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

Study Overview
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Brief Summary
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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.

Detailed Description
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Subjects who qualify will be approached and those consenting will be enrolled to undergo a baseline evaluation. An active run-in-phase of 6 weeks will identify each patient's maximal tolerated dose of Sacubitril/Valsartan. Then, each treatment arm (Sacubitril/Valsartan and placebo) will be 24 weeks duration prior to crossover. At the end of each study arm (24 weeks), data regarding primary and secondary endpoints will be collected. The total duration of the study for the patient will be 15 months. Subjects will undergo regular visits (in-clinic, and/or by phone, or video conferencing) half-way and at the end of each arms.

Official Title
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Prospective Comparison of ARNI Versus plAcebo in Patients With Congenital sYStemic Right Ventricle Heart Failure

Conditions
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Systemic Right Ventricle, Heart Failure

Intervention / Treatment
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* Drug: Sacubitril / Valsartan Oral Tablet
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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. Inability to provide informed consent Unable to exercice Pregnant or planned pregnancy during the study Breastfeeding Severe pulmonary hypertension defined as pulmonary pressure egal or superior to systemic pressure

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This study is a prospective monocentric, randomized, double-blind, placebo-controlled, crossover clinical trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sacubitril/Valsartan<br>Treatment with Sacubitril/Valsartan | Drug: Sacubitril / Valsartan Oral Tablet<br>* 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.<br>* Other names: ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR (ARNI);|
| Placebo Comparator: Placebo<br>Treatment with Placebo | Drug: Placebo<br>* Corresponding placebo: matching tablets for the 50,100 or 200mg of Sacubitril/Valsartan.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of quality of life measured by Kansas City Cardiomyopathy Questionnaire-12 Score | Kansas City Cardiomyopathy Questionnaire-12 Score (KCCQ-12 score) has 4 domains (Physical Limitation Score, Symptom Frequency Score, Quality of Life Score, Social Limitation Score) and one Summary Score. Scores are scaled 0-100, where 0 denotes the lowest reportable health status and 100 the highest. | 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 | Serum potassium level, renal function Serum Creatinine (sCr), estimated Glomerular Filtration Rate (eGFR), blood pressure, adverse clinical events: symptomatic postural hypotension reported by the patient at the examination as fainting, dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, and headache upon standing, occurrence of angioedema. | Half-way of each arm at 20 and 46 weeks and end of each arm treatment at 32 weeks and 58 weeks. |