TROPHY PAH Pivotal Study - TReatment of Pulmonary HYpertension for PAH Pivotal Study

Study Overview
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Brief Summary
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Theis is a prospective, multicenter, blinded, randomized sham controlled pivotal clinical trial with a crossover at 6M, to assess the safety and effectiveness of pulmonary artery denervation with the TIVUS™ System in subjects with PAH. The study will assess improved and/or maintained exercise tolerance in patients with PAH through the analysis of exercise tolerance, hemodynamic changes, clinical worsening and the quality of life who got treated by the TIVUS system.

Official Title
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Clinical Evaluation of the Therapeutic Intra-Vascular Ultrasound (TIVUS™) System for Pulmonary Artery Denervation in Patients With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Device: Pulmonary artery denervation
* Device: Sham procedure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent to participate in the study obtained from the subject, according to local regulations, prior to initiation of any study mandated procedure. Male or female ≥ 18 years of age at the time of screening Subject with known pulmonary arterial hypertension (PAH), which has been diagnosed as idiopathic PAH, connective tissue disease PAH, anorexigen induced, familial PAH or corrected congenital heart defects more than 1 year prior to enrollment, confirmed by right heart catheterization performed prior to screening and showing all of the following: Mean pulmonary artery pressure (mPAP) ≥25 mmHg at rest Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ≤15 mmHg Pulmonary vascular resistance (PVR) at rest >3 Wood units (240 dyne*s/cm^5) Subject is on maximally tolerated medical therapy for PAH, as determined by his PAH physician Subject is adhering to a stable drug regimen (i.e., with no changes of dose or medication for a minimum of 3 months prior to enrollment) Subject is able to tolerate IV contrast used for the angiograms during treatment Subject is WHO functional class II or III Exclusion Criteria: Subject is treated with parenteral prostanoids and has not been on a stable dose for at least 3 months Subjects with portal-pulmonary hypertension, Group 2, 3 and 4 PH Pregnant women or women planning a pregnancy within 12 months of study enrolment Subject with significant co-morbid conditions which, at the discretion of the PI, are deemed to prohibit study entry Subject with life expectancy of less than a year Concurrent enrollment in another device or drug trial except for observational studies (unless specifically approved by the sponsor) Subject with pulmonary artery anatomy that precludes treatment with the TIVUS System Subject who has experienced a myocardial infarction, unstable angina pectoris, or a cerebrovascular accident in the previous 6 months Subject experiencing a current episode of acute decompensated heart failure Subject who has cardiac pacemakers/ICD/CRT-D that were implanted fewer than three months prior to enrollment. Subject who has implantable Cardiomems device, or other implanted device that might be contraindicated for therapeutic ultrasound energy.

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: Crossover Assignment
Interventional Model Description: Subjects will be randomized 2:1 with a sham controlled arm, with subjects and all follow up staff blinded to the subject treatment. Subjects will be unblinded at 6M, and sham control group will be offered treatment at this time if they meet the inclusion/ exclusion criteria. The primary effectiveness endpoint is measured at 6 months. The safety endpoint for blinded patients is at 6 months, and for treated patients again at 12 months.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment group<br>Pulmonary artery denervation with the TIVUS™ System will be performed immediately after the right heart catheterization and pulmonary artery angiography. | Device: Pulmonary artery denervation<br>* The TIVUS system will be used for pulmonary artery denervation using non focused ultrasound<br>|
| Sham Comparator: Sham control group<br>A sham treatment of pulmonary artery denervation with the TIVUS™ System will be performed immediately after the right heart catheterization pulmonary artery angiography. The sham procedure will be identical to the denervation procedure, with the only exception that the procedure will use a sham setting on the control console. | Device: Sham procedure<br>* A sham procedure would be performed using the TIVUS system without delivering the non focused ultrasound<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 minute walking distance (6MWD) | Statistical difference in 6MWD between the treated group and the sham control group | 6 months | 
| The rate of procedure and treatment related SAEs reported |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Statistical difference between the treated group and the sham control group in exercise tolerance as measured using the change in activity parameters using the Actigraph Centrepoint watch |  | 6 months | 
| Difference between time to clinical worsening event between the treated group and the sham control group |  | 6 months | 
| Difference between the number of clinical worsening events between the treated group and the sham control group | The definition of clinical worsening events includes: all cause death, hospitalization for worsening PAH, lung/heart transplant, arterial septostomy, initiation of parenteral prostanoid therapy, change in dose and/or number of PAH specific medication. Each event will be counted as a single event and per each patient the total number of events will be recorded | 6 months | 
| Difference between the treated group and the sham control group in resting mean right atrial pressure (mRAP) |  | 6 months | 
| Difference between the treated group and the sham control group in resting mean pulmonary artery pressure (mPAP) |  | 6 months | 
| Difference between the treated group and the sham control group in resting pulmonary vascular resistance (PVR) |  | 6 months | 
| Difference between the treated group and the sham control group in resting cardiac index (CI) |  | 6 months | 
| Difference between the treated group and the sham control group in Quality of Life (QOL) score using the SF36 questionnaire | The SF36 is a 0-100 score, the lower the score is the lower the quality of life is, so that zero is equivalent to maximum disability and a score of 100 is equivalent to no disability at all | 6 months | 
| Difference between the treated group and the sham control group of NT-pro-BNP levels |  | 6 months | 
| Difference between the treated group and the sham control group in patients' clinical pulmonary arterial hypertension condition defined by worsening of World Health Organization (WHO) functional class | PAH patient's WHO functional class is a scale of 1 to 4 based on the symptoms patient experience when doing everyday activities, were Functional Class 1 and 2 are associated with limited effect on patient activity and lower risk status, and Functional Class 3 and 4 are associated with limited activity and higher risk status | 6 months | 
| Percent of patients who improve or maintain their exercise tolerance (as measured by 6MWD and actigraphy) |  | 6 months |