REDUCE LAP-HF TRIAL II

Study Overview
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Brief Summary
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Multicenter, Prospective, Randomized Controlled, Blinded Trial, with a Non-implant Control group; 1:1 randomization.

Detailed Description
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Following supine bicycle exercise testing to assess eligibility, the eligible patients are randomized to the treatment or control group. All patients will be sedated, and both treatment and control arm patients will undergo placement of a femoral venous access sheath after randomization. Patients randomized to the treatment arm will undergo a fluoroscopically and intra-cardiac echocardiography (ICE), or transesophageal echocardiography (TEE) guided trans-septal puncture and IASD System II 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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A Study to Evaluate the Corvia Medical, Inc. IASD® System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure

Conditions
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Heart Failure

Intervention / Treatment
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* Device: IASD System II implant
* Other: intra-cardiac echocardiography (ICE), or transesophageal echocardiography (TEE)


Participation Criteria
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Eligibility Criteria
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SELECT INCLUSION CRITERIA Chronic symptomatic Heart Failure (HF) documented by one or more of the following: Symptoms of HF requiring current treatment with diuretics for ≥ 30 days AND NYHA class II with a history of > NYHA class II; OR NYHA class III, or ambulatory NYHA class IV symptoms (paroxysmal nocturnal dyspnea, orthopnea, dyspnea on mild or moderate exertion) at screening; or signs (any rales post cough, chest x-ray demonstrating pulmonary congestion,) within past 12 months; AND ≥ 1 HF hospital admission (with HF as the primary, or secondary diagnosis); or treatment with intravenous (IV), or intensification of oral diuresis for HF in a healthcare facility within the 12 months prior to study entry; OR an NT-pro BNP value > 150 pg./ml in normal sinus rhythm, > 450 pg./ml in atrial fibrillation, or a BNP value > 50 pg./ml in normal sinus rhythm, > 150 pg./ml in atrial fibrillation within the past 6 months. Ongoing stable GDMT HF management and management of potential comorbidities according to the 2013 ACCF/AHA Guidelines for the management of Heart Failure (with no significant changes [>100% increase or 50% decrease], excluding diuretic dose change for a minimum of 4 weeks prior to screening) that is expected to be maintained without change for 6 months Age ≥ 40 years old, LV ejection fraction (EF) ≥ 40% within the past 3 months, without previously documented EF <30% (within the past 3 years) Elevated PCWP with a gradient compared to right atrial pressure (RAP), documented by end-expiratory PCWP during supine ergometer exercise ≥ 25mmHg, and greater than RAP by ≥ 5 mmHg SELECT EXCLUSION CRITERIA MI and/or percutaneous cardiac intervention within past 3 months; CABG in past 3 months, or current indication for coronary revascularization; AVR (surgical AVR or TAVR) within the past 12 months. Cardiac Resynchronization Therapy initiated within the past 6 months Advanced heart failure defined as one or more of the below: ACC/AHA/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 m), OR 6 minute walk test > 600m History of stroke, transient ischemic attack (TIA), deep vein thrombosis (DVT), or pulmonary emboli within the past 6 months Presence of significant valve disease defined by the site cardiologist as: Mitral valve regurgitation defined as grade ≥ 3+ MR Tricuspid valve regurgitation defined as grade ≥ 2+ TR Aortic valve disease defined as ≥ 2+ AR or > moderate AS Known clinically significant untreated carotid artery stenosis likely to require intervention Currently requiring dialysis; or estimated-GFR <25ml/min/1.73 m2 by CKD-Epi equation

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>Patients randomized to the treatment arm will undergo a fluoroscopically and intra-cardiac echocardiography (ICE), or transesophageal echocardiography (TEE) guided trans-septal puncture and IASD System II implant procedure. | Device: IASD System II implant<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>Patients randomized to the control arm will undergo ICE from the femoral vein or TEE for examination of the atrial septum and left atrium. | 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 the composite of (a) incidence of and time-to-cardiovascular mortality or first non-fatal, ischemic stroke through 12 months; (b) total rate (first plus recurrent) per patient year of heart failure (HF) events, defined as hospital admissions, acute healthcare facility visits or urgent unscheduled outpatient visits for IV diuresis or intensification of oral diuretics for HF up to 24 months, analyzed when the last randomized subject completes 12 months follow-up, and time-to-first HF event; and (c) change in baseline KCCQ total summary score at 12 months. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite safety endpoint defined as follows: | Cardiovascular mortality Non-fatal, ischemic stroke New onset or worsening of kidney dysfunction (defined as eGFR decrease of > 20 ml/min) Major adverse cardiac events through 12-months defined as: i. Cardiac death; ii. Myocardial infarction; iii. Cardiac tamponade; iv. Emergency cardiac surgery Thrombo-embolic complications (TIA, systemic embolization) Newly acquired persistent or permanent AF or atrial flutter through ≥30% increase in RV size/decrease in TAPSE | 12 months | 
| Rate of heart failure admissions | Total rate (first plus recurrent) per patient year of heart failure (HF) events, defined as hospital admissions, acute healthcare facility visits, or urgent unscheduled outpatient visits for IV diuresis or intensification of oral diuretics for HF up to 24 months, analyzed when the last randomized subject completes 12-month follow-up | Up to 24 months | 
| Change in NYHA Class | Change in NYHA functional Class assessed by a blinded physician between baseline and 12 months | 12 months | 
| Change in Kansas City Cardiomyopathy Questionnaire | Change in KCCQ score between baseline and 12 months, categorized as ≤0, >0 - 5, >5 - 10, >10 - 15, >15 - 20, >20 - 25, >25. | 12 months |