Retrospective and Prospective International EkoSonic® Registry of the Treatment and Clinical OUTcomes of Patients With Pulmonary Embolism
Conditions: Pulmonary Embolism and Thrombosis
Sponsor: Boston Scientific Corporation

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
Protocol Number: 
BTG-001653-01 
Protocol Short Title: 
KNOCOUT PE 
Protocol Name: 
Retrospective and prospective international EKoSoNic® registry Of 
the treatment and Clinical OUTcomes of patients with Pulmonary 
Embolism 
Sponsor: 
EKOS Corporation, a BTG International group company  
11911 North Creek Parkway S. 
Bothell, WA 98011, USA 
Coordinating 
Principal Investigator: 
Keith Sterling, MD 
Inova Alexandria Hospital 
4320 Seminary Road 
Alexandria, VA 22304, USA 
Phone: +1.703.504.7950 
E-mail: keithmsterling@gmail.com  
Medical Monitor: 
Simon Hogan, MD 
Provensis Ltd, a BTG International group company 
Lakeview, Riverside Way, Watchmoor Park 
Camberley Surrey, GU15 3YL, UK 
Phone: +44.1276.902.020 
E-mail: Simon.Hogan@btgplc.com 
Investigational 
Product (IP) 
EkoSonic® Endovascular System (EKOS) 
Clinicaltrials.gov 
identifier 
NCT03426124 
EudraCT Number 
2018-001235-46 
This document is the confidential property of Sponsor. No part of it may be transmitted, reproduced, published, or 
used by other persons without prior written permission. 
 
 
VERSION 
NUMBER 
APPROVAL 
DATE 
BRIEF DESCRIPTION OF CHANGES 
1.0 
22-Nov-2017 
Initial Release. 
1.1 
1-Dec-2017 
Protocol amended to increase number of sites from 50 to 100. 
1.2 
4-Jan-2018 
Protocol amended to include electronic patient reported 
outcomes. 
2.0 
9-May-2018 
Protocol amended to modify eligibility criteria, clarify 
assessments, and time points for follow up. Added details of 
planned analysis.  
2.0.EMEA 
27-Aug-2018 
Removal of appendices; addition of OPTALYSE PE manuscript 
reference; consistency in device name; more inclusive 
regulatory focus.  
2.1.EMEA 
19-Oct-2017 
Removal of r-tPA; change to physician-specified fluid to bring in 
alignment with IFU. 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
Registry Contacts 
Steering Committee 
Principal Investigators listed below, and, 
 
Samuel Z. Goldhaber, MD  
Brigham and Women’s Hospital 
75 Francis Street  
Boston, MA  02115, USA 
Phone: +1 857 307 1932 
E-mail: sgoldhaber@partners.org 
 
Stavros V. Konstantinides, MD, PhD, FESC, FRCP(Glasg)  
Center for Thrombosis and Hemostasis (CTH) 
Johannes Gutenberg University Mainz 
Langenbeckstr. 1, Bldg. 403 
55131 Mainz, Germany 
Phone: +49 6131 17 6255 
Fax: +49 6131 17 3456 
E-mail: stavros.konstantinides@unimedizin-mainz.de 
 
Nicolas Meneveau, MD, PhD 
CHU Besançon 
3 Boulevard Alexandre Fleming 
25030 Besançon, France 
E-mail: nicolas.meneveau@univ-fcomte.fr 
 
Victor F. Tapson, MD, FCCP, FRCP 
Pulmonary Critical Care Medicine 
Cedars-Sinai 
8536 Wilshire Blvd., Suite 201 
Los Angeles, CA 90211, USA 
E-mail: victor.tapson@cshs.org 
 
 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
Principal Investigators 
Prospective US: 
Keith Sterling, MD 
Inova Alexandria Hospital 
4320 Seminary Road 
Alexandria, VA 22304, USA 
Phone: +1 703 504 7950 
E-mail: keithmsterling@gmail.com  
 
Prospective Europe: 
Nils Kucher, MD  
University Clinic of Angiology 
University Hospital Zurich 
8091 Zurich, Switzerland 
E-mail: nils.kucher@usz.ch 
 
Retrospective Acute: 
Robert Maholic, DO 
UPMC Hamot 
201 State Street 
Erie, PA 16550, USA 
Phone: +1 814 456 8980 
E-mail: maholicrl@upmc.edu  
 
Retrospective Long-term: 
Mahir Elder, MD 
Detroit Medical Center 
3990 John Road Ste. 9370 
Detroit, MI 48201, USA 
Phone: +1 313 993 7777 
E-mail: melder@dmc.org 
 
Special Assessments – Echocardiography: 
Gregory Piazza, MD, MS 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA  02115, USA 
Phone: +1 617 732 6984 
E-Mail: gpiazza@partners.org 
 
Integrated Bedside Assessments: 
Andrew SP Sharp, MD 
Department of Cardiology  
Royal Devon and Exeter Hospital and University of Exeter 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
Barrack Road, Exeter  EX2 5DW, UK 
Phone 0044 1392 403990 
E-mail: andrew.sharp5@nhs.net 
 
High Risk Populations: 
Noah Jones, MD 
Mount Carmel Health System 
85 McNaughten Road, Suite 300 
Columbus, OH 43213, USA 
Phone: +1 703 220 8103 
E-mail: noahj4@gmail.com 
Registry Management 
Leslie Cass 
EKOS Corporation, a BTG International group company 
11911 North Creek Parkway S. 
Bothell, WA  98011-8809, USA 
P: +1 425 415 3113 
F: +1 425 415 3107 
M: +1 206 641 4529 
E-mail:  Leslie.Cass@gmail.com 
 
Timothy Keo 
EKOS Corporation, a BTG International group company 
11911 North Creek Parkway S. 
Bothell, WA  98011-8809, USA 
P: +1 425 415 3113 
F: +1 425 415 3107 
M: +1 562 508 7301 
E-mail:  Timothy.Keo@btgplc.com 
EDC Provider/Support 
DATATRAK International Inc. 
5900 Landerbrook Dr., Suite 170 
Mayfield Heights, OH 44124, USA 
 
 
 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
PROTOCOL APPROVAL & RELEASE SIGNATURE PAGE 
Protocol Number: 
BTG-001653-01 
Protocol Short Title: 
KNOCOUT PE 
Protocol Name: 
Retrospective and prospective international EKoSoNic® registry 
study Of the treatment and Clinical OUTcomes of patients with 
Pulmonary Embolism 
Protocol Version: 
2.1.EMEA 
Protocol Approval 
Date: 
19-Oct-2018 
The above-referenced protocol was reviewed and approved for release by the following: 
 
Approver 
 
Signature 
 
Date (DD/MMM/YYYY) 
Coordinating Principal 
Investigator 
 
 
Sponsor: VP, Clinical 
Development 
 
 
Sponsor: Study Manager 
 
 
Sponsor: Project Physician 
 
 
Sponsor: Statistician 
 
 
 
 
 
 
 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
INVESTIGATOR PROTOCOL REVIEW STATEMENT 
Protocol Number: 
BTG-001653-01 
Protocol Short Title: 
KNOCOUT PE 
Protocol Name: 
Retrospective and prospective international EKoSoNic® registry 
study Of the treatment and Clinical OUTcomes of patients with 
Pulmonary Embolism 
Protocol Version: 
2.1.EMEA 
Protocol Approval 
Date: 
19-Oct-2018 
The investigational site Principal Investigator (undersigned) hereby declares that he/she has 
read this protocol and agrees to its contents. 
The undersigned confirms that the registry will be conducted and documented in accordance 
with the Declaration of Helsinki, this protocol, standards of Good Clinical Practice, applicable 
laws and regulatory requirements specified in the protocol, and the stipulations of the Clinical 
Trial Agreement. 
By written consent to this protocol, the Principal Investigator agrees to the above and to fully 
cooperate with all monitoring and audits in relation to this registry by allowing direct access to all 
documentation, including source data, by authorized individuals representing EKOS Corporation, 
BTG International, the relevant institutional review board/ethics committee (IRB/EC) and/or by 
regulatory authorities. 
 
Investigator Name (please print):   _________________________________________ 
 
Investigator Signature:   _________________________________________ 
 
Date (DD/MMM/YYYY):   _________________________________________ 
 
 
 
 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
TABLE OF CONTENTS & LIST OF TABLES 
Registry Contacts _____________________________________________________ 2 
PROTOCOL APPROVAL & RELEASE SIGNATURE PAGE ____________________ 5 
INVESTIGATOR PROTOCOL REVIEW STATEMENT _________________________ 6 
TABLE OF CONTENTS & LIST OF TABLES ________________________________ 7 
1. TERMS, ACRONYMS, ABREVIATIONS________________________________ 10 
2. PROTOCOL SYNOPSIS ____________________________________________ 12 
3. SCHEDULE OF REGISTRY ASSESSMENTS – PROSPECTIVE _____________ 16 
4. BACKGROUND___________________________________________________ 17 
4.1 
Pulmonary Embolism (PE) ____________________________________________ 17 
4.2 
EkoSonic® Endovascular System (EKOS) Product Description ______________ 18 
4.2.1 EKOS Intended Use ______________________________________________________ 18 
4.2.2 EKOS Description ________________________________________________________ 18 
4.2.3 EKOS Regulatory Status ___________________________________________________ 19 
4.3 
EKOS Clinical Summary in Pulmonary Embolism _________________________ 19 
5. REGISTRY OBJECTIVE AND PURPOSE ______________________________ 20 
5.1 
Objectives __________________________________________________________ 20 
5.2 
Design _____________________________________________________________ 20 
5.3 
Outcome Measures __________________________________________________ 21 
6. SUBJECT SELECTION _____________________________________________ 21 
6.1 
Registry Population __________________________________________________ 21 
6.2 
Subject Selection ____________________________________________________ 22 
6.2.1 Inclusion Criteria _________________________________________________________ 22 
6.2.2 Exclusion Criteria ________________________________________________________ 22 
6.3 
Subject Completion __________________________________________________ 22 
6.4 
Withdrawal __________________________________________________________ 22 
7. CASE DATA COLLECTION – RETROSPECTIVE ________________________ 23 
7.1 
Protected Health Information (PHI) Authorization  Waiver __________________ 23 
8. MEASUREMENTS – RETROSPECTIVE _______________________________ 23 
8.1 
Screening/Baseline __________________________________________________ 23 
8.2 
Procedure __________________________________________________________ 23 
8.3 
Post-Procedure ______________________________________________________ 24 
8.4 
Long Term Health Data _______________________________________________ 24 
9. TREATMENT OF SUBJECTS - PROSPECTIVE _________________________ 24 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
9.1 
EkoSonic® Endovascular System (EKOS) ________________________________ 24 
9.1.1 APT Procedure __________________________________________________________ 24 
9.1.2 Post-treatment Management ________________________________________________ 25 
9.1.3 Duration of Treatment and Follow-up _________________________________________ 25 
9.1.4 Adjunctive Interventions ___________________________________________________ 25 
10. 
MEASUREMENTS AND EVALUATIONS - PROSPECTIVE _______________ 25 
10.1 
Screening/Baseline (Day -1) ___________________________________________ 25 
10.2 
Procedure Visit (Day 0) _______________________________________________ 26 
10.3 
Post Procedure Assessments__________________________________________ 26 
10.4 
Follow-Up __________________________________________________________ 26 
11. 
Evaluations ____________________________________________________ 27 
11.1 
Informed Consent Process ____________________________________________ 27 
11.2 
Eligibility Review ____________________________________________________ 27 
11.3 
Assignment of Subject Identification Number ____________________________ 27 
11.4 
Demographics _______________________________________________________ 28 
11.5 
Physical Examination_________________________________________________ 28 
11.6 
Vital Signs __________________________________________________________ 28 
11.7 
Anticoagulation and Concomitant Medications ___________________________ 28 
11.8 
Quality of Life Assessments: PEmb-QoL and EQ-5D-5L ____________________ 28 
11.9 
Integrated Bedside Assessment ________________________________________ 28 
12. 
SAFETY REPORTING ____________________________________________ 29 
12.1 
Definitions __________________________________________________________ 29 
12.1.1 
Adverse Event _________________________________________________________ 29 
12.1.2 
Serious Adverse Event (SAE) _____________________________________________ 29 
12.1.3 
Unexpected Adverse Event _______________________________________________ 30 
12.1.4 
Pre-Existing Medical Condition ____________________________________________ 30 
12.1.5 
Device Failures and Malfunctions __________________________________________ 30 
12.1.6 
Major Bleeding ________________________________________________________ 30 
12.2 
Reporting Requirements ______________________________________________ 30 
13. 
STATISTICAL CONSIDERATIONS __________________________________ 31 
13.1 
Statistical Analysis ___________________________________________________ 31 
13.2 
Determination of Sample Size __________________________________________ 31 
13.3 
Analysis Populations _________________________________________________ 31 
13.4 
Patient Disposition ___________________________________________________ 32 
13.5 
Baseline and Demographics Characteristics _____________________________ 32 
13.6 
Measurement of APT treatment ________________________________________ 32 
13.7 
Efficacy Outcome Measures Analyses __________________________________ 32 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
13.8 
Additional Outcome Analyses _________________________________________ 32 
13.9 
Safety Analyses _____________________________________________________ 32 
13.10 Interim Analysis _____________________________________________________ 33 
13.11 Handling of Missing Data _____________________________________________ 33 
14. 
DATA MANAGEMENT____________________________________________ 33 
15. 
LEGAL/ETHICS AND ADMINISTRATIVE PROCEDURES ________________ 33 
15.1 
Good Clinical Practice/Regulatory Compliance ___________________________ 33 
15.2 
Site and Investigator Qualification ______________________________________ 34 
15.2.1 
Investigator Curriculum Vitae (CV) _________________________________________ 34 
15.2.2 
Statement of Investigator _________________________________________________ 34 
15.3 
IRB/EC Protocol Approval _____________________________________________ 34 
15.4 
Informed Consent – Ethical Compliance _________________________________ 34 
15.5 
Subject Privacy and Confidentiality _____________________________________ 35 
15.6 
Monitoring __________________________________________________________ 35 
15.7 
Modification of the Protocol ___________________________________________ 36 
15.8 
Suspension or Termination of Registry __________________________________ 36 
15.9 
Protocol Deviations/Violations _________________________________________ 36 
15.10 Recording, Access to and Retention of Source Data _______________________ 36 
15.11 Final Data ___________________________________________________________ 37 
15.12 Publications ________________________________________________________ 37 
15.13 Audit/Inspections ____________________________________________________ 37 
LIST OF TABLES 
Table 1: SCHEDULE OF REGISTRY ASSESSMENTS – PROSPECTIVE 
 
 
 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
1. 
TERMS, ACRONYMS, ABREVIATIONS 
The following abbreviations and specialist terms are used in this protocol. 
AE 
Adverse event 
APT  
Acoustic Pulse Thrombolysis  
aPTT 
Activated partial thromboplastin time 
BNP 
Brain natriuretic peptide 
CE 
European Conformity 
CFR 
Code of Federal Regulation 
CRA 
Clinical research associate 
CTA 
Computed tomography angiography 
CTEPH 
Chronic thromboembolic pulmonary hypertension 
CV 
Curriculum vitae 
DM 
Data management  
DMP 
Data management plan 
DVT 
Deep vein thrombosis  
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EP 
Efficacy population 
ePRO 
Electronic Patient Reported Outcomes 
EQ-5D-5L 
Euroqol five dimension five level questionnaire 
FDA 
Food and Drug Administration 
FPI 
Full prescribing information 
GCP 
Good clinical practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
Informed consent form 
ICH 
Intracranial hemorrhage 
ICU 
Intensive care unit 
ID 
Identification 
IDDC 
Intelligent Drug Delivery Catheter 
IFU 
Instructions for Use 
INR 
International normalized ratio 
IP 
Investigational product 
IRB/EC 
Institutional review board/ethics committee 
IVC 
Inferior vena cava 
LV 
Left ventricular 
MHz 
Megahertz 
MSD 
MicroSonic device 
PE 
Pulmonary embolism 
PEmb-QOL 
Pulmonary Embolism Quality of Life 
PHI 
Protected health information 
PT 
Partial thromboplastin time 
Pts 
Patients 
QOL 
Quality of Life 
r-tPA 
Recombinant tissue plasminogen activator 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
RV 
Right ventricular 
RVSP 
Right ventricular systolic pressure 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SoC 
Standard of care 
SP 
Safety population 
sPESI 
Simplified pulmonary embolism severity index 
SpO2 
Peripheral capillary oxygen saturation 
SvO2 
Mixed venous oxygen saturation 
TAPSE 
Tricuspid annular plane systolic excursion 
U.K. 
United Kingdom 
U.S. 
United States 
VTE 
Venous thromboembolism 
 
 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
2. 
PROTOCOL SYNOPSIS  
Protocol Number 
BTG-001163-01 
Protocol Short Title 
KNOCOUT PE 
Protocol Title 
Retrospective and prospective international EKoSoNic® registry 
study Of the treatment and Clinical OUTcomes of patients with 
Pulmonary Embolism 
Intervention 
Device: EkoSonic® Endovascular System (EKOS) employs high 
frequency (2-3 MHz), low power ultrasound to facilitate the 
delivery of physician-specified fluids, including thrombolytics, in 
the pulmonary arteries. 
 
Acoustic Pulse Thrombolysis (APT) Procedure: The clinical use of 
the EKOS device in combination with physician-specified fluids. 
Type of Protocol 
International Registry 
Trial Objectives 
• 
To understand the APT treatment protocol used as SoC 
across institutions and document changes in practice 
following the OPTALYSE PE study results  
• 
To describe the effects of varied APT protocols on long-term 
patient outcomes 
Outcome Measures 
1. Change in the ratio of the measurement of the right 
ventricular to left ventricular diameters (RV/LV) as measured 
on echocardiogram or computed tomography angiography 
(CTA) from baseline to between 24 – 48 hours (hr) after the 
start of the APT procedure (matched pairs as available).  
2. Diagnosis of pulmonary hypertension defined as mean 
pulmonary artery pressure greater than 25mm Hg by 
echocardiogram that persists at least 3 months after PE 
diagnosis  
3. Frequency and safety outcomes of adjunctive therapies post 
APT procedure during hospitalization 
4. Number of patients with non or partial response to other 
interventional procedures prior to APT procedure for index PE 
5. Frequency and severity of serious adverse experiences (SAE) 
related to EKOS or procedure, major bleeding, or venous 
thromboembolic disease (VTE) during index hospitalization 
and during first 12 months post-APT procedure 
6. All-cause mortality during first 12 months post-APT procedure  
7. Recurrent symptomatic PE, PE related death, hemodynamic 
collapse at 30 days (composite measure) 
8. Healthcare utilization during hospitalization: 
a. Time from hospital admission to ICU discharge 
b. Time from hospital admission to discharge 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
9. Quality of life (QOL) as measured by the Pulmonary 
Embolism Quality of Life (PEmb-QOL) and EuroQol five 
dimension five level questionnaire (EQ-5D-5L) at 3 month and 
12 month post-hospitalization follow-up visits 
10. IVC filter placement (measured by number of occurrences) 
Trial Duration 
RETROSPECTIVE 
Data collection is expected to occur over a 6 month period at 
each site  
 
PROSPECTIVE 
Enrollment will take place over approximately a 24 month period. 
For each subject, their participation in the registry lasts 12 
months. 
Trial Design 
A multi-center retrospective and prospective registry of the APT 
treatment of patients (pts) with submassive (Intermediate-High 
Risk) and massive (High Risk) PE. The retrospective portion of 
the registry will consist of consecutive patients treated with APT 
between January 1, 2014 and one year prior to date of site 
activation. The prospective portion of the registry will collect data 
for pts diagnosed and risk-stratified and treated with APT 
procedure. Pts will be followed for 12 months. 
 
Intermediate-High Risk PE will be defined by evidence of RV 
dysfunction (RV/LV > 1.0), hemodynamic stability (normal 
systemic arterial blood pressure >90 mmHg), and troponin 
elevation. 
 
High Risk PE will be defined with hemodynamic instability 
(normal systemic arterial blood pressure <90 mm Hg and/or use 
of vasopressors) 
Number of Patients 
RETROSPECTIVE 
Up to 1000 evaluable cases 
 
PROSPECTIVE 
Up to 550 consented patients to yield 500 evaluable patients 
Number & Location of 
Sites 
Up to 100 sites geographically distributed throughout North 
America, Europe, and Asia 
Eligibility Criteria 
RETROSPECTIVE 
Inclusion Criteria 
1. Treated with APT procedure between January 1, 2014 
and one year prior to date of site activation 
2. RV/LV > 1.0 from diagnostic CTA or echocardiogram 
3. PE symptom duration < 14 days 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
4. Troponin elevation 
 
Exclusion Criteria 
5. Enrollment into the OPTALYSE PE study 
 
PROSPECTIVE 
Inclusion Criteria 
1. Male or female > 18 years of age and < 80 years of age 
2. RV/LV > 1.0 from diagnostic CTA or echocardiogram 
3. PE symptom duration < 14 days 
4. Troponin elevation 
5. Signed informed consent obtained from subject or legally 
authorized representative 
6. Investigator has selected EKOS to treat patient with 
massive or submassive PE 
Exclusion Criteria 
7. Clinician deems the subject high-risk for catastrophic 
bleeding 
8. Life expectancy < one year 
Sample Size 
Justification 
The aim of the registry is to collect observational data on 
standard of care APT treatment. The sample size is calculated 
from the expected enrollment per site based on estimated 
cases per physician across total number of sites. For 
retrospective cases, up to 1000 cases will be collected to 
capture details of PE treatment with EKOS from the time it 
became commercially available to the time the site was 
activated. For prospective, up to 500 patients will be treated to 
collect data on current EKOS use at up to 100 sites.  
Statistical Methods 
Patients will be analyzed according to the APT treatment protocol 
they received (i.e. duration of treatment and dose, type of fluid 
received). Frequency of use of each of the APT treatment 
protocols before and after OPTALYSE PE results were made 
public will be summarized and compared using fisher’s exact test.  
Each outcome measure will be summarized for the full registry 
population as well as separately by the different APT treatment 
protocols, including 95% confidence intervals. Additionally, 
outcome measures will be summarized by the following 
subgroups: submassive and massive PE, each region, and by 
the retrospective and prospective portions of the registry.  
Registry Procedures 
See section 3. SCHEDULE OF REGISTRY ASSESSMENTS – 
PROSPECTIVE below 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1.EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
Registry Follow-up 
Visits 
For prospective subjects, patients should be followed per 
Investigator’s standard of care (SoC). Data will be collected for 
any echocardiograms and CTAs completed throughout the 12 
month follow-up period. At minimum, a health status check 
should be performed at 3 and 12 months. An on-site visit with 
echocardiogram is recommended at 3 months for patients with 
abnormal echocardiogram post-treatment for evaluation of 
chronic pulmonary hypertension, and at 12 months for all 
patients. Safety data should be reported through 12 months 
post-index procedure. For retrospective cases, long term health 
data will be collected as available for up to 12 months post-
index treatment.   
Treatment 
Subjects scheduled for treatment with EKOS will be treated as 
prescribed by the Investigator SoC for treating PE and in 
accordance with the instructions for use (IFU). 
 
Post-procedure care should be performed and prescribed in 
accordance with Investigator’s SoC and as specified in the 
protocol.    
Data Collection 
All data will be collected via an electronic data capture (EDC) 
system. The Investigator and Investigator’s staff will enter 
registry data into the EDC through a web portal. Each 
Investigator and Investigator staff member is granted a unique 
login into the EDC platform.  
 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1 EMEA (19-Oct-2018) 
 
 
 
 
 
 
 
EKOS Corporation 
 
CONFIDENTIAL 
 
 
A BTG International group company 
 
3. SCHEDULE OF REGISTRY ASSESSMENTS – PROSPECTIVE 
Assessments will be performed per Investigator’s SoC and collected according to the schedule below. Assessments marked with 
an asterisk (*) pertain to an outcome measure or eligibility. 
 
Assessment 
 Baseline 
Procedure/Post Procedure  
Follow-up  
Day -1 
Day 0 thru Discharge 
3 Months  
(±14 Days) 
Post APT 
(Phone or Visit) 
12 Months 
(±1 Month) 
Post APT 
(Phone or Visit) 
Informed Consent 
X* 
 
 
 
Demographics 
X* 
 
 
 
Medical history, risk factors 
X* 
 
 
 
Vital signs1 
X* 
X 
 
 
Physical Examination 
X 
 
 
 
CTA 
X* 
X*3 (if collected) 
 
 
sPESI 
X 
 
 
 
APT Procedure 
 
X 
 
 
Echocardiogram2 
X* 
X3 (if collected) 
X* (if collected) 
X* (if collected) 
Quality of life surveys4 
 
X* 
X* 
X* 
Laboratory tests5 
X6 
X 
 
 
Biomarkers7 
X* 
X 
 
 
Adverse/VTE/Bleeding Events 
 
X* 
X* 
X* 
Anticoagulation medications 
X 
X 
X 
X 
1. Record heart rate, blood pressure, respiratory rate, oxygen saturation vital signs at admission, at start and end of treatment, and 
once at same time each day of hospitalization 
2. Includes RV/LV ratio, TAPSE, estimated RVSP, and collapse of the inferior vena cava (IVC) with respiration 
3. Collect 24 – 48 hours after the start of the APT procedure 
4. PEmb-QOL and EQ-5D-5L 
5. Hemoglobin (Hgb), hematocrit (Hct), platelet count, creatinine, activated partial thromboplastin time (aPTT), partial thromboplastin 
time (PT), and international normalized ratio (INR) 
6. Record if collected within 48 hours prior to the start of APT procedure 
7. Troponin, brain natriuretic peptide (BNP)/NT-proBNP, lactate/lactic acid, and D-dimer 

Protocol BTG-001653-01 (KNOCOUT PE) 
Version 2.1 EMEA (19-Oct-2018) 
 
 
 
 
 
 
EKOS Corporation 
CONFIDENTIAL 
 
A BTG International group company 
 
4. 
BACKGROUND 
4.1 Pulmonary Embolism (PE) 
Venous thromboembolism (VTE), comprised of deep vein thrombosis (DVT) and pulmonary 
embolism (PE), is the third most common cardiovascular disorder in the United States after 
myocardial infarction and stroke1. The 2008 United States Surgeon General’s Call to Action to 
Prevent DVT and PE estimates that 100,000 to 180,000 deaths occur annually from PE in the 
U.S. alone2. In the 2003 U.S. Healthcare Cost and Utilization Project Nationwide Inpatient 
Sample database, 196,134 VTE-related events, including symptomatic DVT, symptomatic PE, 
and VTE-related deaths, were calculated to have occurred among acutely ill hospitalized 
Medical Service subjects, afflicting two out of every 100 of these subjects3. 
The mortality rate for acute PE exceeds 15% in the first three months after diagnosis, 
surpassing that of myocardial infarction4. In nearly 25% of all subjects presenting with acute PE, 
the initial presentation is sudden death5. The majority of deaths from acute PE results from right 
ventricular (RV) pressure overload and subsequent RV failure6. Survivors of acute PE are at-risk 
for developing debilitating chronic thromboembolic pulmonary hypertension (CTEPH)7. Subjects 
with CTEPH typically experience a “honeymoon” period after acute PE, during which symptoms 
are absent despite the onset of pulmonary hypertension. Unfortunately, the condition is usually 
detected when pulmonary hypertension has worsened to the point that it causes dyspnea, 
hypoxemia, and RV failure. 
Therapeutic anticoagulation with immediate parenteral anticoagulants followed by oral agents is 
the cornerstone of therapy for acute PE8. However, while the majority of acute PE subjects has 
a benign clinical course with standard therapeutic anticoagulation alone, subjects with massive 
and submassive PE remain at increased risk for adverse clinical events, including RV failure 
and hemodynamic collapse. 
Advanced therapy for patients with acute PE is usually reserved for patients with either massive 
or submassive PE. Options for advanced therapy include peripherally-administered systemic 
fibrinolysis, surgical pulmonary embolectomy, catheter-assisted embolectomy, and inferior vena 
cava (IVC) filter insertion. 
Combined ultrasound/fibrinolytic therapy was developed to accelerate thrombolysis and rapidly 
achieve complete clot lysis while reducing the risk of serious complications such as bleeding.  
High frequency, low power ultrasound accelerates thrombolysis both in vitro and in vivo. This 
idea was pioneered by Kudo9 and confirmed by other investigators10,11,12. Ultrasound temporarily 
alters the local architecture of the fibrin clot, thereby enhancing its permeability by reducing the 
diameter of the fibrin strands and increasing the pore size of the fibrin mesh13. Ultrasound 
energy also provides an acoustic pressure gradient to enable transport of a greater quantity of 
thrombolytic drug into the clot itself. The resulting faster, more complete clot lysis is due to 
increased diffusion of the thrombolytic agent into the clot and not mechanical disruption.  
EkoSonic® Endovascular System (EKOS) is an FDA cleared14 and CE Marked15 drug delivery 
catheter that uses ultrasound delivered through the catheter core to speed the delivery of 

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physician-specified fluids, including thrombolytics, into the interstices of the clot and increase 
the speed of lysis. By making the clot more permeable and pushing the drug into the fibrin 
mesh, EKOS has the potential to reduce time to lysis, effect more complete lysis, reduce drug 
dose and, thereby, reduce the risk of bleeding complications.  
EKOS Corporation investigated the effectiveness of thrombolytics delivered by ultrasound 
catheter in acute PE (symptoms ≤ 14 days) located in at least one main or proximal lobar 
pulmonary artery and with a RV/LV of > 0.9 on chest CTA or echocardiogram in three 
prospective, multi-center studies that provide evidence for the efficacy and safety of the 
Acoustic Pulse Thrombolysis (APT) procedure in the treatment of PE. There are published data 
for 370 subjects treated with the APT procedure. The studies include one randomized-controlled 
study ULTIMA involving 30 of 59 patients (pts); and two prospective studies: SEATTLE II 
involving 150 pts and OPTALYSE PE involving 100 pts.  
4.2 EkoSonic® Endovascular System (EKOS) Product Description 
4.2.1 EKOS Intended Use 
EKOS is intended for the treatment of pulmonary embolism patients with ≥ 50% clot burden in 
one or both main pulmonary arteries or lobar pulmonary arteries, and evidence of right heart 
dysfunction based on right heart pressures (mean pulmonary artery pressure ≥ 25 mmHg) or 
echocardiographic evaluation. 
4.2.2 EKOS Description 
The EkoSonic® Endovascular System (EKOS) generates ultrasound waves in the treatment 
zone of the catheter through the piezoelectric conversion of radiofrequency energy. The 
ultrasound emanates radially from the treatment zone to improve the dispersion of infused 
physician-specified fluids, including thrombolytics.  
EKOS consists of two main components:  
1. Single-use sterile device, consisting of:   
a. Intelligent Drug Delivery Catheter (IDDC)  
b. MicroSonic Device (MSD) 
2. EkoSonic® Control Unit (reusable) 
The IDDC is 5.4 French with a 106 cm or 135 cm working length. It includes two luer ports for 
coolant and fluid delivery and an electrical connector for the thermocouples that monitor the 
catheter system temperature. Radiopaque markers are located approximately 1 cm proximal 
and 1 cm distal to the treatment zone. The IDDC central lumen is compatible with a 0.035” 
guidewire, accepts the MSD and delivers coolant during operation. Fluid and coolant flow 
through distal side holes for delivery in the treatment zone. Each  IDDC requires its own set of 
infusion tubing and infusion pump for fluid and coolant.  

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The MSD locks to the luer connector on the central lumen of the IDDC aligning the ultrasound-
generating segment to the treatment zone of the IDDC. The device uses multiple ultrasound 
transducers to emit ultrasound energy radially from the long axis of the catheter system. 
The EkoSonic® Control Unit provides electrical power to the piezoelectric elements in the 
treatment zone of the device and monitors operating parameters during operation. The Control 
Unit also provides the user interface through the front panel display and keypad.  
4.2.3 EKOS Regulatory Status 
In Europe, EKOS has an EC Design-Examination Certificate (CE 567229) for the treatment of 
pulmonary embolism with a ≥ 50% clot burden in one or both main pulmonary arteries or lobar 
pulmonary arteries, and evidence of right heart dysfunction based on right heart pressures 
(mean pulmonary artery pressure ≥ 25 mmHg) . In this registry study, EKOS is commercially-
available and being used in accordance with its cleared indications for use. Therefore, no 
special labeling or tracking is required for devices.  
4.3 EKOS Clinical Summary in Pulmonary Embolism 
ULTIMA, SEATTLE II, and OPTALYSE PE have shown various APT regimens using 
recombinant tissue plasminogen activator (r-tPA) for thrombolysis to be safe and effective in the 
treatment of PE. Low dose r-tPA and reduction in treatment time of the APT procedure appear 
to reduce bleeding events and costs associated with length of stay in the ICU and hospital.   
Pharmacology studies demonstrate that clot lysis occurs rapidly after r-tPA intravenous 
treatment and is ~90% complete by 90 minutes. A rabbit study demonstrated that thrombolytic 
activity after r-tPA, whether administered as an intravenous bolus dose or infusion is dose-
dependent and the duration of action is dose-independent16. After a single dose (0.5 to 0.4 
mg/kg), to 2.3-3 kg rabbits, r-tPA was rapidly inhibited, resulting in duration of action of 15 
minutes. The maximum extent of lysis after the bolus was 54% for a 0.4 mg/kg dose. During a 4 
hour infusion of r-tPA (0.625 to 1 mg/kg), 90% of the thrombolytic activity occurred within 2 
hours. The maximum extent of lysis after the infusion was 87% for a 0.5 mg/kg dose. After 
administration of either a bolus or infusion, continued lysis activity decreased exponentially with 
time and there remained an undissolved clot at the end of the measurement period 
Similarly, a pharmacodynamics study of r-tPA in man demonstrated that even though the initial 
half-life of r-tPA in the systemic circulation is 3-4 minutes, fibrinolysis after an intravenous 
infusion of 20 to 150 mg continues from 7 to 12 hours17. The prolonged duration of action 
demonstrates that plasmin bound to fibrin continues to be active after r-tPA is cleared from the 
circulation. As fibrin is lysed, r-tPA is released and is metabolized by the liver.  
The ability of r-tPA to lyse clot is dependent upon binding with fibrin and plasminogen in a 
centric ternary complex to activate plasminogen to form plasmin which lyse fibrin into 
degradation products18. Clot lysis is diffusion dependent. By increasing permeation, lysis 
increases. Several in-vitro studies have demonstrated that ultrasound enhances both urokinase 
and r-tPA mediated lysis of plasmin and blood clots. Enhancement is seen at a range of 
frequencies, intensities and lytic concentrations19. This enhancement is seen in both static and 
flowing thrombolytic models. Animal studies report faster recanalization times for clots exposed 

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to ultrasound during lytic treatment using r-tPA. These effects were seen at the frequencies 
produced by the EKOS catheter. The time of clot treatment in the studies was 30 minutes. From 
these studies, we postulate that r-tPA in the presence of ultrasound will produce significant 
fibrinolysis within 2 hours of receptor binding and may continue for another 7 to 12 hours after 
the APT Procedure is complete. Thus, thrombus burden may be significantly reduced within a 
few hours of the APT Procedure to restore pulmonary perfusion, reduce RV dilatation, and 
decrease pulmonary artery pressures.  
The earliest study of the APT procedure in PE demonstrated that doses of approximately 22 mg 
r-tPA delivered with the APT procedure over 25 hours were effective in treating PE in subjects 
suffering from massive PE20. Since that time, doses used in treating PE have ranged from 0.5 to 
1 mg/hr/catheter delivered over an average of 18 hours, with no infusion duration being less 
than 12.9 hours (excluding one subject). Even though efficacy measurements have been made 
at 24 and 48 hours, clinicians have reported subjects often improve within a few hours of the 
start of treatment. These observations, along with the aforementioned pharmacology studies, 
provide evidence to support the scientific rationale for investigating the reduction in ultrasound - 
r-tPA treatment time.  
The OPTALYSE PE study was designed to investigate the lowest r-tPA dose-ultrasound 
treatment time required to achieve the same reductions in thrombus burden and associated 
improvement in physiologic parameters demonstrated in ULTIMA and SEATTLE II. Results of 
the OPTALYSE PE study were intended to inform the study design for further studies of the 
APT procedure. Analysis of the first 100 evaluable subjects in the U.S. study suggested 
equipoise between each study arm and therefore a sample size was extended to additional sites 
in the U.K. Improvement in the RV/LV diameters by core laboratory-assessed 
echocardiographic reads were -0.17, -0.17, -0.12, and -0.29 at 4 hours and -0.22, -0.25, -0.18, 
and -0.32 at 48 hours in patients randomized to 8 mg/2 hrs, 8 mg/4 hrs, 12 mg/6 hrs, and 24 
mg/6 hrs, respectively.21 Improvement in modified Miller score was also seen in all groups22.  
5. REGISTRY OBJECTIVE AND PURPOSE 
5.1 Objectives 
The objectives of this registry are: 
• 
To understand the APT treatment protocol used as SoC across institutions and 
document changes in practice following the OPTALYSE PE study results  
• 
To describe the effects of varied APT protocols on long-term patient outcomes 
5.2 Design 
This multicenter, international registry is designed to retrospectively and prospectively collect 
treatment and outcome data related to pts with submassive (Intermediate-High Risk) or massive 
(High Risk) PE undergoing the APT treatment. Subjects are treated per Investigator’s SoC and 
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Intermediate-High Risk PE will be defined by evidence of RV dysfunction (RV/LV > 1.0), 
hemodynamic stability (normal systemic arterial blood pressure >90 mmHg), and Troponin 
elevation. 
High Risk PE will be defined by hemodynamic instability (normal systemic arterial blood 
pressure <90 mm Hg and/or use of vasopressors).23 
Retrospective case data will consist of treatment and health outcomes of consecutive patients 
treated with APT between January 1, 2014 and one year prior to date of site activation. 
Prospective subject data will consist of treatment and health outcomes of treated subjects since 
the site was activated to participate in the registry. For each treated subject enrolled, 
participation in the registry lasts approximately 12 months. Subjects should be followed per 
Investigator’s SoC. Data will be collected for any echocardiograms and CTAs completed. At 
minimum, a health status check should be performed at 3 and 12 months. For patients with an 
abnormal echocardiogram post-APT treatment, an on-site visit with echocardiogram should be 
performed at 3 months to assess for chronic pulmonary hypertension. An echocardiogram at 12 
months is also requested for all patients. Safety data should be reported through 12 months 
post-index procedure. 
5.3 Outcome Measures 
1. Change in the ratio of the measurement of the RV/LV diameters as measured by 
echocardiogram or CTA from baseline to between 24 – 48 hours after the start of the APT 
procedure (matched pairs as available). 
2. Diagnosis of pulmonary hypertension defined as mean pulmonary artery pressure greater 
than 25 mm Hg by echocardiogram that persists at least 3 months after PE diagnosis  
3. Frequency and safety outcomes of adjunctive therapies post APT procedure during 
hospitalization 
4. Number of patients with non or partial response to other interventional procedures prior to 
APT procedure for index PE 
5. Frequency and severity of SAEs related to EKOS and procedure, major bleeding, or VTE 
during index hospitalization and during first 12 months post-APT procedure 
6. All-cause mortality during first 12 months post-APT procedure 
7. Recurrent symptomatic PE, PE related death, hemodynamic collapse at 30 days (composite 
measure) 
8. Healthcare utilization during hospitalization: 
a. Time from hospital admission to ICU discharge 
b. Time from hospital admission to discharge 
9. Quality of life (QOL) as measured by the PEmb-QOL and EQ-5D-5L at baseline and 3 
month and 12 month post-hospitalization subject follow-up visits 
10. IVC filter placement (measured by number of occurrences) 
6. 
SUBJECT SELECTION  
6.1 Registry Population 

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This registry is designed to collect data related to APT treatment in patients experiencing 
symptoms of submassive or massive PE with a baseline RV/LV > 1.0.Data will be collected for 
up to 1000 retrospective cases and 550 prospective subjects selected by their physician to 
receive APT treatment for PE. Enrollment will occur at up to 100 investigational sites globally.  
6.2 Subject Selection 
6.2.1 Inclusion Criteria 
Retrospective cases must meet all of the following inclusion criteria: 
1. Treated with APT procedure between January 1, 2014 and one year prior to date of site 
activation 
2. RV/LV > 1.0 from diagnostic CTA or echocardiogram 
3. PE symptom duration < 14 days 
4. Troponin elevation 
Prospective subjects must meet all of the following inclusion criteria: 
5. Male or female > 18 years of age and < 80 years of age 
6. RV/LV > 1.0 from diagnostic CTA or echocardiogram 
7. PE symptom duration < 14 days 
8. Troponin elevation 
9. Signed informed consent obtained from subject or legally authorized representative 
10. Investigator has selected EKOS to treat patient with massive or submassive PE 
6.2.2 Exclusion Criteria 
Retrospective cases must not meet the following exclusion criteria: 
11. Enrollment into the OPTALYSE PE study 
Prospective subjects must not meet any of the following exclusion criteria: 
12. Clinician deems the subject high-risk for catastrophic bleeding 
13. Life expectancy < one year 
6.3 Subject Completion 
A subject will be considered to have successfully finished the registry upon completion of their 
12 month follow-up.  
6.4 Withdrawal 
For cases in which the subject does not complete all assessments and follow-up visits, the 
subjects will be classified as follows: 
• 
Investigator withdrawal – Investigator can withdraw a subject from the registry for a 
safety concern or non-compliance. Reason for Investigator withdrawal of a subject and 
last date of contact for the registry will be documented in the EDC system.  

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• 
Subject withdrawal – Subjects may withdraw from participation at any time during the 
registry. All data collected prior to withdrawal shall remain part of the registry data. 
Reasonable effort should be made to encourage the subject to remain in the registry. If 
the subject declines further participation, the reason for withdrawal will be documented in 
the EDC system.  
• 
Lost to follow-up – The site should collect three methods to contact a subject. A subject 
will be considered lost to follow-up if there are at least three documented attempts to 
contact the subject for their last expected follow-up without success. Last date of contact 
will be documented in the EDC system. 
7. 
CASE DATA COLLECTION – RETROSPECTIVE 
7.1 Protected Health Information (PHI) Authorization Waiver 
The sites participating in retrospective case data collection will apply for a PHI authorization 
waiver with the relevant IRB/EC to review, use, and submit specific case data to the Sponsor. 
The specific case data is outlined in the Measurements-Retrospective section of the Protocol 
and will be de-identified before being entered into the EDC system. 
8. 
MEASUREMENTS – RETROSPECTIVE 
8.1 Screening/Baseline 
The following data will be collected for screening, as available. Record most recent 
assessments prior to beginning of APT procedure. 
• 
Review and confirmation of eligibility to participate in the registry 
• 
Demographic information, medical history, and clinical risk factors 
• 
CTA to evaluate the anatomic location of PE and degree of RV enlargement (as part of the 
initial diagnosis of PE). The RV/LV ratio at end-diastole will be determined from this image. 
• 
Echocardiogram to measure: RV/LV ratio, TAPSE, estimated RVSP, and the collapse of the 
IVC with respiration 
• 
Laboratory tests  
o Hemoglobin (Hgb) 
o Hematocrit (Hct) 
o Platelet count 
o Bleeding Times: aPTT, PT, and INR 
o Biomarker measurements: Troponin (to confirm eligibility), BNP/NT-proBNP, 
lactate/lactic acid, and D-dimer 
• 
Anticoagulation medications 72 hours leading up to the APT procedure 
8.2 Procedure 
The following data will be collected: 

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Vital signs prior to initiation of procedure 
• 
APT procedure treatment details 
8.3 Post-Procedure  
The following data will be collected as available: 
• 
First set of vital signs after end of APT procedure 
• 
Laboratory tests  
o Hemoglobin (Hgb) 
o Hematocrit (Hct) 
o Platelet count 
o Creatinine 
o Bleeding Times: aPTT, PT, and INR 
o Biomarker measurements: Troponin, BNP/NT-proBNP, lactate/lactic acid, and D-
dimer  
• 
Echocardiogram 24 – 48 hours after start of APT procedure: RV/LV ratio, TAPSE, estimated 
RVSP, and the collapse of the IVC with respiration 
• 
CTA 24 – 48 hours after start of APT procedure: RV/LV ratio 
• 
Vital signs once at same time each day of hospitalization through discharge 
• 
Length of post-procedure hospitalization (date and time of hospital discharge) 
• 
SAEs related to EKOS or procedure, bleeding events, or VTE events 
8.4 Long Term Health Data  
The following data will be collected as follow up data, up to 12 months post index APT 
procedure, as available: 
• 
Occurrence of VTE or bleeding events,  
• 
Changes in anticoagulation medications 
• 
Echocardiograms: RV/LV ratio, TAPSE, estimated RVSP, and the collapse of the IVC with 
respiration 
• 
Mortality, including cause 
9. 
TREATMENT OF SUBJECTS - PROSPECTIVE 
9.1 EkoSonic® Endovascular System (EKOS) 
9.1.1 APT Procedure 
The APT procedure must be performed by an experienced interventional cardiologist, vascular, 
cardiac or cardiothoracic surgeon, or radiologist in an angiographic suite with digital 
angiographic equipment. Proper placement of EKOS to treat PE will be performed using 
standard image guidance techniques associated with catheterization of the pulmonary artery. 
Choice of venous access is at the discretion of the treating physician and in alignment with the 
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Infusion of physician-specified fluids will be at the physician-prescribed dose. Infusion of fluid 
and saline coolant will be started. The MicroSonic Device will then be activated at start of 
infusion. If technical difficulties are encountered which interfere with proper operation of the 
system or infusion, the Instructions for Use will be consulted to assist in resolution of the issue. 
If the issues cannot be resolved, the affected device will be exchanged for another EKOS 
device. This exchange and serial numbers will be recorded in the EDC system. The affected 
device will be saved and returned to the Sponsor. 
9.1.2 Post-treatment Management 
Following treatment with EKOS, subjects should be treated with the Investigator’s SoC. 
Anticoagulation medication should be prescribed according to physician’s clinical judgement. 
9.1.3 Duration of Treatment and Follow-up 
Following the initial treatment with EKOS, each subject is followed per their Investigator’s SoC 
follow up schedule. At minimum, a 3 and 12 month post-APT procedure phone call or visit 
should be made to record health status. During the follow-up period, subjects are followed for 
re-hospitalizations, recurrence of VTE, and other clinical outcomes. Any echocardiograms 
collected during follow-up should be recorded in the EDC system. The final health status of the 
subject will be reported in the EDC system. A final echocardiogram at 12 months is requested.  
9.1.4 Adjunctive Interventions  
Investigator may utilize any adjunctive interventions as deemed necessary according to their 
clinical judgement. Investigator will note any adjunctive interventions to the APT procedure for 
the treatment of PE including type, start date, and stop date in the EDC system.  
10. 
MEASUREMENTS AND EVALUATIONS - PROSPECTIVE 
10.1 Screening/Baseline (Day -1) 
The screening phase begins when the ICF is fully signed and dated and ends at the initiation of 
the APT procedure.  
The following should be completed prior to data being collected about the patient: 
• 
Review and signing of the ICF 
• 
Review and confirmation of eligibility to participate in the registry 
The following evaluations should be recorded if performed as part of routine clinical care at 
Screening/Baseline (within 48 hours of the initiation of treatment): 
• 
Physical examination and collection of demographic, medical history, and clinical risk factors 
information 
• 
sPESI 
• 
CTA to evaluate the anatomic location of PE and degree of RV enlargement (as part of the 
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• 
Echocardiogram to measure: RV/LV ratio, TAPSE, estimated RVSP, and the collapse of the 
IVC with respiration 
• 
Laboratory tests 
o Hemoglobin (Hgb), Hematocrit (Hct) 
o Platelet count 
o Creatinine 
o Bleeding Times: aPTT, PT, and INR 
o Biomarker measurements: Troponin (required for inclusion), BNP/NT-proBNP, 
lactate/lactic acid, and D-dimer. 
• 
Anticoagulation medications leading up to the APT procedure 
10.2 Procedure Visit (Day 0) 
The following data should be recorded from the procedure: 
• 
Vital signs immediately prior to the procedure  
• 
APT procedure details  
Select sites may also perform an integrated bedside assessment as described in Section 
11.1.8. 
10.3 Post Procedure Assessments 
The following should be recorded if performed after the APT procedure is completed: 
• 
Vital signs immediately after the procedure 
• 
Laboratory test results from clinical routine will be collected at 24 (± 3) hours post-start of 
APT procedure: 
o Hemoglobin (Hgb) 
o Hematocrit (Hct) 
o Platelet count 
o Creatinine 
o Bleeding Times: aPTT, PT, and INR 
o Biomarker measurements: Troponin, BNP/NT-proBNP, lactate/lactic acid, and D-
dimer  
• 
Echocardiogram 24 – 48 hours after the start of the APT procedure to measure: RV/LV 
ratio, TAPSE, estimated RVSP, and the collapse of the IVC with respiration 
• 
CTA 24 – 48 hours after start of APT procedure: RV/LV ratio 
• 
Vital signs once at the same time each day of hospitalization until discharge.  
• 
Quality of Life surveys: PEmb-QOL and EQ-5D-5L 
• 
Change in anticoagulation medications until discharge. 
10.4 Follow-Up 
Patients will be followed per Investigator’s SoC for up to 12 months post-APT procedure. At 3 
months and 12 months post-APT procedure, the following data should be recorded, as 

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available. For patients with an abnormal post-treatment echocardiogram, a 3-month follow-up 
echocardiogram is recommended to assess for chronic pulmonary hypertension. For other 
patients, 3-month data can be collected via phone or on-site visit. 
• 
Echocardiogram: RV/LV ratio, TAPSE, estimated RVSP, and the collapse of the IVC with 
respiration 
• 
Review any SAEs, hospitalizations. Record any SAEs related to occurrence of VTE or 
bleeding events 
• 
Review any changes in anticoagulation medications 
• 
Quality of Life surveys: PEmb-QOL and EQ-5D-5L 
• 
In case of mortality, review cause and time of occurrence 
• 
In case of withdrawal, review cause and time of occurrence 
If additional echocardiogram(s) are collected outside of the 3 and 12 month follow-up, the 
results should be recorded in the EDC. 
11. Evaluations  
11.1 Informed Consent Process 
Patients with the potential to meet eligibility criteria for the prospective arm will be offered the 
opportunity to be evaluated for participation in this registry. All such patients must sign an ICF 
approved by the relevant IRB/EC before any trial-related evaluations can be performed. 
Investigator or qualified delegate will review the registry consent form with the patient and the 
patient must have an opportunity to ask questions about what data will be collected, the follow-
up schedule, and what options the patient has if they do not participate in the registry prior to 
signature. The patient will receive a copy of the signed ICF to keep for their records.  
Subjects will be informed of any revisions of the ICF and relevant revisions will be signed and 
kept in the subject’s file.  
The consenting process, acquisition of the ICF and any revisions should be documented in the 
subject’s medical record and the ICF should be signed and dated by the individual who 
conducted the informed consent discussion. 
11.2 Eligibility Review 
A patient is to review and sign an ICF prior to any evaluations to assess eligibility in the registry. 
Subjects who are found to meet all inclusion criteria and no exclusion criteria will be entered into 
the EDC system.  
11.3 Assignment of Subject Identification Number 
All retrospective cases and prospective subjects who meet eligibility criteria for the registry are 
assigned a subject identification (ID) number by the EDC system. The subject ID number is 
used to de-identify subject data of protected health information in the EDC. Investigator will 
maintain a subject ID list of subjects’ names and associated IDs which allows Investigator to 
determine identity of all subjects.  

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11.4 Demographics 
For each subject, year of birth, and gender are collected. In some countries, race and ethnicity 
are collected. 
11.5 Physical Examination 
All prospective patients will undergo a physical examination at screening, in accordance with the 
Investigator’s current practice, to include height and weight. Available data will be collected for 
retrospective cases. 
11.6 Vital Signs 
Vital signs including systolic/diastolic blood pressure, heart rate, respiratory rate, and SpO2 will 
be collected. Vital signs will be collected at baseline, prior to and immediately after the APT 
procedure, and once per day of post-procedure hospitalization until discharge. 
11.7 Anticoagulation and Concomitant Medications 
History of anticoagulant medication up to three days prior to the start of the APT procedure will 
be obtained. Changes in anticoagulation medications after discharge will be recorded in the 
EDC system throughout the 12-month follow-up period. 
Other concomitant (non-anticoagulation) medications will be recorded in the EDC system 
through 12 month follow-up only for medications prescribed to treat SAEs related to the 
procedure or device, bleeding events, or VTE events. 
11.8 Quality of Life Assessments: PEmb-QoL and EQ-5D-5L 
Two Quality of Life instruments, PEmb-QOL and EQ-5D-5L, will be used in this registry and are 
validated, widely used quality of life assessments.  
The PEmb-QOL quantifies health-related quality of life after experiencing PE. This questionnaire 
consists of 10 questions for six health dimensions: frequency of complaints, activities of daily 
living limitation, work-related problems, social limitations, intensity of complaints, and emotional 
complaints. 
The EQ-5D-5L is a patient reported outcome that provides a simple descriptive profile and 
single index value for health status. The questionnaire consists of 5 questions pertaining to 
specific health dimensions, including mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression, and overall health status rating scale.  
Subjects’ responses to the questionnaires are to be recorded and entered into the EDC system. 
11.9 Integrated Bedside Assessment  
At select participating sites: In addition to the vital signs specified in Section 10, bedside vital 
signs including systolic/diastolic blood pressure, heart rate, respiratory rate, capillary refill time 
and SpO2 will be recorded at 30 minute intervals from the start of the APT procedure through 
four hours after the end of the APT procedure. 

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Along with the echocardiograms specified in Section 10, additional limited echocardiograms will 
be performed at the bedside for RV/LV ratio measurements hourly after the start of the APT 
procedure through four hours after the end of the APT procedure. 
The purpose for the collection of vital signs every 30 minutes and focused echocardiography 
every hour is to correlate change in clinical parameters (vital signs) with change in markers of 
RV strain (RV/LV ratio) documented using echocardiography as a non-invasive imaging 
method. There is preliminary evidence from the first 100 patients in OPTALYSE PE that the 
right heart recovers within a couple hours of treatment. Confirmation for this finding will be 
important in identifying the best APT protocol. The echocardiogram is the most sensitive non-
invasive, real-time method outside of a CT scan to image both ventricles of the heart and 
quantify RV strain. The collection of routine bedside vital signs and limited echocardiograms 
(RV/LV ratio only) does not increase the potential risk to the pts participating in the registry as 
they are non-invasive measurements that will be collected at the bedside from a limited number 
of sites during the conduct of the registry.   
12. 
SAFETY REPORTING  
12.1 Definitions 
12.1.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence observed in a subject that develops 
or worsens from the time of enrollment, whether or not considered intervention-related. An AE 
can be any unfavorable or unintended sign, symptom, or disease temporally associated with the 
use of an intervention and does not imply a judgement about causality.  
12.1.2 Serious Adverse Event (SAE) 
A SAE is any untoward medical occurrence resulting in any of the following outcomes: 
1. Death 
2. Life-threatening (Note: The term “life-threatening” refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
3. Inpatient hospitalization or prolongation of existing hospitalization 
4. Persistent or significant disability/incapacity 
5. Congenital abnormally or birth defect 
6. Important medical event that may not result in death, be life-threatening, or require 
hospitalization but may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 

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12.1.3 Unexpected Adverse Event 
An AE is considered unexpected if it is not listed in the IFU, package insert, or not listed at the 
specificity or severity that has been observed. 
12.1.4 Pre-Existing Medical Condition 
Pre-existing medical conditions are those that are present at enrollment. If the frequency, 
severity, or character of the condition worsens significantly or unexpectedly during the registry, 
the condition will be an AE. 
12.1.5 Device Failures and Malfunctions 
A device failure is defined as the device being used in accordance with the IFU, but does not 
perform according to the IFU and negatively impacts the treatment. 
A device malfunction is defined as an unexpected change to the device that is contradictory to 
the IFU and may or may not affect device performance. 
12.1.6 Major Bleeding 
The following definition24 of major bleeding will be used: As general principles, a definition of 
major bleeding will be based on objective criteria, and major bleeds are those that result in 
death, are life-threatening, cause chronic sequelae or consume major health-care resources. 
With this in mind, the Control of Anticoagulation Subcommittee recommends the following 
criteria for major bleeding in non-surgical subjects: 
1. Fatal bleeding, and/or 
2. Symptomatic bleeding in a critical area or organ, such as 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 gL-1 (1.24 mmol L-1) or more, or leading to 
transfusion of two or more units of whole blood or red cells. 
Note: For this protocol, a fall in Hgb of 20 gL-1 (1.24 mmol L-1) or more with no objective 
evidence of bleeding or symptoms of bleeding will not be considered a major bleeding event. 
12.2 Reporting Requirements 
Investigators are not required to report all AEs that occur in the registry. 
Investigators must report the following SAEs to Sponsor within one working day of becoming 
aware of the event for either retrospective or prospective patients. SAEs should be reported up 
to each subject’s 12-month follow-up:  
• 
those related to EKOS or APT procedure 
• 
those related to a bleed 
• 
VTE events 

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The type of event, severity, and relationship to EKOS, procedure, thrombolytic, and 
anticoagulation drug will be reported by the Investigator. 
Device failures and malfunctions will be reported in the EDC system within one working day 
after Investigator or delegate learns of the event. For prospective patients, these will also be 
reported to the relevant IRB/EC as required per IRB/EC requirements. 
Because EKOS is a commercially-available medical device, Investigators will comply with any 
hospital user reporting requirements.  
If additional safety information becomes available during the course of the registry, Sponsor will 
amend the protocol and ICF as necessary. 
13. 
STATISTICAL CONSIDERATIONS 
13.1 Statistical Analysis 
The statistical analysis plan (SAP) will be a separate document finalized prior to data analysis. 
The SAP will be updated as required, in association with any protocol amendments. The plan 
will include detailed descriptions of analysis methods, tables, listings and figures and will 
describe statistical programming considerations. 
For descriptive statistics, continuous data (e.g., age) will be summarized with n, mean, median, 
standard deviation, minimum and maximum and categorical data (e.g., gender) will be 
summarized with observed counts and percentages for each category. 
Patients will be analyzed according to the APT treatment protocol they received (i.e. duration of 
treatment and dose, type of fluid received). Frequency of use of each of the APT treatment 
protocols before and after OPTALYSE PE results were made public will be summarized and 
compared using fisher’s exact test.  
Each outcome measure will be summarized for the full registry population as well as separately 
by the different APT treatment protocols, including 95% confidence intervals. Additionally, 
outcome measures will be summarized by the following subgroups: submassive and massive 
PE, each region, and by the retrospective and prospective portions of the registry.  
13.2 Determination of Sample Size 
For retrospective cases, up to 1000 cases will be collected to capture details of PE treatment 
with EKOS from the time it became commercially available to the time the site was activated. 
For prospective, up to 500 patients will be treated to collect data on current EKOS use at up to 
100 sites.    
13.3 Analysis Populations  
The SP will be defined as all patients who receive the APT procedure. Safety and effectiveness 
summaries will be reported for the SP. 
The EP will be defined as all patients who meet eligibility criteria. An additional effectiveness 
summary will be reported for the EP. 

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13.4 Patient Disposition 
The number of patients with the study completion status and the reasons for discontinuation will 
be summarized.  
13.5 Baseline and Demographics Characteristics 
Descriptive statistics will be used to summarize demographics and baseline characteristics 
including pertinent PE history. 
13.6 Measurement of APT treatment 
APT treatment and procedure details will be summarized. Patients will be analyzed according to 
the APT treatment protocol they received (e.g., >6h/>24mg; 6h/12-24mg; 6h/6-12mg; 4h/4-8mg; 
2h/4-8mg, other). Frequency of use of each of the APT treatment protocols before and after 
OPTALYSE PE results were made public will be summarized and compared using fisher’s exact 
test.  
13.7 Efficacy Outcome Measures Analyses  
Descriptive statistics will be used to summarize efficacy outcome measures RV/LV, TAPSE, IVC 
Collapse, estimated RVSP and pulmonary arterial pressure by time point and/or study visit 
including change from baseline for continuous endpoints. 
Each efficacy outcome measure will be summarized for the full registry population as well as 
separately by the different APT treatment protocols, including 95% confidence intervals. 
Additionally, efficacy outcome measures will be summarized by the following subgroups: 
submassive and massive PE, each region, and by the retrospective and prospective portions of 
the registry. 
13.8 Additional Outcome Analyses 
Descriptive statistics will be used to summarize additional outcome assessments including:  
• 
Healthcare utilization during hospitalization will be summarized for time from hospital 
admission to ICU and time from hospital admission to discharge. 
• 
Quality of life (QOL) measures PEmb-QOL and EQ-5D-5L will be summarized by time point 
and /or study visit including change from baseline for continuous endpoints and shift tables 
for categorical endpoints. 
• 
Frequency and outcomes of adjunctive therapies post APT procedure during hospitalization 
• 
Number of patients with non or partial response to other interventional procedures prior to 
APT procedure for index PE 
• 
IVC filter placement (measured by number of occurrences) 
13.9 Safety Analyses 
Safety analyses will be conducted on the SP during hospitalization and through the 12-month 
follow-up period. AEs and SAEs will be summarized by MedDRA System Organ Class and 
Preferred Term.  

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In addition, occurrence of safety outcomes will be summarized, including diagnosis of 
pulmonary hypertension, all-cause mortality during first 12 months, composite measure of 
recurrent symptomatic PE, PE related death or hemodynamic collapse at 30 days.  
13.10 Interim Analysis 
Periodic statistical summaries will be prepared annually. 
13.11  Handling of Missing Data 
All observed data will be summarized without imputation for missing values. 
14. 
DATA MANAGEMENT 
All data management (DM) processes up to and including post database lock will be detailed in 
the Data Management Plan (DMP), including the processes for import of external data (e.g. 
Laboratory Data), coding and SAE reconciliation.. 
Data from the study will be collected via EDC. Clinical data will be extracted in the required 
format by BTG DM from the Datatrak EDC database on an ongoing basis. 
Data must be accurately transcribed into the eCRF (ideally within 48 hours after the visit has 
occurred for the patient) by the study site and must be verifiable from source data. Examples of 
source documents are hospital records which include the patient’s medical notes, laboratory 
and other clinical reports etc. 
Where copies supporting source documentation (e.g. CT scan images etc.) are being submitted 
for the study, the patients’ study number must be clearly indicated on all material and any 
patient identifiers removed/redacted prior to sending to maintain confidentiality. 
Training will be provided in the form of eTrain to all users accessing the EDC system from 
Datatrak. Details of the requirement will be outlined in the DMP. 
15. 
LEGAL/ETHICS AND ADMINISTRATIVE PROCEDURES 
15.1 Good Clinical Practice/Regulatory Compliance 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this registry, are designed to ensure that Sponsor and Investigators abide by 
the Declaration of Helsinki, International Conference on Harmonisation Guideline E6 (R2): Good 
Clinical Practice (GCP). 
It is Investigator’s responsibility to ensure that adequate time and appropriate resources are 
available at the investigational site prior to commitment to participate in this registry. Investigator 
should also be able to estimate or demonstrate the potential for recruiting the required number 
of suitable subjects within the agreed recruitment period. Investigator maintains a list of 
appropriately qualified persons to whom Investigator has delegated significant registry-related 
tasks. 

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15.2 Site and Investigator Qualification 
All participating investigational sites are assessed by Sponsor to verify that they are able to 
conduct the registry. Each participating institution must have an established IRB/EC and clinical 
protocol review process that is compliant with the relevant government regulation, ensuring the 
clinical protocol can be adequately evaluated and approved at the institutional level. 
The Institution must have appropriately qualified investigators and clinical and administrative 
support staff in place to adequately conduct the registry according to the principles of 
International Conference on Harmonisation GCP in general and must have the adequate 
expertise and staff to conduct this registry in compliance with the relevant guidelines and 
regulations and to treat PE with EKOS. 
This registry is scheduled to be performed by qualified, experienced investigators at up to 100 
research facilities in the United States, Europe, and Asia. Given that the registry is intended to 
collect data related to SoC treatment with EKOS, special care will be taken to select 
investigators with experience in the treatment of PE with EKOS.  
Site and Investigator qualification is primarily accomplished through a Site Qualification Form 
and a qualification phone interview. In some cases, a remote or on-site qualification visit may be 
performed.  
15.2.1 Investigator Curriculum Vitae (CV) 
Investigator and all investigational site staff will provide Sponsor with his/her current (signed and 
dated within 2 years upon site activation) CV and any revisions/updates.   
15.2.2 Statement of Investigator 
Investigator must sign and date the Statement of Investigator/Protocol Signature Page of this 
protocol for the original and each subsequent amendment of the protocol and return a signed 
copy to Sponsor.  
15.3 IRB/EC Protocol Approval 
It is the responsibility of Investigator or delegate to submit this protocol, the ICF (approved by 
Sponsor), relevant supporting information and all types of subject recruitment information to the 
IRB/EC for review and approval prior to investigational site initiation. A copy of the written 
approval of the protocol and ICF and/or protected health information authorization waiver must 
be received by Sponsor prior to the collection of patient case data or recruitment of subjects.  
Investigator or delegate is responsible for keeping the IRB/EC apprised of the progress of the 
registry, any changes to the protocol, deviations from the protocol and reportable adverse 
events. 
15.4 Informed Consent – Ethical Compliance 
For participation in the prospective portion of the protocol, Investigator or delegate provides 
Sponsor with a copy of the IRB/EC-approved consent form and a copy of the IRB/EC written 

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approval, prior to investigational site initiation. Additionally, if the IRB/EC requires modifications 
to the ICF, the documentation supporting this requirement must be provided to Sponsor. 
It is the responsibility of Investigator or delegate to obtain written informed consent from 
subjects prior to enrolling them into the prospective part of the study. All consent documentation 
must be in accordance with applicable regulations and the principles of International Conference 
on Harmonisation GCP Guidelines. Each subject or the subject’s legally authorized 
representative (where applicable) is requested to sign the ICF after the subject has received 
and read written information and received an explanation of the registry, including but not limited 
to: the objectives, treatment plan, potential benefits and risk, inconveniences, alternative 
treatment options and the subject’s rights and responsibilities. A copy of the ICF must be given 
to the subject or the subject’s legally authorized representative (where applicable). If applicable, 
it is provided in a certified translation of the subject’s local language.  
Acquisition of the informed consent should be documented in the subject medical record and 
the ICF should be signed and dated by the subject and the individual who conducted the 
informed consent discussion. Signed consent forms must remain in each subject’s registry file 
and must be available for review by the clinical research associate (CRA) or auditor at any time. 
15.5 Subject Privacy and Confidentiality  
Sponsor and Investigator affirm and uphold the principle for the subject’s right to protection 
against invasion of privacy. Throughout this registry, all data collected and analyzed by Sponsor 
is treated confidentially and identified by a subject ID number.  
To verify compliance, Sponsor may require access to the subject’s primary medical record to 
review those portions that directly concern this registry (including but not limited to radiology 
images and hospital and outpatient records).  
As part of required content of the ICF, the patient must be informed that his/her records may be 
reviewed by Sponsor, Sponsor representative and/or a representative of the appropriate 
regulatory agency. The ICF or related document must also state that patient privacy will be 
maintained pursuant to local regulations. Should access to such medical records require a 
waiver or authorization separate from the statement of informed consent, Investigator obtains 
such permission in writing from the subject before the subject is entered in the registry. 
Data collected during this registry may be used to support the development or marketing of 
EKOS. Collected data may be reviewed by Sponsor and/or its representatives, independent 
auditors who validate the data on behalf of Sponsor, national or local regulatory authorities and 
the IRB/EC which granted approval for this registry to proceed. 
15.6 Monitoring 
Monitoring the subject data is performed using three methods: centralized, remote and on-site. 
All monitoring activities are performed by qualified personnel from Sponsor. Investigator and 
his/her staff are expected to cooperate with the Sponsor and be available during the visit to 
answer questions and resolve action items.   

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Monitoring activities are documented through various means, which include monitoring visit 
reports and documentation of centralized monitoring activities. For on-site visits, the CRA 
records the date, a summary of the status and progress of the registry, and proposed actions. 
15.7 Modification of the Protocol 
All amendments to this protocol must be documented in writing, reviewed and approved by 
Investigator, Sponsor, and IRB/EC prior to implementation. If the protocol amendment 
substantially alters the design or potential risk to the subject, new written informed consent must 
be obtained from each subject for continued participation in the registry. 
15.8 Suspension or Termination of Registry 
If conditions arise requiring further clarification before the decision can be reached to proceed 
with or terminate the registry, the registry will be suspended until the situation has been 
resolved.  
Sponsor has the right to terminate this registry at any time. Examples of situations where this 
might occur include: 
• 
It becomes apparent that enrollment is unsatisfactory with respect to quality and/or 
quantity or data recording is chronically inaccurate and/or incomplete. 
• 
The incidence and/or severity of adverse events in the registry indicate a potential health 
hazard caused by the treatment. 
15.9 Protocol Deviations/Violations 
Protocol deviations/violations not related to the informed consent process or eligibility are not 
required to be reported to Sponsor for this registry. Every attempt should be made to perform 
procedures and collect data according to this protocol. Protocol deviations/violations related to 
informed consent or eligibility should be reported to the IRB/EC, per IRB/EC reporting 
requirements. Copies of these reports and IRB/EC notification of receipt of these reports shall 
be submitted to Sponsor.  
15.10 Recording, Access to and Retention of Source Data 
Investigators are required to prepare and maintain adequate source documentation which 
includes: 
• 
Documents that verify eligibility criteria 
• 
Records covering subject participation in the registry including basic identification 
information, results of physical examinations and diagnostic tests, treatment 
administration, and visit/consult notes 
All key data must be recorded in the subject’s source documents including the informed consent 
acquisition. 
The CRA, auditors, IRB/EC, or regulatory inspectors may check data entered against the source 
documents. The consent form must include a statement by which the subjects allow the above-
named access to source data that substantiate data entered in the EDC system. These 

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personnel, bound by privacy laws and professional secrecy, will not disclose any personal 
information or personal medical information.  
As described in the International Conference on Harmonisation GCP Guidelines, ‘essential 
documents’, including final data set, source documents, IRB/EC approvals, and consent forms 
should be retained by Investigator until at least two years have elapsed since the formal 
discontinuation of the registry. These documents should be retained for a longer period however 
if required by the applicable regulatory requirements or by an agreement with Sponsor. 
Investigator must obtain written permission from Sponsor prior to destruction of any registry 
document. 
15.11 Final Data 
Investigator is responsible for maintaining adequate and accurate source documents from which 
accurate information is transcribed into the EDC system, which is designed to capture all 
pertinent data for the registry. Data entry should be completed by Investigator or delegate, as 
delegated on the Delegation of Authority Log.  
Once the data have been reviewed by the CRA, queries may be raised in the EDC system if the 
data are missing, unclear or contradictory. Once all data is entered and all queries resolved, 
Investigator will sign the completed data electronically via the Investigator Signature section of 
the EDC system and the database will be locked. The final data set will be provided to the site 
by Sponsor for archiving. 
15.12 Publications 
No individual Investigator may publish results from his/her investigational site until after 
publication of the primary manuscript describing the full population. 
The detailed obligations regarding the publication of any data, material results or other 
information that is generated or created in relation to the registry is set out in the Clinical Trial 
Agreement between Investigator and Sponsor.  
15.13 Audit/Inspections 
To ensure compliance with relevant regulations, data generated by this registry must be 
available for inspection upon request by representatives of Sponsor and the IRB/EC for each 
investigational site. 
 

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14 EKOS received FDA 510k clearance in May 2014 
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18 Verheugt F. Fibrinolytic Therapy in Clinical Practice. Martin Dunitz, London 2003 pg.6-7 
 

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19 Lauer C G, et. al. Effect of ultrasound on tissue-type plasminogen activator-induced 
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