" Evaluation of Safety and Efficacy of Empagliflozin and Sacubitril/Valsartan for CHF With Reduced Ejection Fraction in ACHD "

NCT05580510 | Unknown Phase 2 DMC

• 1 other identifier: 22-1333
• Study Type: interventional
• Target: 160
• Locations: 1 country
• Sites: 1

Brief Summary

The treatment of adult patients with congenital heart disease (ACHD) and heart failure (HF) represents a great challenge since, to date, there is no standardized guideline for this specific population. Although new treatments for HF have been proposed, such as Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors and neprilisin and angiotensin receptor inhibitors, the benefit of these drugs in patients with HF associated with congenital heart disease in adults has not yet been demonstrated. For this reason, this study pretends to evaluate the efficacy of empagliflozin and sacubitril/valsartan in this population.

Conditions

Congenital Heart Disease; Heart Failure; Heart Failure With Reduced Ejection Fraction

Keywords

Adult congenital heart disease; Heart Failure with Reduced Ejection Fraction; Empagliflozin; Sacubitril-valsartan

Outcome Measures

Primary Outcomes (2)

• 3D echocardiographic systemic ventricular end-diastolic volume index

  Change of 8.2 ml or greater in systemic ventricular end-diastolic volume index measured by 3D echocardiogram.

  Twelve weeks

• 3D echocardiographic systemic ventricular end-systolic volume index

  Change of 6.0 ml or greater in end-systolic volume index measured by 3D echocardiogram.

  Twelve weeks

Secondary Outcomes (7)

• Functional class

  Twelve weeks

• Pulmonary congestion

  Twelve weeks

• 6-minute walking test

  Twelve weeks

• Echocardiographic ejection fraction from the systemic ventricle

  Twelve weeks

• Echocardiographic longitudinal overall strain

  Twelve weeks

Study Arms (3)

Conventional treatment of Heart failure and Sacubitril/Valsartan

ACTIVE COMPARATOR

Patients will receive conventional treatment consisting of spironolactone 25 mg orally every 24 hours (maximum dose 50 mg every 24 hours) or eplerenone 25 mg orally every 24 hours (maximum dose 50 mg every 24 hours); beta-blockers: bisoprolol 1.5 mg orally every 24 hours (maximum dose 10 mg every 24 hours) or metoprolol succinate 12.5 mg every 24 hours orally (maximum dose 200 mg every 24 hours) or carvedilol 3125 mg every 24 hours (maximum dose 25 mg every 24 hours) or ivabradine 5 mg every 12 hours (maximum dose 7.5 mg every 12 hours); diuretics: furosemide 20 to 400 mg orally every 24 hours or bumetanide 1 to 15 mg orally every 24 hours and/or chlorthalidone 25 mg orally every 24 hours. Additionally, patients will receive Sacubitril/Valsartan, with the intention to titrate up to 49 mg/51 mg orally every 12 hours.

Drug: Sacubitril 49 MG / Valsartan 51 MG [Entresto] BID

Conventional treatment plus Empagliflozin and Sacubitril/valsartan

EXPERIMENTAL

Patients will receive conventional treatment consisting of spironolactone 25 mg orally every 24 hours (maximum dose 50 mg every 24 hours) or eplerenone 25 mg orally every 24 hours (maximum dose 50 mg every 24 hours); beta-blockers: bisoprolol 1.5 mg orally every 24 hours (maximum dose 10 mg every 24 hours) or metoprolol succinate 12.5 mg every 24 hours orally (maximum dose 200 mg every 24 hours) or carvedilol 3125 mg every 24 hours (maximum dose 25 mg every 24 hours) or ivabradine 5 mg every 12 hours (maximum dose 7.5 mg every 12 hours); diuretics: furosemide 20 to 400 mg orally every 24 hours or bumetanide 1 to 15 mg orally every 24 hours and/or chlorthalidone 25 mg orally every 24 hours. Additionally, patients will use Sacubitril/Valsartan, with the intention to titrate up to 49 mg/51 mg orally every 12 hours and Empagliflozin 10 mg orally every 24 hours.

Drug: Sacubitril 49 MG / Valsartan 51 MG [Entresto] BID; Drug: Empagliflozin 10 MG OD

Conventional treatment plus Empagliflozin

EXPERIMENTAL

Patients will receive conventional treatment consisting of spironolactone 25 mg orally every 24 hours (maximum dose 50 mg every 24 hours) or eplerenone 25 mg orally every 24 hours (maximum dose 50 mg every 24 hours); beta-blockers: bisoprolol 1.5 mg orally every 24 hours (maximum dose 10 mg every 24 hours) or metoprolol succinate 12.5 mg every 24 hours orally (maximum dose 200 mg every 24 hours) or carvedilol 3125 mg every 24 hours (maximum dose 25 mg every 24 hours) or ivabradine 5 mg every 12 hours (maximum dose 7.5 mg every 12 hours); diuretics: furosemide 20 to 400 mg orally every 24 hours or bumetanide 1 to 15 mg orally every 24 hours and/or chlorthalidone 25 mg orally every 24 hours. Additionally, patients will use Empagliflozin 10 mg orally every 24 hours.

Drug: Empagliflozin 10 MG OD

Interventions

Sacubitril 49 MG / Valsartan 51 MG [Entresto] BID DRUG

This group of patients will receive the conventional treatment of heart failure according to the "2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure" and Sacubitril/Valsartan as an active comparator.

Also known as: Entresto

Conventional treatment of Heart failure and Sacubitril/Valsartan; Conventional treatment plus Empagliflozin and Sacubitril/valsartan

Empagliflozin 10 MG OD DRUG

This group of patients will receive the conventional treatment of heart failure according to the "2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure" and Empagliflozin as an experimental drug.

Also known as: Jardiance

Conventional treatment plus Empagliflozin; Conventional treatment plus Empagliflozin and Sacubitril/valsartan

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• NYHA functional class II-IV
• Diagnosis of CHD: repaired, palliated or without previous treatment
• Systemic ventricular ejection fraction \<40%
• Without unplanned hospital admissions within 3 months prior to randomization
• The participant is willing and able to give informed consent for participation in the study

You may not qualify if:

• Pregnant and postpartum women
• Breastfeeding women during the study
• History of drug allergy to any SGLT-2 inhibitor and/or sacubitril/valsartan
• Previous administration of a drug regimen including an SGLT-2 inhibitor and/or sacubitril/valsartan
• Intellectual or physical disability that impedes the subject to perform the 6 minute walk-test
• Patients with any contraindication to SGLT-2 inhibitor and/or sacubitril/valsartan
• Medical history of myocardial infarction, cardiac surgery or fulminant myocarditis within the last three months
• Medical history of type 1 diabetes mellitus
• Medical history of hypertensive crisis in the previous 6-months
• Medical history of cardiogenic shock or heart failure decompensation in the previous 6-months
• Medical history of heart transplantation

Sponsors & Collaborators

• Instituto Nacional de Cardiologia Ignacio Chavez: lead
• Boehringer Ingelheim: collaborator

Study Sites (1)

National Institute of Cardiology Ignacio Chavez

Mexico City, 14080, Mexico

Location

Related Publications (13)

• Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E; PIONEER-HF Investigators. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019 Feb 7;380(6):539-548. doi: 10.1056/NEJMoa1812851. Epub 2018 Nov 11.

  PMID: 30415601 BACKGROUND

• Hu J, Wu Y, Zhou X, Wang X, Jiang W, Huo J, Shan Q. Beneficial Effects of Sacubitril/Valsartan at Low Doses in an Asian Real-World Heart Failure Population. J Cardiovasc Pharmacol. 2020 Oct;76(4):445-451. doi: 10.1097/FJC.0000000000000873.

  PMID: 33030857 BACKGROUND

• McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-3726. doi: 10.1093/eurheartj/ehab368. No abstract available.

  PMID: 34447992 BACKGROUND

• Budts W, Roos-Hesselink J, Radle-Hurst T, Eicken A, McDonagh TA, Lambrinou E, Crespo-Leiro MG, Walker F, Frogoudaki AA. Treatment of heart failure in adult congenital heart disease: a position paper of the Working Group of Grown-Up Congenital Heart Disease and the Heart Failure Association of the European Society of Cardiology. Eur Heart J. 2016 May 7;37(18):1419-27. doi: 10.1093/eurheartj/ehv741. Epub 2016 Jan 18. No abstract available.

  PMID: 26787434 BACKGROUND

• Marelli, A. Gatzoulis, M. Gary, D. Webb, Piers E.F. Daubeney. Adults With Congenital Heart Disease: A Growing Population. Chapter 1 Part I General Principles. Diagnosis and Management of Adult Congenital Heart Disease. (2017): 2-9.

  BACKGROUND

• Stout KK, Broberg CS, Book WM, Cecchin F, Chen JM, Dimopoulos K, Everitt MD, Gatzoulis M, Harris L, Hsu DT, Kuvin JT, Law Y, Martin CM, Murphy AM, Ross HJ, Singh G, Spray TL; American Heart Association Council on Clinical Cardiology, Council on Functional Genomics and Translational Biology, and Council on Cardiovascular Radiology and Imaging. Chronic Heart Failure in Congenital Heart Disease: A Scientific Statement From the American Heart Association. Circulation. 2016 Feb 23;133(8):770-801. doi: 10.1161/CIR.0000000000000352. Epub 2016 Jan 19. No abstract available.

  PMID: 26787728 BACKGROUND

• Konstatinos D. Alonso- González R, D'alto M. Heart Failure, Exercise Intolerance and Physical Training. Chapter 7, Part I General Principles. Diagnosis and Management of Adult Congenital Heart Disease. (2017): 77-87.

  BACKGROUND

• Arnaert S, De Meester P, Troost E, Droogne W, Van Aelst L, Van Cleemput J, Voros G, Gewillig M, Cools B, Moons P, Rega F, Meyns B, Zhang Z, Budts W, Van De Bruaene A. Heart failure related to adult congenital heart disease: prevalence, outcome and risk factors. ESC Heart Fail. 2021 Aug;8(4):2940-2950. doi: 10.1002/ehf2.13378. Epub 2021 May 7.

  PMID: 33960724 BACKGROUND

• Jhund PS, Ponikowski P, Docherty KF, Gasparyan SB, Bohm M, Chiang CE, Desai AS, Howlett J, Kitakaze M, Petrie MC, Verma S, Bengtsson O, Langkilde AM, Sjostrand M, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Sabatine MS, Solomon SD, McMurray JJV. Dapagliflozin and Recurrent Heart Failure Hospitalizations in Heart Failure With Reduced Ejection Fraction: An Analysis of DAPA-HF. Circulation. 2021 May 18;143(20):1962-1972. doi: 10.1161/CIRCULATIONAHA.121.053659. Epub 2021 Apr 9.

  PMID: 33832352 RESULT

• 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.

  PMID: 32865377 RESULT

• Bauersachs J. Heart failure drug treatment: the fantastic four. Eur Heart J. 2021 Feb 11;42(6):681-683. doi: 10.1093/eurheartj/ehaa1012. No abstract available.

  PMID: 33447845 RESULT

• Lee MMY, Brooksbank KJM, Wetherall K, Mangion K, Roditi G, Campbell RT, Berry C, Chong V, Coyle L, Docherty KF, Dreisbach JG, Labinjoh C, Lang NN, Lennie V, McConnachie A, Murphy CL, Petrie CJ, Petrie JR, Speirits IA, Sourbron S, Welsh P, Woodward R, Radjenovic A, Mark PB, McMurray JJV, Jhund PS, Petrie MC, Sattar N. Effect of Empagliflozin on Left Ventricular Volumes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure With Reduced Ejection Fraction (SUGAR-DM-HF). Circulation. 2021 Feb 9;143(6):516-525. doi: 10.1161/CIRCULATIONAHA.120.052186. Epub 2020 Nov 13.

  PMID: 33186500 RESULT

• Nougue H, Pezel T, Picard F, Sadoune M, Arrigo M, Beauvais F, Launay JM, Cohen-Solal A, Vodovar N, Logeart D. Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study. Eur J Heart Fail. 2019 May;21(5):598-605. doi: 10.1002/ejhf.1342. Epub 2018 Dec 6.

  PMID: 30520545 RESULT

MeSH Terms

Conditions

Heart Defects, Congenital; Heart Failure

Interventions

sacubitril; Valsartan; sacubitril and valsartan sodium hydrate drug combination; BID protein, human; empagliflozin

Condition Hierarchy (Ancestors)

Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Study Officials

• Edgar Garcia-Cruz, MD

  National Institute of Cardiology Ignacio Chavez

  PRINCIPAL INVESTIGATOR

• Montserrat Villalobos-Pedroza, MD

  National Institute of Cardiology Ignacio Chavez

  STUDY CHAIR

• Gian Jimenez-Rodriguez, MD

  National Institute of Cardiology Ignacio Chávez

  STUDY CHAIR

• Carlos Guizar-Sanchez, MD

  National Institute of Cardiology Ignacio Chávez

  STUDY DIRECTOR

Central Study Contacts

Edgar Garcia-Cruz, MD

CONTACT

+ 52 55 4340 7152; Edgar.garcia@cardiologia.org.mx

Daniel Manzur-Sandoval, MD

CONTACT

+ 52 55 1291 1916; drdanielmanzur@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open-label randomized clinical trial

Study Record Dates

• First Submitted: October 4, 2022
• First Posted: October 14, 2022
• Study Start: February 6, 2023
• Primary Completion: July 28, 2023
• Study Completion: March 29, 2024
• Last Updated: November 2, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

ME (1)