Triple Combination Therapy (ARNI, SGLT2i, MRA) in Advanced HFpEF

NCT ID: NCT06655480

Last Updated: 2025-02-19

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-03-18
• Study Completion Date: 2026-12-31

Brief Summary

Patients with advanced heart failure with preserved ejection fraction (HFpEF) will be randomly assigned in open-label multicenter study to receive triple combination therapy with [angiotensin receptor/neprilysin inhibitor [ARNI] + sodium-glucose cotransporter 2 inhibitor [SGLTi] + mineralocorticoid receptor antagonist [MRA]) or with individualized medical therapy [SGLTi + renin-angiotensin system inhibitor [RASi] [angiotensin receptor blocker [ARB] or angiotensin-converting enzyme inhibitor [ACE-I]), and will be treated for 52 weeks

Detailed Description

HFpEF has a significant morbidity and mortality, and the therapeutic options for HFpEF are limited. According to the results of clinical HFpEF trials, SGLTis and MRA can improve prognosis (EMPEROR-preserved, DELIVER, FINEARTS-HF trials); and ARNI can reduce the risk of hospitalization due to exacerbation of heart failure (PARAGON-HF trial). There is also clinical and experimental evidence of anti-inflammatory and antifibrotic effects in SGLTi, MRA and ARNI. However, there are currently no randomized clinical trials evaluating the efficacy of the combination therapy with all these drugs in HFpEF. The investigators suppose that triple combination therapy with [ARNI + SGLTi + AMR] in HFpEF will have a pronounced, rapid and safe positive clinical and haemodynamic effect primarily through its effect on fibrosis and inflammation in patients with HFpEF.

Conditions

HFpEF; LVDD; Myocardial Fibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

[ARNI + SGLTi + AMR]

Patients will receive combination therapy with ARNI, gliflozin and AMR

Group Type: EXPERIMENTAL

[ARNI + SGLTi + AMR]

Intervention Type: DRUG

Empagliflozin 10mg tablet, Valsartan+Sacubitril 100-200-400 mg tablet, Finerenone 20-40 mg tablet

[SGLTi + previously taken RAAS blocker]

Patients will receive combination therapy with gliflozin and previously taken RAAS blocker

Group Type: ACTIVE_COMPARATOR

[SGLTi + previously taken RAAS blocker]

Intervention Type: DRUG

Empagliflozin 10mg tablet, previously taken RAAS inhibitor

Interventions

[ARNI + SGLTi + AMR]

Empagliflozin 10mg tablet, Valsartan+Sacubitril 100-200-400 mg tablet, Finerenone 20-40 mg tablet

Intervention Type: DRUG

[SGLTi + previously taken RAAS blocker]

Empagliflozin 10mg tablet, previously taken RAAS inhibitor

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Signed and data informed consent;

2. Symptoms and signs of HF;

3. LV ejection fraction > 50%;

4. NT-proBNP > 300 pg/mL (for patients with atrial fibrillation NT-proBNP > 900 pg/mL)

5. LV diastolic dysfunction II-III grade OR

LV diastolic dysfunction I grade and at least 2 out of 4:

• Е/е' > 14
• LAVi > 34 ml/m2 (for those with persistent atrial fibrillation > 40 ml/m2)
• PASP > 35 mm Hg or TR velocity > 2.8 m/sec
• LV mass index > 95 g/m2 for women / > 115 g/m2 for men or LV interventricular septum or posterior wall thickness ≥ 1.1 sm OR

Chronic atrial fibrillation and at least 3 out of 4:

• Е/е' > 11
• E-wave velocity > 100 sm/s
• TR velocity > 2.8 sm/s
• DT ≤ 160 ms

Exclusion Criteria

1. Evidence of myocardial ischemia during stress echocardiography;

2. Significant lesions of main coronary arteries;

3. Atrial fibrillation with resting HR > 110 beats/min;

4. Continuous (>90 days) treatment with ARNI, SGLTi and/or AMR within 12 months prior to screening. The last administration of these drugs must be at least 30 days prior to randomization. Treatment with these drugs should not be interrupted for the purpose of inclusion in the study.

5. Coronary bypass surgery, stroke or TIA within the last 3 months of screening;

6. Myocardial infarction or myocardial revascularization within the last 3 months of screening;

7. Systolic blood pressure < 90 mmHg or ≥ 180 mmHg at screening or randomization;

8. Genetic forms of HFpEF (HCM, amyloidosis, Fabry disease, glycogen storage diseases etc.);

9. Peripartum cardiomyopathy, chemotherapy-induced cardiomyopathy, viral myocarditis, isolated right-sided HF without left-sided structural disease, constrictive pericarditis, significant pericardial effusion;

10. Dyspnea due to non-cardiac causes such as pulmonary disease, anemia, severe obesity, primary valvular, or myocardial diseases;

11. Significant lung disease (severe lung disease requiring home oxygen or chronic oral steroid therapy);

12. Primary pulmonary artery hypertension;

13. Significant left sided structural valve disease;

14. Anemia (Hb < 100 g/L);

15. Obesity (body mass index > 50 kg/m2);

16. Impaired renal function, defined as estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (CKD-EPI);

17. Impaired liver function (serum levels of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 × upper limit of normal);

18. Addison's disease;

19. Known hypersensitivity to medications used the in the study;

20. Non-cardiac conditions that complicate/exclude participation in the study;

21. Diseases associated with isolated LV insufficiency (idiopathic pulmonary hypertension, chronic thromboembolic pulmonary hypertension, etc.);

22. Serum/plasma potassium >5.0 mmol/L at screening or randomization or a history of hyperkalemia or acute renal failure during AMR treatment for >7 consecutive days leading to discontinuation of AMR treatment.

23. For patients with diabetes mellitus:

• Type 1 diabetes mellitus;
• Presence of more than 4 episodes of moderate hypoglycemia within the past month or at least one episode of severe hypoglycemia within the past year;
• Glycated hemoglobin level > 9% or <6%

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Lomonosov Moscow State University Medical Center

UNKNOWN

Sponsor Role: collaborator

National Medical Research Center for Cardiology, Ministry of Health of Russian Federation

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Central Contacts

Artem G Ovchinnikov, MD, PhD, DSc

Role: CONTACT

artcardio@mail.ru

+74954146612

Other Identifiers

124020200111-6

Identifier Type: -

Identifier Source: org_study_id