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

Sponsor
Montreal Heart Institute (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05117736
Collaborator
Novartis Pharmaceuticals (Industry)
48
Enrollment
2
Arms
35.9
Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or DiseaseIntervention/TreatmentPhase
  • Drug: Sacubitril / Valsartan Oral Tablet
  • Drug: Placebo
N/A

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 Design

Study Type:
Interventional
Anticipated Enrollment :
48 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Intervention Model Description:
This study is a prospective monocentric, randomized, double-blind, placebo-controlled, crossover clinical trial.This study is a prospective monocentric, randomized, double-blind, placebo-controlled, crossover clinical trial.
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
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.
Primary Purpose:
Treatment
Official Title:
Prospective Comparison of ARNI Versus plAcebo in Patients With Congenital sYStemic Right Ventricle Heart Failure
Anticipated Study Start Date :
Nov 15, 2021
Anticipated Primary Completion Date :
Nov 1, 2023
Anticipated Study Completion Date :
Nov 12, 2024

Arms and Interventions

ArmIntervention/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.

    Outcome Measures

    Primary Outcome Measures

    1. Change of sub-maximal total exercise duration [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.

    2. Change of NT-proBNP level [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.

    Secondary Outcome Measures

    1. Change of quality of life measured by Kansas City Cardiomyopathy Questionnaire-12 Score [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.

    2. 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.]

      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.

    Other Outcome Measures

    1. Change of NYHA functional class [End of each arm treatment at 32 weeks and 58 weeks.]

      Evaluation of NYHA functional class

    2. Number of participants with serious cardiac clinical events [Up to 58 weeks]

      Hospitalizations for heart failure, symptomatic and clinically significant arrhythmia (supra-ventricular and ventricular), mortality.

    3. Change of hs troponin-T level [End of each arm treatment at 32 weeks and 58 weeks.]

      Measure of hs troponin-T blood level.

    4. Change of systemic right ventricle size and function by echocardiographic evaluation [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.

    5. Change of cardiopulmonary exercise test [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Montreal Heart Institute
    • Novartis Pharmaceuticals

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Marie-Alexandre Chaix, Principal Investigator, Clinical Professor, Montreal Heart Institute
    ClinicalTrials.gov Identifier:
    NCT05117736
    Other Study ID Numbers:
    • ICM 2021-2942
    First Posted:
    Nov 11, 2021
    Last Update Posted:
    Nov 22, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    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
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Nov 22, 2021