Systemic Right Ventricle, Heart Failure
Conditions
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.
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.
Interventions
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.
DRUGPlacebo
Corresponding placebo: matching tablets for the 50,100 or 200mg of Sacubitril/Valsartan.
Sponsors
Novartis Pharmaceuticals
Montreal Heart Institute
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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.
Intervention model description
This study is a prospective monocentric, randomized, double-blind, placebo-controlled, crossover clinical trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| Change of NYHA functional class | End of each arm treatment at 32 weeks and 58 weeks. | Evaluation of NYHA functional class |
| 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. |
| 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. |
| Change of hs troponin-T level | End of each arm treatment at 32 weeks and 58 weeks. | Measure of hs troponin-T blood level. |
| 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. |
Countries
Canada
Outcome results
None listed