Flow Regulation by Opening the SepTum in Patients with Heart Failure; a prospective, randomized, sham-controlled, double-blind, global multicenter study.

Subjects must meet all inclusion criteria: 1) Written informed consent 2) Aged
>=18 years 3) Presence of chronic symptomatic HF (NYHA >=class 2) and at least
one of the following: a. Prior heart failure hospitalization within 6 months of
informed consent, or b. Increased NT-proBNP within 2 months of informed consent
according to the following: i. If LVEF <=40%, then NT-proBNP >1200 pg/mL (or
BNP >400) ii. If LVEF >40% with Atrial Fibrillation, then NT-proBNP
>900 pg/mL (or BNP >300) iii. If LVEF >40% without Atrial
Fibrillation, then NT-proBNP >300 pg/mL (or BNP >100) 4) If LVEF
documented at screening is >55%, then must have one of either: a. Left
atrial enlargement (LA diameter >2.3 cm/m2 or LA volume index >28 mL/m2),
or b. PCWP >= 15mmHg at rest within previous 12 months, or c. LVEDP >=15mmHg at
rest within previous 12 months 5) 6MWT distance 100-450 meters 6) Treated with
maximally tolerated doses of class I GDMT and class I electrical therapies (CRT
and ICD) according to latest applicable guidelines (e.g., AHA or ESC) for at
least 2 months prior to informed consent, and a stable (no more than 100%
increase or 50% decrease) dose diuretic for at least 1 month prior to informed
consent. Note: lack of insurance coverage or affordability is a valid reason
not to be treated with a class I agent or device. An attempt to reach maximum
dose of GDMT that is not tolerated and followed by successful resumption of the
lower stable dose that had been maintained for at least 2 months without
clinical instability requires a 1-month waiting period.

Subjects are not eligible for clinical study participation if they meet any of
the following exclusion criteria: General Exclusion Criteria 1) Myocardial
infarction and/or revascularization with percutaneous intervention (PCI) or
coronary artery bypass grafting (CABG) within 3 months prior to informed
consent 2) Surgical or transcatheter valve (aortic, mitral, or tricuspid)
repair or replacement within 2 months prior to informed consent 3) Automated
implantable cardioverter defibrillator (AICD) placement within 2 months prior
to informed consent 4) Resynchronization therapy started within 3 months 5)
Major surgery within 3 months prior to informed consent 6) History of stroke,
transient ischemic attack (TIA), deep vein thrombosis (DVT), or pulmonary
emboli within 6 months, or any prior stroke with persistent neurologic deficit,
or any prior intracranial bleed, or known intracerebral aneurysm, AV
malformation or other intracranial pathology increasing the risk of bleeding 7)
Uncontrolled atrial fibrillation with resting heart rate >110 beats per
minute despite medical therapy 8) Advanced heart failure defined as ACC/AHA
Stage D heart failure 9) Current or recent Heart Failure hospitalization within
4 weeks 10) Documented history of non-dilated cardiomyopathy (obstructive
hypertrophic, restrictive, infiltrative) or pericardial disease 11) Clinically
significant valvular heart disease: a. regurgitation grade >=3+ or b. severe
stenosis of mitral or tricuspid valves, or c. moderate or greater stenosis of
aortic valves 12) Prior diagnosis of pulmonary hypertension with current
treatment with one or more pulmonary hypertension specific drugs (e.g.
endothelin receptor antagonists (ERAs), phosphodiesterase inhibitors (PDE 5
Inhibitors) or prostacyclin analogues) 13) Uncontrolled hypertension, Systolic
Blood Pressure (SBP) >=160 or Diastolic Blood Pressure (DBP) >=100 mmHg despite
medical therapy at the time of screening visit 14) Previous interventional or
surgical atrial septal defect (ASD) or patent foramen ovale (PFO) closure 15)
Inadequate vascular access for implantation of shunt, e.g., suboptimal femoral
venous access for transseptal catheterization or inferior vena cava (IVC) is
not patent 16) Sepsis or other infection(s) requiring systemic antibiotics 17)
Chronic kidney disease currently requiring dialysis 18) Allergy or
contraindication to aspirin, or clopidogrel and prasugrel and ticagrelor, or
heparin and bivalirudin 19) Bleeding disorders (international normalized ratio
[INR] >2.0, platelet count <100,000 x 109/L, hemoglobin <10.0 g/dL)
20) Inability to stop oral anticoagulation 4 days before and 4 days after
procedure 21) Known clinically significant untreated carotid artery stenosis
likely to require intervention, at discretion of investigator 22) Current
untreated coronary artery disease with indication for revascularization 23)
Contraindication to transesophageal echocardiography (TEE) or intra-cardiac
echo (ICE) 24) Right ventricular systolic pressure >= 70 mmHg on Screening TTE
25) Significant Right Ventricular dysfunction demonstrated by: a. Tricuspid
Annular Plane Systolic Excursion (TAPSE) <16mm or b. Right Ventricular
Fractional Area Change (RVFAC) <=30% 26) Right Atrial Volume Index (RAVI) >
31 mL/m2 27) Left Ventricular End-Diastolic Diameter (LVEDD) > 8.0 cm as
assessed by echocardiography 28) Class 3 or greater angina pectoris 29) Severe
COPD requiring oral steroid therapy or daytime oxygen 30) Echocardiographic
evidence of intra-cardiac mass, thrombus, or vegetation 31) Congenital heart
defect that interferes with placement of the device, at the discretion of the
investigator 32) On current immunosuppression or systemic oral steroid
treatment 33) Any condition that limits exercise tolerance other than heart
failure (e.g., peripheral vascular disease, orthopedic issues, angina, other),
at the discretion of the Investigator 34) Participating in another
investigational clinical trial that could interfere with this study, at the
discretion of the investigator 35) Vulnerable populations including individuals
with mental disability, persons in nursing homes, impoverished persons,
homeless persons, nomads, refugees and those permanently incapable of giving
informed consent; vulnerable populations also may include members of a group
with a hierarchical structure such as university students, subordinate hospital
and laboratory personnel, employees of the Sponsor, members of the armed forces
and persons kept in detention. 36) Pregnant or breast-feeding or any intended
pregnancy within 12 months after implant 37) Not using an acceptable method of
contraception for the first 12 months 38) Any medical non-cardiac conditions
with life expectancy less than 1-year 39) Other clinically significant
co-morbidities that make the patient unsuitable for study participation, at the
discretion of the investigator Intraprocedural Exclusion Criteria: 40) Previous
ASD or PFO interventional or surgical closure, current atrial septal defect, or
anatomical anomaly (including > 10 mm atrial septal thickness or atrial
septal aneurysm) on TEE or ICE that precludes implantation of the device across
the fossa ovalis (FO) of the interatrial septum 41) Right Atrial Pressure (RAP)
>12 mmHg on invasive hemodynamics 42) On a right heart catheterization, that
should be done within 30 days of implantation, but no later than
intraprocedurally prior to randomization: a. Pulmonary Artery Systolic Pressure
(PASP) >= 70 mmHg regardless of Pulmonary Vascular Resistance (PVR) or b. PASP >=
50 up to < 70 mmHg with PVR >= 3 Wood Units, unless the PVR can be reduced to
less than 3 Wood Units by vasodilator therapy