CHEETAH: A Prospective, Multicenter Study to Evaluate the Safety and Performance of the CAT RX Aspiration Catheter in Patients With a High Thrombus Burden Acute Coronary Vessel Occlusion
Conditions: Coronary Vessel Occlusion
Sponsor: Penumbra Inc.

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CHEETAH: A Prospective, Multicenter Study to Evaluate the Safety 
and Performance of the CAT RX Aspiration Catheter in Patients with a 
High Thrombus Burden Acute Coronary Vessel Occlusion  
 
Protocol  
CLP-15298.B 
 
Date of Protocol 
06 August 2019 
 
Device Name 
Indigo® Aspiration System with CAT RX Aspiration Catheter &  
Indigo SeparatorTM 4 
 
Sponsor 
Penumbra, Inc. 
One Penumbra Place 
Alameda, CA 94502 
USA 
 
 
 

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TABLE OF CONTENTS 
1. 
Introduction and Rationale .................................................................................................. 7 
1.1 Background Information............................................................................................................... 7 
1.2 Development of Percutaneous Coronary Intervention (PCI) with Aspiration Thrombectomy
 
8 
1.3 Major Clinical Research related to PCI with Aspiration Thrombectomy ............................... 8 
1.4 Study Rationale .............................................................................................................................. 9 
2. 
Device Description .............................................................................................................. 10 
2.1 Indigo CAT RX Aspiration Catheter ......................................................................................... 11 
2.2 Indigo SeparatorTM 4 ................................................................................................................... 11 
2.3 Indigo Aspiration Tubing ............................................................................................................ 12 
2.4 Penumbra Aspiration Pump ....................................................................................................... 12 
2.5 Indigo Pump Canister and Tubing ............................................................................................. 12 
3. 
Risk Analysis ....................................................................................................................... 12 
3.1 Risks Related to PCI and Aspiration Thrombectomy .............................................................. 12 
4. 
Study Overview ................................................................................................................... 13 
4.1 Study Design ................................................................................................................................. 13 
4.2 Study Objectives/Endpoints ........................................................................................................ 14 
4.2.1 
Primary Endpoints .............................................................................................................. 14 
4.2.2 
Secondary Endpoints .......................................................................................................... 14 
5. 
Study Population ................................................................................................................. 14 
5.1 Inclusion Criteria ......................................................................................................................... 14 
5.2 Exclusion Criteria ........................................................................................................................ 15 
6. 
Study Procedures ................................................................................................................ 15 
6.1 Overview of Study Flow .............................................................................................................. 15 
6.2 Study Visits ................................................................................................................................... 17 
6.3 Recruitment .................................................................................................................................. 17 
6.4 Screening & Enrollment .............................................................................................................. 17 
6.5 Informed Consent ........................................................................................................................ 17 
6.6 Baseline ......................................................................................................................................... 18 
6.7 Index Procedure ........................................................................................................................... 18 
6.7.1 
Preparation for Treatment ................................................................................................. 19 
6.7.2 
Medication during Intervention ......................................................................................... 19 
6.7.3 
Devices and Equipment ...................................................................................................... 19 
6.7.4 
Index Procedure .................................................................................................................. 20 
6.7.5 
Post-Procedure .................................................................................................................... 21 
6.7.6 
Discharge (or 7 days, whichever occurs first) ................................................................... 21 
6.7.7 
30 Day Visit (± 7 days) ........................................................................................................ 21 
6.7.8 
180 Day Visit (± 30 days) .................................................................................................... 22 
7. 
Investigator Responsibilities .............................................................................................. 24 
7.1 Institutional Review Board ......................................................................................................... 24 
7.2 Informed Consent ........................................................................................................................ 24 
7.3 Adherence to Protocol/Amendments and Applicable Law ...................................................... 24 
7.4 Case Report Form Completion ................................................................................................... 24 
7.5 Image Upload ............................................................................................................................... 24 
7.6 Reporting ...................................................................................................................................... 25 
7.6.1 
Adverse Events .................................................................................................................... 25 
7.6.2 
Analysis of Adverse Events................................................................................................. 26 
7.6.3 
Relationship to the Study Device ....................................................................................... 26 
7.6.4 
Device Deficiency ................................................................................................................. 26 

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7.6.5 
Protocol Deviation(s) ........................................................................................................... 27 
7.7 Records Retention ........................................................................................................................ 27 
8. 
Sponsor Responsibilities ..................................................................................................... 28 
8.1 Training ........................................................................................................................................ 28 
8.2 Investigator List ........................................................................................................................... 28 
8.3 Adverse Event Reporting ............................................................................................................ 28 
8.4 Data Monitoring ........................................................................................................................... 28 
8.4.1 
Site Qualification Visit ........................................................................................................ 28 
8.4.2 
Site Initiation Visit .............................................................................................................. 28 
8.4.3 
Interim Monitoring Visit(s) ................................................................................................ 29 
8.4.4 
Site Close Out Visit ............................................................................................................. 29 
8.5 Data Management ........................................................................................................................ 29 
9. 
Ethical Requirements ......................................................................................................... 30 
9.1 Declaration of Helsinki ................................................................................................................ 30 
9.2 Informed Consent ........................................................................................................................ 30 
9.3 Subject Data Protection ............................................................................................................... 30 
10. Statistical Procedures ......................................................................................................... 30 
10.1 General Statistical Considerations ............................................................................................. 30 
10.2 Sample Size Estimation for the Primary Outcome ................................................................... 31 
10.3 Control of Systematic Error and Bias ........................................................................................ 31 
10.4 Missing Data and Imputation Methods ..................................................................................... 31 
10.5 Definition of Populations ............................................................................................................. 31 
10.5.1 Screened ............................................................................................................................... 31 
10.5.2 Screen Failure ...................................................................................................................... 31 
10.5.3 Enrolled ................................................................................................................................ 31 
10.5.4 Completed ............................................................................................................................ 31 
10.5.5 Early Termination ............................................................................................................... 32 
10.6 Definition of Analysis Populations ............................................................................................. 32 
10.6.1 Intent to Treat Sample ........................................................................................................ 32 
10.7 Interim Analysis ........................................................................................................................... 32 
10.8 Statistical Analysis of Primary Endpoint................................................................................... 32 
10.9 Secondary Statistical Analysis .................................................................................................... 33 
10.10 Analysis of Adverse Events ..................................................................................................... 33 
10.11 Baseline Characteristics .......................................................................................................... 33 
10.12 Pooling Across Centers ........................................................................................................... 33 
10.13 Final Report ............................................................................................................................. 33 
11. Study Committees and Core Labs ..................................................................................... 33 
11.2 Independent Medical Reviewer .................................................................................................. 33 
11.3 Imaging Core Lab ........................................................................................................................ 34 
12. Study Administration ......................................................................................................... 34 
12.1 Stopping the Study Based on Interim Safety Data .................................................................... 34 
12.2 Clinical Study Termination/Withdrawal ................................................................................... 34 
12.3 Missing Visits ................................................................................................................................ 35 
12.4 Protocol Adherence and Amendments ....................................................................................... 35 
12.5 Study Registration ....................................................................................................................... 35 
13. Publication of Information ................................................................................................. 35 
14. Contact Information ........................................................................................................... 36 
15. References ............................................................................................................................ 37 
16. Appendix I – Definitions ..................................................................................................... 41 
16.1 Adverse Event Definitions ........................................................................................................... 41 

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16.2 Events of Interest ......................................................................................................................... 42 
17. Appendix II - TIMI Thrombus Grade32 ........................................................................... 47 
18. Appendix III - TIMI Flow Grade33 ................................................................................... 48 
19. Appendix IV – Myocardial Blush Grade34 ....................................................................... 49 
20. Appendix V - NYHA Classification, Stages of Heart Failure35 ...................................... 50 
21. Appendix VI - Killip Classification36................................................................................. 51 
22. Appendix VII – Canadian Cardiovascular Society Classification37 ............................... 52 
23. Acronyms ............................................................................................................................. 53 
 
 
 

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1. Introduction and Rationale 
1.1 
Background Information 
Acute coronary syndrome (ACS) represents a significant health and economic burden to 
the United States, accounting for approximately 1.36 million hospitalizations per year.1 
ACS encompasses a spectrum of conditions caused by acute myocardial ischemia and/or 
infarct that is usually due to a reduction in coronary blood flow. Myocardial infarction (MI) 
is a severe sub-category of ACS where the ischemia leads to cardiac tissue damage and 
release of cardiac-specific biomarkers.1 Myocardial damage in MI is typically precipitated 
by atherosclerotic plaque disruption and coronary thrombosis formation, leading to 
reduced or completely eliminated blood flow to the heart.1-3   
 
The overall prevalence of MI in the United States (US) in adults ≥ 20 years old is 3.0%.4  
US males in general have a higher prevalence of MI (3.8%) than females (2.3%).4 MI is 
among the leading cause of morbidity and mortality in the US.5 Additionally, it is one of 
the most expensive, leading to >$12 billion annually in hospitalization costs.4 These costs 
are projected to increase by almost 100% between 2013 and 2030.4 The estimated annual 
incidence of MI is 605,000 new and 200,000 recurrent attacks. The average age at first MI 
is 65.6 years for males, and 72.0 years for females.4 In 2015, MI mortality was 114,023.4 
Of patients >45 years of age who experience a first MI, incidence of recurrent or fatal heart 
disease within 5 years ranges from 17%-20%.5 
 
MI is broken broadly into two categories defined by electrocardiogram (EKG) changes: 
Non-ST Elevation Myocardial Infarction (NSTEMI), and ST-Elevation Myocardial 
Infarction (STEMI). NSTEMI is typically the result of a severely narrowed but not 
completely occluded coronary vessel, while STEMI is typically the result of a completely 
occluded coronary vessel. Roughly two-thirds of MI patients present with NSTEMI and 
the rest present with STEMI.1 
 
Rapid myocardial perfusion is a main treatment goal in MI.2,6 First introduced in the 1970s, 
percutaneous coronary intervention (PCI) has evolved to be one of the main treatment 
modalities for MI.1,6-9 In PCI, a guidewire is advanced via arterial access across the stenosis 
or occlusion site and remains in place until the end of the procedure.10 A balloon is then 
passed over the guidewire to the stenosis site, the balloon is then inflated and deflated 
repeatedly until target artery patency is sufficient. After the balloon is removed, a stent is 
commonly deployed at the stenosis site to maintain long-term artery patency.10 Roughly 
60% of ACS patients will receive PCI while the remainder will undergo either open 
surgical coronary artery bypass grafting (CABG) or medical therapy alone.9 The American 
Heart Association’s guidelines for NSTEMI and STEMI management include 
recommendations for utilization of PCI as part of the treatment strategy because the 
benefits of PCI greatly outweigh the risks, and these benefits have been well established 
by multiple clinical trials and meta-analyses.7,8,11 
 
 

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1.2 
Development of Percutaneous Coronary Intervention (PCI) with Aspiration 
Thrombectomy  
Despite its success, a major limitation of PCI alone is microvascular obstruction 
downstream of the infarct-related vessel.12  In PCI alone, a balloon  simply compacts 
atherothrombotic material against the vessel wall and does not remove it, creating an 
opportunity for the atherothrombotic material to embolize.12,13 Increased microvascular 
obstruction is associated with an increased infarct size, reduced recovery of ventricular 
function, and increased mortality.12 Measures of microvascular tissue reperfusion, such as 
degree of ST-segment resolution, or angiographic myocardial blush grade (MBG), have 
been shown to predict the rate of death after PCI.14 
 
PCI with aspiration thrombectomy has been gaining increased attention as a way to prevent 
or reduce embolization of atherothrombotic debris caused by PCI.8 A large meta-analysis 
of randomized controlled trials (30 studies, 6415 patients) investigating the use of 
adjunctive devices with PCI compared to PCI alone found that out of the adjunctive 
therapies studied (aspiration thrombectomy, mechanical thrombectomy, embolic 
protection devices), only aspiration was beneficial for reducing mortality, while the others 
either increased mortality or had a neutral effect.15   
 
To use aspiration with PCI, the aspiration catheter is navigated to the occlusion site using 
the same guidewire that is used during conventional PCI. Aspiration is applied while the 
aspiration catheter is advanced across the target coronary segment to remove 
atherothrombotic material. Once the aspiration is complete, the catheter is removed, and 
PCI is performed as per routine protocol.12 
 
1.3 
Major Clinical Research related to PCI with Aspiration Thrombectomy  
The TAPAS trial was a prospective randomized trial of 1071 consecutive PCI-eligible 
STEMI patients who were treated with either conventional PCI or with manual aspiration 
thrombectomy prior to PCI.12 Atherothrombotic material was retrieved in 73% of patients 
in the aspiration group. Aspiration did not result in a higher rate of intra-procedural 
complications, none of the complications were thought to be related to the aspiration 
device, and there were no intraprocedural deaths or strokes.12 Aspiration prior to PCI 
resulted in clear improvements in MBG, resolution of ST-segment elevation, and residual 
ST-segment deviation. The primary endpoint of MBG 0-1 occurred in only 17.1% of 
patients in the aspiration group compared with 26.3% in the conventional PCI group (p < 
0.001). These benefits of aspiration were consistently present irrespective of baseline 
clinical or angiographic characteristics.12 At 1-year follow-up, the aspiration group had 
significantly lower rates of cardiac death (3.6% vs 6.7%; HR 1.93; 95% CI 1.11-3.37; p = 
0.020).16 These results suggest that manual aspiration prior to PCI does not impact 
procedural safety, and reduces morbidity and mortality as compared with conventional PCI 
alone. 
 
Similarly, the EXPIRA trial randomized 175 consecutive PCI-eligible STEMI patients to 
either conventional PCI or manual aspiration thrombectomy prior to PCI.17 The primary 
endpoints were MBG ≥ 2 and rate of ST-segment resolution. Aspiration resulted in 

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significantly higher rates of MBG ≥2 (88% vs 60%, p = 0.001), ST-segment resolution 
(64% vs 39%, p = 0.001), and reduced incidence of cardiac death at 9-month follow-up 
(0% vs 4.6%, p = 0.02). A sub-analysis of 75 patients using contrast enhanced MRI found 
that the aspiration group had less microvascular obstruction in the acute phase and had 
significantly reduced infarct sizes at 3 months follow-up. At 2-year follow-up, the 
aspiration group showed significant reductions in Major Adverse Cardiac Events (MACE; 
4.5% vs 13.7%, p = 0.038), and cardiac death (0% vs 6.8%, p = 0.012).18 These results 
suggest that manual aspiration prior to routine PCI in STEMI patients prevents thrombus 
embolization, preserves microvascular integrity, and reduces long term risk of cardiac 
death and MACE. 
 
The TASTE trial was a large registry-based trial of 7,244 PCI-eligible STEMI patients who 
were randomized to either manual aspiration thrombectomy followed by PCI, or to 
conventional PCI.19 This study did not record findings with respect to myocardial salvage 
or microvascular obstruction. With respect to safety outcomes, the aspiration group did not 
have increased rates of stroke or neurologic complications, perforation or tamponade, heart 
failure, or left ventricular dysfunction. The primary endpoint, all-cause mortality at 30 
days, was not significantly different between the groups (2.8% with aspiration vs 3.0% 
with PCI-only, p = 0.63). At 1-year follow-up, both groups had similar rates of all cause 
mortality, and rehospitalization for MI.20 The TASTE trial results suggest that manual 
aspiration did not impact key safety outcomes, but also did not provide additional benefit 
over PCI.  
 
The TOTAL trial randomized 10,732 PCI-eligible STEMI patients to manual aspiration 
prior to PCI or PCI-only.14 This study showed significant improvements in ST segment 
resolution and distal embolization with aspiration. But, there was no significant difference 
with respect to the primary outcome (composite of cardiovascular death, recurrent MI, 
cardiogenic shock, or NYHA class IV heart failure) both at 180 days (6.9% with aspiration 
vs 7.0% with PCI-only, p = 0.86) and at 1-year follow-up (8% vs 8%, p = 0.99).21 Subgroup 
analysis for patients with higher thrombus burden or patients with initial TIMI flow grade 
0-1 also revealed no significant differences. Additionally, there was a small but statistically 
significant increase in the rate of stroke within 30 days in the manual aspiration group 
(0.7% vs 0.3%, p = 0.02).14  
 
The TATORT-NSTEMI study is currently the only large randomized study that 
investigated the use of manual aspiration thrombectomy in NSTEMI. Four hundred forty 
(440) PCI-eligible NSTEMI patients were randomized to either aspiration prior to PCI or 
to conventional PCI. The primary endpoint of microvascular obstruction was not different 
between the aspiration group and the PCI-only group (2.0% vs 1.4%, p = 0.17). No 
difference was found between the groups with respect to infarct size, myocardial salvage 
index, MBG, TIMI flow grade, MACE at 1-year, functional outcome at 1-year, or quality 
of life at 1-year.13,22 
 
1.4 
Study Rationale  
Current clinical evidence suggests that manual aspiration thrombectomy is capable of 
removing atherothrombotic material from target MI lesions. However, the utility of using 

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aspiration for all PCI-eligible MI patients is mixed. Some studies have found reduction in 
mortality in patients treated with aspiration prior to PCI,12,17 others have found neutral 
mortality benefit.13,14,19 These variable results may be due to a variety of factors including 
study design (follow-up time period, time to reperfusion, number of centers included), 
technological limitations of manual aspiration catheters,  or inclusion of all patients 
regardless of clot burden. Additionally, most prior studies utilized manual aspiration 
thrombectomy with small volume (e.g. 30-cc) syringes. Compared with power aspiration, 
manual aspiration suffers from decreased aspiration force as the syringe fills with fluid and 
requires the operator to exchange syringes. Power aspiration thrombectomy using a 
continuous aspiration source is an established technique and is commonly used in 
neurovascular clinical practice for endovascular thrombus removal in acute ischemic stroke 
patients.23-27 
 
The role of aspiration in select cardiac populations, particularly those with high thrombus 
burden, is still under active debate.28 By removing thrombus during primary PCI, aspiration 
thrombectomy may prevent distal embolization, prevent microvascular dysfunction and 
improve prognosis in patients with acute coronary vessel occlusion. By studying a cohort 
of subjects with high thrombus burden (TIMI thrombus grade 4 or 5) and treating frontline 
with the Indigo® Aspiration System that utilizes a dedicated power source capable of 
delivering continuous aspiration, the CHEETAH study aims to evaluate initial safety and 
collect performance data on Penumbra’s Indigo® Aspiration System with the CAT RX 
Aspiration Catheter, when used as an adjunctive device prior to standard of care PCI. The 
results of this study can be used for the planning of future aspiration thrombectomy studies.  
2. Device Description  
General Description/Overview 
The Indigo® Aspiration System is comprised of several devices: 
• Indigo CAT RX Aspiration Catheter 
• Indigo SeparatorTM 4 
• Indigo Aspiration Tubing 
• Indigo Pump Canister/Tubing 
• Penumbra Aspiration Pump 
 
The Indigo® Aspiration System is designed to remove thrombus from the vasculature using 
continuous aspiration. The Indigo CAT RX Aspiration Catheter (Aspiration Catheter) is a 
dual lumen rapid exchange catheter that targets aspiration from the Pump directly to the 
thrombus, removing it via the Indigo Aspiration Tubing and depositing it in the Pump 
Canister. The Indigo SeparatorTM 4 (Separator) may be used, if needed, to clear to lumen of 
the Aspiration Catheter should it become blocked with thrombus. The Aspiration Catheter is 
introduced through a guide catheter or guiding sheath, over a guidewire, and advanced to the 
target occlusion site in the coronary vasculature. The Aspiration Catheter is used with the 
Penumbra Aspiration Pump (Pump) to aspirate thrombus from the occluded vessel. If 
utilized, the Separator is advanced and retracted through the Aspiration Catheter at the 
proximal margin of the primary occlusion to facilitate clearing of the thrombus from the 
Aspiration Catheter tip. For the aspiration source, the Aspiration Catheter is used in 

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conjunction with the Pump, which is connected using the Aspiration Tubing and the Pump 
Canister/Tubing. The Aspiration Catheter may be provided with a rotating hemostasis valve 
and a peelable sheath. The Separator is provided with an introducer and torque device. The 
Aspiration Catheters and Separators are both visible under fluoroscopy. 
 
Figure 1: Assembled Indigo® Aspiration System with Indigo SeparatorTM 4 
 
 
Further detailed description of all the devices listed in this protocol can be found within their 
respective Instructions For Use (IFU).  
 
2.1 
Indigo CAT RX Aspiration Catheter 
As part of the Indigo® Aspiration System, the Indigo CAT RX Aspiration Catheter is 
indicated for removal of fresh, soft emboli and thrombi from vessels in the coronary and 
peripheral vasculature. The Indigo CAT RX Aspiration Catheter received US Food and 
Drug Administration (FDA) 510(k) clearance in May 2017 under K163618 and is currently 
available in the United States.  
 
The Aspiration Catheter is a dual lumen, rapid exchange, intravascular catheter. It is 
designed and composed of materials common to interventional devices. The distal lumen 
is polytetrafluoroethylene (PTFE) lined and the shaft is reinforced with both a nitinol round 
wire and a laser cut stainless steel hypotube. The shaft has variable stiffness with 
progressively softer polymer extrusion materials moving distally along its length. The 
distal portion of the shaft is hydrophilically coated for lubricity. The distal tip has a 
radiopaque platinum/iridium markerband. The Aspiration Catheter is provided sterile for 
single use and may be packaged in a kit with the Aspiration Tubing. The kit also contains 
a rotating hemostasis valve (RHV) and an introducer sheath.   
 
2.2 
Indigo SeparatorTM 4 
As part of the Indigo® Aspiration System, the Indigo SeparatorTM 4 is indicated for removal 
of fresh, soft emboli and thrombi from vessels in the coronary and peripheral vasculature. 
The Separator is size-matched to the Aspiration Catheter and may be used as needed to 
clear thrombus from the lumen of the Aspiration Catheter during aspiration. The Separator 
consists of a stainless steel core wire of variable diameter and variable lengths, a soft tip, 
and a cone formed from Pebax® with a variable outer diameter (OD) matched to fit the 
inner diameter (ID) of the Aspiration Catheter. The Separator may be used, if needed, to 
clear the lumen of the Aspiration Catheter should it become blocked by thrombus. The 
Separator is provided sterile with a torque device and introducer sheath. 
 

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2.3 
Indigo Aspiration Tubing 
The Aspiration Tubing is indicated to connect the Aspiration Catheter to the Penumbra 
Aspiration Pump. The Aspiration Tubing has a flow valve which connects directly to the 
Aspiration Catheter hub or RHV and allows the physician to start and stop the flow of 
aspiration.  
 
2.4 
Penumbra Aspiration Pump 
The Penumbra Aspiration Pump is indicated as the aspiration source for the Indigo 
Aspiration System (Penumbra, Inc., Alameda, CA, USA) for the removal of emboli and 
thrombi from vessels of the peripheral arterial, venous and coronary vasculature to aid the 
physician in the removal of tissue and/or fluid during image guided neurosurgery.  
 
The Pump (Pump MAX or Penumbra ENGINE Pump) is an electromechanical device 
designed to generate negative vacuum pressure as a component of the Penumbra Aspiration 
Systems. Intended users are physicians who have received appropriate training in surgical 
procedures and/or interventional techniques for patients who require suction therapy during 
surgical procedures and/or procedures using interventional techniques. The Penumbra 
Aspiration Pump is intended for use in operating rooms or interventional catheterizations 
laboratories and does not come into contact with the patient.   
 
2.5 
Indigo Pump Canister and Tubing 
A 1000 ml minimum canister with a stemmed lid is designed for use with the Pump. Each 
canister has a stop-flow filter to prevent excess fluid from entering the Pump Canister 
Tubing. The patient port on the lid is sized to accept the Suction Connector on the 
Aspiration Tubing. Graduations are placed on the canister in 50-ml and 100-ml increments. 
The canister lid is removable. 
 
For the Pump MAX, Pump Canister Tubing is used to connect the Pump to the Pump 
Canister. This tubing has an inline filter to prevent fluid and contaminants from entering 
the pump. The tubing lumen remains open under full vacuum. The Penumbra ENGINE 
Pump does not require this additional tubing. The Suction Connector is securely attached 
to the Pump Canister lid and Pump via press fit.  
 
3.  Risk Analysis 
A thorough risk analysis was performed as part of design control requirements of the Quality 
System Regulation (21 CFR 820). 
3.1 
Risks Related to PCI and Aspiration Thrombectomy 
It is anticipated that the treatment risks associated with the angiographic procedure and any 
intra-arterial catheterization with the Indigo® Aspiration System devices as part of a PCI 
procedure are the same as other cleared/approved aspiration catheters based on the same 
indication, device size, and device profile. In terms of the clinical risk, adverse events that 
may be associated with the use of the Indigo® Aspiration System or with interventional 
procedures include, but may not be limited to: 

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• 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 thromboembolic 
events
 
Considerable testing has been completed to ensure that the Indigo® Aspiration System does 
not pose a significant risk. Safety of the Indigo® Aspiration System has been demonstrated 
through extensive pre-clinical testing in both bench-top and in vivo models. Critical design 
characteristics were evaluated to ensure that system components can withstand the rigor of 
clinical use. A thorough risk analysis was performed as part of design control 
recommendations of the Quality System Regulation (21 CFR 820). Risk management 
activities performed in accordance with BS EN ISO 14971:2012 did not identify any 
different risks or risk levels compared to other currently marketed devices.  
 
A list of all anticipated adverse events is in the IFU for each device. 
 
4. Study Overview 
The primary aim of mechanical aspiration thrombectomy using the Indigo® Aspiration 
System with the CAT RX Aspiration Catheter is to safely achieve removal of clot burden to 
improve coronary flow and myocardial perfusion in conjunction with PCI. Past studies have 
focused on manual aspiration techniques, currently no prospective study exists to evaluate 
mechanical aspiration thrombectomy using the Indigo® Aspiration System with the CAT RX 
Aspiration Catheter. The purpose of this study is to evaluate the safety and collect 
performance data on mechanical aspiration thrombectomy using the Indigo® Aspiration 
System with the CAT RX Aspiration Catheter as a frontline treatment prior to standard of 
care PCI, in patients presenting with high thrombus burden acute coronary vessel occlusion.  
4.1 
Study Design 
This is a post-market, real world, prospective, multicenter study evaluating the use of the 
Indigo® Aspiration System with the CAT RX Aspiration Catheter (and Indigo SeparatorTM 
4, if needed) as a frontline adjunctive treatment to standard of care PCI. Patients will be 
enrolled who meet the inclusion and none of the exclusion criteria, who (or Legally 

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Authorized Representative (LAR)) consent to participate, and in whom the study device 
has been inserted. 
4.2 
Study Objectives/Endpoints 
4.2.1 Primary Endpoints 
Composite of cardiovascular (CV) death, recurrent MI, cardiogenic shock, or new 
or worsening NYHA Class IV heart failure within 30 days. 
4.2.2 Secondary Endpoints 
Performance: 
1. Final TIMI Flow Grade 
2. Final TIMI Thrombus Grade 
3. Myocardial Blush Grade 
4. Distal Embolization Rate 
5. Stent thrombosis at 180 days 
 
Safety: 
1. Stroke within 30 days  
2. Major bleeding within 30 days 
3. All-cause mortality within 180 days 
4. Cardiovascular (CV) death within 180 days 
5. Recurrent MI within 180 days 
6. Cardiogenic shock within 180 days 
7. Class IV heart failure within 180 days  
8. Incidence of device related SAE(s) 
 
5. Study Population 
5.1 
Inclusion Criteria 
1. Patient age ≥ 18 years 
2. Patient presents to treating facility within 12 hours of symptom onset  
3. High thrombus burden at coronary angiography, defined as TIMI thrombus grade 4 or 
5 by physician visual estimate after the guidewire crosses the target lesion 
4. Frontline treatment with the Indigo® Aspiration System using the CAT RX 
Aspiration Catheter, prior to standard of care PCI 
5. Target lesion is located in a native coronary artery 
6. Informed consent is obtained from either patient or legally authorized representative 
(LAR) 
 
 

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5.2 
Exclusion Criteria 
1. New onset of stroke symptoms and NIHSS > 2, prior to index procedure 
2. Treatment with fibrinolytic therapy for index coronary vessel occlusion 
3. Life expectancy less than 6 months due to any comorbidities 
4. Patient is unwilling or unable to comply with protocol follow up schedule and/or 
based on the Investigator’s judgement the patient is not a good study candidate 
5. Participation in another investigational drug or device study that may confound the 
results of this study. Studies requiring extended follow-up for products that were 
investigational but have since become commercially available are not considered 
investigational studies 
6. Patient is pregnant 
 
6. Study Procedures 
6.1 
Overview of Study Flow 
To ensure that subjects are considered for enrollment, acute coronary vessel occlusion 
patients referred for SOC PCI should be assessed for eligibility. All sites will keep a screen 
failure log of all potential study candidates who are screened and not enrolled or screened, 
consented, and not enrolled. Reason(s) for exclusion will be recorded. Screening 
information will be reported in Electronic Data Capture system (EDC).  
Recruitment rates will be tracked over time for each site. The actual recruitment rates will 
be useful for planning further clinical studies and determining the widespread impact of 
the therapy. 
 
 

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Figure 2: Study Flow 
 
 
 
 

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6.2 
Study Visits 
Subjects enrolled in this study will follow the visit schedule below.  
1. Baseline/Pre-Procedure 
2. Procedure (Day 0) 
3. Post Procedure 
4. Discharge or 7 days, whichever occurs first 
5. 30 days ± 7 days 
6. 180 days ± 30 days 
6.3 
Recruitment 
The target population are subjects ≥18 years of age who are presenting with an acute 
coronary vessel occlusion and who are referred for SOC PCI. No study specific screening 
tests or procedures are required for enrollment in the study. Standard of care evaluations 
will be used to confirm eligibility.  
Potential study participants and/or their legal authorized representative (LAR) will be 
identified by the study team at each site to obtain consent and determine eligibility. The 
study allows for enrollment of up to 400 subjects at up to 25 sites in the United States. 
6.4 
Screening & Enrollment 
Enrollment process: 
1. 
Confirm that the subject meets all inclusion and no exclusion criteria. 
2. 
Obtain informed consent from the patient or LAR. 
3. 
A subject will be considered enrolled when all eligibility criteria are met, 
the subject or LAR has given informed consent and the Indigo CAT RX 
Aspiration Catheter has been inserted into the subject’s body. Subjects who 
have had a procedure (using the Indigo® Aspiration System with the CAT 
RX Aspiration Catheter as a frontline adjunctive to PCI) prior to signing 
informed consent may be consented up to 2 calendar days post-procedure, 
but prior to initial discharge, and enrolled into the study. 
a. The point of enrollment is defined as the date of informed consent 
or introduction of the CAT RX Aspiration Catheter, whichever 
occurs later.  
b. All follow-up visits will be conducted based on date of procedure, 
regardless of enrollment date. 
6.5 
Informed Consent 
The Investigator or designee will obtain written informed consent from the subject or 
approved delegate using the current Institutional Review Board (IRB) approved consent 
form per IRB policy.  

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All informed consent documents used under this protocol will be consistent with applicable 
elements of I.S. EN ISO 14155:2011, Clinical investigation of medical devices for human 
subjects – Good Clinical Practice (GCP) and 21 CFR 50, Protection of Human Subjects, 
and will be approved by the site’s reviewing IRB prior to study initiation.  
Any modification to the sample informed consent form made by the study site must be 
approved by the Sponsor and the IRB before use. Each study site will provide the Sponsor 
with a copy of the IRB approved consent forms. Informed consent completion will be 
monitored regularly by the Sponsor.  
 
6.6 
Baseline  
The following baseline assessments will be performed: 
1. Demographics 
2. NYHA Classification 
3. Killip Classification 
4. Canadian Cardiovascular Society (CCS) Classification 
5. Vital Signs  
6. General and cardiac medical history 
7. Cardiac concomitant medications 
8. Laboratory assessments (most recent results obtained within 30 days prior to 
index procedure are permitted as baseline data) 
a. Troponins, BNP, WBC, RBC, Hgb, Hct, Platelets, Ca, CO2, Creatinine, 
Glucose, K, Na, BUN 
b. Additional SOC labs may be collected, if available 
9. Pregnancy test (only required for women of child bearing potential, serum or 
urine acceptable) 
10. 12 lead electrocardiogram (ECG)  
11. Echocardiogram (if completed per standard of care, most recent results within 
30 days prior to index procedure) 
6.7 
Index Procedure  
The treatment procedure is described below and will involve acute coronary vessel 
occlusion patients that meet standard of care guidelines for treatment with PCI. The 
procedure will occur after completion of baseline assessments and pre-procedural imaging. 
The Indigo® Aspiration System with the CAT RX Aspiration Catheter must be used as a 
frontline treatment per IFU, prior to PCI.  
At a minimum the following information will be collected during Index Procedure: 
1. Coronary cineangiography at the following timepoints: 
a. Initial (pre-procedure) 
b. After crossing target lesion with guidewire 
c. After Indigo CAT RX Aspiration is complete 

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d. After PCI is complete (if additional treatment is not completed after 
PCI, additional images are not required and after PCI images can be 
considered final) 
e. Final (after all treatment is complete)  
2. TIMI Flow Grade 
3. TIMI Thrombus Grade (coronary angiogram after crossing the target lesion 
with the guidewire should demonstrate TIMI thrombus grade 4 or 5 for patient 
inclusion into the study) 
4. Myocardial Blush Grade  
5. Target lesion characteristics 
6. Procedural details, including key procedural timepoints 
7. Adjunctive procedure(s) 
8. Cardiac concomitant medications 
9. Events of interest/Serious Adverse Events 
10. Device Deficiencies/Observations 
6.7.1 Preparation for Treatment  
All physicians will follow routine site practice guidelines to determine patient 
eligibility for PCI treatment. 
6.7.2 Medication during Intervention  
The study recommends the use of optimal medical therapy for patients undergoing 
PCI per site routine standard of care guidelines. These agents include, but may not 
be limited to, aspirin, beta blockers, ACE inhibitors, glycoprotein IIb/IIIa, 
vasodilators, calcium channel blockers, statins, anti-coagulants, and anti-platelet 
agents. 
6.7.3 Devices and Equipment  
The following devices/equipment will be used (as described below) in addition to 
the typical devices used in PCI per site routine standard of care.  
 
Please refer to the device descriptions in Section 2 for complete details. 

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saline to clear blockage. The flow switch should not be turned off until the 
Aspiration Catheter has exited the guide sheath/catheter and the body after 
performing thrombectomy.  
If the Aspiration Catheter does not cross the target lesion, optional pre-dilatation 
may be performed with a small diameter balloon catheter (≤ 2.00 mm diameter) and 
then aspiration can be re-attempted. The Separator may be used at physician 
discretion to clear the lumen of the catheter. 
A minimum 6 Fr, 0.070” (1.78mm) ID guide catheter and 0.014” (0.36mm) 
guidewire should be used with the Aspiration Catheter. The distal OD of the 
Aspiration Catheter is 0.069” (1.75mm). 
 
After aspiration thrombectomy, PCI should be performed per routine site standard 
of care. 
 
6.7.5 Post-Procedure  
Subjects enrolled in the study should receive the SOC post-procedural care for 
patients who have undergone PCI. 
The following information will be collected post-procedure: 
1. Vital Signs 
2. Laboratory assessments 
3. 12 lead ECG 
4. Echocardiogram (if completed as SOC) 
5. Cardiac concomitant medications 
6. Events of interest/Serious Adverse Events 
6.7.6 Discharge (or 7 days, whichever occurs first) 
The following information will be collected during discharge (within 1 day prior 
to discharge or at day 7, whichever occurs first): 
1. Vital Signs 
2. Laboratory assessments 
3. 12 lead ECG 
4. Killip Classification 
5. CCS Classification 
6. Cardiac concomitant medications 
7. Events of interest/Serious Adverse Events  
6.7.7 30 Day Visit (± 7 days) 
The 30-day follow up visit may be conducted either over the phone or in person. 
Records within the study visit window from an outside Institution may be used to 
complete the visit. It is recommended that at a minimum, study patients are 

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contacted via phone by the study site team. The following information will be 
collected during the 30-day follow up visit: 
 
1. Subject status 
2. NYHA Classification 
3. Killip Classification (if visit completed in person) 
4. CCS Classification 
5. Cardiac concomitant medications 
6. Events of interest/Serious Adverse Events  
 
6.7.8 180 Day Visit (± 30 days) 
The 180-day follow up may be completed over the phone or in person. Records 
within the study visit window from an outside Institution may be used to complete 
the visit. It is recommended that at a minimum, study patients are contacted via 
phone by the study site team. The following information will be collected during 
the 180-day follow up visit: 
1. Subject Status 
2. Vital Signs  
3. NYHA Classification 
4. Killip Classification (if visit is completed in person) 
5. CCS Classification 
6. 12 Lead ECG 
7. Echocardiogram (if completed as SOC – assessment can occur anytime 
between the 30 day and 180 day follow up windows) 
8. Cardiac concomitant medications 
9. Events of interest/Serious Adverse Events 

 
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7. Investigator Responsibilities 
7.1 
Institutional Review Board  
Prior to enrolling patients into the study, the Investigator will ensure that proper 
Institutional Review Board (IRB) approval is obtained in accordance with applicable local 
state and federal laws and regulations. The IRB shall approve all study documents as 
appropriate, including but not limited to the final protocol, amendments to the protocol, 
subject facing material and the informed consent form. 
The Investigator will report to the Sponsor or Sponsor’s designee immediately if the 
approval to conduct the investigation is withdrawn by the IRB. The report will include a 
complete description of the reason(s) for which approval was withdrawn. 
7.2 
Informed Consent 
The Investigator is responsible for ensuring that completed informed consent is obtained 
in accordance with Section 6.5 of this protocol and according to country and local 
requirements prior to conducting any study-related assessments and prior to enrollment of 
patients in the study. 
7.3 
Adherence to Protocol/Amendments and Applicable Law 
The Investigator is responsible for overseeing, ensuring that the study is conducted, and 
completing the study according to this protocol and in accordance with the relevant aspects 
of I.S. EN ISO 14155:2011, Declaration of Helsinki, along with any conditions imposed 
by the reviewing IRB and all other applicable regulations. The Investigator shall approve 
and adhere to this protocol and any amendments that arise during the course of the study. 
It is the Investigator’s responsibility to ensure that the Institution’s staff assisting with the 
study have the appropriate qualifications, are fully instructed on the study procedures, and 
will respect study confidentiality.  
7.4 
Case Report Form Completion 
The Investigator and study staff shall complete the case report forms (CRFs) associated 
with this study. Subject numbers shall be used to identify individual participants in this 
study. The CRFs should be a complete and accurate record of subject data collected during 
the study according to relevant aspects of I.S. EN ISO 14155, 21 CFR 11, Electronic 
Records; Electronic Signatures and GCP requirements. It is the Investigator's responsibility 
to ensure the quality of the data collected and recorded is appropriate and collected in 
accordance with GCP and all applicable regulations. Data entry will be performed by the 
investigational site(s). Investigators are responsible for completion and timely submission 
of data to Penumbra, Inc. Every reasonable effort should be made to complete data entry 
within 5 (five) business days of data collection.  
7.5 
Image Upload  
Coronary cineangiography will be uploaded to an image management system for Core Lab 
review. Echocardiogram images and additional images associated with adverse events may 

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be uploaded, if collected as SOC. Required study images should be uploaded within 5 (five) 
business days. Instructions for image collection and upload can be found in the Imaging 
Manual. 
Study staff shall ensure that no images contain any personally identifying information 
about the subject or study site (e.g. Physician name, Institution name, patient name, etc.). 
7.6 
Reporting 
The Investigator will be responsible for reporting the following: 
7.6.1 Adverse Events 
Adverse events (AE) must be recorded by the Investigator on the CRFs and must 
be monitored during the study. Primary and secondary safety endpoint events, all 
device or procedure related events, all Serious Adverse Events (SAE), and all 
Unanticipated Adverse Device Effects (UADE) will be collected starting at 
Procedure (Day 0) through final follow-up visit. Minimum requirements of data to 
be recorded are: event term, event start date, seriousness, action taken, outcome and 
device-relatedness. 
In order to ensure prompt reporting of AEs, all reportable AEs (as well as all related 
study data) are required to be entered into the EDC in a timely manner. Any 
suspected UADEs should be reported immediately by calling the Sponsor. All 
device related SAEs should be reported in the EDC within 72 hours of the site staff 
first being made aware of the occurrence of the SAE. If the EDC is unavailable, an 
email can be sent to Penumbra.  
The Investigator must report adverse events to the IRB according to local 
requirements. The Investigator is responsible for adhering to reporting time frames 
and complying with local and federal requirements. In addition, the Investigator 
will report to the Sponsor and IRB any device deficiencies that could have led to a 
SAE, if required by federal regulations or by local authorities. 
For the purpose of reporting within this protocol, pre-existing conditions or planned 
procedures for pre-existing conditions are not reportable as AEs unless there is 
worsening of the condition with an increase in severity or frequency during the 
course of the study. 
All deaths will be reported regardless of causality. When reporting a death, the 
primary condition or diagnosis that contributed to the fatal outcome should be 
reported as a SAE, with an outcome of death. Only a single cause of death should 
be reported in EDC. If the cause of death is unknown, report “unknown cause of 
death” as a SAE.  
Detailed form and narrative reports will be composed for primary and secondary 
safety endpoints (at a minimum). 
 
 

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7.6.2 Analysis of Adverse Events 
A Medical Monitor will review events related to primary and secondary safety 
endpoints as they are reported.  
In addition to the reporting requirements noted above, pre-defined AE/SAEs as 
listed in the Independent Medical Reviewer (IMR) Charter will be evaluated by the 
IMR. Redacted source documents will be collected for events requiring 
adjudication and for other events where the medical monitor deem necessary.  
7.6.3 Relationship to the Study Device 
General adverse event and serious adverse event definitions can be found in Section 
16 – Appendix I. A (S)AE is considered to be device-related when it is reasonable 
to believe that the event may have been caused by or is related to the study device. 
The following definitions will be used to assess the relationship of the adverse event 
to the use of study device.  
• 
Definite: The temporal sequence is relevant and the event abates upon 
study device application completion/removal, or reappearance of the 
event on repeat study device application.  
• 
Probable: The temporal sequence is relevant or the AE abates upon study 
device application completion/removal or the AE cannot be reasonably 
explained by the subject’s condition or comorbidities. The AE is related 
or most likely associated with the study device. 
• 
Possible: The temporal sequence between the study device and the AE is 
such that the relationship is not unlikely or there is no contradicting 
evidence that can reasonably explain the subject’s condition. There is a 
possibility of a relationship between the AE and the study device. 
• 
Unrelated: The AE is not associated with the device. There is no relation 
between the AE and the study device. 
Similar grading will be used for assessing the relationship to index 
procedure/index coronary vessel occlusion. 
7.6.4 Device Deficiency  
All device deficiencies related to the identity, quality, durability, reliability, safety 
or performance of the study device shall be documented and reported through the 
standard commercial process and within EDC. Investigators must report all 
possible device observations associated with the device during the study. This 
includes unexpected outcomes or device deficiencies that might have led to a 
serious adverse event if: a) suitable action had not been taken; b) intervention has 
not be made; or, c) if circumstances had been less fortunate.  

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Device manufacturers are required to report qualifying medical device incidents to 
the relevant national competent authorities. An incident is defined as “any 
malfunction or deterioration in the characteristics and/or performance of a device, 
as well as any inadequacy in the labeling or the instructions for use which, directly 
or indirectly, might lead to or might have led to the death of a subject or to a serious 
deterioration in their state of health.” A deterioration in state of health is not 
considered unanticipated if the condition leading to the event was considered in a 
risk analysis.  
7.6.5 Protocol Deviation(s) 
Deviations defined in this protocol will be clearly documented, if identified during 
monitoring or through other means. For this study, deviations need to be reported 
for the following categories: 
o Inclusion/exclusion criteria deviation(s) 
o Major Informed Consent deviation(s) 
 
7.7 
Records Retention 
The Investigator shall maintain the records associated with this study for a period of at least 
two years after either the date on which the study is completed or the date that the records 
are no longer required for supporting a premarket approval/notification submission, 
whichever is later. An eTMF will be used as the master repository for all site and Sponsor 
regulatory documents. These records include the following: 
• Correspondence with the Sponsor or designee, the Medical Monitor, and other 
Investigators 
• Subject source records, including but not limited to: Informed Consent Forms, 
copies of all completed CRFs, and supporting documents (laboratory reports and 
reports of diagnostic tests, medical records, etc.) 
• All versions of study protocol with dates and details of reasons for any deviations 
from the protocol that could affect the scientific quality of the study or the rights, 
safety, or welfare of the subjects 
• Instructions For Use 
• Reports of any serious adverse event and/or serious adverse device effects 
• A copy of all approvals related to the clinical investigation 
• The approved, blank, informed consent form  
• All approval/acknowledgment letters from the IRB for all versions of the study 
protocol, ICF and other documents 
• Clinical Trial Agreement(s) 
• Signed and dated curriculum vitae for all study personnel  
• Medical licenses for the Principal Investigator and all participating Sub-
Investigators 
• Financial disclosure for the Principal Investigator and all participating Sub-
Investigators  

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• All required regulatory documents such as, but not limited to, Delegation of 
Authority and training logs 
• Signed Protocol Signature Page(s)  
8. Sponsor Responsibilities 
8.1 
Training 
The Sponsor is responsible for providing training on the protocol, study device, CRF 
completion, and image upload as applicable for all study staff per delegation of authority 
log.  
8.2 
Investigator List 
The Sponsor shall keep a list of the names and addresses of the clinical Investigators for 
the study. 
8.3 
Adverse Event Reporting 
The Sponsor shall evaluate adverse event reports received from the Investigational Sites 
and found during data monitoring and shall report them to the appropriate regulatory bodies 
and other Investigational Sites as necessary. 
8.4 
Data Monitoring 
Penumbra is responsible for ensuring that the study is conducted according to relevant 
aspects of appropriate regulations (21 CFR 812, I.S. EN ISO 14155). A Penumbra 
employee or designate will conduct the following site visits: 
8.4.1 Site Qualification Visit 
Conducted to ensure the Investigational Site has the appropriate staff, facilities, and 
expertise to participate in the study. Site Qualification can be waived under certain 
circumstances. 
8.4.2 Site Initiation Visit 
Conducted to train the investigational staff on use of the device, study requirements, 
and other relevant training. 
 
 

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8.4.3 Interim Monitoring Visit(s) 
Conducted as needed to ensure the investigational site is operating in compliance 
with this protocol, continues to have the appropriate staff and facilities, and is 
correctly completing the CRFs.  
To ensure that Investigators and their staff understand and accept their defined 
responsibilities the Sponsor will maintain regular correspondence and perform 
periodic site visits during the course of the study where they will verify the 
continued acceptability of the facilities, compliance with the investigational plan, 
and maintenance of complete records. Clinical monitoring will include review and 
resolution of missing or inconsistent data and source document checks to ensure 
the accuracy of the reported data. Informed consent, CRFs and medical records for 
all enrolled and screen failed subjects will be made available to the Sponsor for 
review and collection.  
8.4.4  Site Close Out Visit  
Conducted to ensure all study and regulatory-related activities have been completed 
prior to site closure. 
8.5 
Data Management 
CRFs will be used at all investigational sites. All study data will be entered into 
commercially available web-based EDC. Data entry will be performed by the study site 
personnel. The EDC system requires no on-site software installation or specific hardware 
to operate. Investigators, clinical coordinators, data managers, and Penumbra clinical 
personnel will 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 may be used to identify data discrepancies or inconsistencies. The 
study site may be queried for clarification concerning CRF discrepancies or inconsistencies 
identified. If CRF corrections are necessary, they will be made by the Investigator or an 
authorized member of the Investigator's staff that is delegated to complete data entry (e.g. 
CRF/EDC). 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 CRFs for completeness and accuracy and provide his/her electronic 
signature and date to CRFs as evidence thereof. Any data items that have been changed 
will require reapplication of the electronic signature. 
Study personnel will have individual login and password to access the clinical 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. 

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All CRFs and data files will be secured to ensure confidentiality. Investigators are required 
to maintain source documents required by the protocol, including but not limited to 
laboratory results, reports, supporting medical records, and Informed Consent Forms. The 
source documents will be used during the regular monitoring visits to verify information 
entered on the CRFs. 
9. Ethical Requirements 
9.1 
Declaration of Helsinki 
The study will be performed in accordance with the applicable aspects of I.S. EN ISO 
14155:2011, recommendations guiding physicians in biomedical research involving 
human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland (1964 
and later revisions), ICH and US FDA GCP guidelines. 
It is the responsibility of the Investigator to obtain approval of the study protocol from the 
Institutional Review Board (IRB) and to keep the IRB informed of any serious adverse 
event, serious adverse device effects, and amendments to the protocol. All correspondence 
with the IRB should be filed by the Investigator and copies sent to the Sponsor or its 
designee. 
9.2 
Informed Consent 
The Investigator is responsible for ensuring that a completed informed consent is obtained 
in accordance with Section 6.5 of this protocol, as delegated by the site-specific Delegation 
of Authority, and according to country and local requirements. 
9.3 
 Subject Data Protection 
Each subject will be assigned a unique subject identification number at the time of 
enrollment. This subject identification number will be retained throughout the study. Study 
sites will keep a log that notes the subject’s name and corresponding subject identification 
number. All CRFs will be tracked, evaluated, and stored using only the subject ID number. 
No personal identifying information will be included on the CRFs. 
The informed consent form will notify subjects that study monitors, Sponsor’s 
representatives, auditors, and representatives of government agencies and ethics 
committees will have access to personal identifying information to ensure that data 
reported on the CRFs corresponds to the person who signed the consent form and the 
information contained in the source documentation. 
10. Statistical Procedures 
10.1 
General Statistical Considerations 
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, inter-quartile range, minimum 

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and maximum for continuous variables and counts and percentages for discrete variables. 
Analyses will be conducted using SAS (SAS Institute, Cary, NC). The specific details of 
the planned analyses are described completely in the statistical analysis plan. 
10.2 
Sample Size Estimation for the Primary Outcome 
The sample size calculations assume that 6.1% (22/360) of the study subjects experience a 
primary safety event as compared to 6.1% (272/4454) of the TOTAL trial high thrombus 
burden subset.29 Based on a binomial analysis with a non-inferiority margin of 10%, a study 
of 360 Indigo System subjects will have 99% power with a one-sided alpha of 0.025. The 
sample size was adjusted to 400 subjects to account for up to 10% attrition rate. 
 
10.3 
Control of Systematic Error and Bias 
The study will be conducted under a common protocol for each Investigational Site with 
the intention of pooling the data for analysis. Every effort will be made to promote 
consistency in study execution at each Investigational Site.  
10.4 
Missing Data and Imputation Methods 
Every effort will be made to keep all missing data, particularly the 30-day outcomes, to a 
minimum. Some data may be missing, mainly due to lost-to-follow-up (LTFU) subjects. 
The primary analysis will be data as observed. Sensitivity analysis will be performed. 
10.5 
Definition of Populations 
10.5.1 Screened 
Screened patients are all patients considered for participation in the study, whether 
or not they sign informed consent. 
10.5.2 Screen Failure 
Screen failure patient are all patients considered for participation in the study, who 
failed to meet inclusion criteria or met exclusion criteria. Patients can be screen 
failed based on general or imaging criteria. These patients may or may not have 
signed an informed consent form. 
10.5.3 Enrolled  
An eligible patient is considered enrolled when the Indigo CAT RX Aspiration 
Catheter enters the body and informed consent is obtained (whichever is later).  
10.5.4 Completed 
Completed subjects are all subjects who were enrolled and completed the study 
follow-up or were known to have died prior to the follow-up timepoint are 

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considered completed. The completed subject metric will be provided for 180-day 
follow-up. 
10.5.5 Early Termination  
Early termination subjects are all subjects who were enrolled but did not complete 
follow-up and were not known to have died. The early termination subject metric 
will be provided for 180-day follow-up. 
10.6 
Definition of Analysis Populations 
10.6.1  Intent to Treat Sample 
As the primary analysis, all performance and safety outcome measures will be 
analyzed under the intent-to-treat (ITT) principle. Under this principle, the ITT 
sample includes all subjects who are enrolled. This population is the primary 
analysis population.   
10.7 
Interim Analysis 
No interim analyses are planned for the purpose of terminating the study for a positive 
result. No adjustments will be made to the confidence bounds for the final analysis.  
10.8 
Statistical Analysis of Primary Endpoint  
The primary endpoint is the 30-day composite endpoint. The primary effectiveness analysis 
will be the difference between the study group and the historical control rate of 6% 
observed in the TOTAL trial high thrombus burden subset. 
The null hypothesis is that the difference between the composite endpoint rate and the 
historical control at 30 days is greater than or equal to 10%. The alternative hypothesis is 
the difference at 30 days is less than 10%. Formally, the null and alternative hypotheses to 
be tested are as follows: 
H0:  Pstudy - 0.06 ≥ 0.10 
HA:  Pstudy -0.06 < 0.10 
Where Pstudy is the proportion of patient experiencing a composite endpoint event at 30-day 
follow-up visit. 
Statistical analysis of the primary endpoint will be conducted using a binomial comparison 
to test the one-sided null hypothesis that the difference in proportions is less than or equal 
to 0.10.  
The primary safety endpoint is met if the upper limit of the 95% confidence interval of the 
composite primary endpoint rate is less than 16% at a one-sided alpha of 0.025. The 
primary analysis will be unadjusted.   

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10.9 
Secondary Statistical Analysis 
The secondary performance and safety endpoints will be assessed via proportions based on 
the endpoint criteria and 95% confidence intervals will be presented. The Imaging Core 
Lab data supersede the investigator-reported data in all analyses of imaging-based 
endpoints. Survival estimates will also be utilized to evaluate the time-to-event using 
Kaplan-Meier methodology for events through 180 days. With the date of procedure set at 
day 0, any event occurring on or before day 180 will be included.  
10.10 Analysis of Adverse Events 
All adverse events will be summarized by showing the number and percent of subjects 
which report the event.  Events will also be reported by relationship to the procedure or 
device. Adverse events judged as probably or definitely related to the Indigo® Aspiration 
System will be analyzed as device-related. The IMR data will supersede the investigator-
reported data in all analyses of adverse events.  
10.11 Baseline Characteristics 
Baseline data including, but not limited to, demographics, clinical characteristics, and 
angiographic characteristics will be summarized using descriptive statistics.  
10.12   Pooling Across Centers 
Analyses will be presented by treatment group using data pooled across sites. Adjusted 
analysis using key baseline variables and the study site will be used to assess any potential 
site effects. This analysis will be performed on the intent-to-treat population.   
10.13 Final Report  
A final report will be completed, even if the study is prematurely terminated. At the 
conclusion of the study, a multi-center abstract reporting the results will be prepared and 
may be presented at a major meeting(s). A multi-center publication may also be prepared 
for publication in a reputable scientific journal. The publication of results from any single 
center experience within the study is not allowed until the aggregate study results have 
been published, unless there is written consent from the Sponsor. 
11.  Study Committees and Core Labs  
11.2 
Independent Medical Reviewer 
The Independent Medical Reviewer (IMR) will be an independent medical doctor(s) who 
does not participate in the study. There may be more than one IMR. The IMR is responsible 
for assisting in the development of specific criteria used for the categorization of clinical 
events and clinical endpoints in the study. 
The IMR will review and adjudicate appropriate clinical events, mainly related to the 
device and study endpoints. A web-based electronic database will be provided to the IMR 

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for case review and adjudication. The designated Penumbra staff who are responsible for 
reviewing safety data on an ongoing basis will coordinate collection of information for the 
event dossier. Additional details related to the IMR are specified in the IMR Charter.  
11.3 
Imaging Core Lab 
The Imaging Core Lab is composed of independent medical doctor(s) who are not 
participants in the study. The Imaging Core Lab is responsible for assisting in the 
development of specific criteria used for the categorization of clinical endpoints in the 
study. A web-based electronic database will be provided for the Imaging Core Lab to 
review and adjudicate images. Additional details related to the core lab are specified in the 
Imaging Core Lab Charter.  
12.  Study Administration 
12.1 
Stopping the Study Based on Interim Safety Data   
The IMR will receive periodic safety reports of all AEs and SAEs. This study can be 
temporarily suspended or stopped to evaluate any negative safety trends.  
12.2 
Clinical Study Termination/Withdrawal 
Subjects may be terminated or withdrawn from the study for the following reasons: 
• Voluntary withdrawal of consent: meaning that a subject voluntarily chooses 
not to participate further in the study. All data collected up to the withdrawal of 
consent will be maintained in the study database. Withdrawn subjects will not 
have any additional follow-up and will not be replaced. 
       
• Lost to follow-up: a subject will be considered lost-to-follow-up when contact is 
not achieved at the last required follow-up visit window. At a minimum, the effort 
to obtain follow-up information will include three (3) attempts to make contact 
via telephone or e-mail and if unsuccessful, then a letter from the Investigator 
sent via courier or other traceable method will be sent to the subject’s last known 
address. These efforts to obtain follow-up will be recorded in the subject’s study 
files. 
 
• Withdrawn by Investigator: Subjects may be withdrawn at the Investigator’s 
discretion if within their best interest. A subject’s participation in the clinical 
study will be terminated if the Investigator believes that this is in the subject’s 
best medical interest or if the subject no longer complies with the clinical study 
requirements. 
The sponsor may temporarily suspend or prematurely terminate the study at any time for 
the following reasons: 
• Suspicion of risk to subjects 

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• If no positive IRB decision is obtained or if the judgement of the IRB is revoked 
• If the applicable regulatory body has made an irrevocable objection 
• If it transpires that continuation of study cannot serve any scientific purpose, and 
this is confirmed by the IRB 
• Business reasons  
The Sponsor will document reasons for study suspension or premature termination and 
notify the PIs. The Sponsor will ensure that the IRB and regulatory authorities are notified 
in a timely manner.  
The Sponsor will continue to provide resources to fulfill the obligations from the study 
protocol and existing agreements for following up the subjects enrolled in the study. 
The Principal Investigators will promptly inform the enrolled subjects at his/her site, 
if appropriate. 
If the Sponsor temporarily suspends the study and wishes to resume it, the Sponsor will 
inform the PIs, IRB, and (if appropriate) regulatory authorities. The Sponsor will provide 
a rationale for resuming the study. IRB must provide written approval before the study is 
resumed. 
 
12.3 
Missing Visits 
Every effort should be made to bring subject in to scheduled follow-up visits, within the 
visit window specified in the protocol. Any study subject who does not attend a scheduled 
follow-up visit should be contacted by site personnel to reschedule. If the missed visit was 
due to an adverse event, an AE CRF must be completed and any reporting requirements 
met.  
12.4 
Protocol Adherence and Amendments 
Prior to beginning the study, the Principal Investigator must sign the protocol signature 
page documenting his/her agreement to conduct the study in accordance with this protocol. 
An Investigator must not make any changes or deviate from this protocol, except to protect 
the life and physical well-being of a subject in an emergency. Deviations from the protocol 
as defined in Section 7.6.5 must be documented and reported to Penumbra as soon as 
possible, and to the IRB per local guidelines and government regulations. 
12.5 
Study Registration 
The study will be registered in a publicly accessible study database (e.g., clinicaltrials.gov) 
prior to study initiation. 
13.  Publication of Information 
All information and data generated in association with this study will be held in strict 
confidence and remain the sole property of the Sponsor. The Investigator agrees to use this 

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information for the sole purpose of completing this study and for no other purpose without 
written consent from the Sponsor. 
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 test 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. 
14.  Contact Information 
The address of Penumbra Incorporated is: 
Penumbra, Inc. 
One Penumbra Place 
Alameda, CA 94502 
Tel. (510) 748-3200 
Fax (510) 814-8305 
Key contacts for the study include: 
  
 
Clinical Study Manager 
 
 
 
Director of Medical Affairs  
 
 
 
 

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15.  References 
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Kumar, A., & Cannon, C. P. (2009). Acute coronary syndromes: diagnosis and 
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Anderson, J. L., Karagounis, L. A., & Califf, R. M. (1996). Metaanalysis of five reported 
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Davies, M. J., Woolf, N., & Robertson, W. B. (1976). Pathology of acute myocardial 
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Benjamin, E. J., Virani, S. S., Callaway, C. W., Chamberlain, A. M., Chang, A. R., 
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Kayani, W. T., & Ballantyne, C. M. (2018). Improving Outcomes After Myocardial 
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Keeley, E. C., Boura, J. A., & Grines, C. L. (2003). Primary angioplasty versus 
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Levine, G. N., Bates, E. R., Blankenship, J. C., Bailey, S. R., Bittl, J. A., Cercek, B., . . . 
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Intervention: a report of the American College of Cardiology Foundation/American Heart 
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Angiography and Interventions. Circulation, 124(23), e574-651. 
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O'Gara, P. T., Kushner, F. G., Ascheim, D. D., Casey, D. E., Chung, M. K., de Lemos, J. 
A., . . . Zhao, D. X. (2013). 2013 ACCF/AHA Guideline for the Management of ST-
Elevation Myocardial Infarction. A Report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines, 61(4), e78-
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9 
Bhatt, D. L. (2018). Percutaneous Coronary Intervention in 2018. Jama, 319(20), 2127-
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10 
Malik, T., & Tivakaran, V. (2018, December 15, 2018). Percutaneous Transluminal 
Coronary Angioplasty (PTCA). National Institute of Health. Retrieved from 
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Amsterdam, E. A., Wenger, N. K., Brindis, R. G., Casey, D. E., Ganiats, T. G., Holmes, 
D. R., . . . Zieman, S. J. (2014). 2014 AHA/ACC Guideline for the Management of 
Patients With Non–ST-Elevation Acute Coronary Syndromes. A Report of the American 
College of Cardiology/American Heart Association Task Force on Practice Guidelines, 
64(24), e139-e228. doi:10.1016/j.jacc.2014.09.017 
12 
Svilaas, T., Vlaar, P. J., van der Horst, I. C., Diercks, G. F., de Smet, B. J., van den 
Heuvel, A. F., . . . Zijlstra, F. (2008). Thrombus aspiration during primary percutaneous 
coronary intervention. New England Journal of Medicine, 358(6), 557-567. 
doi:10.1056/NEJMoa0706416 

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13 
Thiele, H., de Waha, S., Zeymer, U., Desch, S., Scheller, B., Lauer, B., . . . Eitel, I. 
(2014). Effect of aspiration thrombectomy on microvascular obstruction in NSTEMI 
patients: the TATORT-NSTEMI trial. J Am Coll Cardiol, 64(11), 1117-1124. 
doi:10.1016/j.jacc.2014.05.064 
14 
Jolly, S. S., Cairns, J. A., Yusuf, S., Meeks, B., Pogue, J., Rokoss, M. J., . . . Dzavik, V. 
(2015). Randomized trial of primary PCI with or without routine manual thrombectomy. 
New England Journal of Medicine, 372(15), 1389-1398. doi:10.1056/NEJMoa1415098 
15 
Bavry, A. A., Kumbhani, D. J., & Bhatt, D. L. (2008). Role of adjunctive thrombectomy 
and embolic protection devices in acute myocardial infarction: a comprehensive meta-
analysis of randomized trials. Eur Heart J, 29(24), 2989-3001. 
doi:10.1093/eurheartj/ehn421 
16 
Vlaar, P. J., Svilaas, T., van der Horst, I. C., Diercks, G. F., Fokkema, M. L., de Smet, B. 
J., . . . Zijlstra, F. (2008). Cardiac death and reinfarction after 1 year in the Thrombus 
Aspiration during Percutaneous coronary intervention in Acute myocardial infarction 
Study (TAPAS): a 1-year follow-up study. Lancet, 371(9628), 1915-1920. 
doi:10.1016/s0140-6736(08)60833-8 
17 
Sardella, G., Mancone, M., Bucciarelli-Ducci, C., Agati, L., Scardala, R., Carbone, I., . . . 
Fedele, F. (2009). Thrombus Aspiration During Primary Percutaneous Coronary 
Intervention Improves Myocardial Reperfusion and Reduces Infarct Size. J Am Coll 
Cardiol, 53(4), 309-315. doi:10.1016/j.jacc.2008.10.017 
18 
Sardella, G., Mancone, M., Canali, E., Di Roma, A., Benedetti, G., Stio, R., . . . Fedele, F. 
(2010). Impact of thrombectomy with EXPort Catheter in Infarct-Related Artery during 
Primary Percutaneous Coronary Intervention (EXPIRA Trial) on cardiac death. Am J 
Cardiol, 106(5), 624-629. doi:10.1016/j.amjcard.2010.04.014 
19 
Fröbert , O., Lagerqvist , B., Olivecrona , G. K., Omerovic , E., Gudnason , T., Maeng , 
M., . . . James , S. K. (2013). Thrombus Aspiration during ST-Segment Elevation 
Myocardial Infarction. New England Journal of Medicine, 369(17), 1587-1597. 
doi:10.1056/NEJMoa1308789 
20 
Lagerqvist, B., Fröbert, O., Olivecrona, G. K., Gudnason, T., Maeng, M., Alström, P., . . . 
James, S. K. (2014). Outcomes 1 Year after Thrombus Aspiration for Myocardial 
Infarction. New England Journal of Medicine, 371(12), 1111-1120. 
doi:10.1056/NEJMoa1405707 
21 
Jolly, S. S., Cairns, J. A., Yusuf, S., Rokoss, M. J., Gao, P., Meeks, B., . . . Dzavik, V. 
(2016). Outcomes after thrombus aspiration for ST elevation myocardial infarction: 1-
year follow-up of the prospective randomised TOTAL trial. Lancet, 387(10014), 127-
135. doi:10.1016/s0140-6736(15)00448-1 
22 
Meyer-Saraei, R., de Waha, S., Eitel, I., Desch, S., Scheller, B., Bohm, M., . . . Thiele, H. 
(2017). Thrombus aspiration in non-ST-elevation myocardial infarction - 12-month 
clinical outcome of the randomised TATORT-NSTEMI trial. Eur Heart J Acute 
Cardiovasc Care, 6(1), 10-17. doi:10.1177/2048872615617044 
23 
The-Penumbra-Pivotal-Stroke-Trial-Investigators. (2009). The penumbra pivotal stroke 
trial: safety and effectiveness of a new generation of mechanical devices for clot removal 
in intracranial large vessel occlusive disease. Stroke, 40(8), 2761-2768. 
doi:10.1161/strokeaha.108.544957 
24 
Tarr, R., Hsu, D., Kulcsar, Z., Bonvin, C., Rufenacht, D., Alfke, K., . . . Haass, A. (2018). 
The POST trial: initial post-market experience of the Penumbra system: revascularization 

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of large vessel occlusion in acute ischemic stroke in the United States and Europe. J 
Neurointerv Surg, 10(Suppl 1), i35-i38. doi:10.1136/jnis.2010.002600.rep 
25 
Turk, A. S., Frei, D., Fiorella, D., Mocco, J., Baxter, B., Siddiqui, A., . . . Chaudry, I. 
(2018). ADAPT FAST study: a direct aspiration first pass technique for acute stroke 
thrombectomy. J Neurointerv Surg, 10(Suppl 1), i4-i7. doi:10.1136/neurintsurg-2014-
011125.rep 
26 
Lapergue, B., Blanc, R., Gory, B., Labreuche, J., Duhamel, A., Marnat, G., . . . Piotin, M. 
(2017). Effect of Endovascular Contact Aspiration vs Stent Retriever on 
Revascularization in Patients With Acute Ischemic Stroke and Large Vessel Occlusion: 
The ASTER Randomized Clinical Trial. Jama, 318(5), 443-452. 
doi:10.1001/jama.2017.9644 
27 
Schramm, P., Navia, P., Papa, R., Zamarro, J., Tomasello, A., Weber, W., . . . Lo, T. H. 
(2018). ADAPT technique with ACE68 and ACE64 reperfusion catheters in ischemic 
stroke treatment: results from the PROMISE study. J Neurointerv Surg, neurintsurg-
2018-014122. doi:10.1136/neurintsurg-2018-014122 
28 
Levine, G. N., Bates, E. R., Blankenship, J. C., Bailey, S. R., Bittl, J. A., Cercek, B., . . . 
Zhao, D. X. (2016). 2015 ACC/AHA/SCAI Focused Update on Primary Percutaneous 
Coronary Intervention for Patients With ST-Elevation Myocardial Infarction. An Update 
of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention and the 
2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 
67(10), 1235-1250. doi:10.1016/j.jacc.2015.10.005 
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Jolly, S. S., Cairns, J. A., Lavi, S., Cantor, W. J., Bernat, I., Cheema, A. N., . . . Dzavik, 
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Trial. J Am Coll Cardiol, 72(14), 1589-1596. doi:10.1016/j.jacc.2018.07.047 
30 
Thygesen, K., Alpert, J. S., Jaffe, A. S., Chaitman, B. R., Bax, J. J., Morrow, D. A., & 
White, H. D. (2018). Fourth Universal Definition of Myocardial Infarction (2018). 
Circulation, 138(20), e618-e651. doi:10.1161/cir.0000000000000617 
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van 't Hof, A. W., Liem, A., Suryapranata, H., Hoorntje, J. C., de Boer, M. J., & Zijlstra, 
F. (1998). Angiographic assessment of myocardial reperfusion in patients treated with 
primary angioplasty for acute myocardial infarction: myocardial blush grade. Zwolle 
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16. Appendix I – Definitions 
16.1 Adverse Event Definitions 
Adverse Event (AE): Any undesirable clinical event occurring in a patient during a 
clinical trial, whether or not it is considered related to the study 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. 
 
Adverse Device Effect (ADE): An adverse event related to the use of an investigational 
medical device.  
Serious Adverse Event (SAE): 
A SAE is an adverse event that: 
o Led to death  
o Led to a serious deterioration in the health of the patient that: 
− Resulted in life-threatening illness or injury  
− Resulted in chronic disease 
− Resulted in permanent impairment of a body structure or a body function  
− Required 
in-patient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization  
− Resulted in medical or surgical intervention to arrest permanent impairment 
to body structure or a body function  
− Led to fetal distress, fetal death or a congenital abnormality or birth defect 
o Death 
Report if death was the outcome of an adverse event. The primary cause of death 
should be reported as the adverse event term. 
o 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. 
o 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). 
o 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. 
 
 

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o 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. 
o 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 bronchospasm (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. 
Unanticipated Adverse Device Event (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 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. 
16.2 Events of Interest 
Definitions are adapted from the TOTAL study, the Fourth Universal Definition of 
Myocardial Infarction (2018), and the Academic Research Consortium’s Clinical 
Endpoints Standardized Definitions.14,30,31   
Cardiogenic shock: defined as Systolic Blood Pressure less than 90 mmHg or MAP <60 
mmHg not responsive to fluid resuscitation and or heart rate correction for at least 1 hour 
or need for vasopressor/inotropic therapy to maintain SBP>90 mm Hg or MAP >60 
mmHg for at least 1 hour and, believed to be secondary to cardiac dysfunction and 
associated with at least 1 of the following: 1) signs of pulmonary edema, 2) signs of 
hypoperfusion (cool clammy skin, oliguria, or altered sensorium), or 3) CI <2.2 L/min. 
Death: will be classified as cardiovascular or non-cardiovascular. All deaths with a clear 
cardiovascular or unknown cause will be classified as cardiovascular. Only deaths due to 
a documented non-cardiovascular cause (e.g., cancer) will be classified as non-
cardiovascular. 
Major bleeding: fatal or leading to a drop in hemoglobin of ≥5 g/dl, or significant 
hypotension with the need for inotropes, or requiring surgery (other than vascular site 
repair), or symptomatic intracranial hemorrhage (ICH)), or requiring transfusion of two 
or three units of red blood cells or equivalent whole blood. 
 
 

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Myocardial Infarction: 
a. Non ST-Elevation Myocardial Infarction (NSTEMI):  
Symptoms of myocardial ischemia OR new ischemic ECG Changes OR 
development of pathological Q waves OR imaging evidence of new loss of viable 
myocardium or new regional wall motion abnormality in a pattern consistent with 
an ischemic etiology 
 
AND 
 
Rise and/or fall of cardiac troponin with at least one value above the 99th percentile 
of the upper reference limit 
 
AND 
 
Without ECG changes indicating STEMI. 
 
b. Recurrent MI:  
Diagnosis of MI that occurs after the initial MI. For recurrent MI within 48 hours 
of PCI or CABG, specific diagnostic criteria are listed below.  
 
c. ST-Elevation Myocardial Infarction (STEMI):  
Symptoms of myocardial ischemia OR new ischemic ECG Changes OR 
development of pathological Q waves OR imaging evidence of new loss of viable 
myocardium or new regional wall motion abnormality in a pattern consistent with 
an ischemic etiology 
 
AND 
 
Rise and/or fall of cardiac troponin with at least one value above the 99th percentile 
of the upper reference limit 
 
AND 
 
Definite ECG changes indicating STEMI, defined as ST elevation of greater than 
0.1 mV in two contiguous limb leads or 0.2 mV in two contiguous precordial leads, 
or presumed new left bundle branch block. 
 
d. MI Associated with Percutaneous Coronary Intervention (≤ 48 hours after 
index procedure) 
Elevation of cardiac troponin values greater than five times the 99th percentile upper 
reference limit in patients with normal baseline values. In patients with elevated 
pre-procedural cardiac troponins in whom the cardiac troponin levels are stable (≤ 
20% variation) or falling, the post procedure cardiac troponin must rise by >20%. 
However, the absolute post-procedural value must still be at least five times the 99th 
percentile upper reference limit.  
 

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In addition, one of the following elements is required:  
New ischemic ECG changes OR development of new pathological Q waves OR 
imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality in a pattern consistent with an ischemic etiology OR angiographic 
findings consistent with a procedural flow-limiting complication such as coronary 
dissection, occlusion of a major epicardial artery or a side branch 
occlusion/thrombus, disruption of collateral flow, or distal embolization 
 
e. MI Associated with Coronary Artery Bypass Grafting (≤ 48 hours after the 
index procedure) 
Elevation of cardiac troponin values greater than ten times the 99th percentile upper 
reference limit in patients with normal baseline values. In patients with elevated 
pre-procedural cardiac troponins in whom the cardiac troponin levels are stable (≤ 
20% variation) or falling, the post procedure cardiac troponin must rise by >20%. 
However, the absolute post-procedural value must still be at least ten times the 99th 
percentile upper reference limit.  
 
In addition, one of the following elements is required:  
Development of new pathological Q waves OR angiographic documented new graft 
occlusion or new native coronary artery occlusion OR imaging evidence of new 
loss of viable myocardium or new regional wall motion abnormality in a pattern 
consistent with an ischemic etiology 
 
New or worsening NYHA Class IV heart failure: defined heart failure symptoms at 
rest and  a physician decision to treat HF with IV diuretic, inotropic agent or vasodilator 
plus at least one of the following: 1) presence of pulmonary edema or pulmonary vascular 
congestion on chest radiograph thought to be due to HF; 2) rales reaching above the lower 
1/3 of the lung fields thought to be due to HF; or 3) PCWP or LVEDP ≥ 18 mm Hg. 
No reflow: defined as an acute reduction in coronary flow (TIMI grade 0-1) in the 
absence of dissection, thrombus, spasm or high-grade residual stenosis at the original 
target lesion. 
 
Recurrent Ischemia: Recurrent chest pain (with documented ST depression > 1mm in 
at least 2 contiguous leads on transient ST elevation) lasting more than 5 minutes and 
leading to additional intervention such as thrombolytic therapy for threatened MI, cardiac 
catheterization leading to repeat intervention, or insertion of intra-aortic balloon pump or 
urgent revascularization (UR) by midnight of next calendar day following the initial 
symptoms. 
 
Stent thrombosis: (Categorized by Timing & Level of Certainty) 
a. Timing 
i. 
Acute Stent Thrombosis: 0 to 24 hours after stent implantation 
ii. 
Subacute Stent Thrombosis: > 24 hours to 30 days after stent implantation 
iii. 
Late Stent Thrombosis: >30 days to 1 year after stent implantation 

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iv. 
Very Late Stent Thrombosis: >1 year after stent implantation 
 
b. Level of Certainty 
i. 
Definite Stent Thrombosis:  
Angiographic confirmation of stent thrombosis: (incidental angiographic 
documentation of stent occlusion in the absence of clinical signs or symptoms 
is not considered a confirmed stent thrombosis). 
 
The presence of an intracoronary thrombus that originates in the stent or in 
the segment 5mm proximal or distal to the stent and presence of at least 1 of 
the following criteria within a 48-hour time window: 
1. Acute onset of ischemic symptoms at rest 
2. New ischemic ECG changes that suggest acute ischemia 
3. Typical rise and fall in cardiac biomarkers 
4. Nonocclusive thrombus: 
Intracoronary thrombus is defined as a (spheric, ovoid, or 
irregular) noncalcified filling defect or lucency surrounded by 
contrast material (on 3 sides or within a coronary stenosis) seen in 
multiple projections, or persistence of contrast material within the 
lumen, or a visible embolization of intraluminal material 
downstream. 
5. Occlusive thrombus: 
TIMI 0 or TIMI 1 intrastent or proximal to a stent up to the most 
adjacent proximal side branch or main branch (if originates from 
the side branch). 
 
OR 
 
Pathological confirmation of stent thrombosis: evidence of recent 
thrombus within the stent determined at autopsy or via 
examination of tissue retrieved following thrombectomy. 
 
ii. 
Probable Stent Thrombosis: 
Clinical definition of probable stent thrombosis is considered to have 
occurred after intracoronary stenting in the following cases: 
1. Any unexplained death within the first 30 days 
2. Irrespective of the time after the index procedure, any MI that is 
related to documented acute ischemia in the territory of the 
implanted stent without angiographic confirmation of stent 
thrombosis and in the absence of any other obvious cause 
 
 
 

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iii. 
Possible Stent Thrombosis: 
Clinical definition of possible stent thrombosis is considered to have 
occurred with any unexplained death from 30 days after intracoronary 
stenting until end of trial follow-up. 
 
Stroke: Any stroke is defined as the presence of a new focal neurologic deficit thought 
to be vascular in origin, with signs or symptoms lasting more than 24 hours 
Target Vessel Revascularization (TVR): defined as any revascularization procedure 
(PCI or CABG) involving the vessel treated during the index PCI procedure for MI. 
 
 
 
 

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23. Acronyms 
ACS 
Acute coronary Syndrome 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
CABG 
Coronary Artery Bypass Graft 
CFR 
Code of Federal Regulations 
CHD 
Coronary Heart Disease 
CI 
Cardiac Index 
CK 
Creatine Kinase 
CK-MB 
Creatine Kinase-MB iso-enzyme 
CV 
Cardiovascular 
DSMB 
Data and Safety Monitoring Board 
ECG/EKG 
Electrocardiogram 
eCRF 
Electronic Case Report Forms 
EDC 
Electronic Data Capture 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ID 
Inner Diameter 
IFU 
Instructions for Use 
IMR 
Independent Medical Reviewer 
IRB 
Institution Review Board 
ISO 
International Organization for Standardization 
LAR 
Legally Authorized Representative 
LTFU 
Lost to Follow Up 
MACE 
Major Adverse Cardiac Events 
MBG 
Myocardial Blush Grade 
MI 
Myocardial Infarction 
NSTEMI 
Non-ST Elevation Myocardial Infarction 
NYHA 
New York Heart Association 
OD 
Outer Diameter 
PCI 
Percutaneous Coronary Intervention 
PI 
Principal Investigator 
PTFE 
Polytetrafluoroethylene 
RHV 
Rotating Hemostasis Valve 
SAE 
Serious Adverse Event 
SC 
Steering Committee 
SOC 
Standard of Care 
STEMI 
ST Elevation Myocardial Infarction 
TIMI 
Thrombolysis in Myocardial Infarction 
TMF 
Trial Master File 
TVR 
Target Vessel Revascularization 
UA 
Unstable Angina 
ULN 
Upper Limit of Normal 
US 
United States 
 

SAP for CLP 15298 CHEETAH 
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STATISTICAL ANALYSIS PLAN 
CHEETAH: A Prospective, Multicenter Study to Evaluate the Safety and 
Performance of the CAT RX Aspiration Catheter in Patients with a High 
Thrombus Burden Acute Coronary Vessel Occlusion 
Protocol CLP-15298 
 
 
 
 
 
 
 
 
 
 

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Contents 
1 
Overview ................................................................................................................................ 3 
2 
Sample Size for the Primary Outcome .................................................................................. 4 
3 
Interim Analysis ..................................................................................................................... 4 
4 
General Statistical Considerations ......................................................................................... 4 
5 
Definition of Populations ........................................................................................................ 4 
6 
Definition of Analysis Populations .......................................................................................... 5 
7 
Statistical Analysis ................................................................................................................. 6 
7.1 
Primary Endpoint Analysis .............................................................................................. 6 
7.2 
Secondary Endpoint Analysis ......................................................................................... 6 
7.3 
Analysis of Adverse Events ............................................................................................ 7 
8 
Subgroup Analysis ................................................................................................................. 7 
9 
Pooling Across Centers ......................................................................................................... 8 
10 
Lost to Follow-Up and Missing Data .................................................................................. 8 
11 
Reviewers and Core Lab .................................................................................................... 8 
11.1 Independent Medical Reviewer (IMR) ............................................................................ 8 
11.2 Imaging Core Lab ........................................................................................................... 9 
12 
Changes to Planned Analyses ........................................................................................... 9 
13 
References ......................................................................................................................... 9 
14 
Revision History ............................................................................................................... 10 
 
 
 
 
 
 

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1 Overview  
 
The objective of the CHEETAH study is to demonstrate the safety and performance of the Indigo® 
Aspiration System using the CAT RX Aspiration Catheter in a population presenting with acute 
high thrombus burden coronary vessel occlusion who are referred for Percutaneous Coronary 
Intervention (PCI). Patients will be enrolled who meet the inclusion and none of the exclusion 
criteria, who (or Legally Authorized Representative, LAR) consent to participate, and in whom the 
study device has been inserted.  
 
The study allows for enrollment of up to 400 subjects at up to 25 sites in the United States.  Each 
site will be limited to a maximum enrollment of approximately 80 patients (~20% of total 
enrollment). 
The primary endpoint of the study is the composite of cardiovascular (CV) death, recurrent 
Myocardial Infarction (MI), cardiogenic shock, or new or worsening New York Heart Association 
(NYHA) Class IV heart failure, within 30 days. Secondary endpoints of the study are as following:  
Performance:  
1. Final TIMI Flow Grade 
2. Final TIMI Thrombus Grade 
3. Myocardial Blush Grade 
4. Distal Embolization Rate 
5. Stent thrombosis at 180 days 
 
Safety:  
1. Stroke within 30 days 
2. Major bleeding within 30 days 
3. All-cause mortality within 180 days 
4. Cardiovascular (CV) death within 180 days 
5. Recurrent MI within 180 days 
6. Cardiogenic shock within 180 days 
7. NYHA Class IV heart failure within 180 days  
8. Incidence of device-related SAE(s) 

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This Statistical Analysis Plan (SAP) will provide details to further elaborate statistical methods as 
outlined in the protocol and will describe analysis conventions. The SAP will be approved prior to 
database lock. 
2 Sample Size for the Primary Outcome 
 
The sample size calculation assumes that 6.1% (22/360) of the study subjects experience a 
primary safety event as compared to 6.1% (272/4454) of the TOTAL trial high thrombus burden 
subset.  Based on a binomial analysis with a non-inferiority margin of 10%, a study of 360 Indigo 
System subjects will have 99% power with a one-sided alpha of 0.025.  The sample size was 
adjusted to 400 subjects to account for up to 10% attrition rate. 
 
3 Interim Analysis 
No interim analyses are planned for the purpose of terminating the study for a positive result. No 
adjustments will be made to the confidence bounds for the final analysis. Interim analysis may be 
performed for purpose of regulatory submissions and/or publication of study results. 
4 General Statistical Considerations 
Baseline data including, but not limited to demographics, clinical characteristics, and angiographic 
characteristics will be summarized using descriptive statistics.  
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, which includes the number of 
observations, mean, median, standard deviation, minimum and maximum for continuous 
variables and counts and percentages for discrete variables. Analyses will be conducted using 
SAS (SAS Institute, Cary, NC). 
Results collected at multiple visits will be summarized at each visit for which they are collected as 
described under Schedule of Assessments Table 2 in CHEETAH study protocol version at the 
time of database lock. Summaries for all measures will include all observed data for each visit. 
See Section 10 in SAP for lost to follow-up and missing data.  
5 Definition of Populations 
The number of subjects for each of the following categories will be summarized for final analysis:  

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● Screened:  
Screened patients are all patients considered for participation in the study, whether or 
not they sign informed consent.   
● Screen Failure:  
Screen failure patients are all patients considered for participation in the study, who 
failed to meet inclusion criteria or met exclusion criteria. These patients may or may 
not have signed an informed consent form. Screen failure patients with their reasons 
for screen failure will be summarized.  
● Enrolled:  
Enrolled subjects are all subjects in which the Indigo CAT RX Aspiration Catheter 
enters the body and informed consent is obtained (whichever is later).  
● Completed:  
Completed subjects are all subjects who were enrolled and completed the study follow-
up or were known to have died prior to the final follow-up time point. The completed 
subject metric will be provided for 180-day follow-up.  
● Early Termination:  
Early termination subjects are all subjects who were enrolled but did not complete 
follow-up and were not known to have died. The early termination subject metric will 
be provided for 180-day follow-up. 
6 Definition of Analysis Populations 
● Intent to Treat Sample:   
As the primary analysis, all performance and safety outcome measures will be 
analyzed under the Intent-To-Treat (ITT) principle. Under this principle, the ITT sample 
includes all subjects who are enrolled. This population is the primary analysis 
population. 
● Per-Protocol Sample:  
In addition to the defined ITT analysis sample, a per-protocol (PP) sample is defined 
as a subset of the ITT sample. The per-protocol sample will include ITT population 
who do not have significant protocol deviations (e.g. eligibility violation) according to 
the CHEETAH study protocol version at the time of database lock. 

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7 Statistical Analysis  
7.1 Primary Endpoint Analysis 
The primary endpoint is the composite of cardiovascular (CV) death, recurrent Myocardial 
Infarction (MI), cardiogenic shock, or new or worsening New York Heart Association (NYHA) 
Class IV heart failure within 30 days. The primary safety analysis will be the difference between 
the composite endpoint rate and the historical control at 30 days rate of 6% observed in TOTAL 
trial high thrombus burden subset.  
The null hypothesis is that the difference between the composite endpoint rate and the historical 
control at 30 days is greater than or equal to 10%. The alternative hypothesis is the difference at 
30 days is less than 10%. Formally, the null and alternative hypotheses to be tested are as follows:  
H0: P study – 0.06 ≥ 0.10 
HA: P study – 0.06 < 0.10 
Where P study is the proportion of subjects experiencing a composite endpoint event at the 30-day 
follow-up timepoint.  
Statistical analysis of the primary endpoint will be conducted using a binomial comparison to test 
the one-sided null hypothesis that the difference in proportions is less than or equal to 0.10.  
The primary safety endpoint is met if the upper limit of the 95% confidence interval of the 
composite primary endpoint rate is less than 16% at a one-sided alpha of 0.025. The primary 
analysis will be unadjusted.  
7.2 Secondary Endpoint Analysis 
The secondary performance and safety endpoints (listed in Section 1) will be assessed via 
proportions based on the endpoint criteria and 95% confidence intervals will be presented. The 
Imaging Core Lab data supersede the Investigator-reported data in all analyses of imaging-based 
endpoints (Final TIMI Grade Flow, Final TIMI Thrombus Grade, Myocardial Blush Grade, Distal 
Embolization Rate). The IMR data will supersede the Investigator-reported data in all analyses of 
adverse events. See section 7.3 for analysis of adverse events.   
Survival estimate will also be utilized for the following secondary safety endpoints to evaluate 
the time-to-event using Kaplan-Meier methodology: All-cause mortality within 180 days, 

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Cardiovascular (CV) death within 180 days, Recurrent MI within 180 days, Cardiogenic shock 
within 180 days, NYHA Class IV heart failure within 180 days. With the date of procedure set at 
day 0, any event occurring on or before day 180 will be included.  
7.3 Analysis of Adverse Events 
All adverse events will be summarized by showing the number and percent of subjects which 
report the event. Events will also be reported by relationship to the procedure or device. Adverse 
events judged as probably or definitely related to the Indigo® Aspiration System will be analyzed 
as device-related; events judged as probably or definitely related to the Index Procedure will be 
analyzed as procedure-related. The IMR data will supersede the Investigator-reported data in all 
analyses of adverse events.   
All serious and non-serious adverse events will be coded using the MedDRA dictionary. The 
number and percentage of subjects with AEs and SAEs, and all events leading to death (cause 
of death) will be summarized by body system and preferred term. Each subject will be counted 
only once within a category. Additionally, non-serious AE will be summarized for events that are 
reported by at least one (1) percent of the subjects.   
8 Subgroup Analysis 
To evaluate the impact of baseline condition on outcomes, subgroup analyses will be performed 
for the primary endpoints and secondary safety variables (listed in Section 1). The subgroups 
below will be used for these analyses:  
• 
Age:  < 65 years, ≥ 65 years 
• 
Gender: Male, Female 
• 
Race: American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, Unknown or Not Reported 
• 
Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Unknown or Not Reported 
• 
Baseline NYHA: Class I and II, Class III and IV 
• 
Index event diagnosis: STEMI, NSTEMI 
Descriptive statistics will be presented for each subgroup. The subgroup analysis will be 
conducted using Fisher’s exact test, Wilcoxon rank sum, Kruskal-Wallis test for univariate 
analyses and logistic or linear regression for multivariate analyses. These analyses will be 

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performed on both the Intent-to-Treat and the Per Protocol populations. Subgroup comparisons 
will be considered secondary analyses and will not be adjusted.  
9 Pooling Across Centers 
To assess the validity of data pooling, heterogeneity across sites will be examined using relevant 
methods, such as random effect models (continuous variables), contingency tables or binary 
logistic regression (categorical variables), or Cox proportional hazards (event time variables). Any 
sites containing fewer than 10 subjects will be aggregated in this analysis. 
Monitoring efforts will be allocated to assess whether sites are adhering to the protocol in a 
standardized manner to minimize the presence of heterogeneity across study centers. 
10 Lost to Follow-Up and Missing Data 
Every effort will be made to keep all missing data, particularly the 30-day outcomes, to a 
minimum.  Some data may be missing, mainly due to lost-to-follow-up (LTFU) subjects. Subject 
discontinuation rates will be tabulated by the reason for early termination.   
The primary analysis will be data as observed. Sensitivity analyses of the primary safety endpoint 
will be performed for subjects with missing primary safety endpoint at 30-day follow-up as follows: 
 
• 
The subjects will be excluded from analysis 
• 
Their primary safety outcome will be imputed using the worst clinical scenario assuming 
the subject experienced a primary safety event  
• 
Their primary safety outcome will be imputed using the best clinical scenario assuming 
the subject did not experience a primary safety event  
11 Reviewers and Core Lab 
11.1   Independent Medical Reviewer (IMR) 
The Independent Medical Reviewer will review and adjudicate safety events based on criteria 
established in the IMR charter.  

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11.2   Imaging Core Lab 
The independent imaging core lab will review and score images from the periprocedural 
angiograms to determine at minimum: final TIMI flow grade, final TIMI thrombus grade, myocardial 
blush grade, and occurrence of distal embolization. Additional details related to the core lab are 
specified in the Imaging Core Lab Charter. 
12 Changes to Planned Analyses  
All changes to the statistical analysis plan (SAP) will be documented in a revised SAP or in the 
clinical trial report.  
13 References 
Agresti, Alan. Categorical Data Analysis 3rd edition. John Wiley & Sons: New Jersey. 2012 
Berglund and Heeringa.  Multiple Imputation of Missing Data Using SAS ®, SAS Institute. 2014 
Hosmer, Lemeshow, and May. Applied Survival Analysis: Regression Modeling of Time-to-
Event Data. John Wiley & Sons: New Jersey. 2008 
Jolly, S.S., Cairns, J. A., Yusuf, S., Meeks.B., Pogue, J. Rokoss, M.J., … Dzavik, V. (2015). 
Randomized trial of primary PCI with or without routine manual thrombectomy.  New England 
Journal of Medicine, 372 (15), 1389-1398. Doi: 10.1056/NEJMoa 1415098 
Jolly, S.S., Cairns, J.A., Lavi, S., Cantor, W.J. Bernat, I., Cheema, A.N., … Dzavik, V. (2018).  
Thrombus Aspiration in Patients With High Thrombus Burden in the TOTAL trial. J Am Coll 
Cardiol, 72 (14), 1589-1596. Doi:10.1016/j.jacc.2018.07.047 
Penumbra Inc. CHEETAH: A Prospective, Multicenter Study to Evaluate the Safety and 
Performance of the CAT RX Aspiration Catheter in Patients with a High Thrombus Burden 
Acute Coronary Vessel Occlusion, Charter for Independent Medical Review (IMR) 
Penumbra Inc. CHEETAH: A Prospective, Multicenter Study to Evaluate the Safety and 
Performance of the CAT RX Aspiration Catheter in Patients with a High Thrombus Burden 
Acute Coronary Vessel Occlusion, CLP-15298 Protocol 
Penumbra Inc. CHEETAH: A Prospective, Multicenter Study to Evaluate the Safety and 
Performance of the CAT RX Aspiration Catheter in Patients with a High Thrombus Burden 
Acute Coronary Vessel Occlusion, Imaging Core Lab Charter 
 

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14 Revision History 
 
Version 
Prepared By 
Description of Changes 
1.0 
 
Initial Release 
2.0 
 
• 
Section 1 Overview: included “Recurrent MI 
within 180 days”  
• 
Section 7.2 Secondary Endpoint Analysis: 
specified the secondary safety endpoints 
through 180 days with KM estimates 
• 
Section 7.3 Analysis of Adverse Events: included 
definition of procedure and device related 
events.  
3.0 
 
• 
Section 7.3 Analysis of Adverse Events: included 
definition of procedure and device related events 
– inadvertently not reflected in version 2.0 
4.0 
 
• 
Section 2: reordered text to match the protocol 
verbatim 
• 
Section 7.3: added MedDRA analysis for all 
cause of death, additional summary of non-
serious AE  
• 
Section 8: added diagnosis subgroup analysis