Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Pulmonary Embolism

Study Overview
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Brief Summary
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The objective is to determine the optimum dose of thrombolytic and duration of the ultrasound procedure (together defined as the APT Procedure) as a treatment for acute submassive pulmonary embolism (PE). Symptomatic submassive PE are participants with acute (less than or equal to [≤]14 days) PE with normal systemic arterial blood pressure (greater than [>] 90 mmHg) and evidence of RV dysfunction (right ventricular to left ventricular diameter ratio, that is; RV/LV ratio greater than or equal to [≥] 0.9). Participants with submassive PE will be randomized to one of four APT treatment groups: ultrasound of 2 and 6 hours (hrs) with r-tPA 2 milligrams (mg)/hr/catheter and ultrasound 4 and 6 hours with r-tPA, 1 mg/hr/catheter. On 08 June 2016, randomization into treatment group 4 (APT/6 hours-r-tPA/2 mg/hr/catheter) was closed following a reported intracranial hemorrhage (ICH) and death in a study participant in this arm.

Detailed Description
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This study is designed to investigate the lowest recombinant tissue plasminogen activator (r-tPA) dose-ultrasound treatment time required to achieve the same reductions in thrombus burden and associated improvement in physiologic parameters demonstrated in ULTIMA (EKOS 08 [NCT01166997]) and SEATTLE II (EKOS 09 [NCT01513759]). Results of this study are intended to inform the study design for further studies of the Acoustic Pulse Thrombolysis (APT) Procedure. Analysis of the first 100 evaluable participants in the United States study suggested a degree of equipoise between treatment groups 1, 2 and 3 of the protocol and therefore the sample size has been extended and additional sites in the United Kingdom (UK) National Health Service included, with a view to adding to the findings of the OPTALYSE study from sites in the UK and increasing the number of participants treated by treatment protocol.

Official Title
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Study of the OPTtimum Duration of Acoustic Pulse ThromboLYSis ProcEdure in the Treatment of Acute Submassive Pulmonary Embolism

Conditions
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Pulmonary Embolism and Thrombosis

Intervention / Treatment
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* Device: Ekosonic® Endovascular Device ultrasonic infusion catheter
* Biological: Recombinant tissue plasminogen activator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female greater than or equal to (≥) 18 years of age and less than or equal to (≤) 75 years of age. CTA evidence of proximal PE (filling defect in at least one main or lobar pulmonary artery). PE symptom duration ≤14 days. Submassive PE: RV/LV diameter ≥ 0.9 from CTA and hemodynamically stable. For Participants in UK Sites: Submassive PE: RV/LV diameter ≥ 0.9 from CTA, hemodynamically stable and an elevated biomarker. Must be treated within 48 hours of diagnosis of PE by CTA. Signed Informed consent obtained from subject or Legally Authorized Representative. Exclusion Criteria: Stroke or transient ischemic attack (TIA), head trauma, or other active intracranial or intraspinal disease within one year. Recent (within one month) or active bleeding from a major organ. Major surgery within seven days of screening for study enrollment. Clinician deems the subject high-risk for catastrophic bleeding. History of heparin-induced thrombocytopenia (HIT). Catheter-based pharmacomechanical treatment for PE within 3 days of study enrollment. Systolic blood pressure (SBP) less than 90 mm Hg and/or use of vasopressors. Cardiac arrest (including pulseless electrical activity and asystole) requiring active cardiopulmonary resuscitation (CPR). Evidence of irreversible neurological compromise. Life expectancy < one year. For Participants in UK Sites: Life expectancy < one year or enrollment in hospice care. Use of thrombolytics or glycoprotein IIb/IIIa antagonists within 3 days prior to inclusion in the study. Out-of-Range Laboratory Values: Hematocrit < 30%, Platelets < 100 thousand/microliter (μL), International normalized ratio (INR) > 3. Creatinine outside the normal range for the treating institution. Participant is pregnant (positive pregnancy test; women of childbearing capacity must be tested) or breast feeding. Active cancer (metastatic, progressive, or treated within the last 6 months). Exception: participants with non-melanoma primary skin cancers are eligible to participate in the study. Known allergy, hypersensitivity, or thrombocytopenia from heparin, r-tPA, or iodinated contrast except for mild-moderate contrast allergies for which steroid pre-medication can be used. History of any hematologic disease potentially involving abnormal platelet number or function.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APT/2 Hours-r-tPA/2 mg/hr/Catheter<br>A total of 4 or 8 mg r-tPA (as 2 mg/hour [hr]/catheter) will be delivered through Ekosonic® Endovascular Device (EKOS) ultrasonic infusion catheter for 2 hrs. | Device: Ekosonic® Endovascular Device ultrasonic infusion catheter<br>* r-tPA will be administered via EKOS.<br>* Other names: EKOS;Biological: Recombinant tissue plasminogen activator<br>* Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.<br>* Other names: r-tPA;|
| Experimental: APT/4 Hours-r-tPA/1 mg/hr/Catheter<br>A total of 4 or 8 mg r-tPA (as 1 mg/hr/catheter) will be delivered through EKOS ultrasonic infusion catheter for 4 hrs. | Device: Ekosonic® Endovascular Device ultrasonic infusion catheter<br>* r-tPA will be administered via EKOS.<br>* Other names: EKOS;Biological: Recombinant tissue plasminogen activator<br>* Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.<br>* Other names: r-tPA;|
| Experimental: APT/6 Hours-r-tPA/1 mg/hr/Catheter<br>A total of 6 or 12 mg r-tPA (as 1 mg/hr/catheter) will be delivered through EKOS ultrasonic infusion catheter for 6 hrs. | Device: Ekosonic® Endovascular Device ultrasonic infusion catheter<br>* r-tPA will be administered via EKOS.<br>* Other names: EKOS;Biological: Recombinant tissue plasminogen activator<br>* Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.<br>* Other names: r-tPA;|
| Experimental: APT/6 Hours-r-tPA/2 mg/hr/Catheter<br>A total of 12 or 24 mg r-tPA (as 2 mg/hr/catheter) will be delivered through EKOS ultrasonic infusion catheter for 6 hrs. | Device: Ekosonic® Endovascular Device ultrasonic infusion catheter<br>* r-tPA will be administered via EKOS.<br>* Other names: EKOS;Biological: Recombinant tissue plasminogen activator<br>* Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.<br>* Other names: r-tPA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Right Ventricle (RV) Diameter-to-Left Ventricle (LV) Diameter Ratio to 48 ± 6 Hours After the Start of the APT Procedure | Change from baseline in RV/LV will be determined by computed tomographic angiography (CTA). | Change from Baseline to 48 hrs ± 6 hours | 
| Number of Participants With Major Bleeding Within 72 Hours After Initiating the APT Procedure | Criteria for major bleeding events, as defined by the International Society on Thrombosis and Haemostasis (ISTH): 1. Fatal bleeding and/or; 2. Symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome) and/or; 3. Bleeding causing a fall in hemoglobin level of 20 grams/liter (g/L) or more, or leading to transfusion of two or more units of whole blood or red blood cells. | Day 3 (within 72 hours after initiating the APT procedure) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment Success of an APT Procedure | Treatment success of an APT procedure will be assessed by an Adjudication Committee that is blinded to the participant's treatment. The criteria for treatment success are defined as follows: A decrease in RV/LV from baseline to 48 hours after the start of the procedure of at least 0.2; and no life-threatening adverse events related to PE or its treatment through 30 days after the start of the APT procedure. | From Baseline up to Day 30 | 
| Change From Baseline in RV/LV at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph. | An echocardiogram was obtained at specified timepoints to evaluate RV/LV. | Baseline (Day -2 [within -48 hrs of APT start]), Day 0 (within 4 hours after APT end), Day 2 (48 [± 6] hrs of APT start), Day 30 (± 5 days), Day 90 (± 10 days) and Day 365 (± 14 days) | 
| Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph | The extent of displacement of the tricuspid valves, termed as TAPSE was measured at specified timepoints using echocardiogram. | Baseline (Day -2 [within -48 hrs of APT start]), Day 0 (within 4 hours after APT end), Day 2 (48 [± 6] hrs of APT start), Day 30 (± 5 days), Day 90 (± 10 days) and Day 365 (± 14 days) | 
| Change From Baseline in Estimated Right Ventricular Systolic Pressure (RVSP) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph | RVSP was measured at specified timepoints using echocardiogram. | Baseline (Day -2 [within -48 hrs of APT start]), Day 0 (within 4 hours after APT end), Day 2 (48 [± 6] hrs of APT start), Day 30 (± 5 days), Day 90 (± 10 days) and Day 365 (± 14 days) | 
| Percentage of Participants With Collapse of the Inferior Vena Cava (IVC) With Respiration at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph | The collapse of IVC was measured at specified timepoints using echocardiogram. | Baseline (Day -2 [within -48 hrs of APT start]), Day 0 (within 4 hours after APT end), Day 2 (48 [± 6] hrs of APT start), Day 30 (± 5 days), Day 90 (± 10 days) and Day 365 (± 14 days) | 
| Change From Baseline in Thrombus Burden by Miller Score as Assessed by Pulmonary Arteriogram (PAgram) at Day 0 | Miller score is composed of a score for arterial obstruction (objective score) and a score for reduction of peripheral perfusion of lungs (subjective evaluation). Right pulmonary artery (PA) is assigned 9 segmental arteries (3 to the upper, 2 to the middle, and 4 to the lower lobe), and left PA is assigned only 7 segmental arteries (2 to the upper, 2 to the lingula, and 3 to the lower lobe). Presence of segmental emboli, regardless of the degree of obstruction, is scored 1 point. Proximal emboli to the segmental level are scored a value equal to the number of segmental arteries arising distally. Maximal score of obstruction=16. Reduction of peripheral perfusion is scored by dividing each lung into upper, middle, and lower zones and by using a 4-point scale: 0=normal perfusion; 1=moderately reduced perfusion; 2=severely reduced perfusion; 3=no perfusion. Maximal score of reduced perfusion=18. Thus, the maximal Miller score =34. Higher Miller score=more thrombus burden. | Baseline, Day 0 (within 4 hours after APT end) | 
| Change From Baseline in Thrombus Burden by Modified Miller Score as Assessed by CTA Scan at 48 ± 6 Hours After the Start of the APT Procedure | Modified miller score quantifies thrombus burden on CTA scans. Each segmental pulmonary artery (9 on the right, 7 on the left) that is fully or partly occluded by thrombus is given a score of 1. Any further proximal involves vessels score the number of segmental branches distal to that vessel, thereby giving a modified miller score of 0 (no thrombus) to 16 (thrombus in all segmental arteries or saddle embolism). | From Baseline to 48 hrs ± 6 hours | 
| Change in 6 Minute Walk (6MW) Distance From Day 30 to Day 90 and 365 | The 6 minute Walk Test is a measure of functional exercise capacity. Participants will be asked to walk as far as possible within a 6-minute period, and the distance covered at the end will be noted and recorded. | Days 30, 90, 365 | 
| Change in Borg Scale Score Before and After 6MW Distance Test at Days 30, 90, and 365 | Borg is a 10-point scale rating the maximum level of dyspnea (difficulty in breathing) and fatigue experienced before and after the 6MW distance test. Scores ranges from 0 (for no shortness of breath, or no fatigue) to 10 (for the greatest shortness of breath ever experienced, or maximum amount of fatigue felt). Higher scores indicates worse outcome. | Days 30, 90, and 365 | 
| Number of Participants Who Received Oxygen Therapy | Oxygen source is categorized as room air, nasal prongs, mask, and intubated. | Days 30, 90, and 365 | 
| Change in Participant Reported Outcomes Measurement Information System Physical Function (PROMIS-PF) 6b Score From Day 30 to Day 365 | PROMIS-PF 6b questionnaire is developed by including 2-items from item-improved Health Assessment Questionnaire (HAQ) and 4-items from item-improved Physical Function-10 (PF-10) instruments. Both of these instruments assess participant's present abilities. Both Item-Improved instruments have 5-response options: HAQ - 1=without any difficulty, 2=with a little difficulty, 3=with some difficulty, 4=with much difficulty, 5=unable to do; PF-10 - 1=not at all, 2=very little, 3=somewhat, 4=quite a lot, 5=cannot do. Total score is the average of all scores of component items, which ranges from 0 (no disability) to 100 (worst disability). | Day 30, Day 365 | 
| Change in Pulmonary Embolism Quality of Life (PEmb-QOL) Score From Day 30 to Day 365 | The PEmb-QoL questionnaire contains 6 dimensions that has been created based on the contents of the items, frequency of complaints (Question [Q]1; score range: 1 [every day] to 5 [never]), activities of daily living (ADL) limitations (Q4; score range: 1 [limited a lot] to 3 [not at all]), work-related problems (Q5; response: yes/no), social limitations (Q6; score range: 1 [not at all] to 5 [extremely]), intensity of complaints (Q7 [pain in chest/shoulders]/8 [breathlessness]; score range: 1 [none] to 6 [very serious]) and emotional complaints (Q9; score range: 1 [at all times] to 6 [none of the times]). Total Score for all dimensions are calculated by the sum of the scores for each item of the dimension divided by the number of items. Total score ranges from 1 (better quality of life) to 100 (worst quality of life). Higher scores indicate poorer outcome (decreased quality of life). Questions 1, 4, 5, and 9 are reverse scored. Questions 2 and 3 provide descriptive information. | Day 30, Day 365 | 
| Number of Participants Who Encountered Technical Procedural Complications | Technical complications associated with the use of the EKOS device will be recorded during catheter placement in the pulmonary artery and during the infusion procedure. | From device placement through Day 2 | 
| Number of Participants With Symptomatic Recurrent Pulmonary Embolism (Per Adjudication) | Number of participants with symptomatic recurrent pulmonary embolism up to 365 days following the APT procedure, were reported. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | From Baseline up to Day 365 | 
| Number of Participants Who Die Due to Any Cause | Number of participants who died due to any cause for up to 365 days following the APT procedure, were reported. | From Baseline up to Day 365 | 
| For Participants of UK Sites: Freedom From Major Harm Occurring Between Enrolment and 30 Days | Number of UK participants with freedom from major harms assessed by Safety Monitor using the following criteria: 1) Mortality - all cause and PE related; 2) Cardiovascular (CV) collapse defined as one or more of the following: a) Greater than (>) 40 millimeters of mercury (mmHg) drop in systolic blood pressure (SBP) (for >15 minutes from documented blood pressure as an in-patient) despite intravenous (IV) fluid challenge and absence of new atrial arrhythmia; b) Requirement for emergency systemic thrombolysis; c) Requirement for emergency surgical embolectomy ; d) Requirement for vasopressors; e)and/or Intubation/Ventilation; 3) Major bleeding per ISTH; 4) Recurrent PE (confirmed by imaging); and/or 5) Surgical correction of device related complication. Due to changes in the protocol, there were no subjects enrolled in the UK in Treatment Arm 4. | From Baseline up to Day 30 | 
| For Participants of UK Sites:Change in EuroQual - 5 Dimensions - 5 Levels (EQ-5D-5L) Score From Day 30 to Day 365 | The EQ-5D-5L consists of 2 parts - the descriptive system (Index Score) and the EQ Visual Analogue scale (VAS Score). The EQ-5D-5L descriptive system comprises 5 dimensions (mobility, self care, usual activities, pain/discomfort, anxiety/depression) and each dimension has 5 levels: no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme problems (5). Each one digit number expressing the level selected for each dimension is combined into a 5-digit number describing the respondent's heath state. These 5-digit numbers are converted into an index value, where 1 represents full health and 0 is equivalent to death. The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale with 100 being the best health imaginable and 0 being the worst health imaginable. Due to changes in the protocol, there were no subjects enrolled in the UK in Treatment Arm 4. | Day 30, Day 365 | 
| For Participants of UK Sites: Time From Hospital Admission to Diagnosis of PE | Duration of time between hospital admission and the diagnosis of pulmonary embolism (PE) measured in hours for UK participants.Due to changes in the protocol, there were no subjects enrolled in the UK in Treatment Arm 4. | From Baseline through Day 3 | 
| For Participants of UK Sites: Time From Diagnostic Computed Tomography (CT) Scan to Initiation of Treatment for PE | Duration of time between Diagnostic Computed Tomography (CT) Scan to Initiation of Treatment for pulmonary embolism (PE) measured in hours for UK Participants. Due to changes in the protocol, there were no subjects enrolled in the UK in Treatment Arm 4. | From Baseline through Day 3 | 
| For Participants of UK Sites: Time in Each Level of Care (Level 0 and 1; Level 2; and/or Level 3) Through Discharge | Levels are defined according to National Framework Document: Level 0 - normal acute ward care (patients whose needs can be met through normal ward care in an acute hospital), Level 1 - acute ward care, with additional advice and support from the critical care team (Patients at risk of their condition deteriorating, or those recently relocated from higher levels of care, whose needs can be met on an acute ward with additional advice from a critical care team), Level 2 - more detailed observation or intervention (requiring more detailed observation or intervention including support for a single failing organ system or post-operative care and those 'stepping down' from higher levels of care) and Level 3 - advanced respiratory support alone, or basic respiratory support together with support of at least two organ systems (includes all complex patients requiring support for multi-organ failure). Due to changes in the protocol, there were no subjects enrolled in the UK in Treatment Arm 4. | From Baseline up to Hospital Discharge | 
| Healthcare Resource Utilization: Team Managing the Participant During Hospitalization - Number of Healthcare Professional (HCP) Specialties Involved. (UK Participants Only) | Number of Healthcare Professional (HCP) Specialists involved with care of participant during hospitalization of UK participants.Due to changes in the protocol, there were no subjects enrolled in the UK in Treatment Arm 4. | From Baseline up to Day 365 | 
| Healthcare Resource Utilization: Number of Healthcare Professionals (HCP) Visits for Venous Thromboembolism (VTE) After Hospitalization and During 12month Follow-up. (UK Participants Only) | Number of Healthcare Professional (HCP) Specialists involved with care of participant for Venous Thromboembolism (VTE) after hospitalization through 365 days for UK participants. Due to changes in the protocol, there were no subjects enrolled in the UK in Treatment Arm 4. | From Day 30 up to Day 365 | 
| Healthcare Resource Utilization: Number of Healthcare Professionals (HCP) Visits for Venous Thromboembolism (VTE) After Hospitalization and During 12 Month Follow-up. (UK Participants Only) | Number of Healthcare Professional (HCP) Specialists involved with care of participant for Venous Thromboembolism (VTE) after hospitalization through 365 days for UK participants. Due to changes in the protocol, there were no subjects enrolled in the UK in Treatment Arm 4. | From Day 30 up to Day 365 | 
| Healthcare Resource Utilization: Number of Hospital Re-Admissions After Hospitalization and During 12 Month Follow-up. (UK Participants Only) | Number of Hospital Re-Admissions after hospitalization and during 12 month follow-up for UK Participants. Due to changes in the protocol, there were no subjects enrolled in the UK in Treatment Arm 4. | From Day 30 up to Day 365 | 
| Healthcare Resource Utilization: Duration of Hospital Re-Admissions After Hospitalization and During 12 Month Follow-up. (UK Participants Only) | Duration of Hospital Re-Admissions after hospitalization and during 12 month follow-up for UK Participants. Due to changes in the protocol, there were no subjects enrolled in the UK in Treatment Arm 4. | From Day 30 through Day 365 |