A Prospective, Multicenter Trial to Evaluate the Safety and Efficacy of the Indigo® Aspiration System in Acute Pulmonary Embolism
Phase: NA
Conditions: Pulmonary Embolism
Sponsor: Penumbra Inc.

 
 
  
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EXTRACT-PE: A Prospective, Multicenter Trial to Evaluate the Safety and 
Efficacy of the Indigo® Aspiration System in Acute Pulmonary Embolism  
 
 
 
Protocol  
CLP-11373.D 
 
Release Date 
12 June 2018 
 
Device Name 
Indigo® Aspiration System 
 
Principal Investigator 
Akhilesh K. Sista, M.D. 
NYU Langone Medical Center 
 
Sponsor 
Penumbra, Inc. 
One Penumbra Place 
Alameda, CA 94502 
USA 
 
 
 
 

 
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CLP-11373.D Protocol Synopsis  
Study Title: 
A Prospective, Multicenter Trial to Evaluate the Safety and Efficacy of 
the Indigo® Aspiration System in Acute Pulmonary Embolism 
Study 
Objective: 
The primary objective of this trial is to determine the safety and efficacy of 
the Indigo® Aspiration System for aspiration mechanical thrombectomy in 
patients with acute pulmonary embolism (PE). 
Study Design: 
Prospective, multicenter, single arm design. The planned sample size is up to 
150 patients enrolled at up to 25 centers in the US. Acute PE is defined as 
having clinical signs and symptoms for 14 days or less with an RV/LV ratio 
of >0.9 on CT angiography and systolic BP ≥90 mmHg. Follow-up is 30 
days after initial procedure.  
Patient 
Population: 
Patients presenting with symptoms of acute PE and who meet other study 
entry criteria are eligible for this trial. Enrolled patients will be treated with 
aspiration thrombectomy by the Indigo® Aspiration System. 
Inclusion 
Criteria: 
1. Symptomatic acute PE with duration of 14 days or less. Evidence of PE 
must be from CTA. 
2. Systolic BP ≥90 mmHg with evidence of dilated RV with an RV/LV 
ratio >0.9 
3. Patient is 18 years of age or older 
Exclusion 
Criteria: 
 
1. tPA use within 14 days prior to baseline CTA  
2. Systolic BP <90 mmHg for 15 min or the requirement of inotropic 
support to maintain systolic BP ≥90 mmHg  
3. Pulmonary hypertension with peak PA >70 mmHg by right heart 
catheterization 
4. History of severe or chronic pulmonary hypertension 
5. FiO2 requirement >40% or >6 LPM to keep oxygen saturations >90% 
6. Hematocrit <28% 
7. Platelets <100,000/µL 
8. Serum creatinine >1.8 mg/dL 
9. INR >3 
10. aPTT (or PTT) >50 seconds on no anticoagulation 
11. History of heparin-induced thrombocytopenia (HIT) 
12. Contraindication to systemic or therapeutic doses of anticoagulants 
13. Major trauma < 14 days 
14. Presence of intracardiac lead 
15. Cardiovascular or pulmonary surgery within last 7 days 
16. Cancer which requires active chemotherapy 
17. Known serious, uncontrolled sensitivity to radiographic agents 

 
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CLP-11373.D Protocol Synopsis  
Study Title: 
A Prospective, Multicenter Trial to Evaluate the Safety and Efficacy of 
the Indigo® Aspiration System in Acute Pulmonary Embolism 
18. Life expectancy <90 days 
19. Female who is pregnant  
20. Intracardiac Thrombus 
21. Patients on ECMO 
22. Current participation in another investigational study 
Primary 
Endpoints: 
• Reduction in RV/LV ratio from baseline to 48 hours assessed by CTA. 
• Major Adverse Events, a composite of: 
o Device-related death within 48 hours 
o Major bleeding within 48 hours 
o Device-related SAEs within 48 hours 
▪ Clinical deterioration 
▪ Pulmonary vascular injury 
▪ Cardiac injury   
Secondary 
Endpoint: 
• Secondary Safety Endpoints: 
o Device-related death within 48 hours 
o Major bleeding within 48 hours 
o Clinical deterioration within 48 hours 
o Pulmonary vascular injury within 48 hours 
o Cardiac injury within 48 hours 
o Any-cause mortality within 30 days 
o Device-related SAEs within 30 days 
o Symptomatic PE recurrence within 30 days 
 
Study 
Rationale: 
Use of the Indigo® Aspiration System for mechanical thrombectomy may 
allow for thrombus removal without the use of thrombolytic drugs with an 
acceptable device-related serious adverse event rate. Use of tissue-
plasminogen activator (tPA) during procedure will not be permitted unless 
deemed medically necessary by site investigator. 
Trial 
Success/failure 
Criteria 
The lower limit of the 95% confidence interval of the change in RV/LV ratio 
at 48 hours is >0.20  
Clinical Event 
Committee & 
Data Safety 
Monitoring 
Board 
Clinical Events Committee will adjudicate appropriate adverse events for 
causality and attribution. 
A Data Safety Monitoring Board will monitor safety during the trial. 

 
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CLP-11373.D Protocol Synopsis  
Study Title: 
A Prospective, Multicenter Trial to Evaluate the Safety and Efficacy of 
the Indigo® Aspiration System in Acute Pulmonary Embolism 
Core 
Laboratory 
An independent Core Lab will review imaging scans. 
Duration of the 
Trial 
The trial is anticipated to last 2 years and each patient will be in the trial for 
approximately 30 days. 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................................................................ 7 
1.1 Background ................................................................................................................................... 7 
1.2 Rationale ........................................................................................................................................ 8 
1.3 Study Implementation Plan ..................................................................................................... 9 
2. 
STUDY OBJECTIVES AND STUDY DESIGN ............................................................................ 9 
2.1 Primary Objective ....................................................................................................................... 9 
2.2 Study Design .................................................................................................................................. 9 
3. 
STUDY POPULATION, SCREENING, RECRUITMENT, AND ENROLLMENT 
PROCEDURES .......................................................................................................................................... 9 
3.1 Patient Population ...................................................................................................................... 9 
3.2 Inclusion Criteria ......................................................................................................................... 9 
3.3 Exclusion Criteria ....................................................................................................................... 12 
3.4 Screening and Enrollment ......................................................................................................... 12 
3.5 Enrollment Procedure ................................................................................................................ 12 
4. 
Study Treatment .......................................................................................................................... 13 
4.1 Study Device ................................................................................................................................. 13 
5. 
STUDY PROCEDURE, CLINICAL PROCEDURES, AND LABORATORY EVALUATIONS
 
…………………………………………………………………………………………………………………………14 
5.1 Study Procedure .......................................................................................................................... 14 
5.2 Study Visits ................................................................................................................................... 15 
5.3 Termination of Patient Participation ................................................................................. 18 
5.4 Lost to Follow-up ......................................................................................................................... 18 
5.5 Patient Withdrawal ..................................................................................................................... 18 
6. 
ADVERSE EVENTS .................................................................................................................. 18 
6.1 Adverse Event Reporting........................................................................................................... 18 
6.2 Definition of Adverse Events ................................................................................................. 17 
6.3 Definition of Serious Adverse Event (SAE) ....................................................................... 18 
6.4 Device Malfunction ................................................................................................................... 18 
6.5 Unanticipated Adverse Device Effect (UADE) .................................................................. 19 
6.6 Adverse Event Severity ............................................................................................................ 19 
6.7 Relationship to Study Device ................................................................................................. 19 

 
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6.8 Relationship to Study Procedure ......................................................................................... 19 
6.9 Risk/Benefit Assessment ............................................................................................................ 22 
7. 
STATISTICAL CONSIDERATIONS .................................................................................... 22 
7.1 Study Endpoints ........................................................................................................................... 22 
7.2 Sample Size Justification ........................................................................................................... 23 
7.3 Accrual and Follow-up ............................................................................................................... 24 
7.4 Statistical Analysis....................................................................................................................... 24 
7.5 Analysis of Adverse Events ....................................................................................................... 24 
7.6 Interim Analysis ........................................................................................................................... 24 
7.7 Data Management and Security ............................................................................................... 24 
8. 
PATIENT CONSIDERATIONS .............................................................................................. 25 
8.1 Ethics Review ............................................................................................................................... 25 
8.2 Informed Consent and HIPAA Authorization .................................................................. 26 
8.3 Clinical Trial Termination ........................................................................................................ 26 
8.4 Patient Data Protection .............................................................................................................. 26 
9. 
ADMINISTRATIVE CONSIDERATIONS .......................................................................... 26 
9.1 Study Activation .......................................................................................................................... 27 
9.2 Study Coordination ..................................................................................................................... 27 
9.3 Study Monitoring ........................................................................................................................ 27 
9.4 Protocol Compliance ................................................................................................................... 27 
9.5 Investigator’s Records ................................................................................................................ 28 
   9.6 Imaging…………………………………………………………………………………………………………..…………27 
9.7 Device Inventory Requirements ............................................................................................... 29 
9.8 Publication of Information ........................................................................................................ 29 
10. COMMITTEES ........................................................................................................................... 30 
10.1 Steering Committee ...................................................................................................................... 30 
10.2 Clinical Events Committee ......................................................................................................... 30 
10.3 Data Safety Monitoring Board .................................................................................................. 30 
   10.4 Imaging Core Lab………………………………………………………………………………....……………….29 
APPENDIX I .......................................................................................................................................... 31 
APPENDIX II........................................................................................................................................... 33 
APPENDIX III ....................................................................................................................................... 39 

 
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CLP-11373.D 
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CONTACT LIST 
 
EXTRACT-PE: A Prospective, Multicenter Trial to Evaluate the Safety and Efficacy of the 
Indigo® Aspiration System in Acute Pulmonary Embolism  
 
Protocol 
CLP-11373.D 
 
 
General Information 
Penumbra, Inc.  
One Penumbra Place 
Alameda, CA 94502 
Ph:   510.748.3200 
Fax: 510.814.8305 
 
 
 
 
 
 
 
 
 
 
 
Michaella Corso 
Vice President, Clinical Affairs 
Ph: 510.995.2079 
 
 
 
michaella.corso@penumbrainc.com 
Tatiana Ermakova, MD, MPH 
Director, Medical Affairs 
Ph: 510.748.3318 
termakova@penumbrainc.com 
Priya Guyadeen, RN, BSN, M.S., MBA 
Clinical Project Manager, Peripheral 
Ph:    510.995.4440 
Cell: 510.491.7986 
priya.guyadeen@penumbrainc.com 

 
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1. INTRODUCTION 
 
1.1  Background 
 
Acute massive pulmonary embolism (PE), defined as hemodynamic instability from acute PE, 
and acute submassive PE, defined by right ventricular strain without hypotension, are common 
life-threatening conditions that represent the serious manifestations of venous thromboembolic 
disease.  In the United States, an estimated 530,000 cases of symptomatic PE occur annually1; 
and approximately 300,000 people die every year from acute PE.2 The mortality rate can exceed 
58% in patients with acute massive PE presenting with hemodynamic shock3, and most of these 
deaths occur within 1 hour of presentation. 2-4 Acute massive PE is believed to be the third most 
common cause of death among hospitalized patients.5  
 
The physiologic effect of massive PE is right ventricular failure, which reduces left ventricular 
preload and can lead to systemic hypotension and sudden death. While submassive PE has a 
lower mortality than massive PE, it is associated with a higher mortality and higher rate of 
clinical deterioration than low-risk PE. Therapeutic anticoagulation is the standard of care first-
line treatment.6  Treatment escalation beyond therapeutic anticoagulation is also standard 
practice. Current approved medical therapy for acute massive PE consists of systemic 
thrombolysis with 100 mg of tPA (Alteplase; Genentech, South San Francisco, California) 
infused intravenously (IV) over a period of 2 hours.9 However, there is a known risk of bleeding 
associated with fibrinolysis. A meta-analysis of 15 trials involving a total of 2057 massive and 
submassive PE patients found that major hemorrhage (OR: 2.91; 95% CI: 1.95 to 4.36) and fatal 
or intracranial hemorrhage (OR: 3.18; 95% CI: 1.25 to 8.11) was significantly more frequent 
among patients receiving thrombolysis.10 An international registry on massive PE patients who 
received fibrinolytics and/or inferior vena caval filter placement reported a 90-day mortality rate 
of 52.4% (95% CI, 43.3% to 62.1%).11 The study also concluded that thrombolytics did not 
reduce the 90-day mortality rate.11 Massive PE treatment may be escalated further to surgical 
embolectomy and a case series suggests a mortality rate of approximately 40% despite surgical 
embolectomy.12   
 
The optimal treatment strategy for patients with submassive PE is not as clear.  Experts agree 
that further research is needed to tailor treatment protocols and to evaluate long-term outcomes. 
Several studies have shown higher rates of in-hospital adverse events as well as pulmonary 
hypertension and poor functional status at follow-up in high risk submassive PE patients given 
anticoagulants alone.13-15 Yet, escalating therapy with systemic thrombolytics, while it improves 
short-term and potentially long-term PE related adverse outcomes, is associated with high 
incidence of major bleeding. In a meta-analysis of 8 randomized trials investigating submassive 
PE, major bleeding including intracranial hemorrhage was significantly more common with 
systemic thrombolytics compared to anticoagulants alone.13   
 
For most submassive PE patients, the 2014 European Society of Cardiology (ESC) and 2012 
CHEST PE guidelines recommend using anticoagulation alone and rescue systemic 
thrombolytics if needed.7,8 The American Heart Association (AHA) guidelines suggest, with 
only Class IIb/Level of Evidence (LOE) C, systemic thrombolytics for patients with submassive 
PE with impending hemodynamic collapse.6  Thus, guidelines acknowledge the questionable 

 
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risk-benefit ratio for systemic thrombolysis in the setting of submassive PE.  
 
Given the incomplete efficacy of anticoagulation alone and high bleeding complications of full 
dose systemic thrombolysis, catheter-directed therapy has garnered significant interest. Medical 
expert guidelines differ in treatment recommendations for acute PE, but do suggest catheter 
directed therapy, which could include use of the Indigo Aspiration System, in certain 
circumstances.6-8 In patients who are not candidates for or who fail systemic thrombolysis, 
catheter-directed therapy to achieve rapid central clot debulking can be considered as an 
alternative treatment option for patients with acute massive PE.  While there is more controversy 
regarding submassive PE therapy, guidelines suggest, that catheter-directed therapy can be 
considered for the sickest subset of patients with acute submassive PE.6-8 
 
Catheter-directed therapy (CDT) encompasses catheter-directed mechanical fragmentation 
and/or aspiration of emboli and intraclot thrombolytic agent injection if a local drug is infused. 
Therefore, a variety of devices can be used to treat PE successfully. Depending on anticipated 
bleeding risk, CDT may be performed with no or low-dose local TPA injection. The goal of 
these techniques is to rapidly debulk central thrombus to relieve life-threatening heart strain 
(massive PE), immediately improve pulmonary perfusion, and reduce the risk of mortality and 
clinical deterioration (submassive PE). Catheter intervention is important not only for creating an 
immediate flow channel through the obstruction, but also for exposing a greater surface area of 
thrombus to the locally infused thrombolytic drug. In a meta-analysis of 594 patients with acute 
massive PE treated with CDT, clinical success was achieved in 86.5% of the cases, with success 
defined as hemodynamic stabilization, resolution of hypoxia, and survival to hospital 
discharge.16  In the same study, 33% of cases were initiated with mechanical treatment alone 
without local thrombolytic infusion.16  When injected locally, the required dose of TPA is lower 
compared with full-dose systemic infusion, potentially reducing the bleeding risk. The ULTIMA 
trial demonstrated that patients who receive CDT have faster resolution of heart strain than 
patients treated with anticoagulation alone and equal safety in the 2 arms.17  The PERFECT 
registry demonstrated that CDT use was associated with a high clinical success rate in massive 
and submassive PE patients.18  
 
Recently, percutaneous mechanical thrombectomy procedures in this setting were graded in the 
European guidelines (ESC) as class IIb/LOE C indication, in the American ones as class IIa LOE 
C (AHA guidelines) and as class II/LOE C indication according to the ACCP guidelines.6,7 
These procedures have been classified as aspiration thrombectomy, fragmentation 
thrombectomy, and rheolytic thrombectomy. 
 
Interventionalists across the country have been using the CAT6 and 8 aspiration catheters in the 
setting of submassive and massive PE in a variety of clinical scenarios.  The intention of this 
study is to prospectively study the safety and efficacy of the device in the setting of acute PE. 
 
1.2 
Rationale 
 
Currently, it is unknown if catheter aspiration thrombectomy with the Indigo® Aspiration 
System can safely improve patient outcomes for patients with PE.  This is an exploratory 

 
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prospective analysis to collect outcomes for patients treated with this novel method of 
thrombus aspiration. 
 
The primary aim of this study is to assess the Indigo® Aspiration System in patients with 
PE, which will serve as preliminary data to plan future studies to evaluate this system in this 
disease state.    
 
1.3 
Study Implementation Plan 
 
A sample size of at least 100 evaluable patients is selected for this study.  Evaluable patients 
are defined as those patients who meet eligibility requirements for primary endpoint 
assessment and who received treatment.   
A total population of up to 150 enrolled patients will yield 100 evaluable patients, which 
provides an adequate level of precision to establish if the Indigo® Aspiration System will 
provide acceptable performance in decreasing RV dilation. 
 
2. STUDY OBJECTIVES AND STUDY DESIGN 
 
2.1 
Primary Objective 
 
 
The primary objective of the prospective study is to observe the safety and efficacy of the 
Indigo® Aspiration System for aspiration mechanical thrombectomy in patients with 
acute pulmonary embolism (PE).  
 
 
2.2 
Study Design 
 
This is a prospective, multicenter, single arm design. Up to 150 patients at up to 25 
centers in the United States will be enrolled in order to evaluate 100 patients. Follow-up 
is 30 days after initial procedure.  
 
 
3. Study Population, Screening, Recruitment, and Enrollment Procedures 
 
3.1 
Patient Population 
 
Patients presenting with symptoms of acute PE, and meeting study entry criteria are 
eligible for this trial. Enrolled patients will be treated with aspiration thrombectomy by the 
Indigo® Aspiration System. 
 
3.2 
Inclusion Criteria 
1. Clinical signs and symptoms consistent with acute PE with duration of 14 days or less. 
Evidence of PE must be from CTA. 
2. Systolic BP ≥90 mmHg with evidence of dilated RV with an RV/LV ratio >0.9 
3. Patient is 18 years of age or older 
 

 
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3.3 
Exclusion Criteria 
1. tPA use within 14 days prior to baseline CTA 
2. Systolic BP <90 mmHg for 15 mins or the requirement of inotropic support to maintain 
systolic BP ≥90 mmHg  
3. Pulmonary hypertension with peak PA >70 mmHg by right heart catheterization 
4. History of severe or chronic pulmonary hypertension 
5. FiO2 requirement >40% or >6 LPM to keep oxygen saturation >90% 
6. Hematocrit <28% 
7. Platelets <100,000/µL 
8. Serum creatinine >1.8 mg/dL 
9. INR >3 
10. aPTT (or PTT) >50 seconds on no anticoagulation 
11. History of heparin-induced thrombocytopenia (HIT) 
12. Contraindication to systemic or therapeutic doses of anticoagulants 
13. Major trauma <14 days 
14. Presence of intracardiac lead 
15. Cardiovascular or pulmonary surgery within last 7 days 
16. Cancer requiring active chemotherapy 
17. Known serious, uncontrolled sensitivity to radiographic agents 
18. Life expectancy <90 days 
19. Female who is pregnant  
20. Intracardiac Thrombus 
21. Patients on ECMO 
22. Current participation in another investigational study 
 
3.4 
Screening and Enrollment 
 
Patients presenting with signs and symptoms of acute PE will be screened for possible 
enrollment as a patient into the trial based on Inclusion/Exclusion Criteria (“Entry 
Criteria”) (described in Section 3). 
 
3.4.1 Screen Failures 
• Patients who were evaluated and do not meet the Entry Criteria  
• Patients who meet the Entry Criteria, but decline to participate in the trial. 
• Patients who meet the Entry Criteria, but do not have any component of the study 
device—Indigo System (described in Section 3.5)—introduced into the body. 
 
The reason for screen failure will be captured in the screening/enrollment section of the 
database. 
 
3.5 
     Enrollment Procedure 
 
Consecutive patients presenting with acute PE will be screened for this trial. Those who 
do not meet study Entry Criteria will not be enrolled with the reason recorded.  
 

 
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A patient is considered enrolled if the patient informed consent form and HIPAA 
Authorization are signed by either the patient or LAR, and in whom the Indigo System 
has been introduced into their body.   
 
Any patient enrolled into the trial, but in whom the Indigo System is not able to access a 
pulmonary embolus is considered an Intent to Treat patient and will be monitored per 
protocol until the end of required follow-up period of 30 days. Any patient that 
experiences an adverse event after venous puncture but in whom Indigo is not inserted 
will be monitored through discharge for safety. 
 
 
The Indigo Aspiration System usage for this study follows the FDA approved 
Investigational Instructions For Use.  Refer to Warnings, Precautions, and Potential 
Adverse Events in the Investigational Instructions For Use prior to use. 
 
3.5.1 Co-Enrollment Guidelines 
 
Simultaneous participation in other investigational clinical trials is not permitted. 
 
4. Study Treatment  
 
4.1 
  Study Device 
 
For this Study, the Indigo® Aspiration System is intended for the removal of fresh, soft 
emboli and thrombi for the treatment of pulmonary embolism. The Aspiration Catheter, 
Separator™ and Aspiration Tubing are available in multiple configurations. The devices 
are provided sterile, non-pyrogenic, and intended for single use only. Intended users for 
this device are physicians who have received appropriate training in interventional 
techniques. 
 
The Indigo Aspiration System's fundamental mechanism of action is aspiration. 
Aspiration draws the embolus or thrombus into the catheter to remove the embolus or 
thrombus from the body. 
 
The Indigo Aspiration System is comprised of several devices: 
• Indigo Aspiration Catheter (investigational device) 
• Penumbra Aspiration Pump 
• Pump Canister/Tubing 
• Indigo Aspiration Tubing 
• Indigo Separator (investigational device) 
 
The Indigo® Aspiration System is designed to remove thrombus from the vasculature, 
including the pulmonary artery, using continuous aspiration.  The Indigo Aspiration 
Catheter targets aspiration from the pump directly to the thrombus.  The Indigo 
Separator™ may be used to clear the lumen of the Indigo Aspiration Catheter should it 

 
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become blocked with thrombus. The Indigo Aspiration Catheter is introduced through a 
guide catheter or long femoral sheath and guided over a guidewire to the site of the 
primary occlusion. The Indigo Aspiration Catheter is used with the Penumbra Aspiration 
Pump to aspirate thrombus from an occluded vessel.  As needed, an Indigo Separator may 
be deployed from the Indigo Aspiration Catheter to assist with thrombus removal.  The 
Indigo Separator is advanced and retracted through the Indigo Aspiration Catheter at the 
proximal margin of the primary occlusion to facilitate clearing of the thrombus from the 
Indigo Aspiration Catheter tip. For the aspiration source, the Indigo Aspiration Catheter 
is used in conjunction with the Penumbra Pump Max™ which is connected using the 
Indigo Aspiration Tubing and the Indigo Pump/Canister Tubing. The Indigo Aspiration 
Catheter is provided with a rotating hemostasis valve, and a peelable sheath. The Indigo 
Separator is provided with an introducer and torque device. The devices are visible under 
fluoroscopy. 
 
Recently Penumbra introduced larger bore aspiration catheters, which are variable 
stiffness 0.070” and 0.088” single lumen catheters, reinforced by a PTFE lined stainless 
steel shaft and multi-layer polymers. The aspiration catheters employ multiple layers of 
polymers that are laminated on top of the stainless steel shaft to achieve a gradual 
transition in stiffness from the proximal to distal shaft, and are optimized in design for 
kink resistance, minimum ovalization, and flexibility. The distal segment of the aspiration 
catheters employ three or more different polymers with radio-opaque characteristics and 
is hydrophilically coated. The distal segment has also a marker band which is 
encapsulated. The aspiration catheters are available in multiple length offerings in 
configurations and shapes. The aspiration catheters are inserted through a guide catheter 
or sheath.  Once in place, the aspiration catheters provide a conduit to remove the 
thrombus using a compatible Separator™ if required.  
 
5. STUDY PROCEDURE, CLINICAL PROCEDURES, AND LABORATORY 
EVALUATIONS 
 
5.1 
Study Procedure 
 
5.1.1.Sedation and Lytic Use 
The sedation whether general anesthesia, local anesthesia or conscious sedation will be 
determined at the discretion of the Investigative team. The type of sedation and the 
vascular access time will be captured in the Case Report Form (CRF).  
Any use of thrombolytics during the procedure and up to 48-hours post-procedure will be 
considered a protocol deviation and a treatment failure. The administration of 
thrombolytics to treat clinical deterioration will not be considered a protocol deviation.   
5.1.2 Indigo Aspiration Thrombectomy 
 
The physician will access the pulmonary artery via venous puncture and then perform a 
diagnostic pulmonary angiogram and measure pulmonary artery pressures. The physician 

 
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will perform an exchange and place ≥8Fr sheath from access site to the main pulmonary 
artery trunk over a 0.035 inch guidewire to minimize trauma to the heart or induction of 
arrhythmias. The physician will then introduce the Indigo Aspiration Catheter over the 
0.035 inch guidewire and place the aspiration catheter proximal to the thrombus. The 0.035 
inch guidewire will then be removed and the appropriate coordinating separator will be 
advanced through the hemostatic valve with the “throw” set 1-2cm distal to the tip of the 
catheter. The aspiration tubing will be connected to the Y arm of the rotating hemostatic 
valve.  
Next, the physician will gently embed the distal tip of the aspiration catheter into the 
thrombus.  The Penumbra Aspiration Pump will then be switched to “ON” at -20mmHg or 
greater vacuum.  The flow valve on the aspiration tubing will be turned to the ‘ON’ 
position and aspiration will begin. The physician will gently advance and retract the 
Separator to assist with the thrombus removal.  If the clot has been ingested, the pump will 
be switched to “OFF” before disconnecting the Indigo Aspiration Catheter from the 
Aspiration Tubing. If the clot has not been ingested in the canister, the physician will keep 
the pump in the “ON” position and will gently remove the Indigo Aspiration Catheter and 
flush it before doing another aspiration pass. This will be recorded in the corresponding 
CRF. Finally, at the end of the procedure after all treatments have been performed, an 
angiogram will be performed and Pulmonary Artery Pressures will be recorded in the CRF.   
If a Penumbra device malfunction occurs prior and/or during a procedure, it shall be 
reported as a complaint to the Sponsor or delegate immediately. A specific device 
reporting process, as described in Section 6.4, will be followed since the aspiration catheter 
and separator will be considered investigational.  
5.1.3. Adjunctive Treatments  
 
The Sponsor recognizes there may be circumstances for the need to use other techniques to 
aid the Indigo Aspiration Catheter in recanalizing the targeted vessel. 
 
Adjunctive treatments, will be considered as a protocol deviation unless used to treat 
clinical deterioration. These adjunctive treatments will be recorded on the CRF.  
 
Any use of adjunctive treatments for the purpose of reducing clot burden in the pulmonary 
artery (intra-procedure and up to 48 hours post procedure) will be considered a treatment 
failure. 
5.2 
Study Visits (see Table 1) 
 
5.2.1 Baseline Visit 
• Medical history 
• Demographics 
• Vital signs 
• Hematocrit/FiO2/Creatinine/ Platelets/INR/Troponin 
• CTA 

 
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• RV:LV Ratio 
• Concomitant Medications 
• Pregnancy Test 
• Hospital admission date 
 
5.2.2 Procedure (Day Zero) 
• Date of procedure 
• Vital signs 
• Venous puncture for Indigo Procedure 
• Pre procedure Pulmonary Artery Pressure 
• Post procedure Pulmonary Artery Pressure 
• Concomitant Medications 
• Device Used 
• Time of Indigo Insertion 
• Bleeding: Major and Minor 
• Adverse Events 
 
5.2.3 48 Hour Post-Procedure (±6 hr) 
• Vital signs 
• CTA  
• RV:LV Ratio  
• Concomitant Medications 
• Bleeding: Major and Minor 
• Adverse Events 
 
5.2.4 Discharge 
• Vital signs 
• Concomitant Medications 
• Bleeding: Major and Minor 
• Adverse Events 
• Hospital Discharge Date  
 
5.2.5 30 Day Follow-Up (+/-7 days) 
• Vital signs 
• Concomitant Medications 
• PE Recurrence  
• Adverse Events 
• The “Study Completion Form” CRF will be filled in at the end of the study (even if the 
patient is lost to follow-up before the 30-day visit, withdrew consent, or expired). 
 
 
 

 
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Schedule of Assessments 
 
Table 1 below lists the data to be captured at the various time points in the trial. 
a Procedure is defined as day zero 
b 30 day follow up begins from procedure 
c Pregnancy test can be from urine or blood test 
d Pulmonary pressures will be obtained pre and post procedure 
e Concomitant medications include: anticoagulants, vasopressors, thrombolytics used, 
and all other medications given for AEs and SAEs during the study 
  
 
 
 
 
 
 
 
 
 
 
   
Baseline 
Procedurea 
48 hr Post-
Procedure 
+6 hours 
Discharge 
30 Days 
Follow Up 
(± 7 Days)b 
 
Medical history 
 
X 
 
 
 
 
 
 
 
Vital signs 
 
X 
 
X 
 
X 
 
X 
 
X 
Hematocrit/FiO2/ 
Creatinine/ Platelets/ 
INR/Troponin 
X 
 
 
 
 
CTA 
X 
 
X 
 
 
Pulmonary Artery 
Pressure (mmHg) 
 
Xd 
 
 
 
RV:LV Ratio 
X 
 
X 
 
 
Concomitant 
Medicationse 
X 
X 
X 
X 
X 
Device Used 
 
X 
 
 
 
Time of Procedure 
 
X 
 
 
 
Major/Minor Bleeding 
 
X 
X 
X 
 
Pregnancy Testc 
X 
 
 
 
 
Hospital Stay  
X 
 
 
 
 
X 
 
Adverse Events 
 
X 
X 
X 
X 
PE Recurrence 
 
 
 
 
X 

 
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5.3 
Termination of Patient Participation 
 
All patients have the right to terminate their participation at any point during the study. In 
addition, Principal Investigators also have the ability to terminate patient participation in the 
study. Reasons for termination include: completion of study, patient withdrawal, physician-
directed patient withdrawal, lost-to-follow-up, and death. A description of the reason for 
their termination will be documented in the patient’s medical file and in the appropriate 
study Case Report Forms (CRF). 
 
5.4 
Lost to Follow-up 
 
Every attempt must be made to have all patients complete the follow-up visit schedule. A 
patient will be considered lost-to-follow-up when all efforts to obtain compliance are 
unsuccessful. At a minimum, the effort to obtain follow-up information must include 
attempts to make contact via telephone and if contact via phone is not successful, a certified 
letter from the Principal Investigator must be sent to the patient’s last known address. Both 
telephone and letter contact efforts to obtain follow-up must be documented in both the 
patient’s medical records and on the CRFs. 
 
5.5 
Patient Withdrawal 
 
All study patients have the right to withdraw their consent at any time during the study.  
Whenever possible, the site staff should obtain written documentation from the patient that 
wishes to withdraw his/her consent for future follow-up visits and contact. If the site staff is 
unable to obtain written documentation, all information regarding the patient’s withdrawal 
must be recorded in the patient’s medical record. In addition, the appropriate CRFs must be 
completed for the patient and clear documentation of the patient’s withdrawal will be in the 
patient’s source documents. 
 
Withdrawal of a patient from the study can occur at the direction of the Principal 
Investigator or the Sponsor. Reasons for physician-directed patient withdrawal include, but 
are not exclusive to: the patient has enrolled in another study that conflicts with the 
evaluation of the primary endpoints, or if the physician deems it in the best interest for the 
safety or welfare of the patient to withdraw. 
 
6. ADVERSE EVENTS 
 
6.1 
Adverse Event Reporting 
Safety will be assessed by collecting adverse event data on each patient and will be captured 
in the CRFs.  AE reporting begins with the start of the Indigo procedure (venous puncture) 
and continues through 30-day follow-up. 

 
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All adverse events must be recorded on the CRFs and must be carefully monitored during 
the entire study. At each evaluation, the Investigator or designee will determine whether any 
adverse events (AEs) have occurred.  In addition, patients should be instructed to contact the 
Investigator, and/or study coordinator if any significant adverse events occur between study 
evaluation visits.  
Adverse events should be followed up to resolution or stabilization, and if an on-going AE 
changes in severity, a new AE entry for this event should be recorded. If a mild adverse 
event changes to a moderate or severe adverse event, the end date for the mild event and the 
start date for the moderate or severe event should be the same. Additionally, the mild event 
is considered resolved with the initiation of the moderate or severe event. 
Adverse events that are present at the end of a patient’s participation in the study should be 
marked as unresolved at time of study exit on the CRF and the patient should receive post-
treatment follow-up as appropriate and standard of care at the institution. 
Minimum requirements of data to be recorded are: type of event, duration of adverse event 
or adverse device effects (start through end), severity, seriousness, action taken, outcome 
and, if appropriate, causality. 
The Investigator will report any serious adverse event or adverse device effect to the 
Sponsor or its designee as soon as possible from awareness of the event. All serious adverse 
events or serious device effects must be entered into the database on the Serious Adverse 
Events form along with an explanation of any medical treatment administered.  
An adverse event need not be reported as a serious adverse event if it represents only a 
relapse or an expected change or progression of the condition that was the cause of treatment 
without any symptoms and signs other than those present before treatment. This type of 
event only needs to be reported as an adverse event. The IRB must be informed by the 
Investigator about serious adverse events or device effects associated with the use of the 
product, as requested by their local guidelines. 
 
6.2 
Definition of Adverse Events 
Any undesirable clinical event occurring in a patient during a clinical trial, whether or 
not it is considered related to the investigational product (device).  This includes a 
change in a patient's condition or laboratory results that has or could have a deleterious 
effect on the patient's health or well-being. 
For purposes of reporting within this protocol, pre-existing conditions or planned procedures 
for pre-existing conditions do not need to be reported as an adverse event or a SAE in the 
CRF unless there is an increase in severity or frequency during the course of the study. If an 
intervention is planned prior to enrollment and it has been documented in the medical chart 
then this will not be entered as an AE or a serious adverse event (SAE) in the CRF. 
 

 
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6.3 
Definition of Serious Adverse Event (SAE) 
An adverse event is serious if the patient outcome was: 
a) Death 
Report if death was the outcome of an adverse event. The primary cause of death should 
be reported as the adverse event term. 
 
b) Life-threatening 
Report if suspected that the patient was at substantial risk of dying at the time of the 
adverse event, or use or continued use of the device or other medical product might have 
resulted in the death of the patient. 
c) Hospitalization (initial or prolonged) 
Report if admission to the hospital or prolongation of hospitalization was a result of the 
adverse event. Emergency room visits that do not result in admission to the hospital 
should be evaluated for one of the other serious outcomes (e.g., life-threatening; required 
intervention to prevent permanent impairment or damage; other serious medically 
important event). 
d) Disability or Permanent Damage 
Report if the adverse event resulted in a substantial disruption of a person's ability to 
conduct normal life functions, i.e., the adverse event resulted in a significant, persistent 
or permanent change, impairment, damage or disruption in the patient's body 
function/structure, physical activities and/or quality of life. 
e) Required Intervention to Prevent Permanent Impairment or Damage (Devices) 
Report if you believe that medical or surgical intervention was necessary to preclude 
permanent impairment of a body function, or prevent permanent damage to a body 
structure, either situation suspected to be due to the use of a medical product. 
f) Other Serious (Important Medical Events) 
Report when the event does not fit the other outcomes, but the event may jeopardize the 
patient and may require medical or surgical intervention (treatment) to prevent one of 
the other outcomes. Examples include allergic brochospasm (a serious problem with 
breathing) requiring treatment in an emergency room, serious blood dyscrasias (blood 
disorders) or seizures/convulsions that do not result in hospitalization. The development 
of drug dependence or drug abuse would also be examples of important medical events. 
 
6.4 
Device Malfunction 
 
A device malfunction means the failure of a device to meet its performance specifications or 
otherwise perform as intended. Performance specifications include all claims made in the 
labeling for the device. All device malfunctions must be reported to the Sponsor via the 
eCRF. 
If a device malfunction results in an AE for the patient, then the AE must be reported in a 
CRF.  Device malfunctions that do not result in an adverse event for the patient do not need 
to be recorded as an AE, as they are not considered an AE. 

 
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If a device malfunction occurs with the aspiration catheter and/or separator, contact your 
Penumbra Clinical representative for the return process. All other Penumbra non-
investigational device malfunctions should be reported and returned through the Penumbra 
commercial representative. 
 
6.5 
Unanticipated Adverse Device Effect (UADE) 
 
An unanticipated adverse device effect is any serious adverse effect on health or safety or 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan, investigator brochure, or Investigational Instructions For Use. 
Unanticipated adverse device effect also includes any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects. 
 
6.6 
Adverse Event Severity 
 
The Investigator will use the following definitions to rate the severity of each adverse event: 
Mild 
Awareness of a sign or symptom that does not interfere with the patient’s 
usual activity or is transient, resolved without treatment and with no 
sequelae 
Moderate 
 
Interferes with the patient’s usual activity and/or requires symptomatic 
treatment 
Severe 
 
Symptom(s) causing severe discomfort and significant impact of the 
patient’s usual activity and requires treatment 
 
 
6.7 
Relationship to Study Device 
 
The Investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study device: 
Unrelated 
 
The event is definitely not associated with device application. The 
adverse event is due to an underlying or concurrent illness or effect of 
another device or drug. 
Possible 
 
 
The temporal sequence between device application and the event is 
such that the relationship is not unlikely or patient’s condition or 
concomitant therapy could have caused the AE. 
Probable 
 
The temporal sequence is relevant or the event abates upon device 
application completion/removal or the event cannot be reasonably 
explained by the patient’s condition. 
Definite 
 
The temporal sequence is relevant and the event abates upon device 
application completion/removal, or reappearance of the event on repeat 
device application (re-challenge). 

 
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6.8 
Relationship to Study Procedure 
The Investigator will use the following definitions to assess the relationship of the adverse 
event to the study procedure: 
Unrelated 
 
The event is definitely not associated with the study procedure.  The 
adverse event is due to an underlying or concurrent illness or effect of 
another device or drug. 
Possible 
 
 
The temporal sequence between the study procedure and the event is 
such that the relationship is not unlikely or patient’s condition or 
concomitant therapy could have caused the AE. 
Probable 
 
The temporal sequence is relevant or the event abates upon study 
procedure completion or the event cannot be reasonably explained by 
the patient’s condition. 
Definite 
 
The temporal sequence is relevant and the event abates upon study 
procedure completion, or reappearance of the event on repeat 
interventional procedures (re-challenge). 
 
 
6.9 
Risk/Benefit Assessment 
 
The Indigo® Aspiration System is a FDA-cleared device and part of the current standard of care 
for clot removal in peripheral arteries and veins.  
The risks of intra-arterial thrombectomy/embolectomy are similar to those associated with 
existing intra-arterial methods of recanalization. These risks include: 
• allergic reaction and anaphylaxis from 
contrast media 
• acute occlusion  
• air embolism  
• arteriovenous fistula  
• death 
• device malfunction  
• distal embolization  
• emboli  
• false aneurysm formation 
• hematoma or hemorrhage at access site 
• inability to completely remove thrombus  
• infection  
• hemorrhage 
• ischemia  
• kidney damage from contrast media  
• neurological deficits including stroke  
• vessel spasm, thrombosis, dissection, or 
perforation 
• intimal disruption 
• myocardial infarction 
• emergent surgery 
• fibrillation 
• hypotension 
• respiratory failure 
• peripheral embolic events 
 
7. Statistical Considerations 
 
7.1 
Study Endpoints  
 

 
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7.1.1 Primary Endpoints 
• Primary Efficacy Endpoint  
o Change in RV/LV ratio at 48 hours post-procedure. The primary efficacy analysis 
will be the difference between the baseline and the 48-hour RV/LV diameter 
ratio. The two-sided 95% confidence interval for the mean difference will be 
calculated. The Core Laboratory data supersede the investigator-reported data in 
all analyses of RV/LV diameter. 
 
 
• Primary Safety Endpoint 
The primary safety endpoint is 48 hour major adverse events, a composite of: 
▪ Device-related death within 48 hours 
▪ Major bleeding within 48 hours 
▪ Device-related SAEs within 48 hours, a composite of: 
o Clinical deterioration 
o Pulmonary vascular injury 
o Cardiac injury   
Major bleeding, clinical deterioration, pulmonary vascular injury and cardiac injury are 
defined in the Study Definitions of Appendix I.  
 
The data will be analyzed as a binary variable with each patient counted only once. The 
two-sided 95% confidence interval will be provided for the primary safety rate.   
 
7.1.2 Secondary Endpoints 
The secondary safety endpoints will include the following: 
o Device-related death within 48 hours 
o Major bleeding within 48 hours 
o Clinical deterioration within 48 hours 
o Pulmonary vascular injury within 48 hours 
o Cardiac injury within 48 hours 
o Any-cause mortality within 30 days 
o Device-related SAEs within 30 days 
o Symptomatic recurrence of PE at 30 days  
Recurrent pulmonary embolism is defined in the Study Definitions of Appendix I. 
 
The proportion of patients who experience each secondary endpoint will be calculated along 
with the associated 95% confidence interval. 
 
7.2 
Sample Size Justification 
 
Up to 150 patients are to be enrolled in order to provide 100 evaluable patients treated by 
the Indigo® Aspiration System. Assuming a mean change of 0.42 in the RV/LV ratio from 
baseline to 48 hours and a standard deviation of 0.36, the expected lower bound of the two-

 
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sided 95% normal distribution confidence interval around the change for a sample size of 
100 patients is greater than 0.20.  
 
7.3 
Accrual and Follow-up  
 
The trial is anticipated to last 2 years and each patient will be in the trial for 30 days. 
 
7.4 
Statistical Analysis 
 
This is a prospective, multicenter, single arm study designed to evaluate the safety and 
efficacy of the Indigo® Aspiration System for the extraction of clot in patients with acute 
PE. The efficacy analysis will be conducted in the Intent-to-treat and per protocol 
populations and the safety analysis will be conducted in the safety population.  The 
Statistical Analysis Plan (SAP) will provide details to further elaborate statistical methods 
as outlined in the protocol and will describe analysis conventions. The statistical analysis 
plan will be finalized prior to database lock.  
 
All confidence intervals presented will be two-sided.  All statistical tests will be two-
tailed with a significance level of 0.05.  Descriptive statistics will be provided.  This 
includes the number of observations, mean, median, standard deviation, minimum and 
maximum for continuous variables and counts and percentages for discrete variables.   
Results collected at multiple visits will be summarized at each visit for which they are 
collected as described in Table 1 Schedule of Assessments. Summaries for all measures 
will include all observed data for each visit. 
 
7.5 
Analysis of Adverse Events 
 
All adverse events will be summarized by showing the number and percent of patients 
reporting the event.  Events will also be reported by relationship to the procedure or device.  
The CEC data supersede the investigator-reported data in all analyses of adverse events. 
Adverse events judged as probably or definitely related to the Indigo System will be 
analyzed as device-related. 
 
7.6 
Interim Analysis 
 
No interim efficacy analyses are planned for the purpose of stopping the study early. An 
interim analysis for the purpose of sample size re-estimation will be conducted. Sample 
size will not be decreased regardless of the results of this evaluation. 
 
7.7 
Data Management and Security 
 
All study data will be entered into an electronic data capture (EDC) system provided by a 
vendor. Standardized electronic Case Report Forms (eCRFs) will be provided for use at all 
investigational sites. The patients will be identified in the eCRFs with a unique patient 
identifier. Study personnel will have individual login and password to access the clinical 

 
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study information based upon each individual’s roles and responsibilities. The application 
provides hierarchical user permission data entry, viewing, and reporting options. All data 
entry and data update information, including the date and person performing the action, will 
be available via the audit trail, which is part of the EDC system. This application is 
designed to support compliance with the appropriate regulations and guidance for industry.   
 
Data entry will be performed at the investigational sites. Investigators are responsible for 
completion and timely submission of the data to Penumbra, Inc. Every reasonable effort 
should be made to complete data entry within (seven) 7 days of data collection. The EDC 
system requires no on-site software installation or specific hardware to operate. 
Investigators, clinical coordinators, data managers, and Penumbra clinical personnel access 
project information and study data centrally via a Web browser.  
 
Automated data quality checks will display warnings for invalid data. Additionally, manual 
review of data listings will be used to identify data discrepancies or inconsistencies. The 
study site will be queried for clarification concerning eCRF discrepancies or inconsistencies 
identified. If eCRF corrections are necessary they will be made by the Investigator or an 
authorized member of the Investigator's staff that is delegated to CRF/EDC Data Entry. 
Questions or problems with submitted data will be addressed with the Principal Investigator 
via an electronic querying system, or through direct contact. The Investigator will review 
the eCRFs for completeness and accuracy and provide his/her electronic signature and date 
to eCRFs as evidence thereof. Any data items that have been changed will require 
reapplication of the electronic signature. 
 
All hard copy forms and data files will be secured to ensure confidentiality. Investigators 
are required to maintain source documents required by the protocol, including laboratory 
results, patient report forms, supporting medical records, study worksheet, and informed 
consent forms. The source documents will be used during the regular monitoring visits to 
verify information submitted on the eCRFs. 
 
For each enrolled subject, images will be appropriately de-identified, and sent to the 
imaging Core Lab for evaluation. The Core Lab and CEC reviews will also be entered into 
the EDC system. Each reviewer will provide his/her electronic signature and date to reviews 
as evidence thereof. Queries may be issued to the Core Lab or CEC for clarification 
concerning possible EDC discrepancies or inconsistencies. 
 
8. PATIENT CONSIDERATIONS 
 
8.1 
Ethics Review 
 
Investigator will submit this protocol, site-specific informed consent form and HIPAA 
Authorization, and other requested documents for review and approval to a properly 
constituted independent Institutional Review Board (IRB) responsible for oversight of the 
research conducted at the study site. 
 

 
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Subsequent to initial review and approval, the responsible local IRBs will review the 
protocol at least annually and prior to study termination or completion. Annual progress 
reports accompanying the protocol provided for each IRB’s annual review will include the 
total number of participants enrolled in the study, the number of participants who completed 
the study, all changes to research activity, and all unanticipated problems involving risks to 
patients or others. 
 
All protocol amendments must be submitted to and approved by the relevant IRBs prior to 
implementing the amendment. 
 
8.2 
Informed Consent and HIPAA Authorization 
 
It is the responsibility of the Investigator to give each patient full and adequate verbal and 
written information regarding the objective and procedure of the study and the possible risks 
involved and to obtain signed informed consent and authorization for use of the patient’s 
protected health information from all patients prior to enrollment in the study unless the 
patient's health condition does not allow informed consent, in which case the local hospital 
and state procedures will be applied. Such informed consent and authorization will be 
obtained in accordance with US Code of Federal Regulations for Protection of Human 
Subjects (21 CFR 50.25(a,b), CFR 50.27, and CFR Part 56, Subpart A), the Health 
Insurance Portability and Accountability Act (HIPAA), and local regulations. In the event a 
patient is unable to sign the IRB approved informed consent form and the HIPAA 
authorization, a legally authorized representative (LAR) can sign on behalf of the patient. 
The original, signed consent and authorization are retained at the site with the site’s patient 
study records, and a copy is provided to the patient. 
 
8.3   Clinical Trial Termination 
 
Penumbra or the appropriate regulators, such as ethics committees, may decide to interrupt 
or terminate this clinical trial if they believe that this is necessary.  Regulators will be 
informed of the study completion. 
 
8.4   Patient Data Protection 
 
Information about patients will be kept confidential and managed according to the 
requirements of HIPAA. The patients will be identified in the CRFs with a patient number. 
All patient study records will be kept securely at the site to prevent unauthorized disclosure 
of patient information.   
The patient must be informed that the data will be stored and analyzed by computer, that 
local and national regulations for handling of computerized data will be followed, and that 
only the Investigator and the Sponsor or designee will have access to individual patient data. 
Furthermore, the patients should be informed about the possibility of inspection of relevant 
parts of the hospital records by the Sponsor or appropriate regulatory agency. 
 
9. ADMINISTRATIVE CONSIDERATIONS 
 

 
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9.1 
Study Activation 
 
All Investigators must submit the following documentation to be considered approved 
Investigators: 
• Signed and dated recent curriculum vitae  
• Signed Clinical Trial Agreement  
• Complete site qualification process and site initiation 
 
Pending successful submission of all required documents, Penumbra staff will ‘activate’ the 
site to begin study operations. Study implementation may not be initiated until a study 
activation notice is provided to the site. 
 
9.2 
Study Coordination 
 
Study implementation will be directed by this protocol as well as all study related plans. 
The protocol team will monitor closely and communicate with the study site on a regular 
basis regarding: rates of accrual, adherence, follow-up and AE incidences. 
 
9.3 Study Monitoring 
  
On-site and/or centralized monitoring will be performed in accordance with the study 
specific monitoring plan. The Sponsor or its representatives will visit sites to: 
• Verify compliance with human subjects requirements and other research regulations and 
guidelines; 
• Assess adherence to the study protocol;  
• Confirm the quality and accuracy of information collected at the study site and entered 
into the study database. 
Site Investigators will allow the Sponsor or its representatives to inspect study facilities and 
documentation (e.g. informed consent forms, clinical and laboratory records, other source 
documents, Case Report Forms) as well as observe performance of study procedures. 
Investigators also will allow inspection of all study-related documentation by authorized 
representatives of Penumbra, and US and in-country government and regulatory authorities. 
A site visit log will be maintained at the study site to document all visits. 
 
The Investigator must notify the Sponsor promptly of any inspections scheduled by 
regulatory authorities, and promptly forward copies of inspection reports to the Sponsor. 
 
9.4 
Protocol Compliance 
 
The study will be conducted in full compliance with the protocol. The protocol will not be 
amended without prior written approval of the Sponsor.  
 
 
 

 
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9.4.1 Protocol Deviations 
 
A protocol deviation is defined as any change, divergence, or departure from the study 
design or procedures of a research protocol that is under the Investigator’s control and that 
has not been approved by the IRB.   
Principal Investigators and site staff will follow their patients according to this protocol, 
which meet their routine clinical practices. Nevertheless, deviations during the clinical 
evaluation may occur and efforts should be made to limit them. Deviations include but are 
not limited to follow-up visits outside of the routine visit window. 
The Investigator is responsible for promptly reporting protocol deviations to their IRB 
and/or to the Sponsor per IRB policy.   
The Sponsor will determine the effect of the protocol deviation on the scientific soundness 
of the clinical study and patient safety, and determine if additional reports or actions are 
required. Additional action may include site re-training, removal of the devices, and/or site 
termination.   
 
9.5 
Investigator’s Records 
 
The investigator will maintain and store in a secure manner complete, accurate, and current 
study records throughout the study in compliance with HIPAA and applicable GCP 
guidelines. In accordance with U.S. regulations, the Investigator will retain all study records 
for at least two years following the date of marketing approval for the study product for the 
indication in which it was studied. If no marketing application is filed, or if the application 
is not approved, the records must be retained for two years after the FDA is notified that the 
IDE is discontinued.  
 
All study documents should be uploaded to the Electronic Trial Master File (eTMF) section 
of the Veeva system. Veeva will be used as the master repository for all site and Sponsor 
regulatory documents, and all patient source documents with the exception of DICOMs and 
any records not uploaded to the eTMF (perhaps for confidentiality reasons or due to specific 
site discretion, as might be suitable for financial contracts). Sites generally do not need to 
maintain duplicate local files unless otherwise mandated by local institutional requirements. 
 
Study records include administrative documentation – including protocol registration 
documents and all reports and correspondence relating to the study, as well as 
documentation related to each participant screened and/or enrolled in the study – including 
informed consent forms, case report forms, and all other source documentation. 
 
 
 

 
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9.6 
Imaging 
 
Sites will be required to submit images for sponsor, CEC and Core Lab review.  These 
images should be submitted within 7 days of procedure. Sites will be provided with 
instructions for how images should be collected and submitted to the sponsor. If the site is 
unable to provide the images within this timeframe, the appropriate Sponsor contact 
should be notified. Study staff shall ensure that no images contain PHI as defined by the 
Health Insurance Portability and Accountability Act of 1996 (Pub.L. 104–191, 110 Stat. 
1936, enacted August 21, 1996). 
 
9.7 
Device Inventory Requirements 
 
The Investigator shall maintain records pertaining to device inventory.  Devices are labeled 
for clinical investigation and will be managed by the Sponsor as clinical study lots.  
 
The use of each device including device lot number and the date of device use shall be 
captured in the corresponding patient CRFs and study documents. Each component of the 
product opened and/or used during the procedure will be recorded in the CRFs. 
The Investigator will ensure that, for the purpose of this investigation, only trained 
physicians who are Sub-Investigators in this study will use the Indigo® Aspiration System.   
 
9.8 
Publication of Information 
 
The results of this study may be offered for publication. The Investigators and the Sponsor 
shall collaborate in the writing of the study to ensure accuracy. All information not 
previously published concerning the device and research, including patent applications, 
manufacturing processes, basic scientific data, etc., is considered confidential and should 
remain the sole property of Penumbra. The Investigator agrees to use this information only 
in connection with this study and will not use it for other purposes without written 
permission from the Sponsor. 
 
All information and data generated in association with this study will be held in strict 
confidence until the study completion. The Investigator agrees to use this information for 
the sole purpose of completing this study and for no other purpose without written consent 
from Sponsor. 
 
 
 

 
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10. COMMITTEES 
 
10.1 Steering Committee 
 
The Steering Committee (SC) is the main policy and decision-making committee of the 
study and has final responsibility for the scientific conduct. The specific tasks of the SC are: 
• Proper design and conduct of the trial 
• Ethical and professional standards of the trial 
• Ensuring that the results of the clinical trial and the scientific accomplishments are 
arrived at in the most efficient manner possible 
• Publication policy 
 
The SC will be composed of at least one participating Investigator, and 2 experts in the 
disease, and might have representatives from the Sponsor. 
 
10.2 Clinical Events Committee 
 
The Clinical Events Committee (CEC) is made up of independent medical doctors who 
are not participants in the study. The CEC is charged with the development of specific 
criteria used for the categorization of clinical events and clinical endpoints in the study, 
which are based on the protocol. At the onset of the study, the CEC will establish explicit 
rules outlining the minimum amount of data required, and the algorithm followed in order 
to classify a clinical event.  The CEC will meet regularly to review and adjudicate 
appropriate adverse events for causality and attribution. 
 
10.3 Data Safety Monitoring Board  
 
A DSMB will be comprised of 4 members not participating in the trial and will include a 
statistician and physicians specialized in areas such as Interventional Radiology, Vascular 
or Thoracic Surgery, Cardiology or Pulmonary Disease.  The DSMB will exercise review 
of the overall safety of the trial, periodically review all adverse events occurring in the 
trial, and make recommendations to adjustments in the study protocol, should any be 
considered necessary for safety or other related reasons.  Additional details will be 
specified in the DSMB charter. 
 
10.4    Imaging Core Lab 
 
The independent imaging core lab will review images from baseline to 48 hours post 
procedure to determine the change in RV/LV ratio. Penumbra is responsible for tracking 
images received, basic quality review and forwarding applicable results to the CEC.  

 
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APPENDIX I 
Study Abbreviations and Definitions 
 
Acronyms 
Definition 
ADAPT 
A Direct Aspiration First Pass Technique 
AE 
Adverse Event 
APTT 
Activated Partial Thromboplastin Time 
ASA 
Acetylsalicylic Acid (aspirin) 
CDT 
Catheter Directed Therapy 
CEC 
Clinical Events Committee 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CRF 
Case Report Form 
CSA 
Clinical Study Agreement 
COV 
Close Out Visit 
CT Scan 
Computed Tomography Scan 
CTA 
Computed Tomography Angiography 
CTP 
Computed Tomography Perfusion 
DSA 
Digital Subtraction Angiography 
ECMO 
Extracorporeal membrane oxygenation  
EDC 
Electronic Data Capture 
ENT 
Embolization to Uninvolved or New Territories 
FDA 
Food and Drug Administration 
FUP 
Follow-Up 
GCP 
Good Clinical Practices 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IA 
Intra-Arterial 
ICH 
Intracranial Hemorrhage 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
LV 
Left Ventricle 
LVO 
Large Vessel Occlusion 
MI 
Myocardial Infarction 
 
MRA 
Magnetic Resonance Angiography 
MRI 
Magnetic Resonance Imaging 
MR-DWI 
Magnetic Resonance – Diffusion Weighted Imaging 
mRS 
modified Rankin Scale 
NCCT 
Non-contrast CT 
PE 
Pulmonary Embolism 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
RMV 
Routine Monitoring Visit 
rt-PA 
Recombinant Human Tissue Plasminogen Activator 
RV 
Right Ventricle 
SAE 
Serious Adverse Event 
 
SAH 
Subarachnoid Hemorrhage     
SC 
Steering Committee 
SIV 
Site Initiation Visit 
TIA 
Transient Ischemic Attack  

 
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UADE 
Unanticipated Adverse Device Effect 
 
STUDY DEFINITIONS 
 
ADVERSE EVENT  
Any undesirable clinical event occurring in a patient during a clinical trial, whether or not it is 
considered related to the investigational product.  This includes a change in a patient's 
condition or laboratory results that has or could have a deleterious effect on the patient's 
health or well-being. 
 
ADVERSE DEVICE EFFECT  
Any adverse event related to the study device (or treatment). 
 
BLEEDING 
Loss of blood from the vascular system. Bleeding was classified by the GUSTO19 (Global 
Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) 
bleeding criteria:  
• Major bleeding includes GUSTO Severe/life threatening and Moderate categories: 
o GUSTO Severe: 
▪ Intracranial Hemorrhage 
▪ Fatal/life threatening bleeding 
▪ Resulting in substantial hemodynamic compromise requiring 
intervention 
o GUSTO Moderate: 
▪ Requiring blood transfusion but did not result in hemodynamic 
compromise 
• Minor bleeding includes GUSTO Mild bleeding: 
o GUSTO Mild bleeding that does not meet above criteria 
 
CARDIAC INJURY 
The following events are examples of possible cardiac injury: 
• Acute heart failure 
• Acute myocardial infarction 
• Arrhythmia requiring intervention 
• Cardiac hematoma 
• Tricuspid or Pulmonic valve damage 
 
CASE REPORT FORM 
A record of the data and other information on each patient in the study often abbreviated as 
CRF. 
 
CLINICAL DETERIORATION 
Also referred to hemodynamic collapse15 is defined as having one of the following: 
• need for cardiopulmonary resuscitation, intubation, vasopressors, ECMO/ECLS; or 
systolic blood pressure (SBP) <90 mm Hg for at least 15 minutes, or 

 
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• drop of SBP by at least 40 mm Hg for at least 15 minutes with signs of end-organ 
hypoperfusion (cold extremities or low urinary output <30 mL/h or altered mental 
status); or 
• need for catecholamine administration to maintain adequate organ perfusion and a 
SBP >90 mm Hg (including dopamine at the rate of >5 micrograms/kg per minute). 
 
COMPLICATION (ANGIOGRAPHIC OR CLINICAL) 
An undesirable clinical event that results in death, injury, or invasive intervention.  
Complications may include, but are not limited to acute occlusion, air embolism, 
arteriovenous fistula, death, distal embolization, emboli, false aneurysm formation, 
hematoma or hemorrhage at access site, infection, intracranial hemorrhage, ischemia, 
neurological deficits including stroke, vessel spasm, thrombosis, dissection, or perforation.  
Complications may or may not be related to the investigational product(s). 
 
DEEP VEIN THROMBOSIS 
A clot in a vein deep under the skin usually in a leg. 
 
DEVICE MALFUNCTION 
Device malfunction is defined as the failure of a device to meet its performance specifications 
or otherwise perform as intended [21 CFR 803.3(k)]. Performance specifications include all 
claims made in the labeling for the device. 
 
DISSECTION 
Angiographic evidence of a tear in the arterial wall as defined by the occurrence of intramural 
hematoma. 
 
DISTAL EMBOLIZATION 
Migration of a filling defect or thrombus to distally occlude the target vessel or one of its 
branches. 
 
ECMO 
Extracorporeal membrane oxygenation (ECMO), also known as extracorporeal life support 
(ECLS), is a means of providing both cardiac and respiratory support to persons 
whose heart and lungs are unable to provide an adequate amount of gas exchange to sustain 
life. 
 
EMBOLI 
Blood clots or thrombi transported by blood from a distant source. 
 
EMBOLIZATION TO A NEW TERRITORY 

 
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An embolic occlusion of an artery affecting an area not supplied by the target vessel (site of 
primary occlusion). 
HEPARIN-INDUCED THROMBOCYTOPENIA (HIT) 
Decrease in platelet count during or shortly following exposure to heparin. 
 
HYPERTENSION 
Persistently high arterial blood pressure.  Various criteria for its threshold have been 
suggested, ranging from 140mm Hg systolic and 90 mmHg diastolic to as high as 220 mmHg 
systolic and 110 mmHg diastolic. Hypertension may have no known cause or be associated 
with other primary diseases. 
 
HYPOTENSION 
Sustained Hypotension: Systolic blood pressure less than 80 mmHg lasting more than 
30 minutes or requiring intervention (e.g. pacing, intra-aortic balloon pump (IABP), 
intravenous vasopressors to sustain systolic blood pressure). This excludes transient 
hypotension or vagal reactions, which are self-limited or readily reversible. 
 
INTIMAL FLAP 
An extension of the vessel wall into the arterial lumen. 
 
INTRACRANIAL HEMORRHAGE 
Bleeding in the cranium of the brain. 
 
ISCHEMIA 
The deficiency, or a lack of blood flow to an organ resulting in an imbalance between the 
supply and demand of oxygen (or other nutrients) leading to cell damage or death. 
 
LEUKOPENIA 
A leukocyte count of <3.5 x109/liter for more than 3 days. 
 
MAJOR TRAUMA 
Limb or life-threatening injury due to blunt force, penetrating injury or burn injury.20 
 
NEOINTIMAL HYPERPLASIA  
Thickening of the neointima due to intimal cell accumulation. 
 
NEUTROPENIA 
A decrease in the number of neutrophilic leukocytes in blood to <1,000 mm3 
 
OCCLUSION  
The cessation of blood flow in an artery due to the presence of a clot or thrombus. 

 
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OCCLUSION LOCATION 
Location according to specific artery; a standard code will be provided in the CRF to use for 
location descriptions. 
 
PERFORATION 
The piercing or rupturing of a blood vessel; perforations can be detected or observed 
angiographically. 
 
PROCEDURAL SERIOUS ADVERSE EVENTS 
Serious adverse events that occurred within 24 hours of the procedure. 
 
PULMONARY EMBOLISM 
A DVT clot that dislodges from a vein wall and travels to the lungs resulting in complete or 
partial occlusion of blood supply. 
 
LOW-RISK PULMONARY EMBOLISM6 
Acute PE in the absence of markers defining massive or submassive PE. 
 
MASSIVE PULMONARY EMBOLISM6 
Acute PE with presence of one of the following findings: 
• Sustained hypotension (systolic BP <90 mm Hg for 15 min or requiring ionotropic 
support) 
• Pulselessness 
• Sustained heart rate <40 BPM with signs/symptoms consistent with shock 
 
SUBMASSIVE PULMONARY EMBOLISM6 
Acute PE with Systolic BP ≥90 mm Hg and RV dysfunction or myocardial necrosis 
defined by: 
• RV dilation (apical 4-chamber RV diameter divided by LV diameter >0.9) or RV 
systolic dysfunction on echocardiography 
• RV dilation (4-chamber RV diameter divided by LV diameter >0.9) on CT 
• Elevation of BNP (>90 pg/mL), or N-terminal pro-BNP (>500 pg/mL) 
• EKG changes (new complete or incomplete right bundle branch block, 
anteroseptal ST elevation or depression, or anteroseptal T-wave inversion) 
• Elevation of troponin I (>0.4 ng/mL) or troponin T (>0.1 ng/mL) 
 
RECURRENT PULMONARY EMBOLISM 
Symptomatic PE objectively confirmed on contrast-enhanced chest CT, ventilation-
perfusion lung scan, or invasive contrast pulmonary angiography. 
 

 
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PULMONARY VASCULAR INJURY 
Pulmonary vascular injury may include the following events occurring in the pulmonary 
vasculature: 
• Arterial Venous Fistula  
• Dissection 
• Hemorrhage 
• Intimal flap 
• Perforation 
• Rupture 
• Thromboembolic occlusion resulting in permanent damage i.e. infarction 
 
RIGHT VENTRICLE DYSFUNCTION  
Right ventricle dilation (RV to LV ratio >0.9) or wall motion abnormalities (hypokinesis, 
septal wall deviation). 
 
SERIOUS ADVERSE EVENT (SAE) 
An SAE is an AE with a patient outcome that is life-threatening or results in death, 
hospitalization (initial or prolonged), disability or permanent damage, congenital anomaly or a 
birth defect, or intervention required to prevent permanent impairment or damage. An event may 
also be considered serious if it may jeopardize the patient and may require medical or surgical 
intervention (treatment) to prevent one of the other outcomes. 
 
STROKE 
A new focal neurological deficit of presumed vascular origin persisting more than 24 hours 
and with a neuro-imaging study that does not indicate a different etiology.  The 24-hour 
criterion is excluded if the patient undergoes cerebrovascular surgery or dies during the first 
24 hours.  It includes patients presenting with clinical signs and symptoms suggestive of 
subarachnoid hemorrhage, intracerebral hemorrhage, or cerebral infarction.  It does not 
include stroke events in cases of blood disorders such as leukemia, and it excludes patients 
with a history of stroke secondary to trauma. 
 
TARGET OCCLUSION 
The occlusion being treated or attempted to be treated during the index procedure. 
 
TARGET VESSEL 
The vessel containing a target occlusion. 
 
THROMBUS 
Discrete, mobile intraluminal filling with defined borders with or without associated contrast 
staining; these are classified as either absent or present. 
 
THROMBOCYTOPENIA 

 
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A platelet count of <100,000 mm3 
 
TOTAL OCCLUSIONS 
An occlusion with no flow. 
 
TRANSIENT ISCHEMIC ATTACK (TIA) 
Brief episodes of neurological dysfunction resulting from focal cerebral ischemia not associated 
with permanent cerebral infarction. 
 
UNANTICIPATED ADVERSE DEVICE EFFECT (UADE)  
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the investigational plan or Investigational Instructions 
For Use, or any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects. 
 
VASOSPASM 
Spasm of a blood vessel, resulting in decrease in lumen diameter.  When referring to a 
vasospasm, the anatomic location should be specified (e.g. peripheral vasospasm or cerebral 
vasospasm) 
 
 
 
 

 
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Appendix II 
 
Preferred Sheaths 
 
Company 
Sheath Name Valve 
Type/Tuohy 
Length 
FR Size 
Manufacturer 
Part Number 
Compatibility 
Terumo 
Pinnacle® 
Destination® 
with Tuohy 
Tuohy 
45 cm, 
65 cm, 
90 cm 
8FR or 
Larger 
54-84506, 
54-86506, 
54-89006 
Yes 
Cook®   
Flexor® 
Shuttle® 
with Tuohy 
Tuohy 
90 cm 
8FR or 
Larger 
KSAW-8.0-
38-90-RB, 
SHTL-HC 
Yes 
 
 

 
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APPENDIX III 
 
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