'Thrombectomy in High-Risk Pulmonary Embolism - Device Versus Thrombolysis Netherlands': TORPEDO-NL
Phase: NA
Conditions: Pulmonary Embolism Acute
Sponsor: Leiden University Medical Center

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For clinical trials with medicinal product to be submitted in CTIS 
(CTR studies), please use the following template: 
https://english.ccmo.nl/investigators/publications/publications/2022
/05/25/template-protocol  
 
 
TEMPLATE RESEARCH PROTOCOL 
(March 2024) 
 
- 
May 2015: adaptation section 11.5: text in accordance to old and new Measure 
regarding Compulsory Insurance for Clinical Research in Humans  
- 
Sept 2015: adaptation section 9.1, 9.2 and 12.5: text in accordance to WMO 
amendment on reporting SAE and temporary halt (section 10 of WMO) 
- 
Oct 2015: adaptation section 4.4 – comment [CCMO15], 8.2 and 10.1 with respect to 
methodology/statistics 
- 
Sept 2018: adaptation section 12.1 and comment [CCMO46] due to applicability 
GDPR as of May, 2018 
- 
April 2024: link to template protocol to be used for CTR studies added and additional 
explanation and comments in section 9 Safety reporting 
 
F.A. Klok, W.J.E. Stenger  
Department of Medicine - Thrombosis and Haemostasis 
Leiden University Medical Center, Leiden, The Netherlands 
 
A.O. Kraaijeveld 
Department of Cardiology 
University Medical Center Utrecht, Utrecht, The Netherlands 
 
C.A. den Uil  
Department of Intensive Care 
Maasstad Ziekenhuis, Rotterdam, The Netherlands  
 
W.J.R. Rietdijk 
Department of Institutional Affairs 
VU University, Amsterdam, The Netherlands  

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PROTOCOL TITLE ‘Thrombectomy in high-Risk Pulmonary Embolism – Device  
versus thrombolysis Netherlands’: TORPEDO-NL 
 
Protocol ID 
NL87503.058.24 
ABR 87503 
Short title 
TORPEDO-NL 
EudraCT number  
N.A. 
Version 
2.1 
Date 
16-12-2024 
Project leaders  
 
Dr. C.A. den Uil 
Dr. A.O. Kraaijeveld  
Prof. dr. F.A. Klok  
Coordinating investigators 
Drs. W.J.E. Stenger 
Prof. dr. F.A. Klok 
Trial statistician 
Dr. W.J.R. Rietdijk 
Principal investigator  
 
Principal investigator per site 
Prof. Dr. FA Klok 
 
Amsterdam Universitair Medisch Centrum: Dr. P.R. 
Tuinman 
Amphia Ziekenhuis: Drs. F. Imani  
Catharina Ziekenhuis Eindhoven: Dr. D.A. Kies  
Erasmus Medisch Centrum: Dr. C.L. Meuwese  
Haaglanden Medisch Centrum: Dr. Y.M. Ende-
Verhaar 
Isala: Dr. M.F. Boomsma  
Leids Universitair Medisch Centrum: Dr. I. Al Amri 
Maastricht Universitair Medisch Centrum: Dr. K. 
Winckers  
Maasstad Ziekenhuis: Dr. S. Levolger  
Noordwest Ziekenhuisgroep: Dr. S. Slot 
Radboud Universitair Medisch Centrum: Prof. Dr. 
R.J. van Geuns  
Rijnstate: Dr. M.M.C. Hovens 
St. Antonius Ziekenhuis: Dr. J.A. Vos  

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Universitair Medisch Centrum Utrecht: Dr. M. 
Nijkeuter 
Sponsor 
Leiden University Medical Center 
 
Albinusdreef 2 
2300RC, Leiden, The Netherlands  
Subsidising party 
ZonMw/Zorginstituut Nederland (Projectnummer: 
808620098290002) 
 
Independent expert (s) 
Prof. dr. D.E. (Douwe) Atsma 
 
Department of Cardiology 
Leiden University Medical Center, Leiden, The 
Netherlands 
 
Laboratory sites 
N.A. 
 
Pharmacy 
N.A. 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
Prof. Dr. J Eikenboom, head of division of 
Thrombosis and Hemostasis, LUMC. 
Leiden 
 
 
 
Coordinating Investigator 
Prof. Dr. FA Klok 
 
 
 
 
16-12-2024

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................14 
2. 
OBJECTIVES ................................................................................................................16 
3. 
STUDY DESIGN ...........................................................................................................17 
4. 
STUDY POPULATION ..................................................................................................18 
4.1 
Population (base) ...................................................................................................18 
4.2 
Inclusion criteria .....................................................................................................18 
4.3 
Exclusion criteria ....................................................................................................18 
4.4 
Sample size calculation ..........................................................................................19 
5. 
TREATMENT OF SUBJECTS .......................................................................................20 
5.1 
Investigational product/treatment ............................................................................20 
5.2 
Use of co-intervention (if applicable) ......................................................................21 
5.3 
Escape medication .................................................................................................21 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................22 
6.1 
Name and description of investigational product(s) ................................................22 
6.2 
Summary of findings from non-clinical studies ........................................................22 
6.3 
Summary of findings from clinical studies ...............................................................22 
6.4 
Summary of known and potential risks and benefits ...............................................22 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................22 
8. 
METHODS ....................................................................................................................22 
8.1 
Study parameters/endpoints ...................................................................................22 
8.1.1 
Main study endpoint ........................................................................................22 
8.1.2 
Secondary study endpoints .............................................................................23 
8.2 
Randomization, blinding and treatment allocation ..................................................24 
8.3 
Study procedures ...................................................................................................24 
8.4 
Withdrawal of individual subjects ............................................................................26 
8.5 
Replacement of individual subjects after withdrawal ...............................................26 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................26 
8.7 
Premature termination of the study .........................................................................27 
9. 
SAFETY REPORTING ..................................................................................................27 
9.1 
Temporary halt for reasons of subject safety ..........................................................27 
9.2 
AEs, SAEs and SUSARs ........................................................................................27 
9.2.1 
Adverse events (AEs) ......................................................................................27 
9.2.2 
Serious adverse events (SAEs) .......................................................................27 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................28 
9.3 
Annual safety report ...............................................................................................28 
9.4 
Follow-up of adverse events ...................................................................................28 
9.5 
Data Safety Monitoring Board (DSMB) ...................................................................28 
10. STATISTICAL ANALYSIS .............................................................................................29 
10.1 
Primary study parameter(s) ....................................................................................29 
10.2 
Secondary study parameter(s) ...............................................................................29 

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10.3 
Other study parameters ..........................................................................................31 
10.4 
Interim monitoring ..................................................................................................31 
11. ETHICAL CONSIDERATIONS ......................................................................................31 
11.1 
Regulation statement .............................................................................................31 
11.2 
Recruitment and consent........................................................................................32 
11.3 
Objection by minors or incapacitated subjects (if applicable) ..................................33 
11.4 
Benefits and risks assessment, group relatedness .................................................33 
11.5 
Compensation for injury .........................................................................................33 
11.6 
Incentives ...............................................................................................................34 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .............................34 
12.1 
Handling and storage of data and documents ........................................................34 
12.2 
Monitoring and Quality Assurance ..........................................................................35 
12.3 
Amendments ..........................................................................................................35 
12.4 
Annual progress report ...........................................................................................35 
12.5 
Temporary halt and (premature) end of study report ..............................................35 
12.6 
Public disclosure and publication policy ..................................................................36 
13. STRUCTURED RISK ANALYSIS ..................................................................................36 
13.1 
Potential issues of concern .....................................................................................36 
13.2 
Synthesis ...............................................................................................................36 
14. REFERENCES ..............................................................................................................37 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
 
 
ACT 
General Assessment and Registration form (ABR form), the application form 
that is required for submission to the accredited Ethics Committee; in Dutch: 
Algemeen Beoordelings- en Registratieformulier (ABR-formulier) 
Activated Clotting Time  
AE 
Adverse Event 
AR 
Adverse Reaction 
BARC 
CA 
Bleeding Academic Research Consortium 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV 
CDT 
DOOR 
COPD 
CTEPH 
CTPA 
Curriculum Vitae 
Catheter-directed thrombectomy 
Desirability of Outcome Ranking  
Chronic obstructive pulmonary disease 
Chronic Thromboembolic Pulmonary hypertension  
Computed tomography pulmonary angiography 
DSMB 
ECPR 
Data Safety Monitoring Board 
Extracorporeal cardiopulmonary resuscitation  
EU 
European Union 
EudraCT 
European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
IB 
Investigator’s Brochure 
IC 
ICH 
ICU 
Informed Consent 
Intracranial haemorrhage 
Intensive care unit 
IFU 
IMP 
Instructions for use  
Investigational Medicinal Product  
IMPD 
ITT 
LMWH 
LOS 
Investigational Medicinal Product Dossier  
Intention to treat 
Low molecular weight heparin 
Length of stay 

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METC  
 
MCU 
NYHA 
PE 
PERT 
QoL 
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
Medium Care Unit  
New York Heart Association 
Pulmonary embolism 
Pulmonary Embolism Response Team 
Quality of life 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics; in Dutch: officiële productinformatie IB1-
tekst 
Sponsor 
The sponsor is the party that commissions the organisation or performance of 
the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party 
that provides funding for a study but does not commission it is not regarded 
as the sponsor, but referred to as a subsidising party. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
UAVG 
 
UFH 
VA-ECMO 
Dutch Act on Implementation of the General Data Protection Regulation; in 
Dutch: Uitvoeringswet AVG 
Unfractionated heparin 
Venoarterial Extracorporeal Membrane Oxygenation 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 

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SUMMARY 
Rationale: Patients with high-risk pulmonary embolism (PE) require immediate reperfusion 
therapy on top of anticoagulation. The standard reperfusion treatment in these patients is full-
dose systemic thrombolysis. This carries a significant risk of major bleeding (10-25%) and 
intracranial haemorrhage (ICH, 3%). Catheter-directed thrombectomy (CDT) is a promising 
alternative to systemic thrombolysis with a more direct effect on reducing pulmonary artery clot 
burden and very likely a better safety profile. Randomized trials evaluating the safety and 
efficacy of CDT in high-risk patients are currently unavailable. We hypothesize that in high-risk 
PE patients, CDT is superior to the current standard of systemic thrombolysis in terms of 
mortality and adverse events, i.e., is associated with a lower composite incidence of all-cause 
mortality, treatment failure, major bleeding and all-cause stroke. We also hypothesize that CDT 
will lead to a shorter length of stay (LOS) at the intensive care unit (ICU) and in-hospital, faster 
recovery, and better long-term quality of life (QoL). 
 
Objective: To determine whether CDT in high-risk PE relative to systemic thrombolysis is: 
- 
more effective and safer in terms of a reduction of the composite endpoint on all-cause 
mortality and adverse events defined as treatment failure, major bleeding and all-cause 
stroke at day 30 (primary outcome)  
- 
leads to a better Desirability of Outcome Ranking (DOOR) at day 7 
- 
associated with a lower level of oxygen supplementation at 48 hours 
- 
associated with shorter length of stay (LOS) at the intensive care unit (ICU) and in the 
hospital 
- 
associated with better functional recovery as well as better patient-reported outcomes 
such as QoL at one year 
- 
cost-effective after a time horizon of one year  
 
Study design: TORPEDO-NL will be an investigator-initiated, academically sponsored, 
multicentre, open-label, randomized controlled trial (RCT) designed to show superiority of CDT 
(2 systems; technical variant) on top of regular anticoagulation over systemic thrombolysis plus 
regular anticoagulation in patients with high-risk PE in the Netherlands. A 2:1 (thrombectomy: 
systemic thrombolysis) randomization will be applied. The randomization procedure will be 
web-based, using randomly sized blocks consisting of 3,6 or 9 patients. Randomization will 
occur after the verification that a thrombectomy procedure can be started (randomization-to-
needle time) within 60 minutes. Randomization will be stratified by centre.  
 

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Study population: Patients with acute PE who are at a high-risk for mortality but do not have 
‘catastrophic PE’ and do not have a strict contraindication to either systemic lysis or CDT, as 
defined according to the selection criteria, will be enrolled. 
 
Inclusion criteria 
1. Adult patients with confirmed acute PE, i.e. contrast filling defect in a lobar or more proximal 
pulmonary artery on computed tomography pulmonary angiography (CTPA), and/or ob-
structive shock with echocardiographic confirmed dilatation of the right ventricle and a con-
gested vena cava inferior, both with/without echocardiographic signs of clot in transit or 
deep vein thrombosis of the leg. 
2. High risk for mortality, i.e. 
a. post cardiac arrest (after temporary need for cardiopulmonary resuscitation), OR 
b. obstructive shock (systolic blood pressure <90 mmHg and signs of end-organ hy-
poperfusion (e.g. elevated lactate levels >2 mmol/l) or the need for vasopressors 
(adrenalin or noradrenalin) to maintain an adequate blood pressure), OR 
c. persistent hypotension (systolic blood pressure <90 mmHg or systolic blood pres-
sure drop ≥40 mmHg for at least 15 minutes) not caused by new onset arrhythmia, 
hypovolemia, or sepsis, OR 
d. abnormal RV function on transthoracic echocardiography or CTPA AND elevated 
cardiac troponin levels AND respiratory failure defined as hypoxemia (SaO2 <90%) 
refractory to O2 supplementation by nasal cannula or Venturi mask, requiring full 
face mask O2 supplementation (100% FiO2), high-flow nasal O2, or (non-)invasive 
mechanical ventilation. 
3. CDT available and technically feasible so as to allow for a randomization-to-needle time of 
60 minutes or less. 
Exclusion criteria 
1. “Catastrophic PE”, i.e. ongoing cardiac arrest and/or need for extracorporeal cardiopulmo-
nary resuscitation (ECPR) and/or immediate indication for venoarterial extracorporeal 
membrane oxygenation (VA-ECMO) as judged by the responsible physician(s) 
2. Glascow Coma Scale <8 following resuscitation for cardiac arrest 
3. Alternative diagnosis than acute PE contributing largely to the acute hemodynamic and/or 
respiratory failure, e.g. sepsis, COPD GOLD 3 or 4, or known heart failure with NYHA 
Functional Classification of 4, as judged by the treating physician.  
4. A known “do not admit to the ICU” or “do not resuscitate” directive 
5. An absolute contraindication to systemic thrombolysis, i.e.  
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✓ Ischemic stroke in past 6 months 
✓ Central nervous system neoplasm 
✓ Major trauma, major surgery or major head injury in past 3 weeks (note: mild external 
laceration of the head after, e.g. syncope, does not count as major head injury, espe-
cially when a CT scan of the head shows no hematoma) 
✓ Active bleeding, life-threatening or into a critically organ/area; OR known severe bleed-
ing diathesis with previous bleeding fulfilling these criteria 
6. Reperfusion therapy (systemic thrombolysis, surgical thrombectomy or CDT/other catheter 
directed therapy), or placement of a non-retrieved inferior vena cava filter for acute pulmo-
nary embolism in the past 3 months 
7. Thrombus in transit through a patent foramen ovale. 
8. Known chronic thromboembolic pulmonary hypertension (CTEPH), or strong suspicion of 
CTEPH based on pre-existing clinical findings and combinations of signs of PE chronicity 
on echocardiography and/or CTPA.  
9. Known hypersensitivity to systemic thrombolysis, heparin, or to any of the excipients 
10. If, in the Investigator’s opinion, or after consultation with the local PERT-team or EC-mem-
bers, the patient is not appropriate for thrombectomy 
11. Chronic use of full-dose oral or parenteral anticoagulation before presentation. 
12. Pregnancy 
13. Current participation in another study that would interfere with participation in this study 
14. Previous enrolment in this study 
15. Refusal of deferred consent by the next of kin or by the patient himself to use the data. 
Deferred consent will not be asked to relatives of patients who die in scene, but are in-
cluded in the study.  
 
Intervention: The intervention consists of immediate thrombectomy (FlowTriever, Inari Medical 
or Indigo, Penumbra Inc.) without systemic/locally administered thrombolysis. Thrombectomy 
is performed via jugular or femoral venous access by an interventional cardiologist, 
interventional radiologist or vascular surgeon according to the instructions for use (IFU) for the 
particular device. The catheter is advanced over a preplaced guidewire across the right heart 
into the pulmonary arteries to the location of proximal thrombus. Procedural therapeutic 
anticoagulation with heparin is administered. After removal of the dilator, the thrombus is 
extracted by controlled volume aspiration through an aspiration catheter using a syringe or 
dedicated aspiration system, with multiple aspirations performed as needed. Procedural 
objectives will be clearly stated prior to the intervention and patient’s clinical and hemodynamic 
status and residual thrombus will guide the investigators to determine when to terminate the 
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recompensation. The procedure must be discontinued in case of treatment failure, i.e. lack of 
improvement or hemodynamic deterioration, and major CDT complications such as cardiac 
arrest or severe haemoptysis. Complications will be solved directly, with a procedure/treatment 
best suitable according to the treating physician, to minimalize the risk of damage and promote 
patient recovery. 
 
Main study parameters/endpoints: The primary outcome is the 30-day composite incidence of 
the binary endpoints of  
1) all-cause mortality 
2) treatment failure 
3) major bleeding 
4) and all-cause stroke 
 
Treatment failure in the first six hours after randomization is defined as life-threatening 
hemodynamic or respiratory deterioration. This deterioration is the clinical scenario if, following 
randomisation, the patient develops overt cardiorespiratory instability over at least 15 minutes 
necessitating CPR, escalation of respiratory support, or ECMO. After these first six hours, 
treatment failure will also be defined by increasing dosages of cardiorespiratory support (e.g. 
oxygen, catecholamines), and lack of improvement. Lack of improvement is defined by the 
presence of at least one of the following criteria: i) an equal or rising SCAI SHOCK stage (Table 
1), ii) an equal or rising Fraction of Inspired Oxygen (FiO2) level to maintain adequate oxygen 
saturation (i.e. ≥ 92%), or iii) an equal or decreasing P/F ratio. Treatment failure will be 
determined every 6 hours starting at the moment of randomisation, until the patient is 
considered stable and transferable to the ward. 
 
Secondary endpoints include the individual components of the primary outcome as well as 
DOOR at 7 days as the first secondary outcome; this is defined as (i) survival with no new 
severe functional limitation, no treatment failure and no adverse event; (ii) survival with new-
onset severe functional limitation, but no adverse events and no treatment failure; (iii) survival 
with BARC3b bleeding; (iv) survival with BARC3c bleeding or ischemic stroke; (v) survival with 
treatment failure; and (vi) death. Further ranking will be performed by the number of days that 
a patient needs organ support. Organ support is defined as respiratory organ support with 
high-flow nasal cannula or (non-)invasive mechanical ventilation, or cardiovascular organ 
support with a vasopressor or inotropic agent. Other secondary outcomes include amount and 
mode of O2 delivered (to be assessed at 48 hrs), ICU and hospital LOS, QoL, symptom burden, 
functional recovery and 1-year cost-effectiveness.  
 

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Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness: Thrombectomy requires a procedure but may in part prevent the bleeding risks 
associated with systemic thrombolysis. Further, patients will be followed for 1 year and asked 
to complete a set of patient reported outcome measures several times. Benefit for patients 
involves a potentially lower mortality and incidence of treatment failure and/or adverse events, 
lower short-term oxygen requirement, a faster and better relief of functional limitations, a 
shorter LOS, at the ICU and in-hospital, and better long-term outcomes of care. 
 
 

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1. INTRODUCTION AND RATIONALE 
Patients with acute pulmonary embolism (PE) usually have good outcomes.1 However, their 
prognosis may vary dramatically according to whether the patient is hemodynamically stable. 
High-risk PE (5-7% of hospitalized patients with PE) is defined by hemodynamic instability and 
encompasses the clinical presentations of cardiac arrest, obstructive shock, or persistent 
hypotension.2 These high risk patients have 30-day mortality rates ranging from 15% to as high 
as 77%. However, PE patients with respiratory failure that do not fulfill shock criteria, therefore 
currently not considered as high risk in the ESC guideline, also show a >30% risk of death and 
further respiratory failure.3-6 High-risk PE patients require immediate reperfusion therapy on 
top of anticoagulation. The standard reperfusion treatment in these patients is thrombolytic 
therapy (class 1-B, 2019 European Society of Cardiology (ESC) guidelines), administered at 
last in part at the Intensive Care Unit (ICU), with the idea of accelerated fragmentation of the 
thrombus by lytic medication given systemically.2 This carries a significant risk of major 
bleeding (10-25%) and intracranial hemorrhage (ICH, 3%).2 This risk has been shown to be a 
major barrier for administering lifesaving systemic thrombolysis in daily practice conditions, 
which has been suggested to contribute to the high mortality of these patients.7 The need to 
minimize the risk of serious bleeding or to offer alternatives to systemic thrombolysis in patients 
with a high bleeding risk has driven the development of alternative strategies for pulmonary 
reperfusion. Catheter-directed therapy (CDT), which includes catheter thrombectomy 
(“thrombectomy”) may be associated with lower morbidity and mortality as it offers patients a 
fast and relatively safe relief of thrombus load and associated signs and symptoms, and may 
thus represent a better and safer option than systemic thrombolysis. 
 
Multiple studies have shown that mortality in high-risk PE patients remains high and has not 
improved much compared to the ICOPER study 25 years ago.8 In this study, 2.454 acute PE 
patients were studied, of which 4.4% had high-risk PE. Patients with high-risk PE who received 
systemic thrombolysis had a 90-day mortality of 46%. An analysis of German national data 
showed an in-hospital mortality of 77% in patients with high-risk PE, and a 1.5% risk of ICH.7 
Overall, high-risk PE patients who receive systemic thrombolysis are more prone to adverse 
bleeding events as compared to patients with arterial thrombi such as acute myocardial 
infarction (MI) and stroke.9 In conclusion, mortality associated with high-risk PE is high, as is 
the incidence of systemic thrombolysis-induced major bleeding and other adverse events. 
 
Although ultrasound-facilitated catheter-directed low-dose thrombolysis (EKOS, Boston 
Scientific) may be a safer alternative to systemic full-dose thrombolysis, it still carries a risk of 
bleeding, and reperfusion may not be complete or fast enough for the unstable, high-risk 
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thrombectomy. The most used ones are Inari Medical (FlowTriever) and Penumbra Inc. (Indigo 
Aspiration/Lightning). Both systems are CE mark-approved for the treatment of (central) PE. 
The safety of both systems was assessed in prospective single-arm studies, albeit in 
intermediate-risk PE. In the FLARE study, 106 intermediate-risk patients with FlowTriever: a 
significant reduction in right ventricle/left ventricle (RV/LV) ratio at 48h post-procedure was 
observed, suggesting treatment success.11 Major adverse events and death occurred in 3.8% 
and 1.0%, respectively. Major bleeding occurred in 1.0%. In the EXTRACT-PE study, 119 
intermediate-risk PE patients were treated with the Indigo thromboaspiration device and a 
significant RV/LV ratio reduction at 48h post-procedure was reported.12 Major adverse events 
and death occurred in 1.7 and 0.8%, respectively. Major bleeding occurred in 1.7%. One 
notable difference was the device-specific treatment time, which was faster in the EXTRACT-
PE trial (median 37 min) than in the FLARE trial (approximate mean 57 min). The FlowTriever 
for Acute Massive pulmonary Embolism (FLAME) study was a prospective cohort 
observational study designed to evaluate treatment outcomes in patients with high-risk PE 
being treated with the FlowTriever catheter. The primary endpoint, evaluated through hospital 
discharge or 45 days (whichever came first), was a composite of all-cause mortality, clinical 
deterioration, bailout, and major bleeding. Secondary endpoints included individual elements 
of the primary composite, stroke, device-related complications, and access site injury.13 A 
modest number of 53 patients was enrolled. The primary outcome occurred in 17% of patients 
with the following rates of the individual elements of the endpoint: death 1.9%; clinical 
deterioration 15.1%; bailout 3.8%; major bleeding 11.3%. Device-related complications 
occurred in 22.6%, with individual components of hemoglobin decrease (15.1%), vascular 
access hemorrhage (7.5%), and hypotension (1.9%). The mortality of this cohort of high-risk 
PE patients was remarkably low, however, the most severe (‘catastrophic’) PE cases were not 
enrolled and a proper comparison arm was not available.  
 
Despite the accumulation of data from 3 studies, significant shortcomings in our understanding 
of mechanical thrombectomy remain, particularly in the measurement of outcomes with 
validated clinical impact and the likelihood for significant variability in the performance of 
thrombectomy procedures. Applicable guidelines do not make a difference between different 
thrombectomy devices and the CE approval for both devices is comparable.14 In the multi-
centre prospective FLASH registry of 800 American patients with intermediate-high or high risk 
PE treated with FlowTriever, 63% of the patients did not need an overnight stay in the ICU 
post-procedure, and a reduction in RV/LV ratio and in the number of patients with severe 
dyspnea were observed.15 Major adverse events, including major bleeding, and death occurred 
in 1.8% and 0.8%, respectively.  
 

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These studies highlight that the potential health benefit for patients may well outweigh the 
burden of a catheterization procedure including radiation exposure and contrast fluid load. 
Importantly, such a procedure may further include some delay in treatment time as compared 
to systemic thrombolysis, since thrombectomy requires the (fast) deployment of a (24/7 
available) catheterization team. Other important clinical endpoints that were insufficiently 
explored and reported in the abovementioned studies are ‘treatment failure’ (a lack of 
improvement or deterioration16) and ‘ischemic stroke’, mostly from migrating emboli from the 
venous circulation to the arterial system through a patent foramen ovale or atrial septal defect. 
 
2. OBJECTIVES 
Primary Objective:  
The primary objective of the TORPEDO-NL study is to test the hypothesis that CDT in high-
risk PE patients relative to systemic thrombolysis is more effective and safe in terms of a 
reduction of the composite endpoint on all-cause mortality and adverse events defined as 
treatment failure, major bleeding and all-cause stroke at day 30.  
 
Secondary Objective(s): 
The secondary objectives of the TORPEDO-NL study are to evaluate, after randomization, 
whether CDT in high-risk PE patients relative to systemic thrombolysis is: 
- 
associated with a better survival at day 7 and day 30  
- 
associated with a lower incidence of treatment failure at day 7 and day 30 
- 
associated with a lower incidence of all-cause stroke at day 7 and day 30 
- 
associated with a lower incidence of all-cause mortality at day 7, 30 and day 90  
- 
associated with a lower incidence of BARC3b and BARC3c bleeding, at day 7 and day 
30  
- 
associated with a lower incidence of ISTH major and non-major clinically relevant 
bleeding at day 7 and day 30 
- 
associated with a lower composite incidence of the binary endpoints of all-cause mor-
tality, treatment failure, major bleeding and all-cause stroke at day 7  
- 
associated with a better Desirability of Outcome Ranking (DOOR) at day 7 
- 
associated with a lower level of oxygen supplementation at 48 hours  
- 
associated with shorter LOS at the ICU and in hospital 
- 
associated with better patient-relevant outcomes such as QoL, functional recovery and 
- 
symptom burden at day 7 and after 3, 6, 9 and 12 months according to the ICHOM-
VTE set 
- 
cost-effective after a time horizon of a year  

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- 
associated with an impact on budget  
 
3. STUDY DESIGN 
TORPEDO-NL will be an investigator-initiated, academically sponsored, multicentre, open-
label, randomized controlled trial (RCT) to show superiority of CDT (2 commercially available 
systems; technical variant) on top of regular anticoagulation over systemic thrombolysis plus 
regular anticoagulation in patients with high-risk PE in the Netherlands. A 2:1 (thrombectomy: 
systemic thrombolysis) randomization will be applied. The randomization procedure will be 
web-based, using randomly sized blocks consisting of 3,6 or 9 patients. Randomization will 
occur after the verification that a thrombectomy procedure can be started (randomisation-to-
needle time) within 60 minutes. Randomization will be stratified by centre. Patients will be 
followed for 1 year after randomisation. The primary outcome will be assessed after a 30-day 
follow-up period (Figure 1). The inclusion is estimated to take 2.5 years. Finally, all primary 
study outcomes will be adjudicated, blinded, by an independent critical events committee, a 
more detailed description will be provided in paragraph 8.1.1.  
Figure 1: Study flowchart 

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4. STUDY POPULATION 
4.1 Population (base)  
The TORPEDO-NL trial will enrol consecutive adult patients with acute PE presenting with 
respiratory failure, persistent hypotension or shock who do not have a contraindication for 
systemic thrombolysis or CDT.   
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
1. Adult patients with confirmed acute PE, i.e. contrast filling defect in a lobar or more proximal 
pulmonary artery on computed tomography pulmonary angiography (CTPA), or obstructive 
shock with echocardiographic confirmed dilatation of the right ventricle and a congested 
vena cava inferior, both with/without echocardiographic signs of clot in transit or deep vein 
thrombosis of the leg. 
2. High risk for mortality, i.e. 
a. post cardiac arrest (after temporary need for cardiopulmonary resuscitation), OR 
b. obstructive shock (systolic blood pressure <90 mmHg and signs of end-organ hy-
poperfusion (e.g. elevated lactate levels >2 mmol/l) or the need for vasopressors 
(noradrenalin or adrenalin) to maintain an adequate blood pressure), OR 
c. persistent hypotension (systolic blood pressure <90 mmHg or systolic blood pres-
sure drop ≥40 mmHg for at least 15 minutes) not caused by new onset arrhythmia, 
hypovolemia, or sepsis, OR 
d. abnormal RV function on transthoracic echocardiography or CTPA AND elevated 
cardiac troponin levels AND respiratory failure defined as hypoxemia (SaO2 <90%) 
refractory to O2 supplementation by nasal cannula or Venturi mask, requiring full 
face mask O2 supplementation (100% FiO2), high-flow nasal O2, or (non-)invasive 
mechanical ventilation. 
3. CDT available and technically feasible so as to allow for a randomization-to-needle time of 
60 minutes or less. 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation 
in this study: 
1. “Catastrophic PE”, i.e. ongoing cardiac arrest and/or need for extracorporeal cardiopulmo-
nary resuscitation (ECPR) and/or immediate indication for venoarterial extracorporeal 
membrane oxygenation (VA-ECMO) as judged by the responsible physician(s) 
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3. Alternative diagnosis than acute pulmonary embolism contributing largely to the acute he-
modynamic and/or respiratory failure, e.g. sepsis, COPD GOLD 3 or 4, or known heart 
failure with NYHA Functional Classification of 4, as judged by the treating physician.  
4. A known “do not admit to the ICU” or “do not resuscitate” directive 
5. An absolute contraindication to systemic thrombolysis, i.e.  
✓ History of hemorrhagic stroke 
✓ Ischemic stroke in past 6 months 
✓ Central nervous system neoplasm 
✓ Major trauma, major surgery or major head injury in past 3 weeks (note: mild external 
laceration of the head after, e.g. syncope, does not count as major head injury, espe-
cially when a CT scan of the head shows no hematoma) 
✓ Active bleeding, life-threatening or into a critically organ/area; OR known severe bleed-
ing diathesis with previous bleeding fulfilling these criteria 
6. Reperfusion therapy (systemic thrombolysis, surgical thrombectomy or CDT/other catheter 
directed therapy), or placement of a non-retrieved inferior vena cava filter for acute pulmo-
nary embolism in the past 3 months 
7. Thrombus in transit through a patent foramen ovale. 
8. Known chronic thromboembolic pulmonary hypertension (CTEPH), or strong suspicion of 
CTEPH based on pre-existing clinical findings and combinations of signs of PE chronicity 
on echocardiography and/or CTPA.2,17 
9. Known hypersensitivity to systemic thrombolysis, heparin, or to any of the excipients 
10. If, in the Investigator’s opinion, or after consultation with the local PERT-team or EC-mem-
bers, the patient is not appropriate for thrombectomy 
11. Chronic use of full-dose oral or parenteral anticoagulation before presentation. 
12. Pregnancy 
13. Current participation in another study that would interfere with participation in this study 
14. Previous enrolment in this study 
15. Refusal of deferred consent by the next of kin or by the patient himself to use the data. 
Deferred consent will not be asked to relatives of patients who die in scene, but are in-
cluded in the study.  
 
4.4 Sample size calculation 
For the primary endpoint, which is the composite incidence of all-cause mortality and adverse 
events defined as treatment failure, major bleeding and all-cause stroke at day 30, we 
calculated the desired sample size largely based on the data from the FLAME prospective 
registry.13 This study used a somewhat different composite primary endpoint of all-cause 
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bleeding. These endpoints were however not well enough defined and the clinically important 
endpoint of stroke was not a component of the primary outcome. We can however basically 
state that “bailout” and “clinical deterioration” may match our proposed component of treatment 
failure. The primary endpoint in FLAME occurred in 17.0% and in 63.9% (AR difference 46.9%) 
in the FlowTriever and context arms, respectively. Including ischemic stroke, the event rates 
were 18.9% and 67.2% (AR difference 48.3%), respectively. This study suffered from selection 
bias and confounding by indication, and therefore the treatment effect is likely overestimated. 
Patients were enrolled in the FlowTriever arm in the years 2021 and 2022 where event rates 
in the Context arm were obtained from historical data (years 2010-2020) derived from a meta-
analysis.  
 
To assess statistical power, the probability of the primary outcome was assumed to be 0.19 in 
the thrombectomy arm (based on the most recent data available) and 0.46 in the systemic 
thrombolysis arm (corresponding with a treatment OR of 3.71 and a risk difference of 27.5%; 
number needed to treat 3.6). The minimum clinically important difference was set at 27.5% 
based on discussion within the project group, scientific societies and patient representatives, 
and on clinical relevance for the difference facets of the composite endpoints. The assumed 
ARR of 27.5% consists of 5% decrease in mortality, 21.5% reduction in treatment failure or 
major bleeding and 1% reduction in ischemic stroke (the latter both based on expert opinion).18 
Given a power of 80%, a two-sided α-level of 5%, and a 1:2 (systemic thrombolysis:CDT) 
patient allocation, 35 patients are needed in the systemic thrombolysis and 70 patients in the 
CDT arm. Assuming 5% drop-out, 37 patients (systemic thrombolysis) and 74 patients (CDT; 
total 111 patients) will be recruited. The calculation was done using G*Power (version 3.1.9.6) 
and is based on proportion difference tested with an anticipated OR. 
 
5. TREATMENT OF SUBJECTS 
5.1 Investigational product/treatment 
The standard of care for the patients eligible for the TORPEDO-NL trial is parenteral 
anticoagulation and systemic thrombolysis (Actilyse® [manufactured by Boehringer Ingelheim 
Pharmaceuticals, Inc., Ingelheim am Rhein, Germany] 10mg bolus followed by 90mg in two 
hours). The intervention consists of parenteral anticoagulation and immediate CDT 
(FlowTriever or Indigo) without systemic or locally administered systemic thrombolysis. 
Thrombectomy is performed according to the IFU for the particular device and occurs via 
echoguided femoral or jugular venous access by an interventional cardiologist, interventional 
radiologist or vascular surgeon. The catheter is advanced over a preplaced guidewire across 
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of the dilator, the thrombus is extracted by controlled volume aspiration through an aspiration 
catheter using either a syringe or the dedicated aspiration system depending on the device of 
choise, with multiple aspirations performed as needed. Investigators will determine when to 
terminate the procedure based on their assessment patients respiratory and hemodynamic 
status. Procedural objectives will be clearly stated prior to the intervention and respiratory and 
hemodynamic parameters, including pulmonary artery pressures, will be evaluated pre- and 
post-thrombectomy per protocol to inform each operator’s decision to determine completion. 
Revaluation of the patient’s condition should be carried out using blood loss as a reference, 
establishing 400 cc of blood loss as a cut-off value. The type and dosage of anticoagulant 
prescribed to each patient at discharge will be determined by local practice but administration 
will initially be parenteral for at least 24h after randomization. Participating centres have an 
institutionalized multidisciplinary Pulmonary Embolism Response Team (PERT) or EXPERT-
PE team in place. The intervention team should have ample experience with endovascular 
interventions. At least one member of the intervention team should have sufficient experience 
with thrombectomy for PE and should have completed at least 3 full procedures (logged) with 
one of the devices. Procedures that have been carried out by two team members (for example, 
in a training setting) do count. 
 
5.2 Use of co-intervention (if applicable)  
All study patients will be treated with parenteral therapeutic anticoagulation. Patients will 
receive an intravenous (IV) bolus of 80 U/kg unfractionated heparin (UFH) immediately upon 
confirmation of the diagnosis ‘high risk PE’, before of immediately after randomisation, not to 
exceed a total of 8,000 U. During the CDT procedure, UFH is continued. Within 4 hours (or 
immediately upon completion of the reperfusion therapy), the patient should have been 
transitioned to either full-dose parenteral anticoagulation, either therapeutically dosed LMWH 
or UFH (based on local protocols). Upon stabilization (no longer need for organ support, 
transition to normal hospital ward) and after at least 24 hours, the anticoagulation therapy may 
be switched to oral anticoagulation. 
 
5.3 Escape medication  
As soon as a patient meets the predefined primary study outcome, further therapeutic 
management decisions will be left to the discretion of the treating physician, and are not part 
of this study protocol. 
 

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6. INVESTIGATIONAL PRODUCT  
In this study, endovascular reperfusion of the pulmonary artery will be performed using 
thrombectomy and thromboaspiration. A detailed description of the investigational product will 
be given in Appendix D2.  
 
6.1 Name and description of investigational product(s) 
The 2 most used catheter thrombectomy devices are the FlowTriever (Inari Medical) and Indigo 
Aspiration/Lightning (Penumbra Inc.). Both systems are CE Mark approved for the treatment 
of (central) PE. A detailed description of the investigational product will be given in Appendix 
D2. 
 
6.2 Summary of findings from non-clinical studies 
N.A. 
 
6.3 Summary of findings from clinical studies 
We refer to Appendix K4 the 2023 NICE document on “Interventional procedure overview of 
percutaneous thrombectomy for massive pulmonary embolism”. 
 
6.4 Summary of known and potential risks and benefits 
We refer to Appendix K4 the 2023 NICE document on “Interventional procedure overview of 
percutaneous thrombectomy for massive pulmonary embolism”. 
 
7. NON-INVESTIGATIONAL PRODUCT 
Not applicable, as all other products used (such as cannulas, vascular dilators, echo machines, 
are all used in the clinical ICU setting, and all are CE marked and used within the intended 
use. 
 
8. 
METHODS 
8.1 
Study parameters/endpoints 
8.1.1 Main study endpoint 
The primary outcome is the composite incidence of the binary endpoints of all-cause mortality, 
treatment failure, major bleeding and all-cause stroke at day 30.  
 
 

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Treatment failure in the first six hours after randomization is defined as life-threatening 
hemodynamic or respiratory deterioration. This deterioration is the clinical scenario if, following 
randomisation, the patient develops overt cardiorespiratory instability over at least 15 minutes 
necessitating CPR, escalation of respiratory support, or ECMO. After these first six hours, 
treatment failure will also be defined by increasing dosages of cardiorespiratory support (e.g. 
oxygen, catecholamines), and lack of improvement. Lack of improvement is defined by the 
presence of at least one of the following criteria: i) an equal or rising SCAI SHOCK stage (Table 
1), ii) an equal or rising Fraction of Inspired Oxygen (FiO2) level to maintain adequate oxygen 
saturation (i.e. ≥ 92%), or iii) an equal or decreasing P/F ratio. Treatment failure will be 
determined every 6 hours starting at the moment of randomisation, until the patient is 
considered stable and transferable to the ward. 
 
Upon establishing the outcome ‘treatment failure’ physicians are allowed to escalate therapy 
in whatever way they consider appropriate. Therapy crossover without meeting the primary 
outcome is not allowed. Major bleeding is defined as Bleeding Academic Research Consortium 
(BARC)3b and BARC3c bleeding (=intracranial haemorrhage).21 Ischemic stroke is defined as 
any stroke (National Institutes of Health Stroke Scale ≥1).  
 
All primary study outcomes will be adjudicated by an independent critical events committee. 
This committee will consist of an independent group of three individuals with pertinent expertise 
that reviews and adjudicates important endpoints and relevant AEs reported by study 
investigators. The committee will be blinded to treatment assignment and review safety event 
dossiers, which may include copies of subject source documents provided by study sites, for 
all reported cases where the primary outcome was met. Committee members may include 
(interventional) cardiologists, intensivists, pulmonologists, vascular medicine specialists, and 
(interventional) radiologists, as well as other experts with the necessary therapeutic and 
subject matter expertise to adjudicate the event categories outlined above. 
8.1.2 Secondary study endpoints 
The secondary endpoints are: 
- 
Survival at day 7 and day 30  
- 
Treatment failure at day 7 and day 30 
- 
All-cause mortality at day 7, day 30 and day 90  
- 
All-cause stroke at day 7 and day 30 
- 
The composite incidence of the binary endpoints of all-cause mortality, treatment failure, 
major bleeding and all-cause stroke at day 7  
- 
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- 
BARC3b and BARC3c bleeding, at day 7 and day 30  
- 
ISTH major and non-major clinically relevant bleeding at day 7 and day 30 
- 
Oxygen supplementation (LO2/min) at 48 hours  
- 
Length of stay (days) at the ICU and in hospital at day 30 
- 
Quality of life, functional status and symptom burden symptom burden at day 7 and after 
3, 6, 9 and 12 months according to the ICHOM-VTE set23 
- 
Cost-effectiveness analysis after a time horizon of one year and budget impact analysis 
 
The DOOR concept provides assessment of benefits and harms using endpoints of efficacy, 
safety, and functional outcomes. Patients are classified into an ordinal global outcome based 
on the overall outcome desirability. When patients have been classified, the probability of a 
more desirable result in one treatment relative to the other is assessed. The superiority of the 
investigated treatment is calculated by tabulating the pairwise comparison results after further 
ranking by the number of days that a patient needs organ support. Organ support is defined 
as respiratory organ support with high-flow nasal cannula or (non-)invasive mechanical 
ventilation, or cardiovascular organ support with a vasopressor or inotropic agent. The 
following DOOR outcomes (from most to least desirable) are evaluated: 1. Survival with no 
new severe functional limitations, no treatment failure and no adverse event; 2. Survival with 
new severe functional limitations, but no adverse events and no treatment failure; 3. Survival 
with BARC3b bleeding; 4. Survival with BARC3c bleeding or all-cause stroke; 5. Survival with 
treatment failure; 6. Death. Functional limitations are defined according to the post-venous 
thromboembolism functional status (PVFS) scale; grade 4 = severe limitations.24,25 All 
secondary endpoints will be evaluated after randomization.  
 
8.2 
Randomization, blinding and treatment allocation 
A 2 (CDT: systemic thrombolysis) :1 (TT) randomisation will be applied. The randomization 
procedure will be web-based (castor), using randomly sized blocks consisting of 3,6 or 9 
patients. Randomization will occur after the verification that a thrombectomy procedure can be 
started (randomisation-to-needle time) within 60 minutes. Randomization will be stratified by 
centre.  
 
8.3 
Study procedures 
The study starts as soon as the patients is identified as eligible for inclusion and randomised. 
All patients, i.e. both study arms, will be treated with an UFH bolus after diagnosis. Patients 
randomised to the usual care arm will be treated with UFH or LMWH with systemic 
thrombolysis. Patient randomised to the intervention will be treated with UFH or LMWH (see 

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paragraph 5.2 for specifics) and transferred to the cath lab and subjected to the thrombectomy. 
All further diagnostic tests (e.g. echocardiography, repeated blood test) are used along 
clinically relevant but not dictated by this protocol. No biomarkers or imaging test at baseline 
or follow-up will be required for the study. The SCAI SHOCK stage will be assessed at baseline 
and every 6 hours starting from randomization until the patient is stabilized and transferable to 
a normal ward (Table 1).26,27 At 48 hours following randomisation, the amount of oxygen 
supplementation (l O2/min) is noted in the medical chart. Patients will be contacted by the 
Sponsor on day 7 (± 2 days), at 3 months (± 1 week), at 6 months (± 1 week), at 9 months (± 
1 week) and at 12 months (± 2 weeks) by e-mail to complete the PROMS questionnaire(s) 
(Table 2).   
Stage 
A 
B 
C 
D 
E 
Condition 
Hemodynamically 
stable 
Hemodynamically 
unstable 
Hypoperfusion 
= Shock 
Failure to 
stabilize with 
initial therapy 
Extremis / 
refractory shock 
Hypotension: 
- 
SBP 
- 
MAP 
  
>90 mm Hg 
>65 mm Hg 
  
60-90 mm Hg 
50-65 mm Hg 
  
60-90 mm Hg 
50-65 mm Hg 
  
60-90 mm Hg 
50-65 mm Hg 
  
<60 mm Hg 
<50 mm Hg 
  
  
OR 
AND 
AND 
OR 
Hypoperfusion 
- 
Arterial lac-
tate 
 
- 
ALAT 
- 
pH 
  
  
<2 mmol/L 
 
<200 U/L 
≥ 7.2 
  
  
2-5 mmol/L OR 
 
200-500 U/L 
≥ 7.2 
  
  
2-5 mmol/L OR 
200-500 U/L 
≥ 7.2 
  
  
>5-10 mmol/L 
OR 
>500 U/L 
≥ 7.2 
  
  
>10 mmol/L 
OR 
< 7.2 
  
  
AND 
AND 
OR 
OR 
Treatment 
intensity 
No Drugs 
No Devices 
No Drugs 
No Devices 
No Drugs 
No Devices 
2 Drugs  
≥3 Drugs OR 
Device 
  
  
  
OR 
OR 
OR 
  
  
  
1 Drug without 
hypotension or 
hypoperfusion 
1 Drug with 
persistent 
hypotension or 
hypoperfusion 
Out-of- or in-
hospital cardiac 
arrest 
 
Table 1: SCAI SHOCK stage overview. SBP = systolic blood pressure; MAP = mean arterial 
pressure; ALAT = alanine aminotransferase, Drugs = intravenous vaso-active drugs, Devices = RV 
support or VA-ECMO; hypotension = SBP ≤90 mm Hg or MAP ≤65 mm Hg 
 
 
 

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Table 2: Questionnaire overview. The y-axis represents the type of questionnaire, while the x-axis 
indicates the time points at which the patient receives the questionnaires. 
 
8.4 
Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
 
8.5 
Replacement of individual subjects after withdrawal 
The study will be continued until 111 patients have been randomized and completed the first 
30 days of follow-up (or met the primary outcome within that period). 
 
8.6 
Follow-up of subjects withdrawn from treatment 
The primary outcome will be assessed following the principles of intention to treat (ITT). 
Hence, if the reperfusion treatment to which the patient is allocated to receive is not 
provided, the patient will still be followed for the occurrence of primary and secondary 
outcomes. 
 
 
7 Days  
3 Months 
6 Months  
9 Months 
1 Year 
EQ-5D-5L 
X 
X 
X 
X 
X 
ICHOM-VTE – 
Core set – 
Individual 
Questions  
(Satisfaction 
with treatment 
/ Changes in 
life view) 
X 
X 
X 
X 
X 
PEMB-QoL 40 
items 
X 
X 
X 
X 
X 
PROMIS GH 
ten items 
X 
X 
X 
X 
X 
PROMIS 
Numeric Rating 
Scale v1.0 - 
Pain Intensity 
1a_DUT_FLE 
X 
X 
X 
X 
X 
 
 
 
PROMIS SF 
v1.0 - Dyspnea 
Severity short 
form 10a 
X 
X 
X 
X 
X 
PVFS scale one 
item 
X 
X 
X 
X 
X 

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8.7 
Premature termination of the study 
The study will be prematurely terminated if recommended by the DSMB for safety reasons in 
the intervention arm. The DSMB charter of the trial explains the specific discontinuation criteria. 
 
 
9. 
SAFETY REPORTING 
9.1 
Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardise subject health or safety. 
The sponsor will notify the accredited METC without undue delay of a temporary halt including 
the reason for such an action. The study will be suspended pending a further positive decision 
by the accredited METC. The investigator will take care that all subjects are kept informed.  
 
9.2 
AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to the study intervention. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be recorded. Only 
adverse events related to the study (i.e. as a consequence of the reperfusion therapy the 
patient is randomized to, e.g. bleeding and per procedure complications) will be reported to 
the METC, as no patient benefit is expected from reporting non-study related adverse events. 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- results in death; 
- is life threatening (at the time of the event); 
- requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- results in persistent or significant disability or incapacity; 
- is a congenital anomaly or birth defect; or 
- any other important medical event that did not result in any of the outcomes listed above 
due to medical or surgical intervention but could have been based upon appropriate 
judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The lead investigator (or his/hers representative) of each participating site will report all SAEs 
related to participation in this study protocol to the lead investigator of the LUMC. Since the 
patients under study are expected to be at high risk for developing SAEs, we would like to 

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suggest line-listing every 6 months for reporting SAEs. The main reason for line-listing applies 
to the feasibility of reporting the SAEs besides all other study activities, which is expected to 
be of burden for the accredited METC. If there is an SAE that is thought to be in direct relation 
with the safety of the study we will follow the usual regulations of reporting SAEs. The lead 
investigator of the LUMC will report all SAEs related to participation in this study protocol to 
the sponsor without undue delay after obtaining knowledge of the events. The sponsor will 
report the SAEs related to participation in this study protocol through the web portal 
ToetsingOnline to the accredited METC that approved the protocol, within 7 days of first 
knowledge for SAEs related to participation in this study protocol that result in death or are life 
threatening followed by a period of maximum of 8 days to complete the initial preliminary report. 
 
SAEs that are considered study specific include:    
- 
Laceration of a blood vessel  
- 
Haemothorax  
- 
Cardiac tamponade  
- 
Damage to the heart valve 
- 
Pneumothorax 
 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Not applicable. 
 
 
9.3 
Annual safety report 
Not applicable. 
 
 
9.4 
Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. SAEs need to be 
reported till end of study within the Netherlands, as defined in the protocol. 
 
9.5 
Data Safety Monitoring Board (DSMB) 
The independent Data and Safety Monitoring Board (DSMB) is responsible for the oversight 
review 
of 
all 
AEs. 
The 
DSMB 
will 
include 
leading 
experts 
in 
interventional 
cardiology/cardiology, vascular medicine, pulmonology and biostatistics not participating in the 
study. During the course of the study, the DSMB will review accumulating safety data to 

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monitor the incidence of adjudicated events and other trends that would warrant modification 
or termination of the study. Responsibilities, qualifications, membership, and committee 
procedures are outlined in the DSMB Charter. 
 
Data will be supplied to and reviewed by the DSMB in unblinded fashion. Any DSMB 
recommendations for study modification or termination because of concerns over subject 
safety or issues relating to data monitoring or quality control will be submitted in writing to the 
Executive Committee for consideration and final decision. However, if the DSMB at any time 
determines that a potentially serious risk exists to subjects in this study, the DSMB chairperson 
will immediately notify both the sponsor and the Lead Investigators. Should the sponsor decide 
not to fully implement the advice of the DSMB, the sponsor will send the advice to the reviewing 
METC, including a note to substantiate why (part of) the advice of the DSMB will not be 
followed. 
 
10. 
STATISTICAL ANALYSIS 
The data will be analyzed on an ITT basis in several steps. The ITT populations consist of all 
subjects who have been randomized, i.e. when the subject number and allocated regimen are 
recorded in the eCRF. Patients will be analyzed in accordance with the randomized treatment 
assignment irrespective of the factual implementation of the assigned treatment regimen. The 
baseline characteristics in each trial arm will be described. Continuous variables will be 
described as mean with standard deviation (SD) or median with interquartile range (IQR) for 
continuous variables depending on their normality of distribution. The Shapiro–Wilk test will be 
used to assess normality. Categorical variables are presented as numbers and percentages. 
On top of the ITT analyses a per-protocol (safety population) analysis will be performed.  
A detailed description of the statistical analysis will be provided in the Statistical Analysis Plan.  
 
10.1 
Primary study parameter(s) 
For the primary composite endpoint, we will provide the cumulative incidence (number and 
percentage) for each trial arm and estimate the Odds Ratio (OR, including the 95% Confidence 
Interval using a binary logistic regression) to compare trial arms. In case of imbalance in 
background characteristics we can adjust the logistic regression analysis for the respective 
confounders.  
 
10.2 
Secondary study parameter(s)  
For continuous secondary endpoints (e.g., DOOR in the first 7 days after randomization), we 
will estimate mean or median difference between trial arms using an Independent Samples t 

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Test (mean difference) or a Mann Whitney-U test (median difference), depending on the 
normality of the distribution. Regarding categorical secondary outcomes, differences between 
the trial arms will be analyzed using a Chi-square test or Fisher’s exact test, when appropriate. 
Repeated measures secondary outcomes are analyzed using mixed-effects (longitudinal) 
regression models. Outcomes will be (numerically) stratified according to the type of 
thrombectomy (FlowTriever vs. Indigo). A per-protocol analysis is performed as a sensitivity 
analysis. Both R studio and Graphpad software will be used for statistical analysis and making 
graphs, respectively. A two-sided p-value <0.05 is considered statistically significant. Missing 
data, where applicable, will be imputed with the use of multiple imputation under the missing-
at-random assumption with chained equations. Outcome variables will not be imputed, as is 
the convention in randomized controlled trials. Patient safety will be monitored by a Data Safety 
Monitoring Board (DSMB) that will include several senior researchers. Subgroup analyses will 
be performed (if feasible, i.e. if numbers per subgroup are sufficiently large) for man versus 
women, age below 75 or 75 and older, different devices used and subtype of high-risk PE. 
 
A cost effectiveness analysis (CEA) will be performed after a time horizon of one year for the 
primary outcome and QALYs. QALYs will be estimated using the EQ-5D-5L administered at 
day 7 and after 3, 6, 9 and 12 months, the Dutch tariff, and the “Area under the Curve” 
approach.28,29 
The economic evaluation will be performed in accordance with the ‘Dutch Guideline for  
economic Evaluations’.18 In the main analysis, the societal perspective will be applied, meaning 
that all costs will be included irrespective of who pays or benefits (i.e. the cost of the 
intervention, other healthcare use, informal care, as well as productivity losses from unpaid 
and paid work). Intervention costs will be micro-costed, all other costs will be measured using 
cost questionnaires administered at 7 and after 3, 6, 9 and 12 months, and valued using 
standard prices provided by the ‘Dutch Manual for Costing Studies in Health Care’.30  
 
Cost and effect differences will be estimated, while appropriately accounting for the skewed 
nature of costs (bootstrapping), correlated costs and effects (bivariate regression model), 
missing data (multiple imputation), baseline imbalances (baseline adjustment), and the 
clustered nature of data (mixed model), if applicable.(38) Then, incremental cost-effectiveness 
ratios (ICER) will be calculated by dividing the difference in costs by the difference in effects. 
The uncertainty stratified around the ICER and will be estimated using bias-corrected and 
accelerated bootstrapping with 5.000 replications and graphically presented on cost-
effectiveness planes. These planes will indicate the probability that an intervention is cost-
effective compared to usual care at different values of willingness to pay (cost-effectiveness 
acceptability curve).29 To assess the robustness of the results, various sensitivity analyses will 

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be performed (e.g. healthcare perspective, complete-case analysis, per-protocol analysis, 
human capital approach versus friction cost approach).29 
 
A budget impact analysis (BIA) will be conducted according to ZonMw’s ‘BIA, leidraad en 
rekentool’ and ISPOR’s principles of good practice.31 The budget impact analysis will be based 
on the Dutch population, and hence Dutch incidence data will be used. Perspectives that will 
be considered are the societal, government (Budget Kader Zorg), and insurer perspective. The 
cost of the intervention mix will be valued using Dutch standard costs for the societal 
perspective, actual NZA tariffs for the government perspective, and average tariffs NZA for the 
insurer perspective. Different scenarios will be evaluated including the following: 1) the 
intervention is not implemented, i.e. all patients will receive usual care, 2) the intervention is  
offered to the whole patient population, and 3) the intervention is only offered to specific 
subgroups of the potential patient population. These subgroups will be defined based on the 
results of the study, e.g. subgroups who particularly benefitted from the intervention (e.g., type 
of thrombectomy, sex, presence of cancer). Uncertainty will be estimated using probabilistic 
sensitivity analyses. 
 
10.3 
Other study parameters 
Not applicable. 
 
10.4 
Interim monitoring  
As the anticipated sample size is relatively small, a formal interim analysis is not feasible to 
reach a solid conclusion. For this reason, an interim monitoring will be performed after the 
inclusion of 50 patients.32 This monitoring will entail (i) an evaluation of the consent 
procedures, (ii) a data quality check, (iii) a review of process measures (e.g., screening, drop 
out rates, and adherence), and (iv) safety and serious adverse events. The DSMB will review 
the data of these parameters and report their advice to the sponsor of the trial. 
 
11. ETHICAL CONSIDERATIONS 
11.1 
Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (as 
amended in Tokyo, Venice and Hong Kong, Somerset West and Edinburgh; version of 2013), 
in accordance with the Guideline for Good Clinical Practice (CPMP/ICH/135/95 - 17th July 
1996), the Medical Research Involving Human Subjects Act (WMO) and the European  
regulation (EU) 2017/745 on medical devices (MDR). 
 

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11.2 
Recruitment and consent 
Patients will be screened for inclusion upon arrival of the local EXPERT-PE team. The patients 
eligible for this study are in shock and often respiratory insufficient. Both the study intervention 
and the systemic thrombolysis are emergency interventions that have to be applied without 
delay and the intervention fulfils the ethical requirement of clinical equipoise. The study 
participant can benefit from the intervention, but up to now there is a state of honest, 
professional uncertainty in the community of expert practitioners as to the effect of the 
intervention. All in all, the eligible patients have an extremely high risk of dying (up to 70% if 
left untreated or if appropriate treatment is delayed) and the legal representatives will therefore 
be in a disturbed mental state complicating an immediate informed decision. The patient will 
therefore be randomized upon confirmation by the treating physicians that the patients fulfils 
the criteria of study participation. 
 
The investigator or treating physician will inform the patient about the study and will ask for 
deferred proxy consent for use of the study and medical data (deferred consent) immediately 
if and when the patient is deemed susceptible for this (for the majority of patients, this will be 
shortly after the reperfusion therapy has been delivered), or the legal representative if the 
patient remains unable to communicate within 72 hours after randomisation. If the patient has 
died by  that time, the legal representatives will be informed that the patient participated in the 
study. This can be done either by the local principal investigator or the treating physician, 
provided that the physician has been explicitly informed of the ethical and legal nuances of the 
trial. The legal representatives will not be asked for consent to use the data, since: (1) the legal 
representatives have no independent right on inspection of or say on therapeutic or study data 
(CCMO: “De nabestaanden hebben geen zelfstandig recht op inzage van de tijdens de 
behandeling en het onderzoek verkregen gegevens en hebben daar ook geen zeggenschap 
over. Van toestemming voor het gebruik van de data door de nabestaanden kan daarom ook 
geen sprake zijn”); (2) possible refusal may cause selection bias and this is ethically unwanted 
(CCMO: het introduceren van selectiebias door het moeten vragen van toestemming aan de 
nabestaanden, mocht daar een grond voor zijn, ethisch niet wenselijk is). These patients are 
essential for the internally validity of the study; 3) the data will be coded. Use of the data has 
no implications for the patient or legal representatives; and (4) we consider it unethical to 
burden the grieving relatives with a decision that has no impact on the already performed 
treatment and only pertains the use of already gathered and coded data.  
The legal representatives will be given a letter containing information about the trial. They will 
also receive an invitation for an appointment with the supervising doctor and an investigator 
after 6 to 8 weeks, to answer any remaining questions. 
 

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11.3 
Objection by minors or incapacitated subjects (if applicable) 
Minors will not be included. This study is not including incapacitated subjects. Deferred consent 
will be asked to when the patient becomes susceptible and/or the legal representative, as 
described above. 
 
11.4 
Benefits and risks assessment, group relatedness 
Multiple studies have shown that mortality in high-risk PE patients remains unacceptably high 
and has not improved much compared to 20 years ago. The current standard of care is 
underused because of its associated high risk of major and sometimes fatal bleeding. The 
studies described in chapter 1 of this protocol highlight that the potential health benefit of CDT 
for patients may well outweigh the burden of a catheterization procedure including radiation 
exposure (± 5.70 mSv) and contrast fluid load. Notably, such a procedure may further include 
some delay in treatment time as compared to systemic thrombolysis, since thrombectomy 
requires the (fast) deployment of a (24/7 available) catheterization team. This fast application 
of CDT has been shown feasible in cohort studies. The benefits for patients are clear if our 
hypothesis is proven true: a potential lower mortality and incidence of treatment failure and/or 
adverse events, lower short-term oxygen requirement, a faster and better relief of functional 
limitations, a shorter length of stay at the ICU and in-hospital, and better long-term outcomes 
of care. Importantly, a randomized trial with patient-relevant outcomes is the only way to 
conform our hypothesis with certainty as the inherent methodological problems of cohort 
studies in this setting prevent such study designs to provide the necessary level of evidence. 
 
11.5 
Compensation for injury 
The sponsor has a liability insurance which is in accordance with article 7of the WMO. The 
sponsor (also) has an insurance which is in accordance with the legal requirements in the 
Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical 
Research in Humans of 2015). This insurance provides cover for damage to research  subjects 
through injury or death caused by the study. 
 
1) € 650.000,-- (i.e. six hundred and fifty thousand Euro) for death or injury for each subject 
who participates in the Research; 
2) € 5.000.000,- (i.e. five million Euro) for death or injury for all subjects who participate in the 
Research; 
3) € 7.500.000,- (i.e. seven million five hundred thousand Euro) for the total damage incurred 
by the organisation for all damage disclosed by scientific research for the Sponsor as 'ver-
richter' in the meaning of said Act in each year of insurance coverage.  

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The insurance applies to the damage that becomes apparent during the study or within 4 years 
after the end of the study. 
 
The Insurance company Is CentraMed. 
Adress: Postbus 7374, 2719 DB Zoetermeer. 
Tel.nr.: +31 (0)70-3017070 
 
11.6 
Incentives 
Patients will not receive any compensation or other incentives to participate. 
 
12. 
 ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 
Handling and storage of data and documents 
When a potential patient is presented, informed consent procedure will follow as described 
above in paragraph 11.2. When included in the study all data will be collected, used, and 
stored. This concerns data such as name, address, contact details and date of birth and 
medical Information. Diligent efforts will be made to ensure the study data are stored securely 
and confidential Information is protected. The handling of personal data will comply with the 
General Data Protection Regulation (GDPR). All study participants will receive a study number 
which is a unique identifier (not based on patient initials and birth date). The key to the code 
will be safely stored in the local research institute and safeguarded by the principal investigator. 
The unique study number will be used on the Case Report Form (CRF; Castor EDC). Baseline 
characteristics, contact details, and outcomes will be entered in Castor. The data that will be 
sent to the sponsor/coordinating investigator will include names and contact data as this is 
relevant for the centralised follow-up via telephone/email beyond the first 30 days. This will be 
explicitly mentioned in the patient information letter and mentioned in the deferred informed 
consent conversation. Upon completion of the study for each individual patient, contact details 
will be deleted. All electronic data and records will be saved under their unique study number 
and stored in a secured file (in the 'I drive') on the computer. Access to study files and electronic 
records will be restricted to authorized study personnel only. The local investigators are 
responsible for ensuring that all sections of the CRF are completed correctly, and that entries 
can be verified against source data. The principle investigators will archive all study data 
(subject Identification code list, source data, and investigator's files) and relevant 
correspondence in the Investigator Site File. Only the principle investigator will have access to 
the subject Identification code list and source data. The monitor and Flealthcare and Youth 
Inspectorate also have access to the data in case of safety reviewing. The Investigator Site 

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File, all source data, and other pertinent documents will be archived for 15 years at the 
research location. 
 
12.2 
Monitoring and Quality Assurance  
Monitoring in all sites in the Netherlands will be executed by (internal) monitors of the LUMC 
according to the monitor plan. Monitors and auditors have permission to see uncoded patients 
data. Monitoring and auditing procedures will be followed, in order to comply with GCP 
guidelines. Each center will be monitored at regular intervals to ensure compliance with the 
protocol, GCP and legal aspects. This will include checking of the CRF for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters. 
 
12.3 
Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited 
METC has been given. All amendments will be notified to the METC that gave a favourable 
opinion. Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 
12.4 
Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
 
12.5 
Temporary halt and (premature) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a period 
of 8 weeks. The end of the study is defined as the last patient’s last visit. The sponsor will notify 
the METC immediately of a temporary halt of the study, including the reason of such an action. 
In case the study is ended prematurely, the sponsor will notify the accredited METC within 15 
days, including the reasons for the premature termination.  Within one year after the end of the 
study, the investigator/sponsor will submit a final study report with the results of the study, 
including 
any 
publications/abstracts 
of 
the 
study, 
to 
the 
accredited 
METC.  
 

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12.6 
Public disclosure and publication policy 
Results of this study will be published in open access international peer-reviewed scientific 
journals and will be presented on (inter)national scientific conferences and meetings. This will 
be in accordance to the CCMO statement on publication policy. 
 
13. STRUCTURED RISK ANALYSIS  
13.1 
Potential issues of concern 
Not applicable as all the investigational products will be used within their registered indication 
and not in combination with other (investigational) product. 
 
13.2 
Synthesis 
As described above, we will include a population that is at very high risk of death and for whom 
the current standard of care (systemic thrombolysis) is considered insufficient. The benefits for 
patients in this study randomized to the intervention arm seem clear if our hypothesis is proven 
true. Still, the effectiveness and safety of the intervention are to be proven beyond doubt, even 
despite the favorable data from observational single-arm studies. The main risks for patients 
randomized to the intervention are delayed reperfusion because of logistical issues, and per 
procedure complications. For the first issue, we have very strict criteria for study sites to be 
able to participate. The multidisciplinary organization of care for patients with severe acute PE 
via an EXPERT-PE team must be protocolized and proven in place. This will be checked by 
the principle investigators of this study based on review of relevant local protocols and 
interviewing the members of the local EXPERT-PE team. Furthermore, the interventional team 
that will be responsible for the intervention must be available around the clock, well trained and 
experienced with the intervention, the latter defined as at least 3 uncomplicated procedures in 
patients with hemodynamic and/or respiratory compromise. The training log of the 
interventional team will be checked. Finally, the local EXPERT-PE team must make a quick 
assessment whether it is feasible to initiate the intervention within 1 hour upon randomization. 
For instance, if the team is performing another procedure, or if the device is technically 
unavailable, or when catheters are not in stock, patients cannot be included and enrolled. 
Together with the reported safety and efficacy of the procedure as reported in cohort studies, 
we are confident that the risk related to unacceptable delay as well as per procedure 
complications are mitigated. On top of this, we will install a DSMB that will carefully monitor 
the safety of the study procedures. 
 
 

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