RESPONDER-HF Trial

Study Overview
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Brief Summary
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Multicenter, Prospective, Randomized, Sham Controlled, Double Blinded Clinical Trial, with; 1:1 randomization

Detailed Description
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Following supine bicycle exercise hemodynamic assessment to verify eligibility, patients are sedated then randomized to the treatment or control group. Patients in both arms will undergo placement of femoral venous access sheath. Patients randomized to the treatment arm will undergo a fluoroscopically and intra-cardiac echocardiography (ICE), or transesophageal echocardiography (TEE) guided trans-septal puncture and Corvia Atrial Shunt implant procedure. Patients randomized to the control arm will undergo ICE from the femoral vein or TEE for examination of the atrial septum and left atrium. Patients will be evaluated at pre-specified time intervals and followed for 5 years. All patients will be unblinded after the 24 month follow up visit.

Official Title
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Re-Evaluation of the Corvia Atrial Shunt Device in a Precision Medicine Trial to Determine Efficacy in Mildly Reduced or Preserved Ejection Fraction (EF) Heart Failure (Protocol #2201)

Conditions
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Heart Failure, Heart Failure, Diastolic

Intervention / Treatment
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* Device: Corvia Atrial Shunt System / IASD System II
* Other: Intra-cardiac echocardiography (ICE), or transesophageal echocardiography (TEE)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic symptomatic heart failure (HF) documented by the following: Symptoms of HF requiring current treatment with diuretics if tolerated for ≥ 30 days AND New York Heart Association (NYHA) class II; OR NYHA class III, or ambulatory NYHA class IV symptoms; AND ≥ 1 HF hospital admission (with HF as the primary, or secondary diagnosis); or treatment with intravenous (IV) diuretics; or intensification of oral diuresis within the 12 months prior to study entry; OR an NT-proB-type Natriuretic Peptide (NT-pro BNP) value > 150 pg/ml in normal sinus rhythm, > 450 pg/ml in atrial fibrillation, or a brain natriuretic peptide (BNP) value > 50 pg/ml in normal sinus rhythm, > 150 pg/ml in atrial fibrillation within the past 6 months Ongoing stable guideline-directed medical therapy (GDMT) HF management and management of comorbidities according to the 2022 American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines for the Management of Heart Failure. Stable management includes a minimum period of 4 weeks post-hospitalization for any cause, including treatment with IV diuretics Site determined echocardiographic LV ejection fraction ≥ 40% within the past 6 months, without documented ejection fraction < 30% in the 5 years prior. Site determined echocardiographic evidence of diastolic dysfunction documented by one or more of the following: Left Atrial (LA) diameter > 4 cm; or Diastolic LA volume > 50 or LA volume index > 28 ml/m2 or Lateral e' < 10 cm/s; or e' < 8 cm/s; or Site determined elevated pulmonary capillary wedge pressure (PCWP) with a gradient compared to right atrial pressure (RAP) documented by end-expiratory PCWP during supine ergometer exercise ≥ 25 millimeters of mercury (mm Hg), and greater than RAP by ≥ 5 mm Hg. Resting RAP ≤ 14 mmHg Site determined hemodynamic evidence of peak exercise pulmonary vascular resistance (PVR) < 1.75 Wood units Age ≥ 40 years old Participant has been informed of the nature of the study, agrees to its provisions and has provided written informed consent, approved by the Institutional Review Board (IRB) or Ethics Committee (EC) Participant is willing to comply with clinical investigation procedures and agrees to return for all required follow-up visits, tests, and exams Transseptal catheterization and femoral vein access to the right atrium is determined to be feasible by site interventional cardiology investigator. Exclusion Criteria: Advanced heart failure defined as one or more of the below: ACC/AHA/European Society of Cardiology (ESC) Stage D heart failure, non-ambulatory NYHA Class IV HF Cardiac index < 2.0 L/min/m2 Inotropic infusion (continuous or intermittent) for EF < 40% within the past 6 months Patient is on the cardiac transplant waiting list. Inability to perform 6-minute walk test (distance < 50 meters), OR 6-minute walk test > 600m The patient has verified that the ability to walk 6 minutes is limited primarily by joint, foot, leg, hip or back pain; unsteadiness or dizziness or lifestyle (and not by shortness of breath and/or fatigue and/or chest pain) Right ventricular dysfunction, assessed by the site cardiologist and defined as one or more of the following: More than mild right ventricular (RV) dysfunction as estimated by transthoracic echocardiogram (TTE); OR TAPSE < 1.4 cm; OR Right ventricular (RV) size ≥ left ventricular (LV) size as estimated by TTE; OR Ultrasound or clinical evidence of congestive hepatopathy; OR Evidence of RV dysfunction defined by TTE as an RV fractional area change < 35%. Any implanted cardiac rhythm device Structural heart repair aortic valve replacement (AVR) or mitral valve replacement (MVR) (surgical or percutaneous) within the past 12 months; planned valve intervention in the next 3 months, or presence of hemodynamically significant valve disease as assessed by the site cardiologist and defined as: Mitral valve disease grade ≥ 3+ mitral regurgitation (MR) or > mild Mitral Stenosis (MS); OR Tricuspid valve (TR) regurgitation grade ≥ 2+ TR; OR Aortic valve disease ≥ 2+ aortic regurgitation (AR) or > moderate aortic stenosis (AS) Echocardiographic evidence of intra-cardiac mass, thrombus or vegetation Participants with existing or surgically closed (with a patch) atrial septal defects. Participants with a patent foramen ovale (PFO), who meet PCWP criteria despite the PFO, are not excluded Myocardial Infarction (MI) and/or percutaneous cardiac intervention within past 3 months; Coronary Artery Bypass Graft (CABG) surgery in past 3 months or any planned cardiac interventions in the 3 months following enrollment. Known clinically significant un-revascularized coronary artery disease, defined as: coronary artery stenosis with angina or other evidence of ongoing active coronary ischemia Known clinically significant untreated carotid artery stenosis likely to require intervention Atrial fibrillation with resting heart rate (HR) > 100 beats-per-minute (BPM) Hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, cardiac amyloidosis or infiltrative cardiomyopathy (e.g. hemochromatosis, sarcoidosis) History of stroke, transient ischemic attack (TIA), deep vein thrombosis (DVT), or pulmonary emboli within the past 6 months Participant is contraindicated to receive either dual antiplatelet therapy, or an oral anticoagulant; or has a documented coagulopathy Anemia with Hemoglobin < 10 g/dl Chronic pulmonary disease requiring continuous home oxygen, OR significant chronic pulmonary disease defined as forced expiratory volume (FEV)1 <1Liter Resting arterial oxygen saturation < 95% on room air, <93% when residing at high altitude Currently requiring dialysis; or estimated glomerular filtration rate eGFR < 25ml/min/1.73 m2 by chronic kidney disease (CKD) CKD-Epi equation Systolic blood pressure > 170 mm Hg at screening Significant hepatic impairment defined as 3 times upper limit of normal of transaminases, total bilirubin, or alkaline phosphatase Participants on significant immunosuppressive treatment or on systemic steroid treatment Life expectancy less than 12 months for known non-cardiovascular reasons Known hypersensitivity to nickel or titanium Women of childbearing potential Severe obstructive sleep apnea not treated with continuous positive airway pressure (CPAP) or other measures Body Mass Index (BMI) > 45; BMI 40 - 45 is also excluded unless in the opinion of the investigator, vascular access can be obtained safely Severe depression and/or anxiety Currently participating in an investigational drug or device study that would interfere with the conduct or results of this study. Note: trials requiring extended follow-up for products that were investigational but have since become commercially available are not considered investigational In the opinion of the investigator, the Participant is not an appropriate candidate for the study.

Ages Eligible for Study
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Minimum Age: 40 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Participants randomized to the treatment arm will undergo a fluoroscopic and intra-cardiac echocardiography (ICE), or transesophageal echocardiography (TEE) guided trans-septal puncture and InterAtrial Shunt Device (IASD) System II implant procedure. | Device: Corvia Atrial Shunt System / IASD System II<br>* The primary component of the system is an implant placed in the atrial septum designed to allow left to right flow between the left atrium and right atrium to reduce the elevated left atrial pressure.<br>|
| Sham Comparator: Control<br>Participants randomized to the control arm will undergo fluoroscopy and intracardiac echocardiography from the femoral vein or transesophageal echocardiography, for examination of the atrial septum and left atrial appendage. | Other: Intra-cardiac echocardiography (ICE), or transesophageal echocardiography (TEE)<br>* Intra-cardiac echocardiography (ICE), or transesophageal echocardiography (TEE) for examination of the atrial septum and left atrium.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Primary Endpoint | The primary endpoint is a composite of heart failure event rates and Kansas City Cardiomyopathy Questionnaire (KCCQ) at 12 months. Responses are given on a Likert scale that for each individual item is scored on a scale of 0-100 with higher scores indicating better health. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of cardiovascular mortality | The incidence of cardiovascular mortality through 12 months. | Up to 12 months | 
| The rate of time-to-cardiovascular mortality | Time-to-cardiovascular mortality through 12 months. | Up to 12 months | 
| The rate of major adverse cardiac periprocedural events | Major adverse cardiac periprocedural events through 30 days defined as: Cardiac death Myocardial infarction Cardiac tamponade Emergency cardiac surgery. | Through 30 days | 
| The incidence of non-fatal, ischemic stroke | Incidence of non-fatal, ischemic stroke | Through 12 months | 
| The rate of new onset or worsening of kidney dysfunction | New onset or worsening of kidney dysfunction (defined as estimated glomerular filtration rate (eGFR) decrease of > 20 ml/min/1.73 m2) through 12 months | Through 12 months | 
| The incidence of thrombo-embolic complications including transient ischaemic attack (TIA) and systemic embolization) | The incidence of thrombo-embolic complications (TIA and systemic embolization) through 12 months | Through 12 months | 
| The incidence of newly acquired persistent or permanent atrial fibrillation (AF) or atrial flutter | The incidence of newly acquired persistent or permanent AF or atrial flutter | Through 12 months | 
| The incidence of participants with a ≥30% decrease in Tricuspid Annular Plane Systolic Excursion (TAPSE) | The incidence of participants with a ≥30% decrease Tricuspid Annular Plane Systolic Excursion (TAPSE) | Through 12 months | 
| The rate of heart failure (HF) admissions | Total rate (first plus recurrent) per patient year of heart failure (HF) admissions or healthcare facility visits for intravenous diuresis or urgent visits with intensification of oral diuresis for HF through 24 months, analyzed when the last randomized participant completes 12 months follow-up. | Through 24 months | 
| The change in New York Heart Association (NYHA) Class | Change in NYHA functional Class between baseline and 12 months | 12 months | 
| The change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Score | Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Score between baseline and 12 months, categorized as proportion of patients with changes of ≤0, >0 - 5, >5 - 10, >10 - 15, >15 - 20, >20 - 25, >25 points. Responses are given on a Likert scale that for each individual item is scored on a scale of 0-100 with higher scores indicating better health | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure with preserved ejection fraction (HFpEF), Heart failure with midrange ejection fraction (HFmrEF), Interatrial Shunt