FlowTriever for Acute Massive Pulmonary Embolism (FLAME)
Conditions: PE - Pulmonary Embolism, PE - Pulmonary Thromboembolism
Sponsor: Inari Medical

Inari Medical 
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FLAME Study (Protocol 20-001) 
CONFIDENTIAL 
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FLowTriever for Acute Massive Pulmonary 
Embolism (FLAME) 
Device: FlowTriever® Retrieval/Aspiration System 
Protocol Number: 20-001 
Version: 3.0 
December 6, 2020 
Sponsor 
Inari Medical 
9 Parker, Suite 100 
Irvine, CA 92618 
USA 
CONFIDENTIALITY STATEMENT 
This Clinical Investigation Plan and all attachments are considered confidential information. The contents must not 
be disclosed, unless authorized in writing by Inari Medical, except that this document may be disclosed to the 
appropriate Institutional Review Board (IRB) with similar requests for maintenance of confidentiality. All data and 
study results are similarly subjected to the same disclosure restrictions as the investigational plan, as stated above. 
All copies of this investigational plan remain the property of Inari Medical.  

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CONTENTS 
Protocol Signature Page ................................................................................................................................ 5 
Synopsis ........................................................................................................................................................ 6 
Abbreviations .............................................................................................................................................. 10 
1 
INTRODUCTION AND BACKGROUND .................................................................................................. 12 
1.1 
Incidence and Fatality Rate for Intermediate risk PE and High-risk PE..................................... 12 
1.2 
Diagnosis of Pulmonary Embolism ............................................................................................ 13 
1.3 
Pulmonary Embolism Treatment & Risk Stratification ............................................................. 14 
1.4 
Classification Schema for Pulmonary Embolism ....................................................................... 14 
1.5 
Risk-Based Treatment of Pulmonary Embolism ........................................................................ 16 
1.6 Treatment Options for Pulmonary Embolism ............................................................................... 16 
2 
THE FLOWTRIEVER SYSTEM ................................................................................................................ 19 
2.1 
FlowTriever System ................................................................................................................... 19 
2.2 
Regulatory Status ...................................................................................................................... 19 
2.3 
Intended Use of the Device....................................................................................................... 19 
2.4 
Device Description .................................................................................................................... 19 
2.5 
Rationale for the Use of the FlowTriever System ..................................................................... 20 
3 
Prior Investigations ............................................................................................................................. 21 
3.1 
FLARE Study Design and Summary of Results ........................................................................... 21 
3.1.1 FLARE Study Design ................................................................................................................... 21 
3.1.2 FLARE Study Results .................................................................................................................. 22 
3.2 
FLASH Study Design and Study Status ...................................................................................... 23 
4 
FLAME Study Objective ....................................................................................................................... 24 
5 
FLAME STUDY DESIGN ........................................................................................................................ 24 
5.1 
Endpoints .................................................................................................................................. 24 
5.2 
Study Population and Enrollment ............................................................................................. 26 
5.3 
Study Sites ................................................................................................................................. 27 
5.4 
Eligibility Criteria ....................................................................................................................... 27 
6 
FLAME STUDY Conduct ....................................................................................................................... 28 
6.1 
Enrollment, Study Assessments, and Procedures ..................................................................... 28 
6.2 
Safety Data Handling and Reporting ......................................................................................... 35 
6.3 
Clinical Events Committee (CEC) ............................................................................................... 37 
6.4 
Protocol Modifications .............................................................................................................. 37 
6.5 
Protocol Deviations ................................................................................................................... 37 

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6.6 
Training for Study Personnel ..................................................................................................... 37 
6.7 
Site Monitoring Visits ................................................................................................................ 38 
6.8 
Study Termination ..................................................................................................................... 38 
6.9 
Site Close-out Visits ................................................................................................................... 38 
6.10 Data Collection and Management ............................................................................................ 39 
7 
STATISTICS & DATA ANALYSIS ............................................................................................................. 40 
7.1 
Sample Size ............................................................................................................................... 40 
7.2 
Derivation of Performance Goal ............................................................................................... 40 
7.3 
Analytic Datasets ....................................................................................................................... 42 
7.4 
Endpoint Analysis ...................................................................................................................... 42 
7.4.1 Primary Endpoint Analysis ........................................................................................................ 42 
7.4.2 Secondary Endpoint Analysis .................................................................................................... 42 
7.4.3 Interim Analysis ......................................................................................................................... 43 
7.4.4 Context Arm Analysis ................................................................................................................ 43 
7.4.5 Prior Therapy Arm Analysis ....................................................................................................... 43 
8 
RISK ANALYSIS ..................................................................................................................................... 44 
8.1 
Risks to Subjects ........................................................................................................................ 44 
8.2 
Mitigation of Risks ..................................................................................................................... 44 
8.3 
Study Justification ..................................................................................................................... 44 
9 
Ethics and Confidentiality ................................................................................................................... 45 
9.1 
Institutional Review Board ........................................................................................................ 45 
9.2 
Study Subject Confidentiality .................................................................................................... 45 
9.3 
Electronic Data .......................................................................................................................... 45 
9.4 
Participating Institutions and Investigators .............................................................................. 46 
9.4.1 Investigator Responsibilities ..................................................................................................... 46 
10 Terms and Definitions ......................................................................................................................... 47 
11 REFERENCES ........................................................................................................................................ 50 
Signature Approval Page ............................................................................................................................. 56 
 
 
 
 
 

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Listing of Tables 
Table 1:  Primary Endpoint Definitions ....................................................................................................... 24 
Table 2:  Secondary Endpoint Definitions ................................................................................................... 25 
Table 3:  Schedule of Assessments ............................................................................................................. 30 
Table 4:  Bailout Definitions ........................................................................................................................ 33 
Table 5:  Clinical Deterioration Definition ................................................................................................... 34 
Table 6:  Major Bleeding, BARC 3b/3c/5a/5b Definition ............................................................................ 34 
Table 7: Site Assessment of Adverse Events ............................................................................................... 35 
Table 8: Sample Size 2-stage Group Sequential Design .............................................................................. 40 
Table 9: Safety Performance Goal Literature Summary ............................................................................. 40 
Table 10:  Terms and Definitions ................................................................................................................ 47 
 
Listing of Figures 
Figure 1. Incidence and Case-Fatality Rate for Massive vs non-Massive Pulmonary Embolism11 .............. 13 
Figure 2. European Society of Cardiology Risk Stratification ...................................................................... 15 
Figure 3. Disposition of Subjects in the FLARE Trial .................................................................................... 22 
Figure 4:  Patient Enrollment Flowchart by Study Arm .............................................................................. 29 
 
 

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PROTOCOL SIGNATURE PAGE 
 
 
 
 
Investigator Name 
 
Title 
 
 
 
Site Name 
 
Site Number 
 
I have read the protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined therein.  
I will provide copies of the protocol and all information on the device relating to past non-clinical and 
clinical experience, which were furnished to me by the Sponsor, to all physicians and other study 
personnel responsible to me who participate in this study and will discuss this material with them to 
ensure that they are fully informed regarding the device and the conduct of the study. 
I agree to keep records on all subject information (e.g., source documents) and all other information 
collected during the study, in accordance with local and national regulations. 
 
 
 
Investigator’s Signature 
 
 
Date 
 
 
 
 
 

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SYNOPSIS 
Protocol 
Number 
20-001 
Study Title 
FLAME: FLowTriever for Acute Massive Pulmonary Embolism 
Study Device 
FlowTriever Retrieval/Aspiration System 
Regulatory 
Status 
The FlowTriever System is cleared for the treatment of Pulmonary Embolism under 
510(k) number K180466. The FlowTriever System is indicated for use in the 
peripheral vasculature and for the treatment of pulmonary embolism. 
Sponsor 
Inari Medical 
9 Parker, Suite 100 
Irvine, CA  92618 
Study Objective 
The primary objective of this observational study is to evaluate treatment 
outcomes of patients diagnosed with high-risk (massive) pulmonary embolism who 
have received treatment with the FlowTriever System compared to an established 
performance goal (literature-based goal).   
 
In addition to the primary objective, outcomes of patients diagnosed with high-risk 
(massive) pulmonary embolism who have received treatment with other (non-
FlowTriever) therapies will also be analyzed.  
Study 
Population 
FlowTriever Arm: 
Up to 71 subjects will be enrolled in the FlowTriever Arm.  FlowTriever Arm 
subjects are defined as those subjects where FlowTriever is used as the primary 
treatment for high-risk pulmonary embolism.  Patients presenting with low 
/intermediate-risk PE and treated with anticoagulation alone who subsequently 
progress to high-risk PE and are treated front-line with FlowTriever will be enrolled 
in the FlowTriever Arm.  An interim analysis will be performed on the first 50 
subjects enrolled in the FlowTriever Arm, at which time enrollment may be closed 
based on the results of the interim analysis.   
Context Arm: 
Subjects with high-risk (massive) pulmonary embolism who are treated with non-
FlowTriever therapies (as the primary treatment for high-risk PE) will be enrolled in 
the Context Arm concurrently with subjects in the FlowTriever Arm.   Subjects 
presenting with low/intermediate-risk PE who are initially treated with 
anticoagulation and subsequently progress to high-risk PE should be enrolled in 
the Context Arm if not treated front-line by FlowTriever at this time.   The Context 
Arm will enroll concurrently with the FlowTriever Arm until FlowTriever enrollment 
is completed, with a minimum enrollment of 1:1 subjects in both the FlowTriever 
and Context arms, and a maximum enrollment of 2:1 Context Arm to FlowTriever 
Arm subjects.  Subjects enrolled in the Context Arm will be analyzed separately 
from the endpoint analysis utilizing descriptive methods. 

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Prior Therapy Arm: 
Subjects presenting with low/intermediate-risk PE who receive advanced therapy 
during their hospital stay but subsequently progress to high-risk PE should be 
enrolled in the Prior Therapy Arm.  Enrollment in the Prior Therapy Arm will be 
concurrent with the FlowTriever Arm of the study, and enrollment in this arm will 
cease when enrollment in the FlowTriever Arm is complete.  
 
Data collection for Prior Therapy Arm subjects will include information 
surrounding the PE treatment, progression to High-Risk PE, and patient course 
through hospital discharge.  Safety data will be collected, but not CEC adjudicated 
or analyzed as outlined for the FlowTriever and Context Arm subjects.  Subjects 
receiving prior advanced treatment for low/intermediate-risk PE in the same 
hospital setting as a second treatment for high-risk PE likely have a different 
profile than those receiving advanced care for the first time after diagnosis of high-
risk PE, and therefore should be looked at separately.  In the spirit of the AHA 
guidelines for trial design in this patient population, data will be collected to 
ensure representation of this smaller yet significant group of high-risk PE patients. 
 
Concurrent Enrollment in All Arms: 
Sites participating in the FLAME study will enroll all subjects presenting with high-
risk (massive) PE over the course of the study, regardless of their primary 
thrombus removal strategy or prior therapy to ensure enrollment of all-comers to 
the study.  Subjects will be enrolled in each arm as described above. 
Number of Sites 
The FLAME Study will be conducted at up to 20 sites in the United States. 
Study Design 
Prospective, multicenter, non-randomized, parallel group, observational study of 
subjects concurrently enrolled in the FlowTriever, Context, and Prior Therapy 
Arms.  
Primary 
Endpoint 
In-hospital composite endpoint of:  
• 
All-cause mortality  
• 
Bailout to an alternative thrombus removal strategy  
• 
Clinical deterioration  
• 
Major bleeding, BARC 3b/3c/5a/5b definition   
Secondary 
Endpoints 
Secondary Safety Endpoints 
• 
Frequency of each primary endpoint composite component 
• 
Frequency of Stroke (ischemic or hemorrhagic) 
• 
Frequency of device-related complications 
• 
Access site injury requiring intervention, both venous and arterial 
 
Utility Measures 
• 
Length of hospital stay 
• 
Length of ICU stay 
• 
Use of ECMO, including either pre- or post-treatment initiation and 
duration 
• 
Time to extubation, if intubated 
• 
Discharge location 

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Inclusion 
Criteria 
High-risk pulmonary embolism (PE) subjects must meet each of the following 
criteria to be eligible for enrollment: 
• 
≥18 years of age 
• 
Treatment team determines pulmonary embolism is the cause of shock 
• 
One or more of the following: 
o Systolic blood pressure <90 mmHg for at least 15 minutes or drop 
of >40 mmHg in systolic blood pressure for at least 15 minutes, 
and/or 
o Need for vasopressor support, and/or 
o Resuscitation after cardiac arrest with <30 minutes of CPR and 
Glasgow Coma Scale >8. 
Exclusion 
Criteria 
High-risk pulmonary embolism (PE) subjects will be excluded from the study for 
any of the following criteria: 
• 
Out of hospital cardiac arrest with Glasgow Coma Scale of ≤8 
• 
Witnessed cardiac arrest with ongoing CPR >30 minutes 
• 
Contraindication to anticoagulants, i.e. heparin or alternative 
• 
Hematocrit <28% 
• 
Platelets <25,000/µL 
• 
INR >8 
• 
Intracardiac thrombus and/or intracardiac clot in transit 
• 
Known anaphylactic sensitivity to radiographic agents that cannot be pre-
treated 
• 
History of pulmonary hypertension with systolic pulmonary arterial 
pressure >70 mmHg 
• 
Presence of chronic medical conditions with estimated < 90 days life 
expectancy per physician discretion (should not consider the current 
pulmonary embolism and its treatment) 
• 
Current participation in another drug or device treatment study that, in 
the Investigator’s opinion, would interfere with participation in this study 
• 
Patient is known to be COVID-19 positive at hospital admission (patient 
has active COVID-19)  
Primary 
Endpoint 
Definitions 
All events 
contributing to 
the Primary 
Endpoint will be 
adjudicated by 
the CEC for the 
FlowTriever and 
Bailout to an alternate 
thrombus removal 
strategy 
Need for mechanical circulatory support or another 
thrombus removal strategy after the primary treatment 
strategy was initiated. The additional treatment strategy 
was not an a priori part of the original treatment plan 
(conceived beforehand).   
Clinical Deterioration 
• 
Need for CPR 
• 
Need to start IV vasopressors to keep systolic 
blood pressure > 90 mmHg in a previously 
normotensive patient 
• 
Need for mechanical ventilation in a previously 
spontaneously breathing patient 

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Context Arm 
Subjects 
• 
Need for noninvasive positive pressure 
ventilation in a patient previously on nasal 
cannula 
Major Bleeding, BARC 
3b/3c/5a/5b 
• 
3b:  Overt bleeding plus hemoglobin drop of ≥ 5 
g/dL (provided hemoglobin drop is related to 
bleed); cardiac tamponade, bleeding requiring 
surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid); bleeding 
requiring intravenous vasoactive agents 
• 
3c:  Intracranial hemorrhage (does not include 
microbleeds or hemorrhagic transformation, 
does include intraspinal), subcategories 
confirmed by autopsy or imaging or lumbar 
puncture, intraocular bleed compromising vision. 
• 
5a:  Probable fatal bleeding; no autopsy or 
imaging confirmation but clinically suspicious 
• 
5b:  Definite fatal bleeding; overt bleeding or 
autopsy or imaging confirmation 
Study Schedule 
Subjects will be followed through hospital discharge from the Primary High-Risk PE 
treatment procedure. 
Safety 
Monitoring 
Safety events for the FlowTriever and Context Arm subjects will be adjudicated by 
an external Clinical Events Committee (CEC). 
National 
Principal Co-
Investigators 
Mitchell Silver, DO 
James Horowitz, MD 
 
 

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ABBREVIATIONS 
Abbreviation 
Term 
AC 
Anticoagulation 
ADaM 
Analysis data model 
AE 
Adverse event 
AGC 
Aspiration guide catheter 
AHA 
American Heart Association 
BARC 
Bleeding Academic Research Consortium 
BNP 
B-type natriuretic peptide 
CDISC 
Clinical Data Interchange Standards Consortium 
CDT 
Catheter-directed thrombolysis  
CEC 
Clinical Events Committee 
CPR 
Cardiopulmonary resuscitation 
CRO 
Contract research organization 
CTED 
Chronic thromboembolic disease 
CTEPH 
Chronic thromboembolic pulmonary hypertension 
CTPA 
Computed tomographic pulmonary angiography 
DOAC 
Direct oral anticoagulant 
DVT 
Deep venous thrombosis 
ECMO 
Extracorporeal membrane oxygenation 
eCRFs 
Electronic case report forms 
EDC 
Electronic data capture 
ESC 
European Society of Cardiology 
FDA 
Food and Drug Administration 
FLARE 
FlowTriever Clinical Embolectomy Clinical Study 
FLAME 
FlowTriever for Acute Massive Pulmonary Embolism 
FLASH 
FlowTriever All-Comer Registry for Patient Safety and Hemodynamics 
FT 
FlowTriever 
GLM 
Generalized linear models 
H-FABP 
Heart type fatty acid binding 
ICU 
Intensive care unit 
IFU 
Instructions for use 
INR 
International normalized ratio 
IRB 
Institutional review board 
ISO 
International Organization for Standardization 
ITT 
Intent to treat 
LV 
Left ventricle 
MAE 
Major adverse events 
NT-proBNP 
N-terminal pro B-type natriuretic peptide 
PE 
Pulmonary embolism 
PERT 
Pulmonary Embolism Response Team 
PESI 
Pulmonary Embolism Severity Index 

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Abbreviation 
Term 
PHI 
Protected Health Information 
rt-PA 
Recombinant tissue plasminogen activator 
RV 
Right ventricle 
RV/LV 
Right ventricular to left ventricular diameter ratio 
SAE 
Serious adverse event 
SIV 
Site initiation visit 
sPESI 
Simplified Pulmonary Embolism Severity Index 
TLF 
Tables, lists, and figures 
TNK 
Tenecteplase 
TTE 
Transthoracic echocardiogram 
UAT 
Ultrasound-accelerated thrombolysis 
VTE 
Venous thromboembolism 
 
 
 

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1 
INTRODUCTION AND BACKGROUND 
Pulmonary embolism (PE) comprises one element of venous thromboembolism (VTE), an entity that 
includes deep vein thrombosis (DVT) and PE. PE occur when venous thrombi travel from the peripheral 
veins, through the heart, and lodge in the pulmonary arterial circulation. The emboli arise from 
peripheral locations, usually the large deep veins of the leg and pelvis, but sometimes from the large 
veins of the upper extremities. While small PE may remain asymptomatic and go unnoticed, larger 
emboli may result in significant pulmonary artery obstruction, right heart decompensation, and death. 
Some PEs are immediately fatal, particularly large PE that lodge at the bifurcation of the main 
pulmonary artery into its right and left branches; the so called “saddle embolus.” On the other hand, PE 
may occur in a repeated fashion, often over months or even years, insidiously obliterating the 
pulmonary arterial outflow to culminate in debilitating pulmonary hypertension and the syndrome 
known as chronic thromboembolic pulmonary hypertension, or “CTEPH.”   
High-risk PE carries a significantly high mortality rate. Even after intervention, the morbidity and 
mortality of this disease process is profound.1-4 Medical treatment paradigms for high-risk PE also pose 
risk, with many of these possible therapies utilizing anticoagulants and thrombolytics.5 Surgical 
thrombectomy for high-risk PE has been performed with some success if treated before the 
development of cardiogenic shock but again poses risk of significant morbidity and mortality.6 Systemic 
thrombolysis has long been a treatment option for high-risk PE patients, although the treatment is 
associated with significant bleeding risks. Rates of major bleeding spanning from approximately 10%-
50% have been reported, with rates of intercranial hemorrhage of approximately 3%-4%.2, 3, 7-10 
Accordingly, a non-surgical treatment modality obviating the need for thrombolysis would be an optimal 
addition to the treatment armamentarium.    
1.1 INCIDENCE AND FATALITY RATE FOR INTERMEDIATE RISK PE AND HIGH-RISK PE  
Estimates of VTE incidence range from 75 and 269 cases per 100,000 population.11 While the actual 
incidence of reported VTE differs by global geography, the rate of VTE increases with age, rising to 700 
cases per 100,000 population in patients aged 70 and older. PE itself occurs at differing rates in different 
countries, at least as reported. For instance, the rate of PE as a primary diagnosis of hospitalization in 
the United States is among the highest in the world (Figure 1). 
Data from the Nationwide Inpatient Sample from 1993-2012 showed that US hospital admissions for PE 
rose from 23 per 100,000 in 1993 to 65 per 100,000 in 2012.12 Interestingly, over the same time period 
there was a decrease in admissions for high-risk PE (2.8 to 1.5 per 100,000).12 The rise in detection of PE 
is likely due to better diagnosis with the increased use of computed tomographic pulmonary 
angiography (CTPA) over the years of study. All-cause mortality in PE patients decreased from 7.1% in 
1993 to 3.2% in 2012.12 A study in China also showed a drop in the fatality rate, from 25% in 1997 to less 
than 10% in 2008; a change likely accounted for by an increase in the rate of diagnosis of smaller PE and, 
possibly, improved treatment after recognition.13 However, a recent multicenter U.S. study on 
Pulmonary Embolism Response Teams (PERTs) found the 30-day mortality rate among the centers 
ranged from 9% to 44% (with a mean of 16%) for patients with PE.14 Not surprisingly, the mortality rate 
for patients with high-risk PE is higher compared to intermediate-risk patients. A fivefold increase in 
mortality has been reported for high-risk PE as compared to intermediate-risk patients.8  

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In a study published in Circulation, according to Kucher et al., the incidence of high-risk PE was 4.5%.15 
Of patients with PE, a recent report on PERTs in the U.S. found that 12.3% of PE patients were in the 
high-risk PE category.14 Of all patients presenting with PE, the most significant variables that 
distinguished high-risk PE from non-massive PE were systolic blood pressure, heart rate, days from 
symptom onset to diagnosis, syncope, right ventricular hypokinesis, decreased left ventricular ejection 
fraction, concomitant deep vein thrombosis, congestive heart failure, and elevated serum creatinine. 
 
Figure 1. Incidence and Case-Fatality Rate for Massive vs non-Massive Pulmonary Embolism11 
 
1.2 DIAGNOSIS OF PULMONARY EMBOLISM 
Traditionally, clinical prediction rules have been utilized to guide appropriate patients toward imaging 
analyses. Patients can be subcategorized using, for instance, the Geneva or Wells prediction models.  

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CTPA imaging is performed in most centers today.16 Except for the evaluation of CTEPH, CTPA has 
replaced V/Q scan as the imaging test of choice. The accuracy of CTPA, however, is not uniform. 
Respiratory motion, reconstruction artifacts (e.g., “stair-step” artifact), or beam-hardening artifacts from 
high density structures such as a contrast-filled superior vena cava may be responsible for errors.17 As 
well, CTPA can over-diagnose small, subsegmental emboli of little clinical consequence.18 Irrespective of 
the clinical implications of small, subsegmental emboli on CTPA, these can be false positive findings, and 
duplex ultrasonography of the lower extremity veins can be helpful in these cases.17,19 The terminology 
of massive pulmonary embolism correlates to the “high-risk” pulmonary embolus as defined by the 
European Society of cardiology (ESC).20, 21 
The diagnosis of high-risk PE is typically made clinically using the following criteria: Acute PE with 
sustained hypotension (defined as a systolic blood pressure <90 mm Hg, for at least 15 minutes or 
requiring inotropic support, not due to a cause other than PE, such as arrhythmia, hypovolemia, sepsis, 
or left ventricular dysfunction), pulselessness, or persistent profound bradycardia (heart rate <40 bpm 
with signs or symptoms of shock).20, 21 Other prognostic factors include; right ventricle (RV) dilation, 
hypokinesis, and ischemia/infarction. RV dilation leads to reduced filling of the left ventricle (LV), and an 
increase in short-term mortality is observed with an RV/LV ratio of greater than 0.9 at computed 
tomography (CT).22-24 There is a 2.4 fold increase in mortality associated with RV dysfunction observed at 
echocardiography.25 Increased mortality is also observed with elevated troponin and brain natriuretic 
peptides, which are associated with a four- to eight-fold risk and a six-fold risk, respectively.25-27 
1.3 PULMONARY EMBOLISM TREATMENT & RISK STRATIFICATION 
The treatment of PE depends on its severity. The severity is defined by the risk of death; a risk tightly 
correlated with the hemodynamic consequences of the embolism, namely, acute right ventricular (RV) 
dysfunction. RV dysfunction is the principal determinant of a patient’s clinical course.21, 28 The risk of 
hemodynamic compromise is related to the interplay between the size of the embolus and the baseline 
cardiorespiratory state of the patient. For instance, a PE of moderate size in a healthy patient may be 
unassociated with hemodynamic compromise while the same embolus in an elderly patient with 
preexisting cardiac disease may result in fulminant right heart decompensation and death. In this 
regard, the severity of pulmonary embolism is only partially represented by the presenting 
hemodynamic condition of the patient and baseline comorbidities should be considered. 
A variety of indices have been used in the prediction of outcome after PE. One, the Pulmonary Embolism 
Severity Index (PESI), has been well-validated.29 PESI risk strata I and II patients have a low risk of 30-day 
mortality. A simplified PESI score, sPESI, was also developed and validated.30-32  Patients with a sPESI 
score of 0 have a very low risk of adverse early outcome. Adding the combination of a negative cardiac 
troponin further increases the negative predictive value of the scores.31 It should be noted, however, 
that the PESI and sPESI risk stratifications were developed as epidemiologic tools and were not designed 
to guide the management of PE. The FLAME Protocol will allow enrollment of only high-risk PE that 
would typically carry an overall mortality rate of approximately 50%, and cardiovascular mortality rate 
of nearly 40% at 30 days.1-3 
1.4 CLASSIFICATION SCHEMA FOR PULMONARY EMBOLISM 
American Heart Association. The 2011 American Heart Association (AHA) Scientific Statement on 
Pulmonary Embolism classified PE into three traditional categories utilized in the literature: massive, 

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submassive, and low-risk.20 The AHA document included definitions for each category. Massive (high-
risk) PE is defined as hypotension with systolic blood pressure <90 mm Hg lasting more than 15 minutes 
or requiring ionotropic support, or persistent bradycardia to <40 bpm with shock. Submassive PE is 
defined as PE without hypotension, and either RV dysfunction or myocardial necrosis. RV dysfunction is 
identified when at least one of the following is present: RV/LV ratio >0.9, RV systolic dysfunction on 
echocardiography, elevation of BNP >90 pg/mL, elevation on N-terminal pro-BNP >500 pg/mL, 
electrocardiographic changes of new right bundle-branch block, anteroseptal ST elevation or depression, 
or anteroseptal T-wave inversion. Myocardial necrosis is defined by elevation of troponin I >0.4 mg/mL 
or troponin T >0.1 ng/mL. Low-risk PE is a PE that falls short of the criteria for submassive PE; in other 
words, a PE without RV dysfunction or elevation of biomarkers. 
While these categories correlate roughly with the risk of mortality, the AHA document stresses that 
concurrent comorbidities must be accounted for in the prediction of mortality. For instance, a non- 
massive PE in a patient with preexisting chronic obstructive lung disease or congestive heart failure. That 
said, the short-term mortality approximates 25-50% for massive PE, 1% for low-risk PE, and somewhere 
in between for submassive PE. 
European Society of Cardiology. The 2019 European Society of Cardiology (ESC) guidelines specified 
combinations of clinical presentation, imaging, biomarkers to better risk-classify patients (Figure 2).21 
The ESC risk stratification scheme utilizes four criteria to classify PE patients into four grades of mortality 
risk: high, intermediate-high, intermediate-low, and low. 
 
Figure 2. European Society of Cardiology Risk Stratification 
From Konstantinides et al.21 
BP = blood pressure; CTPA = computed tomography pulmonary angiography; H-FABP = heart-type fatty acid-binding protein; 
NT-proBNP = N-terminal pro B-type natriuretic peptide; PE = pulmonary embolism; PESI = Pulmonary Embolism Severity 
Index; RV = right ventricular; sPESI = simplified Pulmonary Embolism Severity Index; TTE = transthoracic echocardiogram. 
aOne of the following clinical presentations : cardiac arrest, obstructive shock (systolic BP <90 mmHg or vasopressors 
required to achieve a BP >_90 mmHg despite an adequate filling status, in combination with end-organ hypoperfusion), or 
persistent hypotension (systolic BP <90 mmHg or a systolic BP drop >_40 mmHg for >15 min, not caused by new-onset 
arrhythmia, hypovolaemia, or sepsis). 
bPrognostically relevant imaging (TTE or CTPA) findings in patients with acute PE. 
cElevation of further laboratory biomarkers, such as NT-proBNP >_600 ng/L, H-FABP >_6 ng/mL, or copeptin >_24 pmol/L, 
may provide additional prognostic information. These markers have been validated in cohort studies but they have not yet 
been used to guide treatment decisions in randomized controlled trials. 

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dHaemodynamic instability, combined with PE confirmation on CTPA and/or evidence of RV dysfunction on TTE, is sufficient 
to classify a patient into the high-risk PE category. In these cases, neither calculation of the PESI nor measurement of 
troponins or other cardiac biomarkers is necessary. 
eSigns of RV dysfunction on TTE (or CTPA) or elevated cardiac biomarker levels may be present, despite a calculated PESI of I-
IIor an sPESI of 0. Until the implications of such discrepancies for the management of PE are fully understood, these patients 
should be classified into the intermediate-risk category. 
 
High-risk patients include those with all four criteria positive. These patients present in shock, PESI 
scores III or greater or sPESI scores greater than 0, RV dysfunction on imaging, and positive cardiac 
biomarkers indicative of myocardial necrosis. An intermediate-risk category is defined by the ESC 
guidelines, analogous to the submassive category in the literature.26 The intermediate-risk subgroup is 
divided into intermediate high-risk and intermediate low-risk subcategories, depending on whether both 
RV dysfunction and positive cardiac biomarkers are present (intermediate high-risk) or only one of the 
two are present (intermediate low-risk). The last category is the low-risk group and is similar to the AHA 
low-risk category.20 These patients present without hemodynamic compromise, have low PESI/sPESI 
scores, and normal imaging or laboratory assessments when they are performed. While validation of the 
ESC risk scale has been studied in only one large randomized clinical trial, the scale is one method on 
which to guide treatment options.33 
1.5 RISK-BASED TREATMENT OF PULMONARY EMBOLISM 
High-risk PE is defined when a patient presents with shock from acute right ventricular decompensation. 
Early, definitive treatment is necessary to prevent the rapid, downhill spiral that culminates in a 
patient’s demise. Anticoagulation with the removal of the occluding pulmonary artery thrombus is 
indicated, either by pharmacologic, pharmacomechanical, or mechanical means. In certain cases, open 
surgical pulmonary embolectomy and even extracorporeal membrane oxygenation (ECMO) may be 
necessary. Fortunately, high-risk pulmonary embolism occurs in less than 10% of cases.34 
The treatment of high-risk PE patients is clear; definitive intervention is indicated, up to and including 
open surgical thrombectomy with or without ECMO.
35  Once a diagnosis of high-risk PE is made, 
expeditious intervention is warranted in order to optimize outcome. Pharmacomechanical, ECMO, and 
open thrombectomy require anticoagulants and often thrombolytic therapy, with the possibility of 
concomitant morbidity secondary to bleeding.8 Patients with high-risk PE have an increased risk or 
mortality and morbidity with treatment. A systematic review on the use of ECMO in high-risk PE showed 
that patients who were in cardiorespiratory arrest when ECMO was initiated had a higher risk of death.36 
In a study by Secemsky et al. there was a 2.28-fold increase in major bleeding in patients with high-risk 
PE compared to patients with submassive PE.8  
 
1.6 TREATMENT OPTIONS FOR PULMONARY EMBOLISM  
1.6.1 
Anticoagulation 
Anticoagulation is the mainstay of therapy for VTE, directed at decreasing the risk of recurrent embolic 
events and propagation of existing thrombi. Traditionally, unfractionated heparin is used followed by 3 
months of oral vitamin K antagonists such as warfarin.37 Longer treatment with oral agents has been 
controversial, but individualized therapy must balance the risk of hemorrhage and VTE recurrence.37-39 
Some investigators have studied low molecular weight heparin in place of unfractionated heparin and 
Warfarin, with satisfactory results.40 More recently, direct oral anticoagulants (DOACs) have been 

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employed as alternatives to Warfarin in the setting of PE.41-43 However, with high-risk PE a more 
aggressive approach must be attempted, as anticoagulation alone will rarely restore pulmonary artery 
flow, and the patient will remain hemodynamically compromised.5, 33, 44  
 
1.6.2 
Pharmacologic Thrombolysis 
While anticoagulation is effective in preventing recurrent PE, it does little to treat existing emboli. 
Treatment of obstructing pulmonary artery thromboembolism attains relevance in patients with 
intermediate-risk (submassive) and high-risk PE, where normalization of right heart function and 
reduction in mortality is important. Initially, intravenous, systemic thrombolysis was used for PE. After 
initial anecdotal success with intravenous urokinase for PE reported in 1968 by Sasahara,47 the landmark 
randomized clinical trials upon which the initial US Food and Drug Administration (FDA) approval for 
urokinase was based demonstrated improved outcome with thrombolysis versus anticoagulation for 
intermediate-risk and high-risk PE.48-53 The benefits were limited to short-term improvement in cardiac 
function, but the studies were not powered to detect mortality differences. For the first time, however, 
removal of pulmonary artery thrombus was demonstrated to be safe, effective, and appeared 
advantageous compared to anticoagulation alone. 
Over the next five decades, intravenous, systemic thrombolysis was demonstrated to be effective in 
reducing the thrombus load after PE. However, this outcome was achieved at the cost of a five-fold 
increase in major bleeding, which in some cases included intracranial hemorrhage.33, 54, 55  These findings 
remained unchanged despite newer agents and better periprocedural patient management over the 
years. 
Noting the hemorrhagic complications associated with systemic thrombolysis for PE, lower-dose, 
catheter-directed thrombolytic approaches were studied. Catheter-directed thrombolysis for PE was the 
subject of a meta-analysis published in 2009.56 In sum, catheter-directed thrombolysis appeared 
effective and probably safer than the systemic approach. The authors recommended that catheter- 
directed thrombolysis be considered as a first line therapy for acute, high-risk PE. However, recent work 
suggests that even a catheter-directed approach may be associated with significant bleeding 
complications in the treatment of intermediate and high-risk patients.7,57 A study comparing catheter-
directed thrombolysis to systemic thrombolysis in a group of intermediate and high-risk patients showed 
bleeding was higher in the catheter directed group, while in-hospital mortality was lower compared to 
the systematic thrombolysis group.57 
1.6.3 
Ultrasound-Accelerated Thrombolysis 
After demonstrating the possibilities of more effective thrombolysis using ultrasound to accelerate the 
process, catheter-directed, ultrasound-accelerated thrombolysis (UAT) was studied for intermediate-risk 
and high-risk PE. Two multicenter, prospective studies were completed, ULTIMA and SEATTLE-II. ULTIMA 
was a randomized analysis of UAT vs. anticoagulation alone in 59 subjects with intermediate-risk PE.58 
UAT was more effective than anticoagulation in normalizing RV function in intermediate-risk PE patients. 
No intracranial bleeding was observed. The SEATTLE-II trial evaluated differing doses of rt-PA PAT 
infused over varying timeframes in 150 subjects with intermediate-risk and high-risk PE.59 These studies 
concluded that catheter-directed pulmonary artery thrombolysis with rt-PA was safe and effective in the 
treatment of intermediate-risk PE, at least with respect to reductions in RV/LV ratio without intracranial 
hemorrhage. This conclusion, however, has not been without controversy. A 2017 review of 23 studies 

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and 700 subjects found no difference in the rate of bleeding complications between UAT and standard, 
catheter-directed thrombolysis, 12% with UAT vs. 10% with standard catheter-directed thrombolysis.60 
The review, however, documented a trend toward improved survival with UAT; 4% vs. 9% in the UAT 
and standard thrombolytic subjects, respectively. No device has been identified as superior in the 
treatment of high-risk PE subjects, opening the medical opportunity to augment the non-surgical 
armamentarium in the treatment of high-risk PE. 
1.6.4 
Open Surgical Thromboembolectomy 
Open surgical thromboembolectomy is perhaps the first definitive interventional treatment for PE. 
Surgical thromboembolectomy was first conceived by Trendelenburg in 1908, while Kirschner was the 
first to publish the technique in a 1924 report.45 Open surgical thromboembolectomy can result in rapid, 
life-saving hemodynamic improvement in patients with significant PE.35, 46  However, open surgical 
thromboembolectomy is a major invasive procedure, fraught with complications in unstable patients. 
The in-hospital mortality rate is more than 25%, although this figure must be considered in the context 
of alternative therapies in this high-risk PE group. No randomized trials have been performed to 
compare the outcome with alternate therapies in similar patient populations. For these reasons, AHA 
and ESC guidelines suggest that open surgical intervention be reserved for hemodynamically-unstable 
patients with contraindications to thrombolysis.20, 21  However, selected indications remain appropriate 
for open thromboembolectomy; for example, emboli in transit such as within the right heart or a patent 
foramen ovale. In this regard, the American College of Chest Physicians advocates open surgical 
intervention for patients who are severely compromised such that death is likely to occur before 
thrombolytic therapies can improve the patient’s hemodynamic state. 
1.6.5 
Percutaneous Pulmonary Artery Thromboembolectomy 
Interest in percutaneous pulmonary artery thromboembolectomy flourished on a clinical landscape of 
effective but relatively slow thrombolytic treatment of PE and a risk of thrombolytic-related bleeding 
complications even when drugs were administered with a lower-does, catheter-directed approach. 
Direct pulmonary arterial thromboembolectomy offered the opportunity for rapid removal of thrombus 
while limiting hemorrhagic, thrombolytic-related complications in those cases where thrombectomy 
could be utilized as sole therapy, without pharmacologic thrombolysis. 
Historically, percutaneous thromboembolectomy for PE predated catheter-directed thrombolysis. The 
therapy began with the Greenfield suction catheter, first reported in 1969.61After that, other 
technologies were attempted, including fragmentation of proximal emboli,62, 63 rheolytic 
thrombectomy,64-68 and the use of various pulmonary artery thromboembolectomy devices.69-71 To the 
extent that the percutaneous thromboembolectomy devices removed obstructing thromboembolism 
without the need for thrombolytic therapy, such devices presented the potential for normalization of 
pulmonary arterial flow without the hemorrhagic complications associated with thrombolytic agents. 
This is the rationale for FlowTriever as it has the advantages of a percutaneous procedure, with 
expectation that the bleeding complications of thrombolysis will be minimized. 
 
 

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2 
THE FLOWTRIEVER SYSTEM 
Noting the need for rapid restoration of pulmonary arterial flow after pulmonary embolism, Inari 
developed the FlowTriever Retrieval/Aspiration System (FlowTriever System) to extract pulmonary 
arterial thromboembolism without an obligatory need for thrombolytic agents.72, 73 
The FlowTriever System is indicated for the non-surgical removal of emboli and thrombi from blood 
vessels; the injection, infusion, and/or aspiration of contrast media and other fluids into or from a blood 
vessel. The completion of the FLARE prospective clinical trial resulted in FDA clearance for the treatment 
of pulmonary embolism.  It is expected that the use of the FlowTriever System will augment 
effectiveness in the treatment of high-risk PE.  Due to the high risk of mortality with current treatments 
for high-risk PE, with reported in-hospital mortality rates ranging from approximately 17% to 50%, it is 
expected that FlowTriever will also have a safety benefit in this patient group.8, 74-78. 
2.1 FLOWTRIEVER SYSTEM 
The FlowTriever System will be used in the FlowTriever Arm of this study. The System is a catheter-
based mechanical thrombectomy device for percutaneous endovascular retrieval of emboli and is 
intended for use in the proximal pulmonary arterial system. The FlowTriever System is designed to 
mechanically remove emboli and restore blood flow through the pulmonary arteries in the setting of 
acute pulmonary embolism. 
2.2 REGULATORY STATUS  
The FlowTriever System was cleared for the treatment of pulmonary embolism under 510(k) number 
K180466, May 17, 2018. 
2.3 INTENDED USE OF THE DEVICE 
The FlowTriever System is a Class II device, intended for use in the peripheral vasculature and for the 
treatment of pulmonary embolism. 
2.4 DEVICE DESCRIPTION 
The FlowTriever Retrieval/Aspiration System is a single-use over-the-wire catheter-based system for the 
minimally invasive treatment of thromboemboli in the peripheral vasculature and the treatment of 
pulmonary embolism. The system is composed of two main components: the Triever Catheter and the 
FlowTriever Catheter.   
The Triever Catheter is a large-bore catheter used primarily for controlled aspiration of thromboemboli. 
After being positioned adjacent to thrombus, a vacuum is applied to the catheter side port via a 60 mL 
custom large-bore syringe. Opening the side port valve produces an abrupt, high-flow suction to extract 
thrombus through the Triever catheter and into the syringe, while limiting blood loss to 60 mL per 
aspiration. 
The FlowTriever Catheter, often delivered into the body through the Triever Catheter, consists of a 
flexible shaft attached to distal self-expanding nitinol disk(s). It is used to macerate and deliver 

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thrombus to the Triever Catheter for removal via aspiration and is often used for more chronic, wall-
adherent thrombus. 
A complete description of the FlowTriever System is provided in the Instructions for Use.    
2.5 RATIONALE FOR THE USE OF THE FLOWTRIEVER SYSTEM 
The use of thrombectomy for PE offers the opportunity to reduce the pulmonary arterial thrombus 
burden rapidly. As well, there are subpopulations where FlowTriever thrombectomy may be the only 
interventional option; for instance, in patients for whom pharmacologic thrombolysis is contraindicated. 
The effectiveness of the FlowTriever System does not rely on the use of obligatory adjunctive 
pharmacologic therapy. While some may choose to employ thrombolysis during or after FlowTriever 
thrombectomy, the use of thrombolytic agents is not required. 
 
 

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3 
PRIOR INVESTIGATIONS 
The FlowTriever System was evaluated in a US pivotal Investigational Device Exemption trial, the 
FlowTriever Clinical Embolectomy Clinical Study (FLARE) study, in subjects with submassive (i.e., 
intermediate-risk) PE. The study was a prospective, multicenter study to evaluate the safety and 
effectiveness of the FlowTriever System in subjects eligible for endovascular treatment of acute PE.   
Following FDA clearance for the FlowTriever System, a subsequent study (FlowTriever All-Comer 
Registry for Patient Safety and Hemodynamics (FLASH)) was designed and is being conducted to 
evaluate the safety and effectiveness of the FlowTriever System for use in the removal of emboli from 
the pulmonary arteries in the treatment of acute pulmonary embolism (PE). The use of the device is 
being assessed in a real-world population, and enrollment in the study is ongoing.   
3.1 FLARE STUDY DESIGN AND SUMMARY OF RESULTS 
3.1.1 
FLARE STUDY DESIGN 
A maximum of 20 study sites were planned to participate in the study, and no single study site could 
enroll more than 25% of the total subjects. The study population comprised 106 subjects with acute 
submassive PE.  
Primary safety and a primary effectiveness performance goals were used in the study. For the safety 
Performance Goal, the results from seven studies with acute PE patients treated with a heparin control 
arm were used to develop a composite MAE rate. MAEs were defined when one or more of the 
following occurred within 48 hours: Device-related death, major bleeding, treatment-related clinical 
deterioration, treatment-related pulmonary vascular injury, or treatment-related cardiac injury. 
Combining these composite MAE rates yielded an estimate of 16% with a 95% confidence interval of 
6.7% to 25.8% after adjusting for heterogeneity among studies. The Performance Goal was chosen as 
the upper 95% confidence limit rounded down to two digits, for a safety Performance Goal of 25%. 
The primary effectiveness performance goal was the change in RV/LV ratio from baseline to 48 hours. 
The Performance Goal was based on heparin-treated subjects from four studies in which heparin was a 
control to an active pharmaceutical drug. Combining these results in a meta-analysis yielded a mean 
change from baseline of 12% with 95% confidence limits of 4% to 21% after adjusting for heterogeneity 
among studies, for an effectiveness Performance Goal of 12%. 
Subjects were followed for 30 days post-procedure with CTPA at 48 hours and assessment of AEs 
through 30 days. The primary safety endpoint was assessed from the 48-hour MAE rate and the primary 
effectiveness endpoint from the change between the baseline and 48-hour CTPA imaging studies. 
The sample size for effectiveness was computed based on an estimated RV/LV ratio change from 
baseline. For 80% power to detect an RV/LV ratio greater than 0.12 using a one-sided alpha = 0.025, the 
sample size needs to be at least 62, 38, or 26 assuming a true RV/LV ratio of 0.20, 0.225 or 0.25, 
respectively. 
The sample size for safety was based on the Performance Goal of 25% for the composite endpoint. The 
true composite endpoint rate for the FlowTriever was expected to be about 13%, according to data from 
the historical studies used for the Performance Goal estimation. Additionally, rates of 15% and 17% 

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were considered. For 80% power to detect a difference from the expected lower composite endpoint 
rates of 13%, 15% and 17% compared to the performance goal with a one-sided alpha = 0.05, 70, 103 
and 167 subjects would be needed if the true rates were 13%, 15%, and 17%, respectively. Since a 
conservative sample size for safety was calculated to be 103, 103 was used as the sample size for this 
study, not adjusted for subjects receiving thrombolytics. It was assumed that approximately 15% of the 
subjects would receive thrombolytics so that 103/0.85=121.2 or up to 122 subjects could be enrolled. 
3.1.2 
FLARE STUDY RESULTS 
The disposition of subjects in the FLARE trial is depicted in Figure 3. In all, 106 subjects were enrolled 
and treated with the study device; 104 without thrombolytics. Among these, 101 had evaluable CTPA 
studies suitable for the primary effectiveness endpoint. There were also 101 subjects that had 48-hour 
data suitable for the primary safety endpoint. The mean baseline RV/LV ratio was 1.5 ± 0.4, and the 
mean 48-hour RV/LV ratio was 1.2 ± 0.3. Three subjects had missing values for the primary effectiveness 
endpoint at the 48-hour visit resulting in 101 subjects with both a pre- and post- RV/LV ratio for 
comparison. For these paired subjects, the mean change (reduction) in RV/LV ratio from pre- to post- 
was 0.38 ± 0.3, with a range from an increase of 0.4 to a decrease of 1.4. This mean change in RV/LV 
ratio was 0.38 and the p-value < 0.0001, indicating that the null hypothesis was rejected and the 
FlowTriever System met the performance goal.a 
Figure 3. Disposition of Subjects in the FLARE Trial 
 
For the primary safety endpoint, 4 subjects (3.8%) in the modified intention to treat population (all 
patients with treatment attempted and no thrombolytics were administered) population experienced 
one or more MAEs. The composite endpoint of 3.8% was statistically lower than the performance goal of 
25% (p-value <0.0001), with an upper one-sided 95% confidence limit of 8.6%. The upper one-sided 95% 
confidence limit for the ITT population was 8.4%, which was significantly less than the performance goal 
of 25%.  None of the MAEs reported were device related. 
                                                          
a The p-value is from a one-sided t-test (Wald statistic) from the multiple imputation analysis, testing the null 
hypothesis that the mean change is not greater than the performance goal of 0.12.  

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In summary, the FLARE trial met its primary safety and effectiveness endpoints. This trial was the basis 
for the US FDA 510(k) clearance of the device in May 2018. 
3.2 FLASH STUDY DESIGN AND STUDY STATUS 
As described previously, the primary study objective of FLASH is to evaluate the safety and effectiveness 
of the FlowTriever System for use in the removal of emboli from the pulmonary arteries in the 
treatment of acute pulmonary embolism (PE). The use of the device is being assessed in a real-world 
population, with eligibility criteria that closely approximate its use in clinical practice. 
 
The FLASH Study is a prospective, single-arm, multicenter study of the FlowTriever System for 
intermediate (submassive) and high-risk (massive) PE.  Up to 500 subjects will be enrolled at up to 50 
registry sites in the United States.  Enrollment in the FLASH registry is ongoing. 
 
 

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4 
FLAME STUDY OBJECTIVE 
The primary objective of this observational study is to evaluate treatment outcomes of patients 
diagnosed with high-risk (massive) pulmonary embolism who have received treatment with the 
FlowTriever System compared to an established performance goal (literature-based goal).   
 
5 
FLAME STUDY DESIGN 
The FLAME study is a prospective, multicenter, non-randomized, parallel group, observational study of 
subjects with high-risk pulmonary embolism concurrently enrolled in the FlowTriever, Context, and Prior 
Therapy Arms.  FlowTriever Arm subjects will be the primary population utilized to evaluate the study 
Primary and Secondary Endpoints for study success.  Subjects enrolled in the Context Arm will be 
analyzed separately from the endpoint analysis utilizing descriptive methods. 
Data collection for Prior Therapy Arm subjects will include information surrounding the PE treatment, 
progression to High-Risk PE, and patient course through hospital discharge.  Safety data will be 
collected, but not CEC adjudicated or analyzed as outlined for the FlowTriever and Context Arm subjects.  
Subjects receiving prior advanced treatment for low/intermediate-risk PE in the same hospital setting as 
a second treatment for high-risk PE likely have a different profile than those receiving advanced care for 
the first time after diagnosis of high-risk PE, and therefore should be looked at separately.  In the spirit 
of the AHA guidelines for trial design in this patient population, data will be collected to ensure 
representation of this smaller yet significant group of high-risk PE patients. 
   
5.1 ENDPOINTS 
5.1.1 
Primary Endpoint 
The primary endpoint is the in-hospital composite endpoint of all-cause mortality, bailout to an 
alternative thrombus removal strategy, clinical deterioration, and major bleeding (BARC 3b/3c/5a/5b 
definition).  This will be assessed in the FlowTriever Arm compared to a performance goal.  A description 
of the analysis methods is provided in Section 7.  Definitions of each component of the composite 
primary endpoint are provided in Table 1 below. 
Subjects enrolled in the Context Arm will be analyzed separately from the endpoint analysis utilizing 
descriptive methods. 
Table 1:  Primary Endpoint Definitions 
Primary Endpoint 
Definitions 
Bailout to an 
alternate thrombus 
removal strategy 
Need for mechanical circulatory support or another thrombus 
removal strategy after the primary treatment strategy was 
initiated. The additional treatment strategy was not an a priori 
part of the original treatment plan (conceived beforehand).  All 
bailout events will be adjudicated by the CEC. 
Clinical Deterioration 
• 
Need for CPR 

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• 
Need to start IV vasopressors to keep systolic blood 
pressure > 90 mmHg in a previously normotensive 
patient 
• 
Need for mechanical ventilation in a previously 
spontaneously breathing patient 
• 
Need for noninvasive positive pressure ventilation in a 
patient previously on nasal cannula 
Major Bleeding, 
BARC 3b/3c/5a/5b 
• 
3b:  Overt bleeding plus hemoglobin drop of ≥ 5 g/dL 
(provided hemoglobin drop is related to bleed); 
cardiac tamponade, bleeding requiring surgical 
intervention for control (excluding 
dental/nasal/skin/hemorrhoid); bleeding requiring 
intravenous vasoactive agents 
• 
3c:  Intracranial hemorrhage (does not include 
microbleeds or hemorrhagic transformation, does 
include intraspinal), subcategories confirmed by 
autopsy or imaging or lumbar puncture, intraocular 
bleed compromising vision. 
• 
5a:  Probable fatal bleeding; no autopsy or imaging 
confirmation but clinically suspicious 
• 
5b:  Definite fatal bleeding; overt bleeding or autopsy 
or imaging confirmation 
 
5.1.2 
Secondary Endpoints 
Secondary endpoints include safety endpoints as well as utility measures which will be assessed in the 
FlowTriever Arm.  Details of the secondary endpoints are provided in Table 2 below. 
Subjects enrolled in the Context Arm will be analyzed separately from the endpoint analysis utilizing 
descriptive methods.  
Table 2:  Secondary Endpoint Definitions 
Secondary Endpoints 
Secondary Safety Endpoints 
• 
Frequency of each primary endpoint composite component 
• 
Frequency of stroke (ischemic or hemorrhagic) 
• 
Frequency of device-related complications 
• 
Access site injury requiring intervention, both venous and arterial 
 
Utility Measures 
• 
Length of hospital stay 
• 
Length of ICU stay 
• 
Use of ECMO, including either pre- or post-treatment initiation and duration 
• 
Time to extubation, if intubated 
• 
Discharge location 
 

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5.2 STUDY POPULATION AND ENROLLMENT 
Patients diagnosed with high-risk pulmonary embolism will be enrolled in this study.  Subjects will be 
enrolled into one of three arms:  the FlowTriever, Context, or Prior Therapy Arm.  Sites participating in 
the FLAME study will enroll all subjects presenting with high-risk PE over the course of the study, 
regardless of their primary thrombus removal strategy, to ensure enrollment of all-comers to the study.  
Subjects will be concurrently enrolled in all arms as described below. 
Enrollment in the Context Arm will continue until FlowTriever enrollment is completed, with a minimum 
enrollment of 1:1 subjects in each arm, and a maximum enrollment of 2:1 Context Arm to FlowTriever 
Arm subjects.  Enrollment in the Prior Therapy Arm will be concurrent with the FlowTriever Arm of the 
study, and enrollment in this arm will cease when enrollment in the FlowTriever Arm is complete. 
Individual sites will be limited to no more than 25% enrollment (maximum enrollment of 17 subjects) in 
the FlowTriever Arm of the study. 
5.2.1 
FlowTriever Arm Enrollment 
Up to 71 subjects will be enrolled in the FlowTriever Arm.  FlowTriever Arm subjects are defined as 
those subjects where FlowTriever is used as the Primary Treatment for pulmonary embolism. 
An interim analysis is planned for the first 50 subjects enrolled into the FlowTriever Arm.  Based upon 
the interim analysis (as described in Section 7.4.3), a decision will be made whether to continue 
enrollment.  
5.2.2 
Context Arm Enrollment 
Subjects with high-risk pulmonary embolism who are treated with non-FlowTriever therapies (as the 
primary treatment for high-risk PE) will be enrolled concurrently with subjects in the FlowTriever Arm 
(this includes subjects initially presenting with low/intermediate-risk PE who are initially treated with 
anticoagulation alone and subsequently progress to high-risk PE.   Enrollment in the Context Arm will 
continue until FlowTriever enrollment is completed, with a minimum enrollment of 1:1 subjects in each 
arm, and a maximum enrollment of 2:1 Context Arm to FlowTriever Arm subjects.   
Context-Arm therapies may include but are not limited to; thrombolysis (either systemic or catheter 
directed), anticoagulation, surgical thrombectomy, and non-FlowTriever percutaneous thrombectomy. 
5.2.3 
Prior Therapy Arm Enrollment 
Subjects presenting with low/intermediate-risk PE who receive advanced therapy but subsequently 
progress to high-risk PE in the same hospital setting/admission should be enrolled in the Prior Therapy 
Arm.  Enrollment in the Prior Therapy Arm will be concurrent with the FlowTriever Arm of the study, and 
enrollment in this arm will cease when enrollment in the FlowTriever Arm is complete.  
 
For the purposes of this study, advanced therapy for low/intermediate-risk PE is considered therapy 
beyond anticoagulation alone, including: thrombolysis (either systemic or catheter directed), surgical 
thrombectomy, and percutaneous thrombectomy. 
   

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5.3 STUDY SITES 
The FLAME Study will be conducted at up to 20 sites in the United States.  Sites are selected based on a 
variety of factors including, but not limited to; experience with endovascular techniques, access to 
required facilities and equipment, sufficient and adequately trained personnel, and availability of 
potential subjects. The criteria used for determination will be documented.  
Once activated to enroll in the FLAME study, sites should enroll all high-risk pulmonary embolism 
subjects into FLAME, regardless of the primary thrombus removal strategy.  This will help ensure an 
unbiased enrollment of all-comers into the study. 
5.4 ELIGIBILITY CRITERIA 
5.4.1 
Inclusion Criteria 
High-risk pulmonary embolism subjects must meet each of the following criteria to be eligible for 
enrollment: 
• 
Age ≥ 18 years 
• 
Treatment team determines pulmonary embolism is the cause of shock 
• 
One or more of the following: 
o Systolic blood pressure <90 mmHg for at least 15 minutes, or drop of >40 mmHg in 
systolic blood pressure for at least 15 minutes, and/or 
o Need for vasopressor support, and/or 
o Resuscitation after cardiac arrest with <30 minutes of CPR and Glasgow Coma Scale >8. 
 
5.4.2 
Exclusion Criteria 
High-risk pulmonary embolism subjects will be excluded from the study for any of the following criteria: 
• 
Out of hospital cardiac arrest with Glasgow Coma Scale of ≤8 
• 
Witnessed cardiac arrest with ongoing CPR >30 minutes 
• 
Contraindication to anticoagulants, i.e. heparin or alternative 
• 
Hematocrit <28% 
• 
Platelets <25,000/µL 
• 
INR >8 
• 
Intracardiac thrombus and/or intracardiac clot in transit 
• 
Known anaphylactic sensitivity to radiographic agents that cannot be pre-treated 
• 
History of pulmonary hypertension with systolic pulmonary arterial pressure >70 mmHg 
• 
Presence of chronic medical conditions with estimated life expectancy < 90 days (life-expectancy 
should not include the current pulmonary embolism and its treatment) 
• 
Current participation in another drug or device treatment study that, in the Investigator’s 
opinion, would interfere with participation in this study 
• 
Subject is known to be COVID-19 positive at hospital admission (subject has active COVID-19)  
 
 

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6 
FLAME STUDY CONDUCT 
6.1 ENROLLMENT, STUDY ASSESSMENTS, AND PROCEDURES 
6.1.1 
Enrollment Logistics 
Beginning at the point of site activation (approval to begin enrollment), all patients presenting to the 
hospital/ER with PE or who incidentally develop PE while in the hospital should first be reviewed to see 
if they have high-risk PE, and then assessed for eligibility for enrollment in the FLAME study.  This will 
require a regular (approximately daily/weekly) chart and/or database review by site study personnel 
to ensure that all presenting high-risk PE subjects meeting criteria are enrolled. 
Subjects who meet eligibility criteria for the study and have a primary thrombus removal strategy 
initiated, will be considered enrolled.  The time of enrollment will be the initiation of the Primary 
Treatment Strategy for high-risk PE (the time of enrollment for patients in the Prior Therapy Arm will be 
the time of high-risk PE diagnosis).    
Subjects who do not meet eligibility criteria or die before any anticoagulation or other thrombus 
removal strategy could be initiated will not be enrolled and will be considered screen failures.  As such, 
screen failures will not be assigned a subject ID and will not be entered into the electronic data capture 
system (EDC, study database). 
 
 

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6.1.2 
Patient Flow and Schedule of Assessments 
Patient enrollment by study Arm study is provided in the Figure 4 flowchart.  The Schedule of 
Assessments is included in Table 3.  
Figure 4:  Patient Enrollment Flowchart by Study Arm 
 
Patient presents 
with PE
Treatment 
Plan for HR 
PE is 
Determined
Primary Treatment 
initiated
AC Alone, or Systemic Lytics, 
or Catheter Directed Lytics, 
or Mechanical 
Thrombectomy, or Surgical 
Thrombectomy
Document 
Bailout Events
Hospital Discharge & 
Study Exit
Did PE originate
as low/intermediate-
risk?
No
Was advanced therapy 
given for low/int-risk PE?
Yes
No 
(Treatement with AC Alone follows this path)
High-Risk PE?
Yes
Progress to HR 
PE?
Yes
FlowTriever
Document 
Clinical 
Deterioration 
Events
Document 
Major 
Bleeding 
Events
Yes
Not enrolled
No
Advanced Therapy initiated:  
Systemic Lytics, Catheter Directed 
Lytics, FlowTriever, non-FlowTriever 
Mechanical Thrombectomy, 
Surgical Thrombectomy
Pt Progresses
to HR PE in the SAME 
hospitalization?
Enrolled in the Prior Therapy Arm
Collect low/int risk PE data + Tx
Collect progression to HR + Tx for HR PE
Collect LOS, ICU Stay, basic events/course
Events won t be adjudicated by the CEC
Enrolled in the 
Context Arm
Enrolled in the 
FlowTriever Arm
Yes
Document 
Death Events
 
 
 

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Table 3:  Schedule of Assessments 
Assessment 
Baseline 
Procedure 
Post-procedure through
Hospital Discharge 
Eligibility1 
X 
 
 
Medical History2 
X 
 
 
Pre-procedure presentation and status3 
X 
 
 
Anticoagulation4 
X 
X 
X 
Thrombolytic Therapy4 
X 
X 
X 
Primary Treatment Plan Decision for high-risk PE5 
X 
 
 
Primary Treatment Initiated for high-risk PE6 
 
X 
 
Bailout therapies for high-risk PE7 
 
X 
X 
Clinical Deterioration8 
 
X 
X 
Major Bleeding Events8 
 
X 
X 
Adverse Events9 
 
X 
X 
Discharge details 
 
 
X 
1Data used to determine eligibility include pre-treatment data only.     
2Data collected for subject Medical History include pre-treatment data only.   
3Signs and symptoms of high-risk PE beginning should be reviewed for eligibility.  Data should also be collected for 
subjects first presenting with low/intermediate-risk PE who progress to high-risk PE in the same hospital 
setting/admission, including any treatment given to treat the low/intermediate-risk PE.  
4Anticoagulation and thrombolytic therapy administration are not required, but if administered, detailed data will be 
collected including drug name, dosage, start and stop dates/times, route, and reason for administration. 
5The Primary Treatment plan for treating the high-risk PE will be documented including the date and time that the 
Primary Treatment plan was decided. 
6The date and time the Primary Treatment for thrombus removal is initiated will be documented.  The patient is 
considered enrolled at the time the Primary Treatment for high-risk PE is initiated (the time of enrollment for patients in 
the Prior Therapy Arm will be the time of high-risk PE diagnosis).    
7Any bailout therapies for thrombus removal applied after initiation of the Primary Treatment therapy through hospital 
discharge will be documented and subsequently adjudicated by the CEC.  See Section 6.1.4.1 for details. 
8Clinical deterioration occurring after initiation of the Primary Treatment therapy through hospital discharge will be 
documented and subsequently adjudicated by the CEC.  See Section 6.1.4.2 for details. 
8Major bleeding events occurring from the time of initiation of the Primary Treatment therapy through hospital discharge 
will be documented as adverse events and subsequently adjudicated by the CEC.  See Section 6.1.4.3 for details. 
9Only Adverse Events (AEs) related to the subject’s PE condition and its treatment should be reported in the FLAME 
study.  
 
6.1.3 
Baseline 
6.1.3.1 Waiver of Informed Consent in Emergency Research 
Patients with high-risk pulmonary embolism are, by definition, unstable with a life-threatening condition 
and require emergent treatment.  Currently, patients with high-risk pulmonary embolism suffer from 
30-40% acute mortality 1-3, necessitating the analysis of current treatments for this high-risk patient 
population. 
The FLAME registry study will not dictate use of any specific therapy for the pulmonary embolism.  
Treatment will be at the discretion of the physician caring for the patient, utilizing standard of care 
treatment, and the data surrounding the treatment decision and patient outcomes through hospital 
discharge will be collected via retrospective chart review in the FLAME registry. 

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Per the Department of Health and Human Services criteria for a waiver of consent in research for non-
FDA regulated studies (45 CFR 46.116(d)), the FLAME study will include a waiver of consent for the 
following reasons (as listed in the regulation): 
1. The research involves no more than minimal risk to the participants.  
 
The FLAME observational registry will not dictate use of any specific therapy for the pulmonary 
embolism.  Treatment will be at the discretion of the physician caring for the patient, utilizing all 
available standard of care therapies for pulmonary embolism, and the data surrounding the 
treatment decision and patient outcomes through hospital discharge will be retrospectively 
collected in the FLAME registry, therefore additional risks are not introduced specific to the 
study.   
The only known risk to participants is the possible loss of confidentiality which has been guarded 
against by the following:   
• 
Data surrounding the treatment and patient outcomes through hospital discharge will 
be anonymized, re-identified with a study-specific subject ID, and collected for analysis.  
• 
Only the study site (Investigators and research staff) will have access PHI, providing an 
acceptable risk/benefit ratio for data collection and analysis activities performed for the 
study. 
• 
Access to the study database where anonymized data is entered is password protected 
and compliant with 21 CFR 11, Electronic Records. 
• 
Access to study data will be limited to hospital research and Sponsor personnel. 
Evaluating subject records fits the definition of minimal risk. 
2. The research could not practicably be carried out without the waiver or alteration.  
 
As noted above, patients in this high-risk population suffer from 30-40% acute mortality, and 
treatment of these patients would occur regardless of the research.  In order to carry-out 
credible and representative research in this population, all patients presenting with high-risk 
pulmonary embolism should be included in the results, including those who expire in the acute 
period following their pulmonary embolism.  This research could not be practicably carried out 
without the waiver of consent to ensure proper accounting for patient mortality.   
 
This study is a non-interventional, data collection registry.  As described above, patients with 
high-risk pulmonary embolism are, by definition, unstable with a life-threatening condition 
requiring emergent treatment.  Patients with high-risk pulmonary embolism are unable to 
consent for data collection due to their medical condition.  There is no reasonable way to 
prospectively identify potential eligible subjects and the data surrounding the treatment 
decision and patient outcomes will be collected in the FLAME registry via retrospective chart 
review by site research staff. 
 
3. If the research involves using identifiable private information or identifiable biospecimens, the 
research could not practicably be carried out without using such information or biospecimens 
in an identifiable format; 
 

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Identifiable private information will not be collected in the FLAME study.  As described above, 
data surrounding the treatment and patient outcomes through hospital discharge will be 
anonymized, re-identified with a study-specific subject ID, and collected for analysis.  Only the 
study site (Investigators and research staff) will have access PHI, providing an acceptable 
risk/benefit ratio for data collection and analysis activities performed for the FLAME study. 
 
4. The waiver or alteration will not adversely affect the rights and welfare of the participants.  
 
As the study is collecting de-identified real-world treatment data after the patients have already 
left the hospital, and the study is not prescribing the intervention or therapy, the FLAME study 
will not adversely affect the rights and welfare of the participants.  
 
5. Whenever appropriate, the participants will be provided with additional pertinent 
information after participation.  
 
This study is non-interventional and thus providing information to patients is not likely. 
However, if there were information that needed to be provided to the subject, we would work 
with the IRB to approve the correspondence to be provided to the subject.  
 
6.1.3.2 Eligibility 
Subjects will be enrolled by retrospective chart review.  This is especially important for subjects enrolled 
in the Context and Prior Therapy Arms, to help eliminate the potential for enrollment bias.  Once a site is 
activated to enroll in the FLAME study, ALL patients presenting with suspected PE should be assessed for 
high-risk PE status, and potential enrollment into the FLAME study. 
All inclusion criteria must be met, and none of the exclusion criteria can be met for enrollment into the 
study (for all arms).  All eligibility criteria are listed in Section 5.4.  Subjects will be considered enrolled 
when the Primary Treatment for thrombus removal is initiated for high-risk PE (the time of enrollment 
for patients in the Prior Therapy Arm will be the time of high-risk PE diagnosis).      
Patients not meeting eligibility criteria for the study will be considered Screen Failures, will not be 
enrolled, and are not entered into the EDC system. 
6.1.4 
Treatment 
The treating physician should document what the intended initial treatment strategy was for high-risk 
PE (referred to as the Primary Treatment).  Subjects with the Primary Treatment being FlowTriever will 
be enrolled into the FlowTriever Arm of the study.  Subjects with the Primary Treatment being non-
FlowTriever therapy will be enrolled into the Context Arm of the study.  Subjects presenting with 
low/intermediate-risk PE who receive advanced therapy but subsequently progress to high-risk PE in the 
same hospital setting/admission should be enrolled in the Prior Therapy Arm.   
Details of the treatment of PE (Primary Treatment, Bailout measures, Clinical Deterioration, and Major 
Bleeding) will be collected. 
6.1.4.1 Bailout to an Alternate Thrombus Removal Strategy 

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If, during treatment of the high-risk PE, the subject requires additional thrombus removal therapy other 
than the Primary Treatment initiated, the additional therapy should be documented.  The Clinical Events 
Committee (CEC, Section 6.3), will determine if the additional therapy meets the definition of Bailout for 
the purposes of analyzing the Primary Endpoint of the study.  Definitions for Bailout are provided in 
Table 4 below: 
Table 4:  Bailout Definitions 
Initial Treatment 
Strategy/Primary 
Treatment: 
Bailout to an Alternate Thrombus Removal Strategy Definition1: 
Thrombolysis 
(systemic or 
catheter directed) 
A bailout would be defined as the need for mechanical circulatory support or a 
different thrombus removal strategy at any time after the initial thrombolytic 
strategy was initiated. Applies when thrombolytic therapy alone was 
the original treatment plan (conceived beforehand).  Note:  if catheter 
directed thrombolysis (CDT) was the original treatment plan and 
emergent/clinically driven systemic thrombolytic administration (≥ 10 mg tPA 
or 5 mg TNK) was required after CDT was initiated, this would be considered a 
bailout. (Note:  If the length of tPA or TNK administration is simply extended 
and is not emergent or clinically driven, this would not necessarily qualify as a 
bailout). 
Anticoagulation 
(includes 
anticoagulation + 
ECMO) 
A bailout would be defined as the need for thrombolytic therapy, mechanical 
circulatory support (if this was not part of the planned primary treatment), or 
a different thrombus removal strategy (for example, mechanical 
thrombectomy, open embolectomy, etc.) at any time after the initial 
anticoagulation strategy was initiated. Anticoagulation alone was the 
original treatment plan (conceived beforehand). 
Surgical 
Thrombectomy 
A bailout would be defined as the need for a different thrombus removal 
strategy or the addition of mechanical circulatory support once a surgical 
approach was initiated. Surgical thrombectomy alone was the 
original treatment plan (conceived beforehand). 
Mechanical 
Thrombectomy 
(Includes 
FlowTriever and 
non-FlowTriever 
thrombectomy) 
A bailout would be defined as the need for a different thrombus removal 
strategy, the addition of mechanical circulatory support, or surgical 
thrombectomy once a percutaneous mechanical thrombectomy approach was 
initiated. Low-dose catheter directed adjunctive thrombolytic therapy (less 
than 10 mg tPA or 5 mg TNK) that is administered intra-procedurally or post-
procedurally will be discouraged but not considered a bailout.  
Note:   
• 
Completion of the FlowTriever procedure will be defined as the final 
removal of the FlowTriever catheter from the patient. 
• 
If mechanical circulatory support was placed before mechanical 
thrombectomy was initiated as part of the planned treatment 
strategy, this is not considered a bailout.  If, however; mechanical 

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circulatory support was not planned as part of the initial thrombus 
treatment strategy, and mechanical thrombectomy is initiated but 
mechanical circulatory support later becomes necessary, this will be 
recorded as a bailout. 
1Bailout measures will be reviewed and adjudicated by the Clinical Events Committee for the purposes of analyzing the Primary 
Endpoint. 
6.1.4.2 Clinical Deterioration 
Subject clinical status will be monitored and recorded in the study records.  Signs of clinical 
deterioration observed from the time of initiation of the Primary Treatment for high-risk PE through 
hospital discharge will be recorded by the site and adjudicated by the Clinical Events Committee (CEC, 
Section 6.3), and is defined in Table 5 below. 
Table 5:  Clinical Deterioration Definition 
Clinical Deterioration1, defined as: 
• 
Need for CPR after primary treatment initiation, or 
• 
Need to start IV vasopressors to keep systolic blood pressure > 90 mmHg in a 
previously normotensive patient after primary treatment initiation, or 
• 
Need for mechanical ventilation after primary treatment initiation in a 
previously spontaneously breathing patient, or 
• 
Need for noninvasive positive pressure ventilation after primary treatment 
initiation in a patient previously on nasal cannula 
1Clinical Deterioration will be reviewed and adjudicated by the Clinical Events Committee for the purposes of 
analyzing the Primary Endpoint. 
6.1.4.3 Major Bleeding 
All bleeding events related to the patient’s high-risk pulmonary embolism or its treatment should be 
recorded as adverse events by study sites.  The CEC will review and adjudicate bleeding events for the 
purposes of analyzing the primary endpoint.  Bleeding events which meet the BARC 3b/3c/5a/5b 
definition of Major Bleeding will be included in the Primary Endpoint analysis.  The BARC 3b/3c/5a/5b 
Major Bleeding Definition is provided in Table 6 below:   
Table 6:  Major Bleeding, BARC 3b/3c/5a/5b Definition 
Major Bleeding (BARC 3b/3c/5a/5b)1, defined as: 
• 
3b:  Overt bleeding plus hemoglobin drop of ≥ 5 g/dL (provided hemoglobin 
drop is related to bleed); cardiac tamponade, bleeding requiring surgical 
intervention for control (excluding dental/nasal/skin/hemorrhoid); bleeding 
requiring intravenous vasoactive agents 
• 
3c:  Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal), subcategories confirmed by autopsy 
or imaging or lumbar puncture, intraocular bleed compromising vision. 

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• 
5a:  Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious 
• 
5b:  Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
1Major bleeding events will be reviewed and adjudicated by the Clinical Events Committee for the purposes of 
analyzing the Primary Endpoint. 
6.1.5 
Hospital Discharge 
Subjects data will be collected through discharge from the hospital from their index-treatment for high-
risk PE.  Utility measures will be collected including, but not limited to: 
• 
Length of hospital stay 
• 
Length of ICU stay 
• 
Use of ECMO, including either pre- or post-treatment initiation and duration 
• 
Time to extubation, if intubated 
• 
Discharge location 
 
6.1.6 
Study Exit 
Subjects may be exited from the study if they are deceased prior to discharge.  As this study is only 
looking at outcomes through hospital discharge, it is not expected that subjects will be lost to follow-up.  
Subjects who remain in-hospital (from the index hospitalization for high-risk PE) for ≥ 45 days after the 
Primary Treatment for high-risk PE will be exited from the study at that time, as the study is considering 
acute outcomes for the treatment of high-risk pulmonary embolism. 
Study Exit for all subjects, regardless of reason, will be documented on a Study Exit form in the study 
record.  
6.2 SAFETY DATA HANDLING AND REPORTING 
6.2.1 
Adverse Event Definition and Assessment 
An Adverse Event (AE) is an untoward medical occurrence or exacerbation of an existing medical 
condition subsequent to enrollment in the study. AEs are assessed for severity, seriousness, and 
relationship to treatment devices and procedures, as defined in Table 7.  
The study will only capture AEs related to the subject’s PE condition and treatment. Reportable AEs 
include all events considered in the safety analyses, all thrombus removal therapy/device- and/or 
procedure-related AEs, as well as events resulting in death.   
Table 7: Site Assessment of Adverse Events 
AE Assessment 
Categories and Definitions 
Severity: 
Mild: No limitation of usual activities, no therapy or only symptomatic therapy 
required to treat the injury or illness 

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Moderate: Some limitation of usual activities or specific therapy is required 
Severe: Inability to carry out usual activities, hospitalization, emergency treatment, 
life threatening events, or death 
Seriousness: 
Serious Adverse Event (SAE):  An AE which is at least one of the following:  
• 
Is fatal 
• 
Is life-threatening 
• 
Results in persistent or significant disability/incapacity 
• 
Results in permanent impairment of a body function or permanent damage 
to a body structure 
• 
Results in hospitalization or prolongs a hospitalization 
• 
Necessitates medical or surgical intervention to preclude permanent 
impairment of a body function or permanent damage to a body structure 
Relatedness (assessed 
for any thrombus 
removal strategy or 
procedure): 
Not Related:  The clinical event is completely independent of thrombus removal 
therapy or procedure and/or evidence exists that the event is related to another 
etiology. 
Related: The clinical event occurs in a plausible time relationship to the thrombus 
removal therapy or procedure and cannot be explained by any concurrent disease or 
other devices or procedures. 
Unknown: The relationship to the thrombus removal therapy or procedure is not 
known. 
 
6.2.2 
Site Reporting of Adverse Events 
The study was designed to capture real world data regarding the clinical use of the FlowTriever System 
and other high-risk PE treatments.  The study follows guidelines for Instructions for Use and physician 
discretion for PE treatment.  
This is a data collection study only; there is nothing investigational or experimental in the subject’s 
medical treatment and the subject will be treated per standard of care. Therefore, the study will only 
capture AEs related to the subject’s PE condition and treatment.   Reportable AEs include all events 
considered in the safety analyses, all thrombus removal therapy/device- and/or procedure-related AEs, 
as well as events resulting in death. The AEs will be captured on the AE CRF and should include, 
wherever possible, severity, duration, outcome, the Investigator’s description the event, and its 
relationship to the thrombus removal therapy/device, to the thrombus removal procedure or any 
subsequent procedures, or to a thrombolytic agent or anticoagulant. 
• 
Non-serious reportable AEs are to be submitted via the electronic data capture system (EDC) in 
a timely fashion. 
• 
Reportable SAEs must be reported to the Sponsor within 5 business days of the Investigator’s 
knowledge of the event. The event is reported in the EDC.  
 

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6.3 CLINICAL EVENTS COMMITTEE (CEC) 
A Clinical Events Committed (CEC) will be utilized in this study for the purposes of adjudicating the 
primary and secondary endpoints.  Site-reported safety and outcome data will be provided to the CEC 
for review and adjudication of the following items for all FlowTriever and Context Arm subjects enrolled 
in the study: 
• 
Classification as a Serious Adverse Event (SAE) 
• 
Determination of relatedness 
• 
Assessment of severity 
• 
Assessment of endpoint criteria 
Adjudication will be conducted according to the FLAME CEC Charter.   
(Note that the primary endpoint will only be analyzed for subjects in the FlowTriever Arm of the study, 
but the CEC will adjudicate events for subjects enrolled in the Context Arm of the study as well) 
6.4 PROTOCOL MODIFICATIONS 
No changes from the final approved study protocol will be initiated at the site-level without the IRB’s 
prior written approval of the amendment. Site Principal Investigators will acknowledge any protocol 
amendments by signing the associated Protocol Signature Page. 
6.5 PROTOCOL DEVIATIONS 
A protocol deviation is a divergence or non-adherence from the protocol-specific study procedures.  
Protocol deviations should be recorded for all assessments not collected, and issues related to eligibility 
criteria. 
Protocol deviations should be recorded in the study record and entered into the study database as soon 
as possible to ensure Sponsor oversite of the conduct of the study along with implementation of any 
corrective actions as necessary. 
6.6 TRAINING FOR STUDY PERSONNEL 
The Investigator is responsible for giving information about the study to all staff members involved in 
the study or in any element of subject management, both before starting the study procedures and 
during the study; for example, when new staff are involved. The Investigator must ensure that all study 
staff members are qualified by education, experience, and training to perform their specific 
responsibilities. 
The Sponsor or designee is responsible for explaining the protocol to all study staff, including the 
Investigator, and for ensuring their compliance with the protocol throughout the study. Additional 
information will be made available during the study when new staff become involved in the study, and 
as otherwise agreed upon with either the Investigator or the Sponsor. 

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6.6.1 
Physician Device Training 
Each physician selected to participate in this trial who will be enrolling in the FlowTriever Arm will be 
required to have experience treating pulmonary embolism using the FlowTriever device.     
6.6.2 
Site Initiation and Addition of Site Personnel 
A Site Initiation Visit (SIV) will be conducted by the Sponsor or designee, either in-person or via 
teleconference to ensure proper training of the Investigator and study staff members prior to 
participation in the FLAME study.  The SIV will cover training to the study protocol and data collection, 
as well as to any applicable regulatory requirements, and will be documented in the study record.  
Additional site personnel added to the study after the SIV will be required to undergo protocol training, 
to be performed by the Sponsor, or designee, and documented in the study record. 
6.7 SITE MONITORING VISITS 
Interim monitoring visits will be conducted by the Sponsor or designee in-person or remotely to ensure 
compliance with the protocol, and other written instructions and regulatory guidelines according to the 
study-specific monitoring plan. 
The main responsibilities of the monitor are to ensure adherence to the protocol and to verify all data 
are correctly and completely recorded.  The Investigator and assisting staff must agree to cooperate 
with the study monitor to resolve any study-related problems, errors, or possible misunderstandings 
concerning the findings detected during these monitoring visits or data review. 
6.8 STUDY TERMINATION 
The Sponsor and applicable regulatory authorities have the right to terminate the entire study or study 
activities at an individual site at any time. The circumstances which may warrant study termination 
include, but are not limited to: 
• 
As a result of the pre-specified Interim Analysis, or 
• 
Increased incidence of adverse experiences and/or the severity of such, suggestive of a 
potential, device-related health hazard, or 
• 
Insufficient subject enrollment rates, or 
• 
Recurrent protocol deviations or other non-compliances, or 
• 
Inaccurate, incomplete, and/or untimely data recording on a recurrent basis, or 
• 
Lack of cooperation with monitoring visits (e.g., failure to adequately prepare for visits, address 
action items from one visit to the next, or provide access to medical records) 
6.9 SITE CLOSE-OUT VISITS 
Close-out visits will be conducted by the Sponsor or designee in-person or remotely to ensure 
compliance with the protocol, and other written instructions and regulatory guidelines. 

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The close-out visit will be conducted when all subjects at the site have completed the study-specific 
follow-up, or after early termination as described in Section 6.8.   
6.10   DATA COLLECTION AND MANAGEMENT 
The Sponsor and/or designee will be responsible for the processing and quality control of the data. All 
source data, eCRFs, copies of protocols and protocol amendments, correspondence, and other essential 
documents must be retained for a period of at least 2 years after the completion, closure, or 
termination of the study. 
No study document or image will be destroyed without prior written agreement between the Sponsor 
and the Investigator. Should the Investigator wish to assign the study records to another party or move 
them to another location, advance written notice must be given to the Sponsor. 
6.10.1 Site Data Collection and Electronic Data Capture (EDC) 
The Investigator may keep a separate subject identification list showing enrollment numbers, names, 
and dates of birth to provide a local key for unambiguous identification of each subject included in the 
study.  This list will not be collected by the Sponsor. It is recommended a note be made in the subject’s 
medical record that the subject is participating in the study. 
Clinical study data will be collected using source document worksheets and eCRFs. A web-based 
electronic data capture system (EDC) will be used to record and manage study data. All eCRFs must be 
kept in good order and updated so they always reflect the latest observations on the subjects 
participating in the study. 
The Investigator will sign the appropriate eCRF pages and source documentation. Pertinent eCRF 
corrections will be made electronically and signed electronically by the Investigator. An embedded audit 
trail will capture the date, time and user making entries and changes to the electronic data. 
Because it is important to have proper data collection in a timely manner, it is recommended that the 
Investigator or designee complete eCRFs within 5 business days of data availability. When the monitor 
or designee requests additional data or clarification of data for the eCRF (queries), the request must be 
answered satisfactorily as soon as possible. 
6.10.2 Data Security and Integrity 
The Sponsor, auditors, and health authority inspectors (or their agents) will be given access to source 
data and documentation (e.g., medical charts/records, laboratory test results, printouts, videotapes, 
etc.) for source data verification, provided that subject confidentiality is maintained in accordance with 
local requirements. 
The Investigator must maintain the primary records (source documents) of each subject’s data. 
Examples of source documents are hospital records, office visit records, examining physician’s finding or 
notes, consultant’s written opinion or notes, laboratory reports, device label records, and worksheets 
that are used as the source. 
 
 

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7 
STATISTICS & DATA ANALYSIS 
7.1 SAMPLE SIZE 
The sample size of the FlowTriever Arm is calculated using a two-stage group sequential design, where 
the FlowTriever Arm is expected to have a rate of in-hospital composite endpoint of all-cause mortality, 
bailout to an alternative thrombus removal strategy, clinical deterioration, and major bleeding (BARC 
3b/3c/5a/5b definition) of 18%. The rate of the FlowTriever Arm composite endpoint is compared with 
the historical performance goal of 32%, based on meta-analysis results shown in Table 9. A one-sided 
binomial proportion’s test with normal approximation is used against the historical performance goal 
with a power of 80% and a one-sided α = 0.05; O’Brien Fleming boundary was implemented where the 
first stage, or interim analysis, is planned at N = 50 subjects enrolled and consequently arriving at the 
second stage, or final analysis, with N = 71 subjects as shown in Table 8. 
Table 8: Sample Size 2-stage Group Sequential Design 
Analysis Stage 
N 
Z-score 
Threshold 
P-value 
Threshold 
FT Event 
proportion 
Significant 
event number 
Interim  
50 
-2.0311 
0.0211 
0.186 
≤9.3 
Final 
71 
-1.7116 
0.0435 
0.225 
≤16.0 
 
7.2 DERIVATION OF PERFORMANCE GOAL 
The primary safety endpoint performance goal was derived from the following 22 studies, summarized 
in Table 9. 
Table 9: Safety Performance Goal Literature Summary 
First Author 
Subjects 
In-Hospital 
ACM 
Bailout to 
Alternative 
Thrombus 
Removal 
Strategy 
Clinical 
Deterioration 
(within 24 
hours) 
Major Bleeding 
(BARC3b/3c/5a/5b) 
Avgerinos et al. 2017 
90 
15/90, 16.6% 
NS 
NS 
24/90, 26.6% 
Barrett et al. 2010 
SE: 9 
6/9, 66.6% 
NS 
NS 
NS 
TL: 10 
6/10, 60.0% 
AC: 14 
5/14, 35.7% 
Carvalho et al. 2010 
16 
7/16, 43.8% 
NS 
NS 
NS 
Cho et al. 2016 
19 
NS 
4/19, 21.0% 
NS 
NS 
26 
NS 
Corsi et al. 2017 
17 
NS 
NS 
NS 
NS 
de Winter et al. 2019 
33 
NS 
8/33, 24.2% 
NS 
NS 
George et al. 2018 
32 
15/32, 46.9% 
NS 
5/32, 15.6% 
NS 

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First Author 
Subjects 
In-Hospital 
ACM 
Bailout to 
Alternative 
Thrombus 
Removal 
Strategy 
Clinical 
Deterioration 
(within 24 
hours) 
Major Bleeding 
(BARC3b/3c/5a/5b) 
Hartman et al. 2015 
24 
NS 
NS 
NS 
NS 
Kuo et al. 2015 
28 
4/28, 14.3% 
NS 
NS 
0/28, 0.0% 
Minakawa et al. 2018 
63 
23/63, 
36.5%* 
NS 
NS 
NS 
Moon et al. 2018 
Without 
ECMO: 9 
7/9, 77.8% 
NS 
NS 
NS 
ECMO:14 
8/14, 57.1% 
7/14, 50.0% 
Munakata et al. 2012 
10 
3/10, 30.0%† 
NS 
NS 
2/10, 20.0% 
Neely et al. 2015 
49 
5/49, 10.2%* 
NS 
NS 
1/49, 2.0% 
Niwa et al. 2012 
289 
NS 
NS 
NS 
NS 
Pasrija et al. 2018 
Control: 27 
5/27, 18.5% 
NS 
NS 
3/27, 11.1% 
Protocol: 29 
1/29, 3.4% 
4/29, 13.8% 
Roncon et al. 2018 
47 
NS 
NS 
NS 
NS 
30 
Secemsky et al. 2019 
46 
15/46, 32.6% 
NS 
NS 
11/46, 23.9% 
Senturk et al. 2016 
186 
NS 
NS 
NS 
10/186, 5.4% 
Sharifi et al. 2016 
23 
2/23, 8.7% 
NS 
NS 
0/23, 0.0% 
Shiomi et al. 2017 
31 
4/31, 12.9% 
NS 
NS 
NS 
Ucar et al. 2013 
107 
18/107, 
16.8% 
NS 
NS 
4/107, 3.7% 
Wang et al. 2010 
20 
NS 
12/20, 60.0% 
NS 
NS 
20 
4/20, 20.0% 
Total 
1,318 
149/607 
28/92 
5/32 
66/609 
Weighted Average 
[95% Confidence 
Intervals] 
NA 
28.5% 
[20.6%, 
37.9%] 
30.3% 
[15.5%, 50.7%] 
15.6% 
[6.7%, 32.5%] 
11.5% 
[6.0%, 21.0%] 
AC, Anticoagulation; ACM, All-Cause Mortality; BARC, Bleeding Academic Research Consortium; ECMO, Extracorporeal 
Membrane Oxygenation; NA, Not Applicable; NS, Not Specified; SE, Surgical Embolectomy; TL, Thrombolytic Therapy 
*Operative mortality was reported. Only patients in refractory shock were included in the analysis. 
†All patients died within 15 hours of the procedure. 
 
The Performance Goal is a weighted average calculated from each individual component of the 
composite endpoint; each component is a result of a meta-analysis across previous publications using 
the random-effects model. The Performance Goal weighted average is 21.5%, and by using a 10% 
margin with rounding up to the nearest percent, the Performance Goal for the study is 32%. 

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7.3 ANALYTIC DATASETS 
The CDISC process would be implemented to generate analytical datasets similar to the Analysis Data 
Model (ADaM) to be used for tables, lists, and figures (TLFs). 
7.4 ENDPOINT ANALYSIS 
7.4.1 
PRIMARY ENDPOINT ANALYSIS 
The primary endpoint is the in-hospital composite endpoint of all-cause mortality, bailout to an 
alternative thrombus removal strategy, clinical deterioration, and major bleeding (BARC 3b/3c/5a/5b 
definition) from the FlowTriever Arm. The rate of the composite endpoint is expected to be 18% and 
compared with performance goal of 32%: 
H0:  PS ≥ Performance GoalS versus HA: PS < Performance GoalS 
where Ps is the proportion of subjects with in-hospital composite endpoint and Performance GoalS is the 
performance goal of proportion of subjects with in-hospital composite endpoint derived from previous 
publications and expert opinions on subjects who were non-FlowTriever treatments. 
The one-sided binomial’s proportion test with normal approximation would be used at a one-sided α = 
0.05. Primary endpoint analysis can be carried out at interim analysis and/or final analysis stage. 
7.4.2 
SECONDARY ENDPOINT ANALYSIS 
Secondary Endpoints include both Secondary Safety Endpoints and Utility Measures as listed below: 
Secondary Safety Endpoints 
• 
Frequency of each primary endpoint composite component 
• 
Frequency of Stroke (ischemic or hemorrhagic) 
• 
Frequency of device-related complications 
• 
Access site injury requiring intervention, both venous and arterial 
 
Utility Measures 
• 
Length of hospital stay 
• 
Length of ICU stay 
• 
Use of ECMO, including either pre- or post-treatment initiation and duration 
• 
Time to extubation, if intubated 
• 
Discharge location 
 
Descriptive statistics will be used for secondary endpoints for both the FlowTriever Arm and Context 
Arm populations. Continuous variable will report min, max, mean, SD, IQR, Q1, Q3 etc. as deemed 
appropriate. Categorical variable will report frequency counts and percentage. Time-to-event variable 
may be reported with Kaplan-Meier and/or Cox proportional hazards model estimates.  
Additional exploratory analyses on secondary endpoints may include confounder adjustment in 
generalized linear models (GLMs).  

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7.4.3 
INTERIM ANALYSIS 
The interim analysis population will be N = 50 enrolled subjects in the FlowTriever Arm with adjudicated 
in-hospital composite endpoint. Primary endpoint analysis method in Section 7.4.1 will be used on the 
interim analysis population to decide whether the study should be stopped early due to achieving early 
decision rule based on the primary endpoint. The |𝑧−𝑠𝑐𝑜𝑟𝑒| threshold is 2.031, which translates to in-
hospital composite endpoint proportion being ≤ 0.186. Therefore, having ≤ 9 in-hospital composite 
endpoint events out of N = 50 may qualify for stopping the study early and conclude achieving 
significant difference from performance goal = 32% (see Table 9). 
Secondary endpoint analysis may be conducted in a descriptive fashion without hypothesis testing, 
therefore not spending any Type I error (α).   
7.4.4 
CONTEXT ARM ANALYSIS 
The Context Arm may be analyzed with methods mentioned in primary and secondary endpoint 
analyses along with descriptive statistics and will not be used to determine study success. 
7.4.5 
PRIOR THERAPY ARM ANALYSIS 
Data collection for Prior Therapy Arm subjects will include information surrounding the PE treatment, 
progression to High-Risk PE, and patient course through hospital discharge.  Safety data will also be 
collected, but not CEC adjudicated or analyzed as outlined for the FlowTriever and Context Arm subjects.  
Subjects receiving prior advanced treatment for low/intermediate-risk PE in the same hospital setting as 
a second treatment for high-risk PE likely have a different profile than those receiving advanced care for 
the first time after diagnosis of high-risk PE, and therefore should be looked at separately.  In the spirit 
of the AHA guidelines for trial design in this patient population, data will be collected to ensure 
representation of this smaller yet significant group of high-risk PE patients and will be reported in a 
descriptive manner 
 
 
 
 

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8 
RISK ANALYSIS 
8.1 RISKS TO SUBJECTS 
The study involves the use and disclosure of health information. It collects only information relevant to 
the subject’s PE condition and treatment.  The information is for research, development, and 
educational purposes only. It does not specify how the physician will treat PE, and decisions regarding a 
subject’s treatment are not influenced by the study.  
Physicians participating in the study are expected to review the indications, contraindications, warnings, 
precautions, and safety events described in the IFU. As with any endovascular procedure, the treating 
physician is expected to counsel the subject on the risks and benefits specific to the planned treatment 
and to obtain the local, procedure-related informed consent per institutional policies and procedures. 
8.2 MITIGATION OF RISKS 
The study was designed to capture real world data regarding the treatment of high-risk PE. The risk of 
providing this health information is believed to be minimal, as information directly identifying the 
subject will not be collected in the study database. 
8.3 STUDY JUSTIFICATION 
The FlowTriever System offers an efficient treatment option for high-risk PE patients while obviating the 
need for thrombolytic drugs and their consequent high bleeding risk including intracranial hemorrhage.  
Furthermore, FlowTriever may offer quicker relief given the mechanical approach to clot removal versus 
a pharmacologic approach which can take several hours to have an effect.  The current study is designed 
to assess high-risk PE outcomes in a real-world population that would be encountered in clinical 
practice. 
 
 

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9 
ETHICS AND CONFIDENTIALITY 
9.1 INSTITUTIONAL REVIEW BOARD 
This study must be approved by an appropriate IRB representing each investigational site. Securing the 
approval is the responsibility of the Investigator, as defined by ISO 14155-1 and FDA regulations (21 CFR 
Part 56), prior to starting the study.  
The Sponsor must receive a copy of the IRB approval letter (or equivalent documentation) for the study 
protocol before the study can be started at that site. 
The IRB and Sponsor must approve any significant changes to the protocol, as well as a change of the 
Principal Investigator. Documentation of IRB approval must be provided to the Sponsor. Records of all 
study review and approval documents must be maintained by the Investigator in a Regulatory Binder or 
other appropriate repository and are subject to inspection by the Sponsor or regulatory authority during 
or after completion of the study.  
The Investigator must notify the IRB, as per their reporting guidelines, and the Sponsor when he or she 
deviates from the protocol. The Sponsor must be notified of all relevant action taken by the IRB and 
must receive a copy of all study-related correspondence between the Investigator and the IRB. 
The IRB must receive notification of the completion of the study and final report after study completion 
or termination. A copy of these reports must be provided to the Sponsor. The Investigator must 
maintain an accurate and complete record of all submissions made to the IRB, including a list of all 
reports and documents submitted. 
9.2 STUDY SUBJECT CONFIDENTIALITY 
The Investigator must ensure that the privacy of all subjects, including their personal identity and all 
personal health information, will be maintained at all times. Subjects will not be identified by their 
names in CRFs or other documents or image material submitted to the Sponsor or designee. Rather, the 
subject’s unique identifier will be utilized. 
A subject’s Protected Health Information (PHI) will always be treated as confidential. PHI, however, may 
be reviewed by authorized study staff (e.g., the monitor) to verify data recorded in the eCRFs. The 
monitor may conduct source-document verification on behalf of the Sponsor, the quality assurance unit, 
or regulatory authorities. 
9.3 ELECTRONIC DATA 
Electronic data will only be accessible to authorized personnel with a unique user identifier and 
password for the EDC. Passwords will be set to expire periodically. Access to electronic study data will be 
provided to research personnel upon completion of training. Read and write access will be provided to 
investigational sites but only for information and subject data at their site. The CRO will have read-only 
access and can post queries for potential data-related discrepancies. 

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9.4 PARTICIPATING INSTITUTIONS AND INVESTIGATORS 
Study sites and Investigators will be selected based on a variety of factors including, but not limited to, 
experience with endovascular techniques, access to required facilities and equipment, sufficient and 
adequately trained personnel, and availability of potential subjects. The criteria used for determination 
will be documented.  
9.4.1 
INVESTIGATOR RESPONSIBILITIES 
Investigator responsibilities include, but are not limited to, the following: 
• 
Conducting the study in accordance with this investigational plan, signed agreement, and applicable 
regulations protecting the rights and safety of study subjects 
• 
Ensuring that IRB approval is secured prior to starting the study and ensuring continuing review and 
approval as required throughout the investigation 
• 
Ensuring all associates, colleagues, and employees assisting in the conduct of the study are informed 
about their obligations, are adequately qualified and trained, and meet their commitments 
• 
Maintaining adequate and accurate records and ensuring those records are available for inspection 
at any time 
• 
Ensuring that conducting the study does not give rise to a conflict of interest (financial disclosure is 
required)  
 
 

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10 
TERMS AND DEFINITIONS 
Table 10 contains categories, terms, and definitions that are utilized throughout the study and for 
reporting purposes. 
Table 10:  Terms and Definitions 
Term or Phrase 
Definition 
Access site injury 
requiring 
intervention, 
both venous and 
arterial 
An injury to an access site (both venous and arterial) utilized for treatment of PE which 
requires intervention in order to resolve.  This includes for example, an arterial injury 
associated with ECMO support as part of PE treatment. 
Advanced 
therapy for PE 
For the purposes of this study, advanced therapy for low/intermediate- risk PE is considered 
therapy beyond anticoagulation alone, including: thrombolysis (either systemic or catheter 
directed), surgical thrombectomy, and percutaneous thrombectomy. 
Adverse event 
(AE) 
An Adverse Event (AE) is an untoward medical occurrence or exacerbation of an existing 
medical condition subsequent to enrollment in the study. AEs are assessed for severity, 
seriousness, and relationship to thrombus removal therapies/devices/procedures. 
 
The study will only capture AEs related to the subject’s PE condition and treatment. 
Reportable AEs include all events considered in the safety analyses, all thrombus removal 
therapy/device- and/or procedure-related AEs, as well as events resulting in death.   
All-cause 
mortality 
Mortality for any reason, does not need to be related to a device, treatment, or pulmonary 
embolism. 
Bailout to an 
alternative 
thrombus 
removal strategy 
New need for mechanical circulatory support or another thrombus removal strategy after the 
Primary Treatment strategy was initiated. The additional treatment strategy was not an a 
priori part of the original treatment plan (conceived beforehand).  All bailout events will be 
adjudicated by the CEC.  See Table 4 for more guidance on bailout events. 
Clinical 
Deterioration 
Clinical deterioration is defined as: 
• 
Need for CPR 
• 
Need to start IV vasopressors to keep systolic blood pressure > 90 mmHg in a 
previously normotensive patient 
• 
Need for mechanical ventilation in a previously spontaneously breathing patient 
• 
Need for noninvasive positive pressure ventilation in a patient previously on nasal 
cannula 
Clinical deterioration occurring after initiation of the Primary Treatment therapy will be 
adjudicated by the CEC for analysis of the Primary Endpoint. 
Context Arm 
Context Arm subjects are defined as those subjects with PE who are treated with non-
FlowTriever therapies (as the Primary Treatment for PE). Context-Arm therapies may include 
but are not limited to; thrombolysis (either systemic or catheter directed), anticoagulation, 
surgical thrombectomy, and non-FlowTriever thrombectomy. 
Endpoints will be evaluated in the Context Arm population in a descriptive manner and will 
not be used to determine study success. 

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Term or Phrase 
Definition 
Device-related 
complications  
Complications related to devices used for thrombus removal.  Complications related to 
Primary Treatment devices and bailout devices used will be adjudicated by the CEC.  Note 
that complications related to ECMO should be included here where ECMO was part of the 
Primary Treatment strategy. 
Discharge 
Location 
The location where the patient is discharged from the hospital, may include but not limited to 
home, home with home healthcare, skilled nursing facility, hospice, etc. 
FlowTriever Arm 
FlowTriever Arm subjects are defined as those subjects where FlowTriever is used as the 
primary thrombus removal treatment for pulmonary embolism. 
 
FlowTriever Arm subjects will be the primary population utilized to evaluate the study 
Primary Endpoints for study success.  
Glasgow Coma 
Scale 
The Glasgow Coma Scale provides a practical method for assessment of impairment of 
conscious level in response to defined stimuli. 
High-risk 
Pulmonary 
Embolism (PE) 
Pulmonary embolism with the following signs/symptoms: 
o 
Systolic blood pressure <90 mmHg for at least 15 minutes or drop of >40 
mmHg in systolic blood pressure for at least 15 minutes, and/or 
o 
Need for vasopressor support, and/or 
o 
Resuscitation after cardiac arrest with <30 minutes of CPR and Glasgow 
Coma Scale >8. 
Length of 
Hospital Stay 
Time from admission to the hospital for pulmonary embolism treatment until discharge from 
the hospital post-treatment. For subjects who do not survive until hospital discharge, the 
length of hospital stay will be from the time of admission until the time of death. 
Length of ICU 
Stay 
Time from admission to the ICU until time of discharge from the ICU.  Multiple ICU stays 
within the same hospital admission (index hospitalization for high-risk PE) will be recorded. 
Major Bleeding, 
BARC 
3b/3c/5a/5b 
definition 
• 
3b:  Overt bleeding plus hemoglobin drop of ≥ 5 g/dL (provided hemoglobin drop is 
related to bleed); cardiac tamponade, bleeding requiring surgical intervention for 
control (excluding dental/nasal/skin/hemorrhoid); bleeding requiring intravenous 
vasoactive agents 
• 
3c:  Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal), subcategories confirmed by autopsy or 
imaging or lumbar puncture, intraocular bleed compromising vision. 
• 
5a:  Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious 
• 
5b:  Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
Primary 
Endpoint 
In-hospital composite endpoint of:  
• 
All-cause mortality  
• 
Bailout to an alternative thrombus removal strategy  
• 
Clinical deterioration  
• 
Major bleeding, BARC 3b/3c/5a/5b definition   
Primary 
Treatment 
Strategy 
The initial treatment strategy for thrombus removal (for the high-risk PE) determined by the 
treatment team prior to treatment initiation and documented.   
Prior Therapy 
Arm 
Subjects presenting with low/intermediate-risk PE who receive advanced therapy during their 
hospital stay but subsequently progress to high-risk PE in the same hospital stay should be 
enrolled in the Prior Therapy Arm.   

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Term or Phrase 
Definition 
Protocol 
Deviation 
A protocol deviation is a divergence or non-adherence from the protocol-specific study 
procedures.  Protocol deviations should be recorded for all assessments not collected and 
issues related to eligibility criteria. 
Relatedness of 
Adverse Event 
Unrelated:  The clinical event is completely independent of study procedure/study 
device/study treatment and/or evidence exists that the event is related to another etiology. 
 
Related: The clinical event occurs in a plausible time relationship to study procedure/study 
device/treatment and cannot be explained by any concurrent disease or other devices, drugs 
or chemicals. 
 
Unknown: The relationship to the study procedure/study device/treatment is not known. 
Screen Failure 
Patients who do not meet eligibility criteria for enrollment in the study.  Screen failure 
patients will not be entered into the study database/EDC system, and will not be assigned a 
study subject ID. 
Serious Adverse 
Event (SAE) 
Serious Adverse Event (SAE):  An AE which is at least one of the following:  
• 
Is fatal 
• 
Is life-threatening 
• 
Results in persistent or significant disability/incapacity 
• 
Results in permanent impairment of a body function or permanent damage to a 
body structure 
• 
Results in hospitalization or prolongs a hospitalization 
• 
Necessitates medical or surgical intervention to preclude permanent impairment of 
a body function or permanent damage to a body structure 
Secondary 
Endpoints 
Secondary Safety Endpoints 
• 
Frequency of each primary endpoint composite component 
• 
Frequency of Stroke (ischemic or hemorrhagic) 
• 
Frequency of device-related complications 
• 
Access site injury requiring intervention, both venous and arterial 
 
Utility Measures 
• 
Length of hospital stay 
• 
Length of ICU stay 
• 
Use of ECMO, including either pre- or post-treatment initiation and duration 
• 
Time to extubation, if intubated 
• 
Discharge location 
Severity of 
Adverse Event: 
Mild: No limitation of usual activities, no therapy or only symptomatic therapy required to 
treat the injury or illness 
 
Moderate: Some limitation of usual activities or specific therapy is required 
 
Severe: Inability to carry out usual activities, hospitalization, emergency treatment, life 
threatening events, or death 
Site activation 
The date the site receives approval from the Sponsor to begin enrolling in the study. 
 
 

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11 
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FLowTriever for Acute Massive Pulmonary Embolism (FLAME) 
Protocol Number: 20-001 
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December 6, 2020 
 
 
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