EMPA-AHF: Early Treatment With a Sodium-glucose Co-transporter 2 Inhibitor in High-risk Patients With Acute Heart Failure

• Sponsor: Juntendo University (Other)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05392764
• Collaborator: Boehringer Ingelheim (Industry)
• Enrollment: 500
• Locations: 47
• Arms: 2
• Anticipated Duration (Months): 6.7
• Patients Per Site: 10.6
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

The EMPA-AHF trial is a multicentre, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of early initiation of once-daily oral empagliflozin 10 mg in patients hospitalized for patients with acute heart failure (AHF) who are at a high risk of adverse events.

Condition or Disease	Intervention/Treatment	Phase
Acute Heart Failure	Drug: Empagliflozin 10 MG; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Empagliflozin in Patients With Acute Heart Failure
• Anticipated Study Start Date: Sep 10, 2022
• Anticipated Primary Completion Date: Apr 1, 2023
• Anticipated Study Completion Date: Apr 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Empagliflozin Patients will be randomized 1:1 to either empagliflozin or placebo.	Drug: Empagliflozin 10 MG; once-daily oral empagliflozin 10 mg
Placebo Comparator: Placebo Placebo matching empagliflozin	Drug: Placebo; Placebo matching empagliflozin 10 mg

Outcome Measures

Primary Outcome Measures

1. A hierarchical composite endpoint consisting of death within 90 days, heart failure rehospitalization within 90 days, WHF during hospitalization, and urine output up to 48 hours after treatment initiation, assessed by the win ratio [Up to 90 days]

   WHF, worsening heart failure

Secondary Outcome Measures

1. A hierarchical composite endpoint consisting of death within 90 days, heart failure readmission within 90 days, and WHF during hospitalization [Up to 90 days]

   WHF, worsening heart failure

2. A composite endpoint consisting of WHF during hospitalization, death, heart failure rehospitalization, urgent visit for WHF, intensification of diuretic therapy, and worsening NYHA class within 90 days [Up to 90 days]

   WHF, worsening heart failure

3. Change in NT-proBNP from randomization to 48 hours [Evaluated at 48 hours after randomization]

4. Diuretic response, calculated as urine output achieved by loop diuretics (40 mg intravenous furosemide-equivalent dose) at 48 h after treatment initiation [Evaluated at 48 hours after randomization]

5. Improvement in KCCQ-TSS of ≥5 points from randomization to 30 and 90 days after treatment initiation [Up to 90 days]

   KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire - Total Symptom Score. The scores range from 0 to 100, with 100 being the best possible score.

6. Time to hemodynamic stabilization during index hospitalization [During index hospitalization]

7. Re-worsening of heart failure during index hospitalization [During index hospitalization]

8. Heart failure rehospitalization [Up to 90 days]

9. Death [Up to 90 days]

10. Urine output during the 48 h after randomization [Evaluated at 48 hours after randomization]

11. Cardiovascular death [Up to 90 days]

12. Change in the visual analog scale score for dyspnea from after randomization to 24 and 48 h [Evaluated at 24 and 48 hours after randomization]

    The scores range from 0 to 100, with 100 being the best possible score.

13. Change in high sensitivity cardiac troponin T [Evaluated at 48 hours after randomization]

14. Change in the KCCQ-TSS after randomization to 30 and 90 days [Up to 90 days]

    KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire - Total Symptom Score. The scores range from 0 to 100, with 100 being the best possible score.

15. Composite of renal replacement therapy, renal transplantation, eGFR <15 mL/min/1.73m2, ≥50% decrease in eGFR compared to the first sample or a ≥2-fold increase in creatinine level compared to the first sample within 90 days of randomization [Up to 90 days]

16. Trend in eGFR after randomization to 24 h, 48 h, 30 days, and 90 days [Up to 90 days]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 89 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Patients who meet the below inclusion criteria will be randomized within 12 h after presentation to the hospital

1. Age of ≥20 and <90 years

2. Hospitalized with a diagnosis of acute heart failure, requiring intravenous loop diuretic therapy, and with all of the following characteristics:

1. Dyspnoea at rest or induced by slight exertion ii. At least two of the following findings: jugular venous distention, pulmonary rales, lower leg edema, and pulmonary congestion on chest X-ray iii. If the patient has a sinus rhythm at the time of admission, BNP ≥350 pg/mL or NT-proBNP ≥1400 pg/mL; if the patient has atrial fibrillation at the time of admission, BNP ≥500 pg/mL or NT-proBNP ≥2000 pg/mL. For patients taking an angiotensin receptor neprilysin inhibitor, only the reference value for NT-proBNP will be applicable.

1. At least one of the following characteristics:

1. eGFR <60 mL/min/1.73m2, as calculated using the CKD Epidemiology Collaboration for JapaneseModification of Diet in Renal Disease formula ii. Already taking ≥40 mg of oral furosemide during the period before hospitalization. For patients on loop diuretics other than furosemide, the following conversion should be used: oral furosemide 20 mg = oral azosemide 30 mg = oral torasemide 5 mg.

1. Urine output of <300 mL during the 2 h following an appropriate dose of intravenous furosemide administered after hospitalization. An appropriate dose of intravenous furosemide is 20 mg for patients who have not been taking furosemide regularly before hospitalization and is the same as, or greater than, the daily oral dose for patients who have been taking furosemide regularly before hospitalization.

1. Provided written consent to participate in the study

Exclusion Criteria:

1. eGFR <20 mL/min/1.73m2 at the time of admission

2. Already taking an SGLT2i within 3 months prior to hospitalization

3. Type 1 diabetes mellitus

4. Systolic blood pressure <90 mmHg

5. Expected to newly require treatment with thiazide, tolvaptan, or carperitide within 48 h after hospitalization

6. Main cause of acute heart failure hospitalization is not fluid retention (e.g., persistent ventricular tachycardia, persistent atrial fibrillation/atrial flutter with a ventricular response rate of ≥130 bpm, persistent bradycardia with a ventricular response rate of <45 bpm, an infection, severe anemia, and an acute exacerbation of COPD)

7. Acute coronary syndrome, pulmonary thromboembolism, or a cerebrovascular accident is the main cause of the present hospitalization.

8. At risk of ketoacidosis or hyperosmolar hyperglycaemia

9. On dialysis, including peritoneal dialysis, or the initiation of dialysis during hospitalization is planned

10. Pregnant or lactating women

11. Underwent the following therapeutic interventions within 30 days: cardiovascular surgery (e.g., coronary artery bypass grafting, surgery for valvular heart disease, transcatheter aortic valve implantation, percutaneous coronary intervention, percutaneous edge-to-edge mitral valve repair, and other types of surgery at the investigator's discretion) and implantation of an implantable defibrillator, cardiac resynchronization therapy defibrillator, or implantable ventricular-assist device

12. A diagnosis of acute coronary syndrome, cerebral infarction, or transient ischemic attack made within 90 days

13. Ventricular tachycardia with syncope within 90 days

14. Heart transplant recipient or listed for heart transplantation and expected to undergo transplantation during the present treatment; implanted with an implantable ventricular-assist device or expected to require an implantable ventricular-assist device during the present treatment; or expected to switch to palliative care

15. Intubated at the time of screening or expected to require intubation within 48 h after hospitalization

16. Severe valvular heart disease expected to be treated with thoracostomy or catheterization (a reason to exclude secondary mitral or tricuspid regurgitation due to reduced cardiac function does not exist, except for the absence of a plan to perform cardiac surgery or therapeutic catheterization)

17. A diagnosis of secondary cardiomyopathy such as amyloidosis, cardiac sarcoidosis, hemochromatosis, Fabry disease, and muscular dystrophy.

18. Heart failure due to takotsubo cardiomyopathy, obstructive hypertrophic cardiomyopathy, complex congenital heart disease (as determined by the investigator), or pericardial constriction.

19. A diagnosis of peripartum cardiomyopathy made within 6 months

20. Active myocarditis

21. Presence of uncontrolled thyroid disease

22. Acute cardiac structural abnormalities (e.g., acute mitral regurgitation due to ruptured chordae tendineae)

23. Symptomatic bradycardia or complete atrioventricular block, being treated with a temporary pacemaker implantation at the time of admission, or expected to require a temporary pacemaker implantation in the future. Patients who have already been treated with a permanent pacemaker implantation do not meet the exclusion criteria.

24. Serious liver disorder (an increase in AST, ALT, or ALP level ≥3 times the upper limit of normal) or cirrhosis with varices or other findings suggestive of portal hypertension

25. Alcohol use disorder of at least mild severity according to the DSM-V

26. A diagnosis of active malignancy or suspected active malignancy made within 2 years

27. Coexisting diseases other than heart failure with an expected survival prognosis of ≤1 year

28. Participation in a clinical study of another drug 30 days before hospitalization

29. Other conditions likely to interfere with the patient's safety or compliance with the protocol

30. Other patients who are considered unsuitable by the principal investigator or other investigators

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Anjo Kosei Hospital	Anjo	Aichi	Japan
2	Nagoya University Hospital	Nagoya	Aichi	Japan
3	Hirosaki University Hospital	Hirosaki	Aomori	Japan
4	Hyogo Prefectural Awaji Medical Center	Sumoto	Awaji	Japan
5	Funabashi Municipal Medical Center	Funabashi	Chiba	Japan
6	Kameda Medical Center	Kamogawa	Chiba	Japan
7	Juntendo University Urayasu Hospital	Urayasu	Chiba	Japan
8	Fukuokaken Saiseikai Futsukaichi Hospital	Chikushino	Fukuoka	Japan
9	Kurume University Hospital	Kurume	Fukuoka	Japan
10	Gunma University Hospital	Maebashi	Gunma	Japan
11	Sapporo Higashi Tokushukai Hospital	Sapporo	Hokkaido	Japan
12	Hyogo Brain and Heart Center	Himeji	Hyogo	Japan
13	Tsuchiura Kyodo General Hospital	Tsuchiura	Ibaraki	Japan
14	Iwate Prefectural Cyuou Hospital	Morioka	Iwate	Japan
15	Tokai University Hospital	Isehara	Kanagawa	Japan
16	St.Marianna University School of Medicine Hospital	Kawasaki	Kanagawa	Japan
17	Kochi Medical School Hospital	Nankoku	Kochi	Japan
18	Nara Medical University Hospital	Kashihara	Nara	Japan
19	Urasoe General Hospital	Urasoe	Okinawa	Japan
20	Kindai University Hospital	Osakasayama	Osaka	Japan
21	National Cerebral and Cardiovascular Center Hospital	Suita	Osaka	Japan
22	Kasukabe Chuo General Hospital	Kasukabe	Saitama	Japan
23	Kawaguchi Cardiovascular and Respiratory Hospital	Kawaguchi	Saitama	Japan
24	Juntendo University Shizuoka Hospital	Izunokuni	Shizuoka	Japan
25	Saiseikai Utsunomiya Hospital	Utsunomiya	Tochigi	Japan
26	Nishiarai Hospital	Adachi	Tokyo	Japan
27	Tokyo Metropolitan Bokutoh Hospital	Bokutoh	Tokyo	Japan
28	Mitsui Memorial Hospital	Chiyoda	Tokyo	Japan
29	Sakakibara Heart Institute	Fuchū	Tokyo	Japan
30	Tokyo Medical University Hachioji Medical Center	Hachiōji	Tokyo	Japan
31	International University of Health and Welfare Mita Hospital	Minato	Tokyo	Japan
32	Toranomon Hospital	Minato	Tokyo	Japan
33	Juntendo University Nerima Hospital	Nerima	Tokyo	Japan
34	Tokyo Women's Medical University Hospital	Shinjuku	Tokyo	Japan
35	National Disaster Medical Center	Tachikawa	Tokyo	Japan
36	Japanese Red Cross Fukuoka Hospital	Fukuoka		Japan
37	Hiroshima City Hospital	Hiroshima		Japan
38	Chikamori Hospital	Kochi		Japan
39	Nara Prefecture General Medical Center	Nara		Japan
40	Sakakibara Heart Institute of Okayama	Okayama		Japan
41	Nakagami Hospital	Okinawa		Japan
42	Kitano Hospital	Osaka		Japan
43	Osaka General Medical Center	Osaka		Japan
44	Saitama Citizens Medical Center	Saitama		Japan
45	Tokushima University Hospital	Tokushima		Japan
46	Juntendo University Hospital	Tokyo		Japan
47	Yokohama City University Medical Center	Yokohama		Japan

Sponsors and Collaborators

• Juntendo University
• Boehringer Ingelheim

Investigators

• Principal Investigator: Yuya Matsue, MD, Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Yuya Matsue, Associate Professor, Juntendo University
• ClinicalTrials.gov Identifier: NCT05392764
• Other Study ID Numbers: jRCTs031210682
• First Posted: May 26, 2022
• Last Update Posted: Aug 10, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Heart Failure; Empagliflozin

Study Results

No Results Posted as of Aug 10, 2022