ARNI Versus plAcebo in Patients With Congenital sYStemic Right Ventricle Heart Failure

NCT05117736 | Terminated DMC

• 1 other identifier: ICM 2021-2942
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a prospective monocentric, randomized, double-blind, placebo-controlled, crossover clinical trial to assess the efficacy of Sacubitril/Valsartan over placebo in improving exercise capacity and neurohormonal activation in adults with moderate to severe systemic RV dysfunction and NYHA class II or III symptoms.

Conditions

Systemic Right Ventricle; Heart Failure

Outcome Measures

Primary Outcomes (2)

• Change of sub-maximal total exercise duration

  Co-primary endpoint (each at an alpha of 0.025): change in sub-maximal total exercise duration during a sub-maximal cardiopulmonary exercise testing between baseline and end of each treatment arm.

  End of each arm treatment at 32 weeks and 58 weeks.

• Change of NT-proBNP level

  Co-primary endpoint (each at an alpha of 0.025): Change in NT-proBNP level between baseline and end of each treatment arm.

  End of each arm treatment at 32 weeks and 58 weeks.

Secondary Outcomes (2)

• Change of quality of life measured by Kansas City Cardiomyopathy Questionnaire-12 Score

  End of each arm treatment at 32 weeks and 58 weeks.

• Change of number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  Half-way of each arm at 20 and 46 weeks and end of each arm treatment at 32 weeks and 58 weeks.

Other Outcomes (5)

• Change of NYHA functional class

  End of each arm treatment at 32 weeks and 58 weeks.

• Number of participants with serious cardiac clinical events

  Up to 58 weeks

• Change of hs troponin-T level

  End of each arm treatment at 32 weeks and 58 weeks.

Study Arms (2)

Sacubitril/Valsartan

EXPERIMENTAL

Treatment with Sacubitril/Valsartan

Drug: Sacubitril / Valsartan Oral Tablet

Placebo

PLACEBO COMPARATOR

Treatment with Placebo

Drug: Placebo

Interventions

Sacubitril / Valsartan Oral Tablet DRUG

For the first phase of the trial, each patient will be randomized to active therapy (50, 100, or 200 mg bid of Sacubitril/Valsartan based on the run-in phase) or the corresponding placebo (matching tablets for the 50,100 or 200mg of Sacubitril/Valsartan), with the sequence reversed in the second phase.

Also known as: Entresto, ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR (ARNI)

Sacubitril/Valsartan

Placebo DRUG

Corresponding placebo: matching tablets for the 50,100 or 200mg of Sacubitril/Valsartan.

Placebo

Eligibility Criteria

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

You may qualify if:

• Age \> or egal18 years with clinical follow-up at the Montreal Heart Institute Adult Congenital Heart Center
• Systemic right ventricle (transposition of great vessels and atrial switch or congenitally corrected transposition of great vessels)
• Moderate to severe systemic right ventricle dysfunction by transthoracic echocardiography (TTE) or right ventricle ejection fraction (RVEF) \<40% by MRI
• NYHA Functional class II-III symptoms or peak exercise capacity \<80% of predicted on a previous standard treadmill exercise stress test (usually done every two years in our congenital clinic).
• Ability to provide informed consent to the study
• Access or own a telephone and/or access to internet connection for teleconference call
• Own a mailing address to receive the medication by post (FedEx or Dicom)
• Able to perform self-measurement of the blood pressure using Upper Arm Digital Blood Pressure Monitor as recommended by Hypertension Canada.

You may not qualify if:

• Participation in a clinical trial of an investigational drug, concurrently, or within the last 30 days prior enrolment
• Planned cardiac surgery (e.g., severe tricuspid regurgitation with planned tricuspid valve replacement or repair)
• Previous cardiac transplantation, or on heart transplant wait list
• Myocardial infarction, stroke, or open-heart surgery in the previous 4 weeks
• NYHA Functional class I or IV symptoms
• Symptomatic hypotension (fainting, dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, and headache) with a systolic blood pressure \<100 mmHg at screening, or asymptomatic \<90 mmHg at screening
• eGFR \<30 mL/min/1.73 m2
• Reduction in eGFR \>35% from screening to randomization
• Potassium \>5.2 mmol/L at screening or \>5.4 mmol/L at randomization
• Known history of angioedema related to previous ACEI or ARB therapy or patients with a history of hereditary or idiopathic angioedema.
• Patients who require concomitant treatment with an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) or a renin inhibitor for other indication than heart failure
• Evidence of hepatic disease as determined by any one of the following: serum glutamate oxaloacetate transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) values exceeding 3x upper limit of normal, bilirubin \>1.5 mg/dl at screening.
• Unacceptable side effects with ACE-inhibitors or ARBs
• Patient known with bilateral renal artery stenosis
• Cyanosis; substantial left-to-right shunting (Qp/Qs \>1.5); severe mitral, aortic, or pulmonary regurgitation; systemic or pulmonary inflow obstruction with a peak velocity \>1.5 m/s by transthoracic echocardiography; and severe outflow tract obstruction with a peak systolic gradient \>80 mm Hg.

Sponsors & Collaborators

• Montreal Heart Institute: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

Montreal Heart Institute

Montreal, Quebec, H1T1C8, Canada

Location

Related Publications (11)

• Brida M, Diller GP, Gatzoulis MA. Systemic Right Ventricle in Adults With Congenital Heart Disease: Anatomic and Phenotypic Spectrum and Current Approach to Management. Circulation. 2018 Jan 30;137(5):508-518. doi: 10.1161/CIRCULATIONAHA.117.031544.

  PMID: 29378757 BACKGROUND

• Dore A, Houde C, Chan KL, Ducharme A, Khairy P, Juneau M, Marcotte F, Mercier LA. Angiotensin receptor blockade and exercise capacity in adults with systemic right ventricles: a multicenter, randomized, placebo-controlled clinical trial. Circulation. 2005 Oct 18;112(16):2411-6. doi: 10.1161/CIRCULATIONAHA.105.543470. Epub 2005 Oct 10.

  PMID: 16216961 BACKGROUND

• van der Bom T, Winter MM, Bouma BJ, Groenink M, Vliegen HW, Pieper PG, van Dijk AP, Sieswerda GT, Roos-Hesselink JW, Zwinderman AH, Mulder BJ. Effect of valsartan on systemic right ventricular function: a double-blind, randomized, placebo-controlled pilot trial. Circulation. 2013 Jan 22;127(3):322-30. doi: 10.1161/CIRCULATIONAHA.112.135392. Epub 2012 Dec 17.

  PMID: 23247302 BACKGROUND

• Zaragoza-Macias E, Zaidi AN, Dendukuri N, Marelli A. Medical Therapy for Systemic Right Ventricles: A Systematic Review (Part 1) for the 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Apr 2;139(14):e801-e813. doi: 10.1161/CIR.0000000000000604.

  PMID: 30586770 BACKGROUND

• Reddy S, Bernstein D. Molecular Mechanisms of Right Ventricular Failure. Circulation. 2015 Nov 3;132(18):1734-42. doi: 10.1161/CIRCULATIONAHA.114.012975.

  PMID: 26527692 BACKGROUND

• Lluri G, Lin J, Reardon L, Miner P, Whalen K, Aboulhosn J. Early Experience With Sacubitril/Valsartan in Adult Patients With Congenital Heart Disease. World J Pediatr Congenit Heart Surg. 2019 May;10(3):292-295. doi: 10.1177/2150135119825599.

  PMID: 31084317 BACKGROUND

• Appadurai V, Thoreau J, Malpas T, Nicolae M. Sacubitril/Valsartan in Adult Congenital Heart Disease Patients With Chronic Heart Failure - A Single Centre Case Series and Call for an International Registry. Heart Lung Circ. 2020 Jan;29(1):137-141. doi: 10.1016/j.hlc.2018.12.003. Epub 2018 Dec 17.

  PMID: 30686641 BACKGROUND

• Maurer SJ, Pujol Salvador C, Schiele S, Hager A, Ewert P, Tutarel O. Sacubitril/valsartan for heart failure in adults with complex congenital heart disease. Int J Cardiol. 2020 Feb 1;300:137-140. doi: 10.1016/j.ijcard.2019.06.031. Epub 2019 Jun 13.

  PMID: 31242968 BACKGROUND

• Zandstra TE, Nederend M, Jongbloed MRM, Kies P, Vliegen HW, Bouma BJ, Tops LF, Schalij MJ, Egorova AD. Sacubitril/valsartan in the treatment of systemic right ventricular failure. Heart. 2021 Nov;107(21):1725-1730. doi: 10.1136/heartjnl-2020-318074. Epub 2021 Jan 15.

  PMID: 33452121 BACKGROUND

• Therrien J, Provost Y, Harrison J, Connelly M, Kaemmerer H, Webb GD. Effect of angiotensin receptor blockade on systemic right ventricular function and size: a small, randomized, placebo-controlled study. Int J Cardiol. 2008 Sep 26;129(2):187-92. doi: 10.1016/j.ijcard.2008.04.056. Epub 2008 Jul 30.

  PMID: 18672299 BACKGROUND

• Ezekowitz JA, O'Meara E, McDonald MA, Abrams H, Chan M, Ducharme A, Giannetti N, Grzeslo A, Hamilton PG, Heckman GA, Howlett JG, Koshman SL, Lepage S, McKelvie RS, Moe GW, Rajda M, Swiggum E, Virani SA, Zieroth S, Al-Hesayen A, Cohen-Solal A, D'Astous M, De S, Estrella-Holder E, Fremes S, Green L, Haddad H, Harkness K, Hernandez AF, Kouz S, LeBlanc MH, Masoudi FA, Ross HJ, Roussin A, Sussex B. 2017 Comprehensive Update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure. Can J Cardiol. 2017 Nov;33(11):1342-1433. doi: 10.1016/j.cjca.2017.08.022. Epub 2017 Sep 6.

  PMID: 29111106 BACKGROUND

MeSH Terms

Conditions

Heart Failure

Interventions

sacubitril and valsartan sodium hydrate drug combination

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Study Officials

• Marie-A. Chaix, MD

  Montreal Heart Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: A randomization sequence list will be performed by the statistical department. Patients will be randomized according to a computer-generated randomization sequence with 1:1 distribution using randomly permuted blocks of 4 and 6.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, Clinical Professor

Model Details: This study is a prospective monocentric, randomized, double-blind, placebo-controlled, crossover clinical trial.

Study Record Dates

• First Submitted: September 24, 2021
• First Posted: November 11, 2021
• Study Start: March 15, 2022
• Primary Completion: March 1, 2023
• Study Completion: March 12, 2023
• Last Updated: March 13, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)