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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03057977




Registration number
NCT03057977
Ethics application status
Date submitted
16/02/2017
Date registered
20/02/2017
Date last updated
18/05/2021

Titles & IDs
Public title
EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced)
Scientific 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)
Secondary ID [1] 0 0
2016-002280-34
Secondary ID [2] 0 0
1245.121
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart Failure 0 0
Condition category
Condition code
Cardiovascular 0 0 0 0
Coronary heart disease
Cardiovascular 0 0 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Empagliflozin
Treatment: Drugs - Placebo

Experimental: Empagliflozin -

Placebo comparator: Placebo -


Treatment: Drugs: Empagliflozin
once daily

Treatment: Drugs: Placebo
once daily
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Time to the First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF)
Timepoint [1] 0 0
From randomisation until completion of the planned treatment period, up to 1040 days.
Secondary outcome [1] 0 0
Occurrence of Adjudicated Hospitalisation for Heart Failure (HHF) (First and Recurrent)
Timepoint [1] 0 0
From randomisation until completion of the planned treatment phase, up to 1040 days.
Secondary outcome [2] 0 0
eGFR (CKD-EPI) cr Slope of Change From Baseline
Timepoint [2] 0 0
Assessed at baseline, week 4, 12, 32, 52, 76, 100, 124, 148 and at end of treatment (EOT), up to 1040 days.
Secondary outcome [3] 0 0
Time to First Event in Composite Renal Endpoint: Chronic Dialysis, Renal Transplant or Sustained Reduction of eGFR(CKD-EPI)cr
Timepoint [3] 0 0
From randomisation until completion of the planned treatment period, up to 1040 days.
Secondary outcome [4] 0 0
Time to First Adjudicated Hospitalisation for Heart Failure (HHF)
Timepoint [4] 0 0
From randomisation until completion of the planned treatment period, up to 1040 days.
Secondary outcome [5] 0 0
Time to Adjudicated Cardiovascular (CV) Death
Timepoint [5] 0 0
From randomisation until completion of the planned treatment period, up to 1040 days.
Secondary outcome [6] 0 0
Time to All-cause Mortality
Timepoint [6] 0 0
From randomisation until completion of the planned treatment period, up to 1040 days.
Secondary outcome [7] 0 0
Time to Onset of Diabetes Mellitus (DM)
Timepoint [7] 0 0
From randomisation until completion of the planned treatment period, up to 1040 days.
Secondary outcome [8] 0 0
Change From Baseline in KCCQ (Kansas City Cardiomyopathy Questionnaire) Clinical Summary Score at Week 52
Timepoint [8] 0 0
Assessed at baseline, week 12, week 32 and week 52.
Secondary outcome [9] 0 0
Number of All-cause Hospitalizations (First and Recurrent)
Timepoint [9] 0 0
From randomisation until completion of the planned treatment phase, up to 1040 days.

Eligibility
Key inclusion 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
6/03/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
28/05/2020
Sample size
Target
Accrual to date
Final
3730
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 0 0
John Hunter Hospital - New Lambton Heights
Recruitment hospital [2] 0 0
CORE Research Group - Milton
Recruitment hospital [3] 0 0
Mater Hospital Brisbane - South Brisbane
Recruitment hospital [4] 0 0
SA-Heart Ashford Specialist Centre - Ashford
Recruitment hospital [5] 0 0
Heart and Vascular Research - Fullarton
Recruitment hospital [6] 0 0
The Northern Hospital - Epping
Recruitment hospital [7] 0 0
St Vincent's Hospital Melbourne - Fitzroy
Recruitment hospital [8] 0 0
University Hospital Geelong - Geelong
Recruitment hospital [9] 0 0
Royal Melbourne Hospital - Parkville
Recruitment postcode(s) [1] 0 0
2305 - New Lambton Heights
Recruitment postcode(s) [2] 0 0
4064 - Milton
Recruitment postcode(s) [3] 0 0
4101 - South Brisbane
Recruitment postcode(s) [4] 0 0
5035 - Ashford
Recruitment postcode(s) [5] 0 0
5063 - Fullarton
Recruitment postcode(s) [6] 0 0
3076 - Epping
Recruitment postcode(s) [7] 0 0
3065 - Fitzroy
Recruitment postcode(s) [8] 0 0
3220 - Geelong
Recruitment postcode(s) [9] 0 0
3050 - Parkville
Recruitment outside Australia
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Boehringer Ingelheim
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Eli Lilly and Company
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT03057977
Trial related presentations / publications
Ferreira JP, Zannad F, Butler J, Filippatos G, Pocock SJ, Brueckmann M, Steubl D, Schueler E, Anker SD, Packer M. Association of Empagliflozin Treatment With Albuminuria Levels in Patients With Heart Failure: A Secondary Analysis of EMPEROR-Pooled. JAMA Cardiol. 2022 Nov 1;7(11):1148-1159. doi: 10.1001/jamacardio.2022.2924. Erratum In: JAMA Cardiol. 2022 Nov 1;7(11):1177. doi: 10.1001/jamacardio.2022.4032.
Ferreira JP, Zannad F, Butler J, Filipattos G, Ritter I, Schuler E, Kraus BJ, Pocock SJ, Anker SD, Packer M. Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-Pooled. Eur Heart J. 2022 Aug 14;43(31):2984-2993. doi: 10.1093/eurheartj/ehac306. Erratum In: Eur Heart J. 2022 Nov 1;43(41):4377. doi: 10.1093/eurheartj/ehac428.
Ferreira JP, Butler J, Zannad F, Filippatos G, Schueler E, Steubl D, Zeller C, Januzzi JL, Pocock S, Packer M, Anker SD. Mineralocorticoid Receptor Antagonists and Empagliflozin in Patients With Heart Failure and Preserved Ejection Fraction. J Am Coll Cardiol. 2022 Mar 29;79(12):1129-1137. doi: 10.1016/j.jacc.2022.01.029.
Ferreira JP, Anker SD, Butler J, Filippatos G, Iwata T, Salsali A, Zeller C, Pocock SJ, Zannad F, Packer M. Impact of anaemia and the effect of empagliflozin in heart failure with reduced ejection fraction: findings from EMPEROR-Reduced. Eur J Heart Fail. 2022 Apr;24(4):708-715. doi: 10.1002/ejhf.2409. Epub 2022 Jan 9.
Verma S, Dhingra NK, Butler J, Anker SD, Ferreira JP, Filippatos G, Januzzi JL, Lam CSP, Sattar N, Peil B, Nordaby M, Brueckmann M, Pocock SJ, Zannad F, Packer M; EMPEROR-Reduced trial committees and investigators. Empagliflozin in the treatment of heart failure with reduced ejection fraction in addition to background therapies and therapeutic combinations (EMPEROR-Reduced): a post-hoc analysis of a randomised, double-blind trial. Lancet Diabetes Endocrinol. 2022 Jan;10(1):35-45. doi: 10.1016/S2213-8587(21)00292-8. Epub 2021 Nov 30.
Ryden L, Ferrannini G. Is the impact of add on heart failure therapy influenced by background therapy? Lancet Diabetes Endocrinol. 2022 Jan;10(1):3-5. doi: 10.1016/S2213-8587(21)00311-9. Epub 2021 Nov 30. No abstract available.
Bohm M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, Mahfoud F, Brueckmann M, Jamal W, Ofstad AP, Schuler E, Ponikowski P, Wanner C, Zannad F, Packer M; EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure. J Am Coll Cardiol. 2021 Sep 28;78(13):1337-1348. doi: 10.1016/j.jacc.2021.07.049.
Januzzi JL Jr, Zannad F, Anker SD, Butler J, Filippatos G, Pocock SJ, Ferreira JP, Sattar N, Verma S, Vedin O, Schnee J, Iwata T, Cotton D, Packer M; EMPEROR-Reduced Trial Committees and Investigators. Prognostic Importance of NT-proBNP and Effect of Empagliflozin in the EMPEROR-Reduced Trial. J Am Coll Cardiol. 2021 Sep 28;78(13):1321-1332. doi: 10.1016/j.jacc.2021.07.046.
Packer M, Butler J, Zannad F, Filippatos G, Ferreira JP, Pocock SJ, Carson P, Anand I, Doehner W, Haass M, Komajda M, Miller A, Pehrson S, Teerlink JR, Schnaidt S, Zeller C, Schnee JM, Anker SD. Effect of Empagliflozin on Worsening Heart Failure Events in Patients With Heart Failure and Preserved Ejection Fraction: EMPEROR-Preserved Trial. Circulation. 2021 Oct 19;144(16):1284-1294. doi: 10.1161/CIRCULATIONAHA.121.056824. Epub 2021 Aug 29.
Pocock SJ, Ferreira JP, Gregson J, Anker SD, Butler J, Filippatos G, Gollop ND, Iwata T, Brueckmann M, Januzzi JL, Voors AA, Zannad F, Packer M. Novel biomarker-driven prognostic models to predict morbidity and mortality in chronic heart failure: the EMPEROR-Reduced trial. Eur Heart J. 2021 Nov 14;42(43):4455-4464. doi: 10.1093/eurheartj/ehab579.
Lam CSP, Ferreira JP, Pfarr E, Sim D, Tsutsui H, Anker SD, Butler J, Filippatos G, Pocock SJ, Sattar N, Verma S, Brueckmann M, Schnee J, Cotton D, Zannad F, Packer M. Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J. 2021 Nov 14;42(43):4442-4451. doi: 10.1093/eurheartj/ehab360.
Ferreira JP, Zannad F, Pocock SJ, Anker SD, Butler J, Filippatos G, Brueckmann M, Jamal W, Steubl D, Schueler E, Packer M. Interplay of Mineralocorticoid Receptor Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced. J Am Coll Cardiol. 2021 Mar 23;77(11):1397-1407. doi: 10.1016/j.jacc.2021.01.044.
Packer M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, Sattar N, Brueckmann M, Jamal W, Cotton D, Iwata T, Zannad F; EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial. J Am Coll Cardiol. 2021 Mar 23;77(11):1381-1392. doi: 10.1016/j.jacc.2021.01.033.
Butler J, Anker SD, Filippatos G, Khan MS, Ferreira JP, Pocock SJ, Giannetti N, Januzzi JL, Pina IL, Lam CSP, Ponikowski P, Sattar N, Verma S, Brueckmann M, Jamal W, Vedin O, Peil B, Zeller C, Zannad F, Packer M; EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J. 2021 Mar 31;42(13):1203-1212. doi: 10.1093/eurheartj/ehaa1007.
Anker SD, Butler J, Filippatos G, Khan MS, Marx N, Lam CSP, Schnaidt S, Ofstad AP, Brueckmann M, Jamal W, Bocchi EA, Ponikowski P, Perrone SV, Januzzi JL, Verma S, Bohm M, Ferreira JP, Pocock SJ, Zannad F, Packer M. Effect of Empagliflozin on Cardiovascular and Renal Outcomes in Patients With Heart Failure by Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial. Circulation. 2021 Jan 26;143(4):337-349. doi: 10.1161/CIRCULATIONAHA.120.051824. Epub 2020 Nov 11.
Zannad F, Ferreira JP, Pocock SJ, Zeller C, Anker SD, Butler J, Filippatos G, Hauske SJ, Brueckmann M, Pfarr E, Schnee J, Wanner C, Packer M. Cardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function: Insights From EMPEROR-Reduced. Circulation. 2021 Jan 26;143(4):310-321. doi: 10.1161/CIRCULATIONAHA.120.051685. Epub 2020 Oct 23. Erratum In: Circulation. 2021 Jan 26;143(4):e29. doi: 10.1161/CIR.0000000000000953.
Packer M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, Carson P, Anand I, Doehner W, Haass M, Komajda M, Miller A, Pehrson S, Teerlink JR, Brueckmann M, Jamal W, Zeller C, Schnaidt S, Zannad F. Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial. Circulation. 2021 Jan 26;143(4):326-336. doi: 10.1161/CIRCULATIONAHA.120.051783. Epub 2020 Oct 21. Erratum In: Circulation. 2021 Jan 26;143(4):e30. doi: 10.1161/CIR.0000000000000954.
Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Bohm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct 8;383(15):1413-1424. doi: 10.1056/NEJMoa2022190. Epub 2020 Aug 28.
Nassif ME, Kosiborod M. Effects of sodium glucose cotransporter type 2 inhibitors on heart failure. Diabetes Obes Metab. 2019 Apr;21 Suppl 2:19-23. doi: 10.1111/dom.13678.
Public notes

Contacts
Principal investigator
Name 0 0
Boehringer Ingelheim
Address 0 0
Boehringer Ingelheim
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT03057977