A Randomized Placebo-procedure Controlled Trial of the Enhancor System (PULmonary Artery Denervation) to Evaluate Safety and Efficacy in Patients With Combined Pre- and Post-capillary Pulmonary Hypertension Associated With Left Heart Disease

A Randomized Placebo-procedure Controlled Trial of the Multi-Pole Pulmonary Artery Radiofrequency Ablation Enhancor System PULmonary Artery Denervation Safety and Efficacy in Patients With Combined Pre- and Post-capillary Pulmonary Hypertension Associated With Left Heart Disease

The goal of this clinical study is to evaluate the safety and efficacy of percutaneous pulmonary artery denervation with the Multi-Pole Pulmonary Artery Radiofrequency Ablation Enhancor System in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH) associated with left heart disease (LHD). This randomized control trial will compare the investigational device (The Enhancor System) to control (medical therapy.)

Participants who will consist of patients with chronic heart failure (HF) who are receiving maximally tolerated guideline-directed medical therapy (GDMT) for left heart failure, are clinically stable, and who have been diagnosed with CpcPH by right heart catheterization (RHC), will be treated with PADN and followed for 3 years.

Roll-in Subjects:

Prior to enrollment of the first randomized subject at each site, up to two roll-in subjects per operator (maximum 2 operators per site) who meet all eligibility criteria for the randomized trial may be enrolled. Roll-in subjects will receive PADN plus GDMT. Roll-in subjects will undergo all protocol-specified assessments. The sponsor will determine when each operator has achieved acceptable experience with the PADN procedure to advance to the randomized trial, after which no further roll-in patients will be enrolled. Operators who have performed ≥3 prior PADN procedures may not need to enroll a roll-in patient prior to beginning randomization.

Randomized Subjects:

Subjects with CpcPH due to LHD who meet all eligibility criteria will be randomized in a 1:1 ratio (stratified by investigational site and by core laboratory assessed LVEF [≤40% vs >40%]) to one of the two treatment arms:

1. Intervention: PADN plus GDMT
2. Control: Placebo-procedure plus GDMT Subjects will undergo clinical follow-up at 1, 6, 12, 24 and 36 months. At 24 months, control subjects who have experienced a primary efficacy endpoint event and who still meet all eligibility criteria will be offered the opportunity to cross over to the PADN plus GDMT group.

Inclusion Criteria:

1. Subject is ≥18 and ≤85 years of age

2. Subject is diagnosed with chronic HF due to left-sided heart disease for at least 6 months prior to screening (regardless of LVEF), and remains symptomatic despite maximally tolerated class I GDMT for left heart failure and CRT as appropriate per US or EU guidelines according to region of enrollment

3. Subject is clinically stable, defined as:

   • No hospitalizations for heart failure for at least 1 month; no major changes in societal guideline-recommended class I oral GDMT for left heart failure for at least 1 month; no CRT or ICD implant in the prior 3 months; and no anticipated major changes in any HF-GDMT (other than possibly diuretic dose) or planned cardiac rhythm management device implantation after the procedure
   • SBP is ≥90 and ≤160 mmHg and resting HR is ≥50 and ≤100 bpm (≤110 bpm for atrial fibrillation)

4. PASP (RVSP) is ≥30 mmHg on the baseline TTE.

5. Subject has New York Heart Association (NYHA) class II, III or IVa symptoms (IVa is defined as symptoms with minimal exertion or at rest, but the patient is able to ambulate and does not require continuous intravenous medications).

6. Subject has 6MWD at baseline ranging from 100 to 450 m limited by dyspnea or fatigue and not orthopedic or other non-HF-related issues

7. Subject has NT-proBNP ≥600 pg/mL for patients with LVEF ≤40% or ≥200 pg/mL for patients with LVEF >40% at the time of screening (a central lab will be made available for sites that cannot measure NT-proBNP)

8. Subject is able and willing to follow all aspects of the research protocol including medication compliance and follow-up visits and testing.

9. Subject or the subject's legally designated representative signs an IRB/EC approved informed consent form prior to study participation.

Exclusion Criteria:

1. Subject has a life expectancy of less than 1 year due to non-cardiovascular causes.
2. Subject has known hypertrophic cardiomyopathy with either left ventricular (LV) outflow tract obstruction or systolic anterior motion (SAM) of the anterior leaflet of the mitral valve; pericardial disease; or infiltrative or active inflammatory myocardial disease, including known amyloidosis
3. Subject has severe stenosis or regurgitation of any heart valve, moderate or severe stenosis of the aortic valve, or any degree of stenosis of the pulmonic valve
4. Subject has symptomatic carotid stenosis, or transient ischemic attack (TIA) or stroke in the prior 30 days or any prior stroke with a permanent residual deficit with modified Rankin Scale (mRS) score ≥4
5. Subject has any prior intracranial hemorrhage with or without a residual deficit, or any known intracranial pathology pre-disposing to bleeding (e.g. mass, AV fistula, aneurysm, etc.)
6. Subjects with a known bleeding diathesis or who will refuse blood transfusions
7. Subjects allergic to heparin (including heparin induced thrombocytopenia), unless bivalirudin or argatroban can be used for procedural anticoagulation
8. Subjects with life threatening allergy to contrast dye that cannot be adequately pre-medicated, or any prior contrast-related anaphylaxis
9. Subject has congenital heart disease other than mitral valve prolapse or a PFO
10. Subject had coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in the prior 6 months or is anticipated to undergo CABG or PCI within 12 months after randomization.
11. Subject has any pacemaker with an intracardiac sensing or pacing lead or wire implanted in the prior 3 months, or CardioMEMS HF System or other intracardiac pressure monitoring system, or cardiac contractility modulation system or baroreceptor activation therapy implanted within the prior 3 months, or any plans to implant any of these devices within 12 months after the procedure.
12. Subject has undergone atrial fibrillation ablation within the prior 6 months or is anticipated to undergo atrial fibrillation ablation within 12 months after randomization.
13. Subject has undergone heart valve surgery or transcatheter valve intervention within the prior 6 months or is anticipated to undergo heart valve surgery or transcatheter valve intervention (e.g., valve repair or replacement, valvuloplasty) within 12 months after randomization.
14. Subject has any tricuspid or pulmonic valve implants (implanted annuloplasty rings are allowed).
15. Subject has an inferior vena cava (IVC) filter implant.
16. Subject has received a prior heart or heart-lung transplantation or is listed for heart or heart-lung transplantation or is anticipated to receive a ventricular assist device (VAD) implant within 6 months after randomization.
17. Subjects with intracardiac thrombus on TTE.
18. Subjects with pericardial effusion ≥10 mm on TTE
19. Subject's PH is predominantly due to WHO Group 1, 3, 4, or 5. Note: Multifactorial features of PH may be present, but the predominant diagnosis must be WHO Group 2 CpcPH.
20. Subject has been treated with any group 1 PAH-targeted drugs, including sotatercept, within the prior month or is planned to receive such therapy after randomization.
21. Subject is anticipated to undergo any surgery within 6 months after randomization (other than minor surgeries requiring only local anesthesia).
22. Subject has severe renal insufficiency (eGFR <30 mL/min/1.73m2 by the CKD-EPI formula, or on dialysis).
23. Subject has severe liver insufficiency (Child-Pugh classification C).
24. Subject has platelet count <100 × 109/L.
25. Subject has systemic inflammatory or other disease requiring long-term use of oral glucocorticoids or immunosuppressants.
26. Subject has active infection requiring oral or intravenous antibiotics.
27. Subject has a body mass index (BMI) >45 kg/m².
28. Subjects with severe respiratory disease, defined as any disorder of the respiratory system with diffusing capacity of the lungs for carbon monoxide (DLCO) <40% AND total lung capacity (TLC) <60% AND forced expiratory volume in one second (FEV1) <70% by plethysmography; OR who require ambulatory or long-term oxygen therapy
29. Subject has known severe untreated sleep apnea. Note: Subjects with sleep apnea treated with CPAP/BiPAP for at least the prior 3 months are not excluded.
30. Subjects with pulmonary embolism or deep vein thrombosis in the prior 6 months.
31. Subject is a pregnant or breastfeeding woman, or a woman planning to become pregnant within one year. Women of child-bearing potential must have a negative pregnancy test within 1 week of randomization.
32. Subject is participating in another clinical trial of an investigational drug or device that has not reached its primary endpoint.
33. Subject has severe cachexia/frailty, substance abuse, or any other condition that the investigator believes may affect the subject's ability to comply with or complete all the study requirements including follow-up visits.
34. Subject is a member of a vulnerable population who, in the judgment of the investigator, is unable to give Informed Consent for reasons of incapacity, immaturity, adverse personal circumstances or lack of autonomy. This may include individuals with mental disability, children, impoverished persons, persons in prisons, persons in emergency situations, homeless persons, nomads, refugees, and those incapable of giving informed consent. Vulnerable populations may also 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.