A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH

Study Overview
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Brief Summary
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Pulmonary arterial hypertension (PAH) is characterized by premature death mainly because of progressive and severe right ventricular failure. Target drugs are reported to be associated with significant improvement of clinical outcome for PAH patients. However, previous studies using those target drugs focused on the change of 6-minute walk distance (6MWD) and or hemodynamic responses. As 6MWD has weak correlation with clinical outcome (time to clinical worsening, TTCW), benefits from target drugs for PAH patients are not clear. We previously reported the safety and efficacy of pulmonary artery denervation (PADN) for treatment of PAH patients who were unresponsive to target drugs. Hence, we design the randomized study to identify the effect of PADN on PAH.

Detailed Description
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The current study is designed as a multicenter, randomized and prospective study aiming to compare the effect of PADN on PAH patients. Based on the previous studies, the rate of pulmonary arterial hypertension (PAH)-related event was around 30% after 6-month treatment using target drugs. And our previous data showed that this PAH-related event at 6-month after PADN procedure was 15%. As a result, a total of 270 PAH patients was required, with 135 patients/per group at a ratio of 1:1 randomization. All patients underwent an 18F-DOPA PET/CT scan of pulmonary arteries and the heart, performed at basement.

Official Title
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A Prospective, Multi-center, Randomized Control Trial to Investigate the Efficacy of Pulmonary Artery Denervation to Improved Functional Capacity and Hemodynamics in Patients With Pulmonary Artery Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Procedure: PADN
* Procedure: sham PADN
* Drug: Sildenafil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study specific procedures; Men and women 18 years and older; Group I PAH, defined as a mPAP≥25mmHg, PCWP<15mmHg and PVR[The PVR =(mPAP-PCWP)/CO]>3.0 Woods unit. Exclusion Criteria: General exclusion criteria: Pregnancy and breast feeding mother; Estimated life expectancy <12 months; Scheduled major surgery in the next 6 months; Inability to follow the protocol and comply with follow-up requirements or any other reason that the investigator feels would place the patient at increased risk; Previous enrolment in this study or treatment with an investigational drug or device under another study protocol in the past 30 days. Procedural exclusion criteria: WHO group II, III, IV, V PH Severe Renal dysfunction (Ccr<30 ml/min) Blood platelet count<100,000/L Expected life span<6-month Systematical inflammation Malignant cancer(s) Tricuspid valve stenosis, Supra-pulmonary valve stenosis Allergic to studied drugs or metal materials.

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PADN + sildenafil<br>Two to three ablations at 1-15 W for 120 seconds at each point were performed in the distal bifurcation area of the main PA. | Procedure: PADN<br>* Contrast pulmonary artery angiography is performed to localize the pulmonary artery bifurcation level and to calculate the PA diameter. Once the anatomy is deemed acceptable, the radiofrequency ablation catheter is introduced into the distal bifurcation area of the main PA. The catheter is then maneuvered within the PA to allow energy delivery to ensure that the electrodes are tightly in contact with the endovascular surface. Two to three ablations at 1-15 W for 120 seconds at each point were performed in the distal bifurcation area of the main PA.<br>* Other names: Pulmonary artery denervation;Drug: Sildenafil<br>* Participants initially received 5 mg tadalafil for the first 2 weeks in the two groups. The tadalafil dose may have been up titrated to 40 mg after 2 weeks, with maximum effects being obtained. The up titrated of tadalafil to 40 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.<br>* Other names: Viagra;|
| Sham Comparator: sham PADN + sildenafil<br>The radiofrequency ablation catheter placed, no ablations. | Procedure: sham PADN<br>* The radiofrequency ablation catheter placed, no ablations for patients in the sham PADN group.<br>* Other names: sham pulmonary artery denervation;Drug: Sildenafil<br>* Participants initially received 5 mg tadalafil for the first 2 weeks in the two groups. The tadalafil dose may have been up titrated to 40 mg after 2 weeks, with maximum effects being obtained. The up titrated of tadalafil to 40 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.<br>* Other names: Viagra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary artery hypertension (PAH)- related events | Including all-cause death, lung transplantation, atrial septostomy, worsening of PAH, initiation of treatment with intravenous or subcutaneous prostacyclin | Baseline to month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-minute walk distance | The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). | Baseline to month 6 | 
| Pulmonary arterial pressure | Pulmonary arterial pressure was obtained with a 7-F flow-directed Swan-Ganz catheter at end-expiration. | Baseline to month 6 | 
| Right atrial pressure | Right atrial pressure was obtained with a 7-F flow-directed Swan-Ganz catheter at end-expiration. | Baseline to month 6 | 
| Pulmonary Vascular Resistance | PVR=[mean pulmonary arterial pressure-pulmonary artery occlusion pressure] / cardiac output | Baseline to month 6 | 
| Cardiac output | The amount of blood the heart pumps through the circulatory system in a minute. Measured by right heart catheterization. | Baseline to month 6 | 
| Trans-pulmonary pressure gradient | The transpulmonary pressure gradient (TPG), defined by the difference between mean pulmonary arterial pressure (P(pa)) and left atrial pressure (P(la). | Baseline to month 6 | 
| Diastolic pressure gradient | The diastolic pressure gradient (DPG), defined by the difference between mean pulmonary arterial pressure and PA occlusion pressure. | Baseline to month 6 | 
| Pulmonary arterial compliance | Pulmonary arterial compliance was obtained with a 7-F flow-directed Swan-Ganz catheter. | Baseline to month 6 | 
| Borg Dyspnea Index | Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). | Baseline to month 6 | 
| World Health Organization (WHO) Functional Class | WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest. | Baseline to month 6 | 
| New York functional class | NYHA Classes: I) Patients with no limitation of activities; they suffer no symptoms from ordinary activities. II) Patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion. III) Patients with marked limitation of activity; they are comfortable at rest. IV) Patients who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest. | Baseline to month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary arterial hypertension