the planned treatment phase, up to 1403 days. ]

    Chronic dialysis was defined as dialysis with a frequency of twice per week or more for at least 90 days.

    Sustained was determined by two or more consecutive post-baseline central laboratory measurement separated by at least 30 days.

    Reduction in glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr) was defined as reduction in eGFR from baseline ≥40%, eGFR <15 mL/min/1.73 m^2 for patients with baseline eGFR ≥30 mL/min/1.73 m^2, or eGFR <10 mL/min/1.73 m^2 for patients with baseline eGFR <30 mL/min/1.73 m^2.

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

    Abbreviation:

    Patient-years (pt-yrs).


  4. Time to First Adjudicated Hospitalisation for Heart Failure (HHF) [ Time Frame: From randomization until completion of the planned treatment phase, up to 1403 days. ]

    Time to first adjudicated HHF. The incidence rate per 100 patient years (pt-yrs) is presented and calculated as followed:

    Incidence rate per 100 pt-yrs = 100 * number of patients with event / time at risk [years].

    Time at risk [years] = 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.


  5. Time to Adjudicated Cardiovascular (CV) Death [ Time Frame: From randomization until completion of the planned treatment phase, up to 1403 days. ]

    Time to adjudicated CV death. The incidence rate per 100 patient years (pt-yrs) is presented and calculated as followed:

    Incidence rate per 100 pt-yrs = 100 * number of patients with event / time at risk [years].

    Time at risk [years] = 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.


  6. Time to All-cause Mortality [ Time Frame: From randomization until completion of the planned treatment phase, up to 1403 days. ]

    Time to all-cause mortality. The incidence rate per 100 patient years (pt-yrs) is presented and calculated as followed:

    Incidence rate per 100 pt-yrs = 100 * number of patients with event / time at risk [years].

    Time at risk [years] = 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.


  7. Time to Onset of Diabetes Mellitus (DM) in Patients With Pre-DM [ Time Frame: From randomization until completion of the planned treatment phase, to 1403 days. ]

    Time to onset of DM (defined as HbA1c ≥6.5% or as diagnosed by the investigator) in patients with pre-DM.

    Pre-DM was defined as no history of DM and no HbA1c ≥6.5% before treatment, and a pre-treatment HbA1c value of ≥5.7% and <6.5%.

    The incidence rate per 100 patient years (pt-yrs) is presented and calculated as followed:

    Incidence rate per 100 pt-yrs = 100 * number of patients with event / time at risk [years].

    Time at risk [years] = 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.


  8. Change From Baseline in Kansas City Cardiomyopathy Questionaire (KCCQ) Clinical Summary Score at Week 52 [ Time Frame: At baseline and at week 12, week 32 and 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, self-efficacy, 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) was imputed for the score at all subsequent scheduled visits after the date of death where the score would have been assessed.

    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. Occurrence of All-cause Hospitalisation (First and Recurrent) [ Time Frame: From randomization until completion of the planned treatment phase, up to 1403 days. ]
    Occurrence of all-cause hospitalisation (first and recurrent). Total number of all cause hospitalisations is reported.


Eligibility Criteria
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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 preserved EF (Ejection Fraction)(LVEF (Left Ventricular Ejection Fraction) > 40 %) and elevated NT-proBNP (N-terminal of the prohormone brain natriuretic peptide) > 300 pg/ml for patients without AF, OR > 900 pg/ml for patients with AF, analysed at the Central laboratory at Visit 1
  • Structural heart disease within 6 months prior to Visit 1, OR documented HHF (Hospitalisation for Heart Failure) within 12 months prior to Visit 1
  • Stable dose of oral diuretics, if prescribed
  • 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 (Heart Failure)
  • 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))cr 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 trial
  • 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 may apply
Contacts and Locations
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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): NCT03057951


Locations
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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 9, 2016
Statistical Analysis Plan  [PDF] February 21, 2017

More Information
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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: NCT03057951    
Other Study ID Numbers: 1245.110
2016-002278-11 ( EudraCT Number )
First Posted: February 20, 2017    Key Record Dates
Results First Posted: June 6, 2022
Last Update Posted: June 6, 2022
Last Verified: June 2022

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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