ARNI Versus plAcebo in Patients With Congenital sYStemic Right Ventricle Heart Failure (PARACYS-RV)

March 11, 2024 updated by: Marie-Alexandre Chaix, Montreal Heart Institute

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

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

15

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Quebec
      • Montreal, Quebec, Canada, H1T1C8
        • Montreal Heart Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Sacubitril/Valsartan
Treatment with Sacubitril/Valsartan
Drug: Sacubitril / Valsartan Oral Tablet
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.
Other Names:
  • Entresto
  • ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR (ARNI)
Placebo Comparator: Placebo
Treatment with Placebo
Drug: Placebo
Corresponding placebo: matching tablets for the 50,100 or 200mg of Sacubitril/Valsartan.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of sub-maximal total exercise duration
Time Frame: End of each arm treatment at 32 weeks and 58 weeks.
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
Time Frame: End of each arm treatment at 32 weeks and 58 weeks.
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
Time Frame: End of each arm treatment at 32 weeks and 58 weeks.
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
Time Frame: Half-way of each arm at 20 and 46 weeks and end of each arm treatment at 32 weeks and 58 weeks.
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.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of NYHA functional class
Time Frame: End of each arm treatment at 32 weeks and 58 weeks.
Evaluation of NYHA functional class
End of each arm treatment at 32 weeks and 58 weeks.
Number of participants with serious cardiac clinical events
Time Frame: Up to 58 weeks
Hospitalizations for heart failure, symptomatic and clinically significant arrhythmia (supra-ventricular and ventricular), mortality.
Up to 58 weeks
Change of hs troponin-T level
Time Frame: End of each arm treatment at 32 weeks and 58 weeks.
Measure of hs troponin-T blood level.
End of each arm treatment at 32 weeks and 58 weeks.
Change of systemic right ventricle size and function by echocardiographic evaluation
Time Frame: End of each arm treatment at 32 weeks and 58 weeks.
Measure of TAPSe, S'wave, fractional area change, global longitudinal strain, end diastolic area, end systolic area and evaluation of tricuspid regurgitation during transthoracic echocardiogram.
End of each arm treatment at 32 weeks and 58 weeks.
Change of cardiopulmonary exercise test
Time Frame: End of each arm treatment at 32 weeks and 58 weeks.
Measure of anaerobic threshold, functional capacity METs, heart rate response, blood pressure response, oxygen saturation response during exercise, respiratory exchange ratio VE/VO2 slope, VE/VCO2 slope.
End of each arm treatment at 32 weeks and 58 weeks.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Montreal Heart Institute

Collaborators

Novartis Pharmaceuticals

Investigators

  • Principal Investigator: Marie-A. Chaix, MD, Montreal Heart Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 15, 2022

Primary Completion (Actual)

March 1, 2023

Study Completion (Actual)

March 12, 2023

Study Registration Dates

First Submitted

September 24, 2021

First Submitted That Met QC Criteria

November 2, 2021

First Posted (Actual)

November 11, 2021

Study Record Updates

Last Update Posted (Actual)

March 13, 2024

Last Update Submitted That Met QC Criteria

March 11, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ICM 2021-2942

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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