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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Device: Pulmonary artery denervation; Device: Sham procedure

• Study Type: Interventional
• Enrollment (Anticipated): 205
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dalit Shav, PhD; Phone Number: +19784600773; Email: info@sonivie.com
• Study Contact Backup: Name: Charles S Carignan, MD; Phone Number: +19784600773; Email: info@sonivie.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent to participate in the study obtained from the subject, according to local regulations, prior to initiation of any study mandated procedure.
2. Male or female ≥ 18 years of age at the time of screening

3. 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)
4. Subject is on maximally tolerated medical therapy for PAH, as determined by his PAH physician
5. 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)
6. Subject is able to tolerate IV contrast used for the angiograms during treatment
7. Subject is WHO functional class II or III

Exclusion Criteria:

1. Subject is treated with parenteral prostanoids and has not been on a stable dose for at least 3 months
2. Subjects with portal-pulmonary hypertension, Group 2, 3 and 4 PH
3. Pregnant women or women planning a pregnancy within 12 months of study enrolment
4. Subject with significant co-morbid conditions which, at the discretion of the PI, are deemed to prohibit study entry
5. Subject with life expectancy of less than a year
6. Concurrent enrollment in another device or drug trial except for observational studies (unless specifically approved by the sponsor)
7. Subject with pulmonary artery anatomy that precludes treatment with the TIVUS System
8. Subject who has experienced a myocardial infarction, unstable angina pectoris, or a cerebrovascular accident in the previous 6 months
9. Subject experiencing a current episode of acute decompensated heart failure
10. Subject who has cardiac pacemakers/ICD/CRT-D that were implanted fewer than three months prior to enrollment.
11. Subject who has implantable Cardiomems device, or other implanted device that might be contraindicated for therapeutic ultrasound energy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Treatment group; Pulmonary artery denervation with the TIVUS™ System will be performed immediately after the right heart catheterization and pulmonary artery angiography.	Device: Pulmonary artery denervation; The TIVUS system will be used for pulmonary artery denervation using non focused ultrasound
SHAM_COMPARATOR: Sham control group; 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; A sham procedure would be performed using the TIVUS system without delivering the non focused ultrasound

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical change of pulmonary arterial hypertension condition defined by escalation of PAH specific drug therapy	Change in the dose of medication	6, 12, 24, 36 month
Clinical change of pulmonary arterial hypertension condition defined by escalation of PAH specific drug therapy	Change in the number of PAH specific medication	6, 12, 24, 36 month
Clinical change of pulmonary arterial hypertension condition defined by escalation of concomitant drug therapy	Change in the number of concomitant medication	6, 12, 24, 36 month
Clinical change of pulmonary arterial hypertension condition defined by escalation of concomitant drug therapy	Change in dose of a medication	6, 12, 24, 36 month
Clinical change of pulmonary arterial hypertension condition defined by change from baseline of ECG parameters demonstrating initiation or worsening of heart block	Heart block is defined as long PR interval, wide or narrow QRS complex and/or QRS complex in various leads are oriented rightward and anteriorly. Heart block will be noted as either present or not present. Any change from baseline will be noted.	6, 12, 24, 36 month
Clinical change of pulmonary arterial hypertension condition defined by change from baseline of ECG parameters indicating initiation or worsening of arrhythmia	Arrhythmia is defined when the P-P interval and/or R-R interval has differences of more than 10% and/or there are no visible P waves and/or irregularly irregular QRS complex is present. Arrhythmia will be noted as either present or not present. Any change from baseline will be noted.	6, 12, 24, 36 month
Clinical change of pulmonary arterial hypertension condition defined by change from baseline of ECG parameters indicating initiation or worsening of right ventricular hypertrophy (RVH)	Right ventricular hypertrophy is when the following are present: right axis deviation > 90 degrees, tall R-waves in RV leads; deep S-waves in LV leads, slight increase in QRS duration and ST-T changes directed opposite to QRS direction (i.e., wide QRS/T angle). Right ventricular hypertrophy will be noted as either present or not present. Any change from baseline will be noted.	6, 12, 24, 36 month
Clinical change of pulmonary arterial hypertension condition defined by change from baseline of ECG parameters indicating initiation or worsening of axis deviation	Axis deviation is present when QRS axis is greater than +90° or smaller than +30°. Axis deviation will be noted as either present or not present. Any change from baseline will be noted.	6, 12, 24, 36 month
Change from baseline of 6MWD		12, 24, 36 month
Change from baseline of NT-pro BNP levels		12, 24, 36 month
Change from baseline of actigraphy measures as will be measured using an Actigraph Centrepoint Insight Activity monitor		12, 24, 36 month
Change from baseline of Quality of Life (QOL) score using the SF36 questionnaire	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	12, 24, 36 month
Survival or the cause of mortality		6, 12, 24, 36 month
Amount of Hospitalizations events due to pulmonary arterial hypertension		6, 12, 24, 36 month
Number of patients with clinical worsening of PAH condition resulting with interventional or surgical procedures, such as heart/lung transplant or atrial septostomy.		6, 12, 24, 36 month
Clinical change of pulmonary arterial hypertension condition defined by worsening of patients' 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	12, 24, 36 month
Clinical change of pulmonary arterial hypertension condition defined by escalation of concomitant drug therapy	Change in the dose of medication	6, 12, 24, 36 month
Clinical change of pulmonary arterial hypertension condition defined by escalation of concomitant drug therapy	Change in the number of concomitant medications	6, 12, 24, 36 month

Collaborators and Investigators

• Sponsor: SoniVie Inc.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): January 1, 2023
• Primary Completion (ANTICIPATED): December 1, 2023
• Study Completion (ANTICIPATED): December 1, 2025

Study Registration Dates

• First Submitted: September 8, 2020
• First Submitted That Met QC Criteria: September 24, 2020
• First Posted (ACTUAL): September 30, 2020

Study Record Updates

• Last Update Posted (ACTUAL): April 1, 2022
• Last Update Submitted That Met QC Criteria: March 30, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: CLNS03-001 - TROPHY 3 Protocol

Drug and device information, study documents

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