Trial Outcomes & Findings for Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Pulmonary Embolism (NCT NCT02396758)

NCT ID: NCT02396758

Last Updated: 2021-07-19

Results Overview

Change from baseline in RV/LV will be determined by computed tomographic angiography (CTA).

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 131 participants
• Primary outcome timeframe: Change from Baseline to 48 hrs ± 6 hours
• Results posted on: 2021-07-19

Participant Flow

A total of 131 subjects were randomized (ITT population) and 129 were treated (safety population). Two subjects were randomized into the trial but were not treated. One subject was randomized but prior to initiation of therapy, it was discovered the subject had chronic PE and was ineligible. One subject was randomized but decompensated prior to the initiation of therapy and expired. Due to changes in the protocol, there were no subjects enrolled in the UK in Treatment Arm 4.

Participant milestones

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Overall Study STARTED	38	37	38	18
Overall Study COMPLETED	26	31	34	13
Overall Study NOT COMPLETED	12	6	4	5

Reasons for withdrawal

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Overall Study Withdrawal by Subject	2	0	0	1
Overall Study Lost to Follow-up	8	5	3	3
Overall Study Death	1	1	0	1
Overall Study Randomized but not treated	1	0	1	0

Baseline Characteristics

Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Pulmonary Embolism

Baseline characteristics by cohort

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	Total n=131 Participants Total of all reporting groups
Age, Continuous	56.0 years STANDARD_DEVIATION 13.05 • n=5 Participants	57.9 years STANDARD_DEVIATION 13.03 • n=7 Participants	57.9 years STANDARD_DEVIATION 12.3 • n=5 Participants	58.2 years STANDARD_DEVIATION 14.0 • n=4 Participants	57.4 years STANDARD_DEVIATION 12.84 • n=21 Participants
Sex: Female, Male Female	16 Participants n=5 Participants	18 Participants n=7 Participants	21 Participants n=5 Participants	7 Participants n=4 Participants	62 Participants n=21 Participants
Sex: Female, Male Male	22 Participants n=5 Participants	19 Participants n=7 Participants	17 Participants n=5 Participants	11 Participants n=4 Participants	69 Participants n=21 Participants
Race/Ethnicity, Customized Caucasian, not of Hispanic origin	24 Participants n=5 Participants	24 Participants n=7 Participants	27 Participants n=5 Participants	11 Participants n=4 Participants	86 Participants n=21 Participants
Race/Ethnicity, Customized African American, not of Hispanic origin	12 Participants n=5 Participants	10 Participants n=7 Participants	9 Participants n=5 Participants	6 Participants n=4 Participants	37 Participants n=21 Participants
Race/Ethnicity, Customized Hispanic or Latino	0 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Race/Ethnicity, Customized Asian or Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	4 Participants n=21 Participants
Region of Enrollment United States	28 participants n=5 Participants	27 participants n=7 Participants	28 participants n=5 Participants	18 participants n=4 Participants	101 participants n=21 Participants
Region of Enrollment United Kingdom	10 participants n=5 Participants	10 participants n=7 Participants	10 participants n=5 Participants	0 participants n=4 Participants	30 participants n=21 Participants

PRIMARY outcome

Timeframe: Change from Baseline to 48 hrs ± 6 hours

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

Change from baseline in RV/LV will be determined by computed tomographic angiography (CTA).

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
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 Baseline	1.53 ratio Standard Deviation 0.38	1.47 ratio Standard Deviation 0.35	1.52 ratio Standard Deviation 0.39	1.51 ratio Standard Deviation 0.58
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 at 48 ± 6 hours	-0.43 ratio Standard Deviation 0.35	-0.37 ratio Standard Deviation 0.26	-0.41 ratio Standard Deviation 0.31	-0.48 ratio Standard Deviation 0.51

PRIMARY outcome

Timeframe: Day 3 (within 72 hours after initiating the APT procedure)

Population: Safety population included all enrolled participants for whom the APT procedure was initiated.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Number of Participants With Major Bleeding Within 72 Hours After Initiating the APT Procedure	0 Participants	2 Participants	1 Participants	2 Participants

SECONDARY outcome

Timeframe: From Baseline up to Day 30

Population: ITT population included all randomized participants. Here, 'Overall number of participants analyzed' signifies evaluable participants per clinical judgement of Adjudication Committee.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=23 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=25 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=26 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Percentage of Participants With Treatment Success of an APT Procedure	73.9 Percentage of participants Interval 53.5 to 87.5	68.0 Percentage of participants Interval 48.4 to 82.8	69.2 Percentage of participants Interval 50.0 to 83.5	61.6 Percentage of participants Interval 38.6 to 79.7

SECONDARY outcome

Timeframe: 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)

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

An echocardiogram was obtained at specified timepoints to evaluate RV/LV.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Change From Baseline in RV/LV at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph. Baseline	1.19 Ratio Standard Deviation 0.25	1.20 Ratio Standard Deviation 0.23	1.13 Ratio Standard Deviation 0.17	1.20 Ratio Standard Deviation 0.35
Change From Baseline in RV/LV at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph. Change at 48 hrs post-APT	-0.23 Ratio Standard Deviation 0.22	-0.29 Ratio Standard Deviation 0.25	-0.17 Ratio Standard Deviation 0.20	-0.29 Ratio Standard Deviation 0.32
Change From Baseline in RV/LV at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph. Change at Day 30 post-APT	-0.38 Ratio Standard Deviation 0.27	-0.37 Ratio Standard Deviation 0.23	-0.30 Ratio Standard Deviation 0.20	-0.37 Ratio Standard Deviation 0.39
Change From Baseline in RV/LV at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph. Change at Day 90 follow-up	-0.41 Ratio Standard Deviation 0.29	-0.39 Ratio Standard Deviation 0.23	-0.31 Ratio Standard Deviation 0.22	-0.43 Ratio Standard Deviation 0.41
Change From Baseline in RV/LV at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph. Change at Day 365 follow-up	-0.44 Ratio Standard Deviation 0.30	-0.46 Ratio Standard Deviation 0.24	-0.35 Ratio Standard Deviation 0.15	-0.32 Ratio Standard Deviation 0.13

SECONDARY outcome

Timeframe: 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)

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

The extent of displacement of the tricuspid valves, termed as TAPSE was measured at specified timepoints using echocardiogram.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph Baseline	16.32 Millimeters Standard Deviation 5.06	17.20 Millimeters Standard Deviation 5.14	16.39 Millimeters Standard Deviation 5.36	18.02 Millimeters Standard Deviation 5.54
Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph Change at 4 hrs post-APT	0.27 Millimeters Standard Deviation 6.09	0.79 Millimeters Standard Deviation 4.86	0.51 Millimeters Standard Deviation 4.68	2.17 Millimeters Standard Deviation 4.15
Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph Change at 48 hrs post-APT	2.86 Millimeters Standard Deviation 4.56	1.75 Millimeters Standard Deviation 4.65	2.61 Millimeters Standard Deviation 4.82	3.34 Millimeters Standard Deviation 6.14
Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph Change at Day 30 post-APT	5.42 Millimeters Standard Deviation 5.59	5.39 Millimeters Standard Deviation 4.64	2.36 Millimeters Standard Deviation 4.75	2.26 Millimeters Standard Deviation 5.55
Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph Change at Day 90 follow-up	6.32 Millimeters Standard Deviation 5.64	3.69 Millimeters Standard Deviation 5.44	3.97 Millimeters Standard Deviation 6.29	2.07 Millimeters Standard Deviation 5.86
Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph Change at Day 365 follow-up	6.83 Millimeters Standard Deviation 5.88	5.22 Millimeters Standard Deviation 4.72	4.79 Millimeters Standard Deviation 5.97	3.50 Millimeters Standard Deviation 5.98

SECONDARY outcome

Timeframe: 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)

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

RVSP was measured at specified timepoints using echocardiogram.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Change From Baseline in Estimated Right Ventricular Systolic Pressure (RVSP) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph Baseline	31.59 Millimeters Standard Deviation 14.89	36.64 Millimeters Standard Deviation 19.02	35.57 Millimeters Standard Deviation 16.32	25.75 Millimeters Standard Deviation 11.09
Change From Baseline in Estimated Right Ventricular Systolic Pressure (RVSP) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph Change at 4 hrs post-APT	-2.18 Millimeters Standard Deviation 13.04	-10.87 Millimeters Standard Deviation 15.32	-3.54 Millimeters Standard Deviation 14.23	2.13 Millimeters Standard Deviation 13.74
Change From Baseline in Estimated Right Ventricular Systolic Pressure (RVSP) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph Change at 48 hrs post-APT	0.98 Millimeters Standard Deviation 9.36	-5.35 Millimeters Standard Deviation 18.45	-9.31 Millimeters Standard Deviation 10.53	-7.80 Millimeters Standard Deviation 11.69
Change From Baseline in Estimated Right Ventricular Systolic Pressure (RVSP) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph Change at Day 30 post-APT	-7.92 Millimeters Standard Deviation 11.69	-13.84 Millimeters Standard Deviation 15.47	-14.06 Millimeters Standard Deviation 15.41	-4.86 Millimeters Standard Deviation 18.07
Change From Baseline in Estimated Right Ventricular Systolic Pressure (RVSP) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph Change at Day 90 follow-up	-8.30 Millimeters Standard Deviation 15.38	-15.60 Millimeters Standard Deviation 16.90	-16.39 Millimeters Standard Deviation 24.18	-7.08 Millimeters Standard Deviation 15.30
Change From Baseline in Estimated Right Ventricular Systolic Pressure (RVSP) at Days 0, 2, 30, 90, and 365, as Assessed by Echocardiograph Change at Day 365 follow-up	-9.78 Millimeters Standard Deviation 12.79	-12.87 Millimeters Standard Deviation 13.17	-18.96 Millimeters Standard Deviation 12.23	-7.16 Millimeters Standard Deviation 16.57

SECONDARY outcome

Timeframe: 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)

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

The collapse of IVC was measured at specified timepoints using echocardiogram.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
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 Baseline	96.55 percentage of participants Interval 82.82 to 99.39	100.00 percentage of participants Interval 88.3 to 100.0	96.00 percentage of participants Interval 80.46 to 99.29	81.25 percentage of participants Interval 56.99 to 93.41
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 4 hrs post-APT	89.66 percentage of participants Interval 73.61 to 96.42	96.00 percentage of participants Interval 80.46 to 99.29	89.29 percentage of participants Interval 72.8 to 96.29	87.50 percentage of participants Interval 63.98 to 96.5
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 48 hrs post-APT	100.00 percentage of participants Interval 86.2 to 100.0	100.00 percentage of participants Interval 88.97 to 100.0	92.86 percentage of participants Interval 77.35 to 98.02	82.35 percentage of participants Interval 58.97 to 93.81
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 Day 30 post-APT	96.55 percentage of participants Interval 82.82 to 99.39	96.30 percentage of participants Interval 81.72 to 99.34	96.67 percentage of participants Interval 83.33 to 99.41	92.31 percentage of participants Interval 66.69 to 98.63
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 Day 90 post-APT	100.00 percentage of participants Interval 86.68 to 100.0	92.00 percentage of participants Interval 75.03 to 97.78	96.43 percentage of participants Interval 82.29 to 99.37	100.00 percentage of participants Interval 75.75 to 100.0
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 Day 365 post-APT	94.44 percentage of participants Interval 74.24 to 99.01	100.00 percentage of participants Interval 85.69 to 100.0	86.96 percentage of participants Interval 67.87 to 95.46	83.33 percentage of participants Interval 55.2 to 95.3

SECONDARY outcome

Timeframe: Baseline, Day 0 (within 4 hours after APT end)

Population: ITT population included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants with available pre and post PAgrams. 'Number analyzed' = participants evaluable for this outcome measure at specified timepoints.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=21 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=24 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=24 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=15 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Change From Baseline in Thrombus Burden by Miller Score as Assessed by Pulmonary Arteriogram (PAgram) at Day 0 Baseline	23.71 units on a scale Standard Deviation 3.21	23.29 units on a scale Standard Deviation 6.00	24.21 units on a scale Standard Deviation 3.01	22.93 units on a scale Standard Deviation 2.99
Change From Baseline in Thrombus Burden by Miller Score as Assessed by Pulmonary Arteriogram (PAgram) at Day 0 Change at 4 hrs post-APT	-1.00 units on a scale Standard Deviation 3.46	-2.29 units on a scale Standard Deviation 5.62	-3.11 units on a scale Standard Deviation 3.89	-9.20 units on a scale Standard Deviation 3.11

SECONDARY outcome

Timeframe: From Baseline to 48 hrs ± 6 hours

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoint.

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).

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
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 Baseline	20.72 units on a scale Standard Deviation 2.76	20.00 units on a scale Standard Deviation 4.14	20.92 units on a scale Standard Deviation 2.31	20.44 units on a scale Standard Deviation 4.12
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 Change at 48 hrs post-APT	-1.24 units on a scale Standard Deviation 1.71	-2.20 units on a scale Standard Deviation 2.29	-2.62 units on a scale Standard Deviation 2.47	-5.22 units on a scale Standard Deviation 5.83

SECONDARY outcome

Timeframe: Days 30, 90, 365

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants with evaluable data at specified timepoint.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Change in 6 Minute Walk (6MW) Distance From Day 30 to Day 90 and 365 Day 30	355.4 meters Standard Deviation 78.62	366.90 meters Standard Deviation 157.76	362.3 meters Standard Deviation 103.81	327.3 meters Standard Deviation 99.70
Change in 6 Minute Walk (6MW) Distance From Day 30 to Day 90 and 365 Change at Day 90	23.8 meters Standard Deviation 133.98	70.6 meters Standard Deviation 59.62	33.8 meters Standard Deviation 65.85	-6.3 meters Standard Deviation 62.98
Change in 6 Minute Walk (6MW) Distance From Day 30 to Day 90 and 365 Change at Day 365	21.6 meters Standard Deviation 67.33	2.0 meters Standard Deviation 175.11	57.9 meters Standard Deviation 217.99	-1.9 meters Standard Deviation 155.78

SECONDARY outcome

Timeframe: Days 30, 90, and 365

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure for specified categories

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Change in Borg Scale Score Before and After 6MW Distance Test at Days 30, 90, and 365 Day 30: Dyspnea	0.75 units on a scale Interval 0.0 to 2.0	0 units on a scale Interval 0.0 to 2.0	0.5 units on a scale Interval 0.0 to 2.0	0 units on a scale Interval 0.0 to 2.0
Change in Borg Scale Score Before and After 6MW Distance Test at Days 30, 90, and 365 Day 30: Fatigue	0.25 units on a scale Interval 0.0 to 1.3	0 units on a scale Interval 0.0 to 0.5	0 units on a scale Interval 0.0 to 1.0	0 units on a scale Interval 0.0 to 0.0
Change in Borg Scale Score Before and After 6MW Distance Test at Days 30, 90, and 365 Day 90: Dyspnea	1 units on a scale Interval 0.0 to 2.0	0.5 units on a scale Interval 0.0 to 1.0	0.5 units on a scale Interval 0.0 to 2.0	0 units on a scale Interval 0.0 to 3.0
Change in Borg Scale Score Before and After 6MW Distance Test at Days 30, 90, and 365 Day 90: Fatigue	0 units on a scale Interval 0.0 to 1.0	0 units on a scale Interval 0.0 to 1.0	0 units on a scale Interval 0.0 to 0.5	0 units on a scale Interval 0.0 to 0.5
Change in Borg Scale Score Before and After 6MW Distance Test at Days 30, 90, and 365 Day 365: Dyspnea	0.25 units on a scale Interval 0.0 to 2.0	0.5 units on a scale Interval 0.0 to 1.0	0 units on a scale Interval 0.0 to 1.0	0 units on a scale Interval 0.0 to 3.0
Change in Borg Scale Score Before and After 6MW Distance Test at Days 30, 90, and 365 Day 365: Fatigue	0 units on a scale Interval 0.0 to 1.0	0 units on a scale Interval 0.0 to 1.0	0 units on a scale Interval 0.0 to 1.0	0 units on a scale Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: Days 30, 90, and 365

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure for specified categories.

Oxygen source is categorized as room air, nasal prongs, mask, and intubated.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Number of Participants Who Received Oxygen Therapy Day 30: Before 6MW test - Room air	29 Participants	30 Participants	34 Participants	10 Participants
Number of Participants Who Received Oxygen Therapy Day 30: After 6MW test - Room air	28 Participants	30 Participants	33 Participants	10 Participants
Number of Participants Who Received Oxygen Therapy Day 90: Before 6MW test - Room air	26 Participants	30 Participants	36 Participants	10 Participants
Number of Participants Who Received Oxygen Therapy Day 90: After 6MW test - Room air	26 Participants	30 Participants	36 Participants	10 Participants
Number of Participants Who Received Oxygen Therapy Day 365: Before 6MW test - Room air	21 Participants	27 Participants	30 Participants	10 Participants
Number of Participants Who Received Oxygen Therapy Day 365: After 6MW test - Room air	21 Participants	28 Participants	30 Participants	10 Participants

SECONDARY outcome

Timeframe: Day 30, Day 365

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

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).

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=28 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=27 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=28 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Change in Participant Reported Outcomes Measurement Information System Physical Function (PROMIS-PF) 6b Score From Day 30 to Day 365 Day 30	42.00 units on a scale Standard Deviation 10.905	43.86 units on a scale Standard Deviation 7.980	44.53 units on a scale Standard Deviation 6.695	41.40 units on a scale Standard Deviation 13.238
Change in Participant Reported Outcomes Measurement Information System Physical Function (PROMIS-PF) 6b Score From Day 30 to Day 365 Change at Day 365	3.61 units on a scale Standard Deviation 7.140	4.91 units on a scale Standard Deviation 8.909	2.14 units on a scale Standard Deviation 8.184	4.39 units on a scale Standard Deviation 8.699

SECONDARY outcome

Timeframe: Day 30, Day 365

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=38 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Change in Pulmonary Embolism Quality of Life (PEmb-QOL) Score From Day 30 to Day 365 Day 30	38.30 units on a scale Standard Deviation 25.723	27.85 units on a scale Standard Deviation 20.715	24.25 units on a scale Standard Deviation 18.109	25.63 units on a scale Standard Deviation 26.923
Change in Pulmonary Embolism Quality of Life (PEmb-QOL) Score From Day 30 to Day 365 Change at Day 365	-16.79 units on a scale Standard Deviation 16.500	-8.86 units on a scale Standard Deviation 26.576	-8.75 units on a scale Standard Deviation 15.549	-12.01 units on a scale Standard Deviation 14.832

SECONDARY outcome

Timeframe: From device placement through Day 2

Population: Safety population included all enrolled participants for whom the APT procedure was initiated.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Number of Participants Who Encountered Technical Procedural Complications	0 Participants	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: From Baseline up to Day 365

Population: Safety population included all enrolled participants for whom the APT procedure was initiated.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Number of Participants With Symptomatic Recurrent Pulmonary Embolism (Per Adjudication)	0 Participants	1 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: From Baseline up to Day 365

Population: Safety population included all enrolled participants for whom the APT procedure was initiated.

Number of participants who died due to any cause for up to 365 days following the APT procedure, were reported.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=37 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Number of Participants Who Die Due to Any Cause	1 Participants	1 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: From Baseline up to Day 30

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants with evaluable data at specified timepoint.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
For Participants of UK Sites: Freedom From Major Harm Occurring Between Enrolment and 30 Days	10 Participants	9 Participants	9 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 30, Day 365

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
For Participants of UK Sites:Change in EuroQual - 5 Dimensions - 5 Levels (EQ-5D-5L) Score From Day 30 to Day 365 Day 30 - EQ-5D-5L Index Score	0.732 units on a scale Standard Deviation 0.2624	0.819 units on a scale Standard Deviation 0.195	0.934 units on a scale Standard Deviation 0.134	—
For Participants of UK Sites:Change in EuroQual - 5 Dimensions - 5 Levels (EQ-5D-5L) Score From Day 30 to Day 365 Day 30- EQ-5D-5L VAS Score	66.7 units on a scale Standard Deviation 19.04	77.8 units on a scale Standard Deviation 12.02	82.5 units on a scale Standard Deviation 7.91	—
For Participants of UK Sites:Change in EuroQual - 5 Dimensions - 5 Levels (EQ-5D-5L) Score From Day 30 to Day 365 Change at Day 365 - EQ-5D-5L Index Score	0.039 units on a scale Standard Deviation 0.0418	-0.107 units on a scale Standard Deviation 0.252	-0.042 units on a scale Standard Deviation 0.149	—
For Participants of UK Sites:Change in EuroQual - 5 Dimensions - 5 Levels (EQ-5D-5L) Score From Day 30 to Day 365 Change at Day 365 - EQ-5D-5L VAS Score	-1.6 units on a scale Standard Deviation 35.97	-0.4 units on a scale Standard Deviation 22.01	7.1 units on a scale Standard Deviation 9.12	—

SECONDARY outcome

Timeframe: From Baseline through Day 3

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
For Participants of UK Sites: Time From Hospital Admission to Diagnosis of PE	10.77 hour Standard Deviation 10.78	9.30 hour Standard Deviation 19.08	7.29 hour Standard Deviation 9.64	—

SECONDARY outcome

Timeframe: From Baseline through Day 3

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=9 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
For Participants of UK Sites: Time From Diagnostic Computed Tomography (CT) Scan to Initiation of Treatment for PE	25.33 hour Standard Deviation 12.58	24.53 hour Standard Deviation 13.93	30.08 hour Standard Deviation 18.42	—

SECONDARY outcome

Timeframe: From Baseline up to Hospital Discharge

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
For Participants of UK Sites: Time in Each Level of Care (Level 0 and 1; Level 2; and/or Level 3) Through Discharge Level 0 and 1	74.64 hour Standard Deviation 100.20	57.04 hour Standard Deviation 40.36	64.39 hour Standard Deviation 41.70	—
For Participants of UK Sites: Time in Each Level of Care (Level 0 and 1; Level 2; and/or Level 3) Through Discharge Level 2	86.77 hour Standard Deviation 45.84	62.34 hour Standard Deviation 18.82	94.56 hour Standard Deviation 84.96	—
For Participants of UK Sites: Time in Each Level of Care (Level 0 and 1; Level 2; and/or Level 3) Through Discharge Level 3	—	66.80 hour	14.10 hour Standard Deviation 2.40	—

SECONDARY outcome

Timeframe: From Baseline up to Day 365

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=10 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Healthcare Resource Utilization: Team Managing the Participant During Hospitalization - Number of Healthcare Professional (HCP) Specialties Involved. (UK Participants Only)	3.9 HCP per participant Standard Deviation 2.23	4.2 HCP per participant Standard Deviation 1.93	4.0 HCP per participant Standard Deviation 2.21	—

SECONDARY outcome

Timeframe: From Day 30 up to Day 365

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=2 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=3 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=3 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Healthcare Resource Utilization: Number of Healthcare Professionals (HCP) Visits for Venous Thromboembolism (VTE) After Hospitalization and During 12month Follow-up. (UK Participants Only)	1.5 HCP visits per participant Standard Deviation 0.71	1.3 HCP visits per participant Standard Deviation 0.58	1.0 HCP visits per participant Standard Deviation 0.00	—

SECONDARY outcome

Timeframe: From Day 30 up to Day 365

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=2 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=3 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=3 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Healthcare Resource Utilization: Number of Healthcare Professionals (HCP) Visits for Venous Thromboembolism (VTE) After Hospitalization and During 12 Month Follow-up. (UK Participants Only)	1.5 HCP visits per participant Standard Deviation 0.71	1.3 HCP visits per participant Standard Deviation 0.58	1.0 HCP visits per participant Standard Deviation 0.00	—

SECONDARY outcome

Timeframe: From Day 30 up to Day 365

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=1 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Healthcare Resource Utilization: Number of Hospital Re-Admissions After Hospitalization and During 12 Month Follow-up. (UK Participants Only)	0 Participants	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: From Day 30 through Day 365

Population: ITT population included all randomized participants. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

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.

Outcome measures

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=1 Participants 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Healthcare Resource Utilization: Duration of Hospital Re-Admissions After Hospitalization and During 12 Month Follow-up. (UK Participants Only)	—	—	2 Days per subject Standard Deviation 0	—

Adverse Events

APT/2 Hours-r-tPA/2 mg/hr/Catheter

Serious events: 11 serious events

Other events: 9 other events

Deaths: 1 deaths

APT/4 Hours-r-tPA/1 mg/hr/Catheter

Serious events: 15 serious events

Other events: 22 other events

Deaths: 1 deaths

APT/6 Hours-r-tPA/1 mg/hr/Catheter

Serious events: 12 serious events

Other events: 10 other events

Deaths: 0 deaths

APT/6 Hours-r-tPA/2 mg/hr/Catheter

Serious events: 4 serious events

Other events: 6 other events

Deaths: 1 deaths

Serious adverse events

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=37 participants at risk 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 participants at risk 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=37 participants at risk 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 participants at risk 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Blood and lymphatic system disorders Aneamia	5.4% 2/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Blood and lymphatic system disorders Anaemia postoperative	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Cardiac disorders Atrial fibrillation	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Cardiac disorders Cardiac arrest	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Cardiac disorders Cardiac failure	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Cardiac disorders Cardiac failure congestive	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Cardiac disorders Cardiogenic shock	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Gastrointestinal disorders Intra-abdominal haemorrhage	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
General disorders Chest pain	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	11.1% 2/18 • From Baseline up to Day 365
General disorders Fatigue	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
General disorders Multi-organ failure	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
General disorders Pyrexia	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Infections and infestations Appendicitis	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Infections and infestations Bronchitis	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Infections and infestations Herpes zoster disseminated	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Infections and infestations Orchitis	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Infections and infestations Pneumonia	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.4% 2/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Infections and infestations Sepsis	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Infections and infestations Septic shock	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Injury, poisoning and procedural complications Hip fracture	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Injury, poisoning and procedural complications Thermal burn	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Investigations Anticoagulation drug level below therapeutic	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Investigations Blood creatinine increased	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myeloproliferative disorder	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Nervous system disorders Cerebral haemorrhage	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Nervous system disorders Haemorrhage intracranial	0.00% 0/37 • From Baseline up to Day 365	5.4% 2/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Nervous system disorders Syncope	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Psychiatric disorders Delirium	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Psychiatric disorders Mental status changes	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Renal and urinary disorders Acute kidney injury	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Renal and urinary disorders Haematuria	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	2.7% 1/37 • From Baseline up to Day 365	5.4% 2/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/37 • From Baseline up to Day 365	5.4% 2/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Pleural effusion	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	2.7% 1/37 • From Baseline up to Day 365	8.1% 3/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Pulmonary infarction	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Respiratory failure	5.4% 2/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Skin and subcutaneous tissue disorders Skin necrosis	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Vascular disorders Deep vein thrombosis	2.7% 1/37 • From Baseline up to Day 365	5.4% 2/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Vascular disorders Haemorrhage	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Vascular disorders Hypotension	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Vascular disorders Peripheral arterial occlusive disease	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Vascular disorders Post thrombotic syndrome	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365

Other adverse events

Measure	APT/2 Hours-r-tPA/2 mg/hr/Catheter n=37 participants at risk 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/4 Hours-r-tPA/1 mg/hr/Catheter n=37 participants at risk 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/1 mg/hr/Catheter n=37 participants at risk 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.	APT/6 Hours-r-tPA/2 mg/hr/Catheter n=18 participants at risk 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. Ekosonic® Endovascular Device ultrasonic infusion catheter: r-tPA will be administered via EKOS. Recombinant tissue plasminogen activator: Recombinant tissue plasminogen activator will be administered as per the dose and schedule specified in the arm.
Blood and lymphatic system disorders Anaemia	5.4% 2/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	11.1% 2/18 • From Baseline up to Day 365
Blood and lymphatic system disorders Anaemia postoperative	2.7% 1/37 • From Baseline up to Day 365	5.4% 2/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Cardiac disorders Atrial fibrillation	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Cardiac disorders Cardiac failure congestive	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Cardiac disorders Cardiac flutter	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Congenital, familial and genetic disorders Antithrombin III deficiency	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Gastrointestinal disorders Abdominal distension	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Gastrointestinal disorders Constipation	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Gastrointestinal disorders Dyspepsia	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
General disorders Chest pain	5.4% 2/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	11.1% 2/18 • From Baseline up to Day 365
General disorders Fatigue	0.00% 0/37 • From Baseline up to Day 365	5.4% 2/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
General disorders Gravitational oedema	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
General disorders Oedema peripheral	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
General disorders Peripheral swelling	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
General disorders Pyrexia	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
General disorders Vessel puncture site haemorrhage	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Infections and infestations Cellulitis	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Infections and infestations Device related infection	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Infections and infestations Herpes zoster	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Infections and infestations Urinary tract infection	2.7% 1/37 • From Baseline up to Day 365	8.1% 3/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Infections and infestations Viral infection	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Injury, poisoning and procedural complications Laceration	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Investigations Coagulation factor VIII level increased	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Investigations Heart rate decreased	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Metabolism and nutrition disorders Diabetes mellitus	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Metabolism and nutrition disorders Type 2 diabetes mellitus	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Musculoskeletal and connective tissue disorders Bursitis	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Nervous system disorders Dizziness	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Nervous system disorders Headache	2.7% 1/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Nervous system disorders Neuralgia	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Nervous system disorders Seizure	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Nervous system disorders Syncope	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Psychiatric disorders Anxiety	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Psychiatric disorders Delirium	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Psychiatric disorders Mental Status Changes	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Renal and urinary disorders Acute kidney injury	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Renal and urinary disorders Haematuria	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Renal and urinary disorders Postoperative renal failure	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Reproductive system and breast disorders Withdrawl bleed	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/37 • From Baseline up to Day 365	5.4% 2/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/37 • From Baseline up to Day 365	5.4% 2/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.4% 2/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Pleurisy	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Pulmonary alveolar haemorrhage	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Respiratory, thoracic and mediastinal disorders Pulmonary mass	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Skin and subcutaneous tissue disorders Rash	0.00% 0/37 • From Baseline up to Day 365	8.1% 3/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Vascular disorders Deep vein thrombosis	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	5.6% 1/18 • From Baseline up to Day 365
Vascular disorders Haematoma	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365
Vascular disorders Hypertension	2.7% 1/37 • From Baseline up to Day 365	2.7% 1/37 • From Baseline up to Day 365	0.00% 0/37 • From Baseline up to Day 365	0.00% 0/18 • From Baseline up to Day 365

Additional Information

Nancy O'Connell

Boston Scientific

Phone: 763-494-2706

Email: nancy.oconnell@bsci.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place