A Trial to Evaluate the Safety and Efficacy of Pulmonary Artery Denervation for the Treatment of Pulmonary Hypertension Associated With Left Heart Failure (PADN-HF-PH)

A Prospective, Multicenter, Randomized Controlled Trial to Evaluate the Safety and Efficacy of Single-use Ring-shaped Pulmonary Artery Radiofrequency (RF) Ablation Catheter and Pulmonary Artery RF Ablation Generator for the Treatment of Pulmonary Hypertension Associated With Left Heart Failure

It's a phase III, prospective, multicenter, randomized controlled trial to evaluate the safety and efficacy of the pulmonary artery denervation (PADN) for heart failure (HF) patients diagnosed with pulmonary hypertension associate with left heart disease (PH-LHD) by right heart catheterization.

Study Overview

• Status: Recruiting
• Conditions: Cardiovascular Diseases; Vascular Diseases; Heart Failure; Hypertension; Pulmonary Hypertension; Heart Failure With Reduced Ejection Fraction; Heart Failure With Preserved Ejection Fraction; Heart Failure With Mid Range Ejection Fraction
• Intervention / Treatment: Procedure: Pulmonary arterial denervation; Drug: Guideline-directed medical therapy (GDMT) for heart failure

Detailed Description

Chronic heart failure (CHF) patients who have received guideline-directed medical therapy (GDMT) based on the 2023 ESC Guidelines for HF and have reached clinical stable, and diagnosed with PH-LHD by right heart catheterization, will be randomized to the PADN group or control group in a 1:1 ratio to receive PADN combined with HF GDMT or HF GDMT, respectively. After the 12-month follow-up visit is completed, participants in the control group who still meet the inclusion and exclusion criteria can also choose to receive PADN.

Approximately 264 participants will be enrolled at up to 39 centers in China and followed for 3 years. The safety and efficacy of the PADN system, including RF ablation catheter and generator will be evaluated by comparing the therapeutic effect of the PADN group and the control group.

• Study Type: Interventional
• Enrollment (Estimated): 264
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Mark Gu; Phone Number: 13774217349; Email: guwen@pulnovomed.com
• Study Contact Backup: Name: Yanyan Lu; Phone Number: 13914766820; Email: co@pulnovomed.com

Study Locations

• China
  • Liaoning
    • Shenyang, Liaoning, China
      • Recruiting
      • General Hospital of Northern Theater Command
      • Principal Investigator: Yaling Han, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18, ≤75 years old;
2. Diagnosed with chronic heart failure for at least 3 months, and have received the GDMT pharmacological treatment based on the 2023 ESC Guidelines for Heart Failure for at least 1 month;

3. Clinically stable defined by

   1. No intravenous diuretics, inotropes or vasodilators for at least 1 month, and
   2. Systolic blood pressure (SBP) ≥ 100 and < 160 mmHg and resting heart rate (HR) ≥50 and <100 bpm (<110 bpm for atrial fibrillation) on the day of the procedure
4. New York Heart Association (NYHA) class II-IVa;
5. 6MWD ≥ 100 m and < 450 m;
6. NT-proBNP > 125 pg/mL (BNP > 35 pg/mL);

7. Hemodynamic indicators (RHC) :

   1. Mean pulmonary arterial pressure (mPAP) > 20 mmHg
   2. Pulmonary capillary wedge pressure (PCWP) >15 mmHg
8. Understand and be willing to sign informed consent, and be willing to follow the follow-up plan required by the protocol.

Exclusion Criteria:

1. Any of the following:

   1. Hypertrophic cardiomyopathy with left ventricular outflow tract obstruction or systolic anterior motion; pericardial disease; infiltrative or inflammatory myocardial disease; valvular stenosis of any of the 4 valves, or severe regurgitation of aortic and pulmonary valves, or active endocarditis; or
   2. Symptomatic carotid stenosis, or transient ischemic attack (TIA) or stroke within 30 days prior to randomization; or
   3. Untreated congenital heart disease; or
   4. Have received any revascularization, including coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) within 6 months prior to randomization; or anticipated to undergo coronary revascularization (CABG or PCI) within 6 months; or
   5. Artificial pacemakers, including single-chamber, dual-chamber and three-chamber pacemakers, have been implanted or are anticipated to be implanted within 6 months; or
   6. Anticipated to undergo ablation of atrial fibrillation within 6 months; or
   7. Anticipated to undergo heart valve surgery (valve replacement, valvuloplasty) within 6 months; or
   8. Listing for heart/heart-lung transplantation or anticipated to implant a ventricular assist device (VAD)
2. Other types of pulmonary hypertension, including WHO Group1, Group3, Group4, Group5;
3. Received pulmonary arterial hypertension (PAH) targeted drugs within 1 month prior to randomization;
4. Anticipated to undergo any surgery within 6 months;
5. The cardiac index (CI) of RHC < 1.5L/min/m²;
6. Severe renal insufficiency (eGFR <30mL/min/1.73m² by MDRD formula);
7. Severe liver insufficiency (Child-Pugh classification C);
8. Platelet count < 50 × 10^9/L;
9. Life expectancy <1 year;
10. Systemic inflammation or other disease requiring long-term use of glucocorticoids or immunosuppressants;
11. Active infection requiring oral or intravenous antibiotics;
12. Body mass index (BMI) >40 kg/m²;
13. Pregnant or lactating women, or plan to pregnant in one year;
14. Participated in other clinical trials within 3 months prior to signing the informed consent;
15. Any other circumstances that investigators deem inappropriate to participate in this trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pulmonary Artery Denervation (PADN); Patients in the PADN group will receive pulmonary artery denervation procedure.	Procedure: Pulmonary arterial denervation; Contrast pulmonary artery (PA) angiography will be performed to localize the pulmonary artery bifurcation level and calculate the PA diameter. Once the anatomy deemed acceptable, the radiofrequency ablation catheter will be introduced into ostium of the left PA and the distal bifurcation area of the main PA. The catheter will be manoeuvred within the PA to allow energy delivery in a circumferential manner to ensure that the electrodes are tightly in contact with the endovascular surface. About three ablations at 45-55 ℃ for 120 seconds each will be performed in ostium of the left PA and the distal bifurcation area of the main PA. For non-atrial fibrillation patients, dual antiplatelet therapy for 1 month after PADN is recommended. Patients with atrial fibrillation should continue new oral anticoagulants and patients who underwent metal valve replacement should continued oral warfarin anticoagulation according to guidelines, which could determined by the physician.; Other Names: PADN; Drug: Guideline-directed medical therapy (GDMT) for heart failure; GDMT medication recommendation including: Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) or angiotensin receptor-neprilysin inhibitor (ARNI); Beta-receptor blocker (BB); Mineralocorticoid receptor antagonist (MRA); Sodium-glucose co-transporter 2 (SGLT2) inhibitor; Diuretics The medication regimen (type and dosage) will be the investigator's discretion in accordance with the 2023 ESC Guidelines for Heart Failure. The type and dosage of all GDMT medications (except for diuretics) should remain unchanged through follow-up duration (at 12-month visit), unless the participant's conditions need adjust of GDMT regimens. Dosage and single or combination of diuretics are all left at physician's discretion.; Other Names: GDMT medication for heart failure
Active Comparator: Guideline-directed medical therapy (GDMT) for heart failure; Patients in the control group will take their baseline anti-heart failure medications at the original doses according to 2023 ESC Guidelines for heart failure, without any changes except when medically required. The anti-heart failure drugs treatment is consistent in both arms.	Drug: Guideline-directed medical therapy (GDMT) for heart failure; GDMT medication recommendation including: Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) or angiotensin receptor-neprilysin inhibitor (ARNI); Beta-receptor blocker (BB); Mineralocorticoid receptor antagonist (MRA); Sodium-glucose co-transporter 2 (SGLT2) inhibitor; Diuretics The medication regimen (type and dosage) will be the investigator's discretion in accordance with the 2023 ESC Guidelines for Heart Failure. The type and dosage of all GDMT medications (except for diuretics) should remain unchanged through follow-up duration (at 12-month visit), unless the participant's conditions need adjust of GDMT regimens. Dosage and single or combination of diuretics are all left at physician's discretion.; Other Names: GDMT medication for heart failure

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Worsening, defined as the occurrence of any of the followings:	Requiring intravenous medication (inotropes, diuretics or vasodilators) due to worsening of heart failure; Rehospitalization due to heart failure; 6MWD decreased by > 10% or > 30m compared with baseline; Referral for heart/heart-lung transplantation; All-cause death	immediately after the randomization to the last enrolled subject having at least 6 months follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parameters measured by transthoracic echocardiography(TTE)	Changes in left ventricular Tei index from baseline.	6 months, 1 year, 3 years
Parameters measured by transthoracic echocardiography(TTE)	Changes in left ventricular ejection fraction (LVEF) from baseline.	6 months, 1 year, 3 years
Parameters measured by transthoracic echocardiography(TTE)	Changes in left ventricular end-diastolic diameter (LVDd) from baseline.	6 months, 1 year, 3 years
Parameters measured by transthoracic echocardiography(TTE)	Changes in left ventricular end-systolic diameter (LVSd) from baseline.	6 months, 1 year, 3 years
Parameters measured by transthoracic echocardiography(TTE)	Changes in E/E' ratio from baseline.	6 months, 1 year, 3 years
Parameters measured by transthoracic echocardiography(TTE)	Changes in septum E' from baseline.	6 months, 1 year, 3 years
Parameters measured by transthoracic echocardiography(TTE)	Changes in lateral wall E' from baseline.	6 months, 1 year, 3 years
Parameters measured by transthoracic echocardiography(TTE)	Changes in left ventricular global longitudinal strain (LVGLS) from baseline.	6 months, 1 year, 3 years
N-terminal pro-B-type natriuretic peptide (NT-proBNP)	Changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline	6 months
6 minute walk distance(6MWD) difference from baseline	The 6MWD test was conducted according to the American Thoracic Society guidelines.	6 months, 1 year, 3 years
Changes in the Kansas City Cardiomyopathy Questionnaire(KCCQ) overall summary score from baseline	The KCCQ is a self-administered, 23-item questionnaire to provide a better description of quality of life in patients with heart failure. The overall summary score range from 0 to 100, higher score means higher quality of life.	1 month, 6 months, 1 year, 2 years, 3 years
Intravenous medication due to worsening of heart failure	Number of patients requiring intravenous medication (inotropes, diuretics or vasodilators) due to worsening of heart failure	1 month, 6 months, 1 year, 2 years, 3 years
Rehospitalization due to heart failure	Number of patients with rehospitalization due to heart failure	1 month, 6 months, 1 year, 2 years, 3 years
Heart/heart-lung transplantation	Number of patients referred for heart/heart-lung transplantation	1 month, 6 months, 1 year, 2 years, 3 years
All-cause death	Number of death due to any cause	1 month, 6 months, 1 year, 2 years, 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Outcome: AESI	Adverse events of special interest (AESI), defined as complications occurring within 30 days after the procedure, include: Thrombosis and embolism; Perforation or dissection of the pulmonary artery requiring surgical treatment; Pulmonary aneurysm; Pulmonary artery stenosis; Hemoptysis requiring surgical treatment; Recurrent laryngeal nerve injury; Complications at puncture site (including pain, infection, bleeding, hematoma, etc.); All-cause death; Endotracheal intubation; Mechanical circulation support; Permanent implantation of a pacemaker or defibrillator	within 30 days after the procedure
Safety Outcome: AE and SAE	Adverse events (AE) and serious adverse events (SAE)	throughout the clincialtrial

Collaborators and Investigators

• Sponsor: Pulnovo Medical (Wuxi) Co., Ltd.
• Collaborators: The First Affiliated Hospital with Nanjing Medical University; The First Affiliated Hospital of Nanchang University; First Affiliated Hospital, Sun Yat-Sen University; RenJi Hospital; West China Hospital; Tongji Hospital; First Affiliated Hospital of Fujian Medical University; Shengjing Hospital; First Affiliated Hospital Xi'an Jiaotong University; Shanghai 10th People's Hospital; The First Affiliated Hospital of Soochow University; Guangdong Provincial People's Hospital; Beijing Anzhen Hospital; The First Affiliated Hospital of Guangzhou Medical University; Zhongnan Hospital; Gansu Provincial Hospital; The First Hospital of Jilin University; Hunan Provincial People's Hospital; Wuhan Union Hospital, China; Tianjin Medical University General Hospital; Renmin Hospital of Wuhan University; Zhejiang University; Tianjin Medical University Second Hospital; First Affiliated Hospital of Wenzhou Medical University; Sichuan Academy of Medical Sciences; Cangzhou Central Hospital; Second Hospital of Jilin University; First Affiliated Hospital of Chongqing Medical University; China-Japan Union Hospital, Jilin University; First Affiliated Hospital of Harbin Medical University; TEDA International Cardiovascular Hospital; Shanxi Cardiovascular Hospital; Xiamen Cardiovascular Hospital, Xiamen University; Huaihe Hospital of Henan University; First Hospital of Tsinghua University; Zhengzhou Cardiovascular Hospital; The General Hospital of Northern Theater Command; Fuwai Central China Cardiovascular Hospital; Yanan Hospital of Kunming City
• Investigators: Principal Investigator: Yaling Han, The General Hospital of Northern Theater Command

Study record dates

Study Major Dates

• Study Start (Actual): August 14, 2023
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: January 10, 2023
• First Submitted That Met QC Criteria: April 10, 2023
• First Posted (Actual): April 24, 2023

Study Record Updates

• Last Update Posted (Actual): September 20, 2024
• Last Update Submitted That Met QC Criteria: September 18, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Heart Failure; pulmonary hypertension; left heart failure; Pulmonary Artery Denervation; Pulmonary Hypertension Due to Left Heart Disease
• Additional Relevant MeSH Terms: Heart Diseases; Respiratory Tract Diseases; Lung Diseases; Heart Failure; Hypertension; Cardiovascular Diseases; Vascular Diseases; Hypertension, Pulmonary
• Other Study ID Numbers: Pulnovo-CO-2022-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No