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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment group | Active Comparator | Pulmonary artery denervation with the TIVUS™ System will be performed immediately after the right heart catheterization and pulmonary artery angiography. |
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| Sham control group | Sham Comparator | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pulmonary artery denervation | Device | The TIVUS system will be used for pulmonary artery denervation using non focused ultrasound |
|
| 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 |
| 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 |
| 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 |
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:
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:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Dalit Shav, PhD | Contact | +19784600773 | info@sonivie.com | |
| Charles S Carignan, MD | Contact | +19784600773 | info@sonivie.com |
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| ID | Term |
|---|---|
| D000081029 | Pulmonary Arterial Hypertension |
| ID | Term |
|---|---|
| D006976 | Hypertension, Pulmonary |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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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.
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| Sham procedure | Device | A sham procedure would be performed using the TIVUS system without delivering the non focused ultrasound |
|
| 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 |
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 |