ALT-FLOW II Trial of the Edwards APTURE Transcatheter Shunt System

Study Overview
=================
Brief Summary
-----------------
This is a prospective, multi-center, randomized, sham-controlled clinical trial.

Detailed Description
-----------------
The objectives of this trial are to assess the safety, performance, and effectiveness of the Edwards APTURE transcatheter shunt system when used for the treatment of patients with heart failure with preserved (HFpEF) or mildly reduced (HFmrEF) ejection fraction (LVEF >40%) who remain symptomatic despite guideline-directed medical therapy (GDMT)

Official Title
-----------------
A Randomized, Sham-controlled Clinical Trial for Evaluation of the Edwards APTURE Transcatheter Shunt System (ALT-FLOW II)

Conditions
-----------------
Heart Failure

Intervention / Treatment
-----------------
* Device: Edwards APTURE transcatheter shunt system
* Diagnostic Test: Sham procedure


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Symptomatic heart failure A primary diagnosis of HFmrEF or HFpEF (LVEF > 40%), and NYHA class II to ambulatory NYHA class IV (IVa), and Documentation of at least one of the following from the date of initial informed consent: ≥ 1 prior HF hospitalization(s) requiring IV HF therapy in the prior 12 months; AND/OR EITHER BNP value > 35 pg/ml or > 125 pg/ml in permanent or long-term persistent atrial fibrillation; OR NT-proBNP > 125 pg /ml or > 375 pg /ml in permanent or long-term persistent atrial fibrillation There is objective evidence of cardiogenic pulmonary congestion based on hemodynamic criteria obtained by right heart catheterization (RHC) at exercise, and confirmed by hemodynamics core lab as: o Pulmonary capillary wedge pressure at 20 Watts exercise (PCWP 20W) as measured at end-expiration is elevated to ≥ 25 mmHg and PCWP 20W exceeds right atrial pressure (RAP 20W) by ≥ 8 mmHg In the judgment of the treating physician and the Central Screening Committee the patient is on GDMT for HFpEF/HFmrEF for >30 days prior to screening and baseline assessments, that is expected to be maintained without change for 6 months. Key Exclusion Criteria: Severe heart failure defined as one or more of the below: ACC/AHA/ESC Stage D HF, non-ambulatory NYHA Class IV HF If Body Mass Index (BMI) < 30, cardiac index < 2.0 L/min/m2 If BMI ≥ 30, cardiac index < 1.8 L/min/m2 Inotropic infusion (continuous or intermittent) within the past 6 months Patient is on the cardiac transplant waiting list Prior diagnosis of HF with reduced ejection fraction (HFrEF), including patients with improvement in LVEF to > 40% Valve disease: Degenerative mitral regurgitation > moderate Functional or secondary mitral valve regurgitation defined as grade > moderate Mitral stenosis > mild Primary or secondary tricuspid valve regurgitation defined as grade > moderate Aortic valve disease defined as aortic regurgitation grade > moderate or aortic stenosis > moderate More than mild right ventricular (RV) dysfunction as determined by the echo core lab, taking into account the following available parameters: Tricuspid annular plane systolic excursion (TAPSE) <1.4 cm, or RV size ≥ LV size Right ventricular ejection fraction (RVEF) < 35%; OR Imaging or clinical evidence of congestive hepatopathy Mean right atrial pressure (mRAP) > 15 mmHg at rest Pulmonary vascular resistance (PVR) ≥ 5.0 WU BMI ≥ 45 Myocardial infarction (MI) and/or any therapeutic invasive, non-valvular cardiovascular procedure within past 3 months or current indication for coronary revascularization Stroke, transient ischemic attack (TIA), deep vein thrombosis (DVT) or pulmonary embolus within the past 6 months Renal insufficiency as determined by creatinine (sCr) level > 2.5 mg/dL or estimated glomerular filtration rate (eGFR) < 25ml/min/1.73 m2 by CKD-Epi equation; or currently requiring dialysis Performance of the six-minute walk test (6MWT) with a distance < 50m OR > 450m Active endocarditis or infection requiring intravenous antibiotics within 3 months

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APTURE shunt + medical therapy<br> | Device: Edwards APTURE transcatheter shunt system<br>* Treatment with APTURE shunt<br>|
| Sham Comparator: Sham + medical therapy<br> | Diagnostic Test: Sham procedure<br>* CS angiography<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Device + Medical Therapy: Subjects with Early Major Adverse Events | Shunt implant safety: proportion of patients in the APTURE shunt group without any serious device or procedure-related (CEC adjudicated) complications (i.e., Major Adverse Cardiovascular, Cerebrovascular, and Renal Events [MACCRE]; at 30 days post index procedure or hospital discharge, whichever is later. | 30 days | 
| Mean change in PCWP from baseline at 20W exercise | Hemodynamic Effectiveness: change in PCWP at 20W exercise from baseline (mmHg) at 6 months. | 6-months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| KCCQ-OSS change from baseline at 6-month follow-up |  | 6-months | 
| Proportion of individual patient success defined as being free from death, disabling stroke, and HF hospitalization with at least (≥) a 15-point improvement from baseline KCCQ-OSS or at least (≥) a 25m improvement from baseline 6MWT. |  | 6-months | 
| 6MWT change from baseline at 6-month follow-up |  | 6-months |