A Study of the Pipeline™ Vantage Embolization Device With Shield Technology™ for Endovascular Treatment of Wide-Necked Intracranial Aneurysms
Phase: NA
Conditions: Intracranial Aneurysm
Sponsor: Medtronic Neurovascular Clinical Affairs

Neurovascular 
5290 California Ave. 
Irvine, CA 92617 
United States 
 
Tel: 1.949.837.3700 
Fax: 1.949.490.3742 
 
www.medtronic.com 
 
Study Protocol Title: A Study of the Pipeline™ Vantage Embolization DeVice with 
Shield Technology™ for EndovAscular TreatmeNt of Wide-NeCked Intracranial 
AnEurysms (ADVANCE) 
 
NCT#: NCT03873714 
 
Document Date: 02-Jan-2020 

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Clinical Investigation Plan (CIP) 
Clinical Investigation Plan/Study Title  A Study of the Pipeline™ Vantage Embolization 
DeVice with Shield Technology™ for 
EndovAscular TreatmeNt of Wide-NeCked 
Intracranial AnEurysms  
Clinical Investigation Plan Identifier COVSHLD0569 
Study Product Name Pipeline™ Vantage Embolization Device with 
Shield Technology™ 
Sponsor/Local Sponsor Micro Therapeutics, Inc. d/b/a ev3 Neurovascular 
(a wholly owned subsidiary of Medtronic) 
5290 California Avenue 
Irvine, California, 92617 
United States 
Telephone: 949-837-3700 
Fax: 949-490-3742 
Local Sponsor - Canada: 
Medtronic of Canada ULC.  
99 Hereford St.  
Brampton, ON 
L6Y 0R3  
Canada 
Telephone: 1-800-268-5346 
Document Version PR-NV16099 Rev C 
Lead Principal Investigator(s) Demetrius Klee Lopes, M.D. 
Director, Cerebrovascular Surgery and        
Surgical Director, Comprehensive Stroke Program 
Advocate Health 
Aurora, IL 
 
Pascal Jabbour, M.D. 
Professor of Neurological Surgery 
Chief Division of Vascular Neurosurgery and 
Endovascular Neurosurgery 
Thomas Jefferson University Hospital 
Philadelphia, PA 

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Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of 
Medtronic. Any distribution, copying, or disclosure without the prior written authorization of 
Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that it is 
confidential and that it may not be further disclosed by them. 

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1. Investigator Statement 
(Attached Separately) 
 
 
 
 
 

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Table of Contents 
1. 
Investigator Statement ...............................................................................................................3 
Table of Contents ...............................................................................................................................4 
2. 
Glossary ................................................................................................................................... 10 
3. 
Synopsis ................................................................................................................................... 25 
4. 
Introduction ............................................................................................................................. 33 
4.1. Background ........................................................................................................................... 33 
4.2. Clinical Experience with the Pipeline™ device .......................................................................... 37 
4.2.1. 
PITA: Pipeline for Intracranial treatment of Aneurysms ................................................... 37 
4.2.2. 
PUFs: Pipeline™ Embolization Device for Uncoilable or Failed Aneurysms ........................ 37 
4.2.3. 
IntrePED: International Retrospective Study of the Pipeline™ Embolization Device........... 38 
4.2.4. 
ASPIRe: Aneurysm Study of Pipeline™ in an Observational Registry ................................. 38 
4.2.5. 
PREMIER: Prospective Study on Embolization of Intracranial Aneurysms with the Pipeline™ 
Device 39 
4.2.6. 
INSPIRE: Innovative Neurovascular Product Surveillance Registry .................................... 39 
4.2.7. 
SHIELD OUS: Pipeline™ Flex with Shield Technology Embolization- An International 
Multicenter Observational Post Market Study of treated Intra Cranial Aneurysms ........................ 40 
4.2.8. 
PFLEX: Pipeline™ Flex Embolization Device with Shield Technology™ Clinical Study .......... 42 
4.3. Purpose ................................................................................................................................ 43 
5. 
Objectives and Endpoints.......................................................................................................... 44 
5.1. Objectives ............................................................................................................................. 44 
5.1.1. 
Primary Objective(s) ..................................................................................................... 44 
5.1.2. 
Secondary Objective(s) ................................................................................................. 46 
6. 
Study Design............................................................................................................................. 47 
6.1. Duration ............................................................................................................................... 47 
6.2. Rationale............................................................................................................................... 47 
7. 
Product Description .................................................................................................................. 53 
7.1. General ................................................................................................................................. 53 
Shield Technology™ (same as Pipeline™ Flex Embolization Device with Shield Technology™) ......... 55 

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Wire Design and Braid Pattern ................................................................................................... 56 
7.1.1. 
Key Design Modifications of the Pipeline™ Vantage compared to the Pipeline™ Flex Device
 
56 
7.2. Manufacturer ........................................................................................................................ 61 
7.3. Pre-clinical Summary ............................................................................................................. 61 
7.3.1. 
Biocompatibility Summary ............................................................................................ 61 
7.3.2. 
Animal Studies Summary............................................................................................... 61 
7.4. Packaging .............................................................................................................................. 64 
7.5. Intended Population .............................................................................................................. 64 
7.6. Contraindications .................................................................................................................. 64 
7.7. Product Training Requirements .............................................................................................. 64 
7.8. Product Accountability........................................................................................................... 65 
8. 
Selection of Subjects ................................................................................................................. 66 
8.1. Study Population ................................................................................................................... 66 
8.2. Subject Enrollment ................................................................................................................ 66 
8.3. Inclusion Criteria ................................................................................................................... 66 
8.4. Exclusion Criteria ................................................................................................................... 68 
9. 
Study Procedures...................................................................................................................... 70 
9.1. Schedule of Events................................................................................................................. 70 
9.2. Baseline ................................................................................................................................ 72 
9.2.1. 
Baseline Imaging........................................................................................................... 72 
9.2.2. 
Medical History ............................................................................................................ 73 
9.2.3. 
Concomitant Medications ............................................................................................. 73 
9.2.4. 
Pre-Procedure Antiplatelet/Anticoagulation agents ........................................................ 73 
9.3. Subject Consent..................................................................................................................... 74 
9.4. Pre-Procedure Assessment..................................................................................................... 76 
9.5. Procedure ............................................................................................................................. 77 
9.5.1. 
Ancillary Devices........................................................................................................... 78 
9.5.2. 
Usage of Multiple Pipeline™ Vantage Devices................................................................. 79 

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9.5.3. 
Adjunctive Device Use................................................................................................... 79 
9.5.4. 
Day 0 Imaging............................................................................................................... 79 
9.5.5. 
Screen Failure............................................................................................................... 80 
9.5.6. 
No Treatment of an Eligible Subject with the Pipeline™ Vantage Device .......................... 80 
9.6. Post-Placement Antiplatelet Agents........................................................................................ 81 
9.7. Discharge Exam ..................................................................................................................... 81 
9.8. Retreatment.......................................................................................................................... 82 
9.9. Follow-up Evaluations ............................................................................................................ 83 
9.9.1. 
30-Day ......................................................................................................................... 83 
9.9.2. 
180-Day ....................................................................................................................... 83 
9.9.3. 
1-Year .......................................................................................................................... 84 
9.9.4. 
2-Year .......................................................................................................................... 84 
9.9.5. 
3-Year .......................................................................................................................... 85 
9.9.6. 
Unscheduled Visits ....................................................................................................... 85 
9.10. 
Assessment of Effectiveness ............................................................................................. 86 
9.11. 
Assessment of Safety ....................................................................................................... 86 
9.12. 
New Information ............................................................................................................. 86 
9.13. 
Recording Data ................................................................................................................ 86 
9.14. 
Deviation Handling........................................................................................................... 87 
9.15. 
Subject Withdrawal or Discontinuation ............................................................................. 87 
9.15.1. 
Subject Withdrawal ................................................................................................... 88 
9.15.2. 
Subject Discontinuation by Investigator ...................................................................... 88 
9.15.3. 
Lost to Follow-up....................................................................................................... 88 
10. Risks and Benefits ..................................................................................................................... 89 
10.1. 
Potential Risks ................................................................................................................. 89 
10.2. 
Risk Mitigations ............................................................................................................... 91 
10.3. 
Potential Benefits ............................................................................................................ 92 
10.4. 
Risk-Benefit Rationale ...................................................................................................... 93 
11. Adverse Events and Device Deficiencies .................................................................................... 97 

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11.1. 
Adverse Event Definitions................................................................................................. 97 
11.1.1. 
Adverse Event ........................................................................................................... 97 
11.1.2. 
Serious Adverse Event ............................................................................................... 98 
11.1.3. 
Adverse Device Event ................................................................................................ 98 
11.1.4. 
Serious Adverse Device Event..................................................................................... 98 
11.1.5. 
Unanticipated Serious Adverse Device Event (USADE) ................................................. 99 
11.1.6. 
Unanticipated Adverse Device Event .......................................................................... 99 
11.1.7. 
Event Severity ........................................................................................................... 99 
11.1.8. 
Causality Assessment of Events .................................................................................. 99 
11.2. 
Reporting of Adverse Events........................................................................................... 102 
11.3. 
Device Deficiency........................................................................................................... 103 
12. Data Review Committees ........................................................................................................ 105 
12.1. 
Clinical Events Committee .............................................................................................. 105 
12.2. 
Imaging Core Laboratory ................................................................................................ 105 
12.2.1. 
Screening Eligibility Review ...................................................................................... 105 
12.2.2. 
Pre-Procedure Anatomy .......................................................................................... 105 
12.2.3. 
Aneurysm Occlusion ................................................................................................ 106 
12.2.4. 
Parent Artery Stenosis ............................................................................................. 106 
12.3. 
Data Monitoring Committee........................................................................................... 106 
13. Statistical Design and Methods ............................................................................................... 108 
13.1. 
General Principles .......................................................................................................... 108 
13.2. 
Sample Size Determination............................................................................................. 108 
13.3. 
Analysis Populations ...................................................................................................... 109 
13.4. 
Eligibility of Subjects, Exclusions, and Missing Data .......................................................... 110 
13.5. 
Justification of Pooling ................................................................................................... 110 
13.6. 
Subgroup Analysis.......................................................................................................... 111 
13.7. 
Interim Analysis ............................................................................................................. 111 
13.8. 
Statistical Analysis.......................................................................................................... 111 
13.8.1. 
Demographics, Clinical Baseline and Procedure Characteristics .................................. 112 

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13.8.2. 
Primary Endpoint Analysis........................................................................................ 112 
13.8.3. 
Secondary Endpoint Analysis.................................................................................... 113 
13.8.4. 
Adverse Events........................................................................................................ 114 
14. Ethics ..................................................................................................................................... 115 
14.1. 
Statement(s) of Compliance ........................................................................................... 115 
14.2. 
Institutional Review Boards/Research Ethics Board.......................................................... 115 
15. Study Administration .............................................................................................................. 117 
15.1. 
Steering Committee ....................................................................................................... 117 
15.2. 
Clinical Site Selection ..................................................................................................... 117 
15.3. 
Monitoring .................................................................................................................... 118 
15.3.1. 
Direct Access to Source Data/Documents ................................................................. 118 
15.3.2. 
Clinical Site Training ................................................................................................ 119 
15.3.3. 
Monitoring Reports ................................................................................................. 119 
15.3.4. 
Close-Out Visit ........................................................................................................ 119 
15.4. 
Data Management ......................................................................................................... 119 
15.4.1. 
Data Quality Assurance............................................................................................ 120 
15.4.2. 
Data Handling ......................................................................................................... 120 
15.4.3. 
Data Ownership ...................................................................................................... 120 
15.5. 
Compliance ................................................................................................................... 120 
15.5.1. 
Sponsor Compliance ................................................................................................ 120 
15.5.2. 
Investigator Compliance .......................................................................................... 121 
15.5.3. 
Onsite Audits .......................................................................................................... 121 
15.6. 
Confidentiality ............................................................................................................... 122 
15.7. 
Liability ......................................................................................................................... 122 
15.8. 
CIP Amendments ........................................................................................................... 122 
15.9. 
Record Retention ........................................................................................................... 122 
15.10. 
Publication and Use of Information ................................................................................. 123 
15.11. 
Suspension or Early Termination..................................................................................... 123 
16. References ............................................................................................................................. 124 

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17. Version History ....................................................................................................................... 141 
18. Appendices............................................................................................................................. 144 
18.1. 
Appendix I: Center for Medicare and Medicaid Services (CMS) IDE Study Criteria .............. 144 
 
List of Tables 
Table 4-1. Summary of Primary Endpoints of SHIELD Study ................................................................. 41 
Table 4-2. Summary of Primary Endpoints of PFLEX Study ................................................................... 42 
Table 7-1. Pipeline™ Vantage Embolization Device with Shield Technology™ Implant ........................... 54 
Table 7-2. Implant Wire Comparison of Pipeline™ Flex and Pipeline™ Vantage ..................................... 58 
Table 7-3. Implant Property Comparison of Pipeline™ Flex and Pipeline™ Vantage ............................... 59 
Table 9-1. Visit and Assessment Schedule .......................................................................................... 70 
Table 9-2. Size ranges: Pipeline™ Vantage Embolization Device with Shield Technology™ ..................... 78 
Table 11-1. Expedited Adverse Event and Device Specific Event Reporting Requirements ................... 103 
Table 12-1. Stenosis Grading Scale ................................................................................................... 106 
Table 13-1. Estimated Power Over a Range of Possible Primary Safety Outcomes with 100 Patients (a priori 
threshold of 14%) ........................................................................................................................... 108 
List of Figures 
Figure 7-1. Pipeline™ Vantage Embolization Device with Shield Technology™ Implant .......................... 53 
Figure 7-2. Pipeline™ Vantage System................................................................................................ 53 
Figure 7-3. Wire Design and Braid Pattern .......................................................................................... 56 
Figure 7-4. Cross sectional view of Drawn Filled Tubes (DFT) (Left), Drawn Filled Tubes (DFT) Visualization 
(Right) of the Pipeline™ Vantage Device............................................................................................. 57 
Figure 7-5. Pore Density of the Pipeline™ Vantage Device (left) and the Pipeline™ Flex Device (right).... 59 
Figure 9-1. Overview of Study Procedures .......................................................................................... 71 
Figure 12-1. Raymond Roy Scale for Grading Aneurysm Occlusion ..................................................... 106 
 
 

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2. Glossary 
Term 
Definition 
Access Site Complications 
Include complications of the study procedure(s) that 
arise from access site puncture and introduction of 
devices required to establish access to the intended 
vascular territory being treated. These include the 
following: 
• 
Hematomas/Hemorrhage – to be further 
subcategorized as 
o 
Localized: Painful swelling with indurated 
tissue around the access site which is usually 
treated with manual compression and 
analgesia, OR 
o 
Retroperitoneal: Clinical signs including 
hypotension, lower abdominal or flank pain 
with an acute drop in hematocrit or 
hemoglobin. A high puncture at the site of 
arterial access (typically along the inguinal 
ligament) may also be noted. Confirmed with a 
computed tomography (CT) scan of the 
abdomen. May require blood transfusion to 
maintain stable hematocrit, and an 
endovascular or surgical intervention to treat. 
• 
Pseudoaneurysm (PSA) - an arterial rupture of 
one or more layers of its walls, contained by 
overlaying fibromuscular tissue, which 
communicates with an artery by a neck or sinus. 
Clinically presents with pain at arterial access site 
with a pulsatile mass with or without an audible 
bruit, with a duplex ultrasound or Doppler 
evidence of extra-arterial flow 
• 
Vessel Occlusion - Pain, pallor, paresthesia or 
decreased movement in the respective limb. 
Clinical examination that may reveal a cold 
ischemic limb with absent pulses or decreased 
ankle-brachial index (ABI). Condition may require 
endovascular or surgical intervention. 

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• 
Arteriovenous Fistula (AVF) - New femoral bruit, 
thrill, fresh hematoma or pain in the lower limbs 
on the following day after sheath removal 
confirmed by color Doppler ultrasonography 
demonstrating an AVF with continuous systolic 
and diastolic flow. 
• 
Deep Vein Thrombosis (DVT) - Lower limb pain 
and swelling shortly following the endovascular 
intervention, confirmed by venous 
ultrasonography of the lower limb. 
• 
Local Neurogenic/Nerve Complications - 
Hypoesthesia, dysesthesia and hyperalgesia of the 
thigh caused by compression of femoral or 
cutaneous nerves or as a result of hematoma from 
the femoral artery access site. 
• 
Pain: Pain reported by the subject-specific to 
access site 
Adverse Device Effect (ADE) 
An adverse event related to the use of an 
investigational medical device. (ISO 14155:2011 3.1) 
Note 1: This definition includes adverse events 
resulting from insufficient or inadequate instructions 
for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational 
medical device. 
Note 2: This definition includes any event resulting 
from use error or from intentional misuse of the 
investigational medical device. 
Adverse Event (AE) 
Any untoward medical occurrence, unintended 
disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or 
other persons, whether or not related to the 
investigational medical device. (ISO 14155:2011 3.2) 
Note 1: This definition includes events related to the 
investigational medical device or the comparator. 
Note 2: This definition includes events related to the 
procedures involved. 

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Note 3: For users or other persons, this definition is 
restricted to events related to investigational medical 
devices.  
Aneurysm Dome 
Maximum horizontal diameter of the aneurysm. 
Aneurysm Neck 
Opening of the aneurysm where it meets the parent 
vessel 
Aneurysm Occlusion 
According to the Raymond–Roy Scale1: 
• 
Class 1: Complete Occlusion – complete 
obliteration of the aneurysm. 
• 
Class 2: Residual Neck – persistence of any 
portion of the original defect of the arterial 
wall as seen on any single projection, but 
without opacification of the aneurysmal sac. 
• 
Class 3: Residual Aneurysm – any 
opacification of the aneurysmal sac. 
Attempted Procedure 
Any procedure where Pipeline™ Vantage Embolization 
Device with Shield Technology™ was attempted i.e., 
successful puncture at the arterial access site. 
Bleeding Complications per GUSTO 
Bleeding complications shall be adjudicated using the 
GUSTO bleeding criteria which includes categorizing all 
bleeding events into the following categories: 
• 
Severe or Life-threatening: 
○ 
Intracerebral hemorrhage 
○ 
Resulting in substantial hemodynamic 
compromise requiring treatment 
• 
Moderate: 
○ 
Requiring blood 
transfusion but 
not 
resulting in hemodynamic compromise 
• 
Mild 
○ 
Bleeding that does not meet above criteria  
Cerebral Infarction 
Evidence of new ischemic changes (infarction) on 
imaging. Further characterized as: 

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• Asymptomatic: no associated focal 
neurological deficit symptoms (i.e., Silent 
Infarctions) 
• Symptomatic: focal neurological deficit 
symptoms lasting less than 24 hours  
Contrast Induced Complications 
Complications arising due to the use of contrast agent 
used for imaging requirements during study 
procedure(s).  
Delayed Intra-Cranial Hemorrhage (ICH) 
Any intracranial hemorrhage occurring >30 days post-
procedure 
Device Deficiency (DD) 
Inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety or 
performance. (ISO 14155:2011 3.15) 
Note: Device deficiencies include malfunctions, use 
errors, and inadequate labeling. 
Device Movement 
Unintended Pipeline stent (braid) Movement (as 
observed/discerned on imaging) of the implanted 
device following deployment. 
Device movement will be further characterized by: 
Timing: 
• 
Intra-procedural: Observed during the study 
index procedure 
• 
Post-procedural: Observed at a follow-up time 
point 
Type: 
• 
Foreshortening: Movement on either or both 
ends of the device in opposite direction towards 
the aneurysm neck. 
• 
Migration: Movement of device where both ends 
move in a single direction away from the 
aneurysm neck. 
• 
Device Embolization into Aneurysm: Herniation 
into the aneurysm 

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Clinical Significance: 
• 
Clinically Significant: When device movement 
causes unintended opening of the aneurysm neck 
leading to incomplete occlusion or is a reason for 
retreatment of the aneurysm. 
• 
Not 
Clinically 
Significant: 
When 
device 
movement does not cause unintended opening of 
the aneurysm neck leading to incomplete 
occlusion nor is a reason for retreatment of the 
aneurysm. 
Device Technical Success 
Device level analysis providing the rate of successful 
study device implantations at the target site with the 
total number of devices attempted to be deployed. 
Device Thrombosis 
Post-procedural, de novo formation of flow limiting 
thrombus within the device visualized on imaging. 
Each Device Thrombosis event will also be reported 
with reference to symptoms reported for the subject: 
• 
Asymptomatic: No symptoms reported that are 
presumed 
to 
be 
related to 
the 
device 
complication. 
• 
Symptomatic: Symptoms reported that are 
presumed to be related to device complication. 
Dome-to-Neck Ratio 
Aneurysm dome max diameter/aneurysm neck width 
Enrollment 
Point at which the subject signs the study authorized 
Informed Consent. 
Excessive Radiation Complications 
Any noted procedural complications that are 
presumed to result from excessive radiation exposure 
due to imaging modalities. 
Index Procedure 
The first intended procedure to implant the study 
device where a successful puncture at the arterial 
access site is completed. 
Institutional Review Board/Research Ethics Board 
Institutional Review Board (IRB) is an appropriately 
constituted group that has been formally designated 

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to review and monitor biomedical research involving 
human subjects. 
The Research Ethics Board (REB) helps ensure that this 
research meets the highest ethical standards, and that 
the greatest protection is provided to participants who 
serve as research subjects. 
Intention to Treat Population (ITT) 
 
All subjects who were consented and in whom 
deployment of the Pipeline™ Vantage Embolization 
Device with Shield Technology™ was attempted 
(successful puncture at the arterial access site), 
independent of the procedure being completed 
successfully. 
Intra-Cranial Hemorrhage  
 
• Intra-Cranial Hemorrhage: 
Hemorrhage within the fixed vault of the cranium 
(skull). ICH will be further categorized as: 
o 
Intracerebral Hemorrhage: 
 
Intra-Parenchymal Hemorrhage (IPH): 
• 
Bleeding within the cerebral matter (brain 
parenchyma), not involving the ventricles. 
Note: Acute Ischemic Stroke with hemorrhagic 
transformations included in the IPH will be explained 
in comments. 
 
Intra-Ventricular Hemorrhage (IVH): 
• 
Bleeding within the brain ventricles 
o 
Sub Arachnoid Hemorrhage (SAH): 
 
Bleeding into the subarachnoid space- the 
area between the arachnoid membrane and 
the pia mater surrounding the brain 
o 
Subdural Hematoma (SDH): 
 
Occurs when there is tearing of the bridging 
vein between the cerebral cortex and a 
draining venous sinus 
o 
Epidural Hematoma (EDH): 
 
A rapidly accumulating hematoma between 
the dura mater and the cranium 

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o 
Carotid Cavernous Fistula (CCF): A fistula 
formation within cavernous sinus or due to 
aneurysm perforation/rupture 
 
Acute (intraoperative) 
 
Delayed (any time post-index procedure) 
In the event that a single hemorrhage event results in 
bleeding in multiple locations, the most severe 
category or primary hemorrhage should be selected. 
Each ICH etiology shall be further classified as: 
 
Due to Target Aneurysm Rupture 
 
Due to Non-Target Aneurysm Rupture 
 
Due to Hemorrhagic Transformation of core 
ischemic infarct 
 
Hemorrhagic due to dual antiplatelet 
therapy (DAPT) risk 
 
Hemorrhagic due to other causes 
Intraparenchymal Hemorrhage 
Bleeding within the cerebral matter (brain 
parenchyma), not involving the ventricles. 
Investigator 
Individual member of the investigation site team 
designated and supervised by the Principal 
Investigator at an investigation site to perform critical 
clinical-investigation-related procedures or to make 
important clinical-investigation-related decisions (ISO 
14155:2011 3.24) 
Neurological Deficit 
Events other than Strokes/Neurological Death that 
cause a decline in the mRS of the subject during follow 
up. 
These will be characterized by: 
Focal:  
Along the distribution of a cranial nerve or territory 
supplied by a particular intracranial vessel that is 
related to Target Aneurysm outcome (Ipsilateral) or 
Non-Target Aneurysm outcome (Contralateral): 
 
Cranial Nerve Palsy  

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 
Visual Field Deficit/Visual Loss 
 
Localized Ipsilateral Headache 
 
NOS (not otherwise specified)  
 
Generalized:  
Due to disease process other than intra-cranial 
aneurysms 
 
Amyotropic Lateral Sclerosis  
 
Motor Neuron Disease (Multiple Sclerosis 
etc) 
 
Myasthenia Gravis  
 
Spondylosis  
 
Alcoholism  
 
Depression 
 
Intra-Cranial mass 
 
Arthritis 
 
Trauma 
 
Malaise 
 
NOS (not otherwise specific) 
Ipsilateral Localized Headache 
Localized headache with a presumed treated vascular 
territory origin, that is new or worsening from baseline. 
Ipsilateral Visual Loss 
Events that cause a decrease in visual acuity and result 
in transient or permanent visual loss due to the 
intracranial aneurysm or its treatment. 
Modified Rankin Scale (mRS) 
Scale for measuring general neurologic function 
0- No symptoms at all 
1- No significant disability despite symptoms; able to 
carry out all usual duties and activities 
2- Slight disability; unable to carry out all previous 
activities, but able to look after own affairs without 
assistance 
3- Moderate disability; requiring some help, but able 
to walk without assistance 

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4- Moderately severe disability; unable to walk 
without assistance and unable to attend to own bodily 
needs without assistance 
5- Severe disability; bedridden, incontinent and 
requiring constant nursing care and attention 
6- Dead 
mRS certified independent assessor 
To become a certified independent assessor for mRS, 
the assessor should have passed a certification exam 
via online portal BlueCloud (or have evidence of a 
previous certification within the last 2 years). The 
assessor, once certified, will only be tasked with 
performing the mRS assessment for the trial and will 
have no other responsibilities or duties associated 
with the trial. 
National Institute of Health Stroke Scale (NIHSS) 
Tool to quantify neurological impairment caused by 
stroke 
Neurological Death 
Any subject death where the primary cause is 
identified as neurological. 
Parent Artery Stenosis 
Any visually assessed parent artery stenosis report of > 
1% stenosis of the parent vessel in the region of 
device placement on follow-up imaging. Stenosis will 
be classified in the bellow quartiles: 
• 
1-25% 
• 
>25%- ≤ 50 %  
• 
>50% - ≤ 75 %  
• 
>75-100 %  
 
Each Parent Artery Stenosis event will also be 
adjudicated with reference to symptoms reported for 
the subject: 
-Asymptomatic: No symptoms reported that 
are presumed to be related to the device 
complication. 
-Symptomatic: Symptoms reported that are 
presumed 
to 
be 
related 
to 
device 
complication. 

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Per-protocol (PP) population 
Per-protocol population is ITT subjects excluding the 
following subjects: 
- 
Subjects with use of more than 1 treatment 
device other than Pipeline™ Vantage 
Embolization Device with Shield Technology™ 
(e.g., adjunctive coils) during index procedure 
- 
Subjects with failed implantation of study 
device at index procedure 
- 
Subjects assessed as mRS ≥3 at baseline by 
independent and certified assessors 
Principal Investigator (PI) 
Qualified person responsible for conducting the 
clinical investigation at an investigation site (ISO 
14155:2011 3.33) 
Procedure 
The primary study procedure involving the placement 
of the Pipeline™ Vantage Embolization Device with 
Shield Technology™ at Day 0. 
Procedural Technical Success 
Procedural Technical Success is measured by the rate 
of successful implantation of the study device during 
the study index procedure at the target site regardless 
of the number of devices deployed and implanted at 
the target site. 
Recurrence 
Aneurysm achieving complete occlusion (Raymond 
Roy 1) followed by incomplete occlusion (Raymond 
Roy 2 or 3) at follow-up exam, as assessed by Core Lab 
Serious Adverse Device Effect (SADE) 
An adverse device effect that has resulted in any of 
the consequences characteristic of a serious adverse 
event. (ISO 14155:2011 3.36) 
Serious Adverse Event (SAE) 
An adverse event that: 
a) Led to death, 
b) Led to serious deterioration in the health of the 
subject, that either resulted in 
1. A life-threatening illness or injury, or 
2. A permanent impairment of a body 
structure or a body function, or 

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3. In-subject or prolonged hospitalization, or 
4. Medical or surgical intervention to prevent 
life-threatening illness or injury or 
permanent impairment to a body structure 
or a body function, 
c) Led to fetal distress, fetal death or a congenital 
abnormality or birth defect (ISO 14155:2011 
3.37) 
Note: Planned hospitalization for a pre-existing 
condition, or a procedure required by the CIP, without 
serious deterioration in health, is not considered a 
SAE. 
Stroke 
Stroke is defined as a focal neurological deficit of 
presumed vascular origin persisting ≥24 hours from 
symptom onset and a neuro-imaging study or other 
quantitative study that does not indicate a different 
etiology. The 24-hour criterion is excluded if the 
subject undergoes cerebrovascular surgery or dies 
during the first 24 hours. 
The definition includes: 
• Subjects presenting with clinical signs and 
symptoms suggestive of SAH, intracerebral 
hemorrhage, or cerebral infarction. 
• Sudden loss or worsening of visual acuity due to 
retinal artery occlusion or retinal emboli. 
The definition excludes: 
• Slowly progressive cranial nerve palsies or 
progressive visual field deficits due to continued 
aneurysm growth. 
• Stroke events in cases of blood disorders such as 
leukemia or external events such as trauma. 
Stroke severity will be graded as: 
• Major Stroke: A stroke, which is present for≥24 
hours and increases the NIHSS of the subject by ≥ 
4. 

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• Minor Stroke: A stroke, which is present for ≥ 24 
hours and increases the NIHSS of the subject by ≤ 
3. 
NIHSS will be documented at the time of presenting 
with Stroke Symptoms, 24 hours later and at the time 
of discharge from the hospital where applicable with 
date and time of assessment. 
Stroke Etiology Will be noted as: 
• Ischemic (when the primary cause of the stroke is 
ischemic) 
• Hemorrhagic: Stroke occurring following an 
aneurysm rupture or rapidly progressing sub 
arachnoid or IPH. 
Stroke Outcome will be noted with respect to mRS 
(assessed at a minimum of 90 days post stroke event) 
at each yearly study follow- up (1 year, 2 year, 3 year).: 
o 
Disabling (mRS with poor functional 
outcome i.e. ≥3 points) 
o 
Non-Disabling (mRS with good functional 
outcome 0-2 points) 
Successful puncture at the arterial access site 
Successful placement of sheath into the arterial access 
site 
Target Aneurysm Retreatment 
Any retreatment of the target aneurysm after the 
primary study procedure implantation with the study 
device 
These events will be further categorized by: 
• Planned: Retreatment procedure that pre-planned 
(elective) and occurs in patients with no decline in 
neurological status. 
• Unplanned: Retreatment procedure that is either 
treatment emergent or occurs in patients with 
decline in neurological status 
Target Aneurysm Rupture 
Any rupture of the target aneurysm (aneurysm treated 
during the study index procedure). This will be further 
characterized as: 

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• Intra-procedural – occurring during the index 
procedure 
• Post-Procedural- occurring anytime post-index 
procedure 
Thromboembolic Complications 
Procedural complication due to clot (thrombus 
formation) during the procedure that is visualized on 
angiography, limits blood flow through the vessel 
under treatment and requires intervention or causes 
neuro-imaging changes (infarctions). Further 
categorization will be provided for those events that 
meet the definition of: 
• Distal Thromboembolic Complication: Thrombus 
(or part of) that has broken off from the territory 
where it formed (e.g. treated vascular territory) 
and traveled to a distal location (e.g. untreated 
vascular territory) presumed to have occurred 
during the study procedure. 
For each thromboembolic complication, the 
disposition of patient impact status will be provided in 
terms of: 
• Symptomatic: Resulting in focal neurological 
status decline (Stroke, Symptomatic Cerebral 
infarction, TIA) 
• Asymptomatic: Resulting in no focal neurological 
status decline and includes silent cerebral 
infarctions.  
Transient Ischemic Attack (TIA) 
 
Focal neurological deficit symptoms lasting ≤24 hours 
(transient) with no evidence of cerebral infarction on 
imaging. 
Unanticipated Adverse Device Effect (UADE) 
Any serious adverse effect on health or safety or any 
life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, 
or degree of incidence in the investigational plan or 
application (including a supplementary plan or 
application), or any other unanticipated serious 

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problem associated with a device that relates to the 
rights, safety, or welfare of subjects (21 CFR 812.3 (s)) 
Unanticipated Serious Adverse Device Effect (USADE) 
A serious adverse device effect which by its nature, 
incidence, severity or outcome has not been identified 
in the current version of the risk analysis report. (ISO 
14155:2011 3.42) 
Vascular Complications 
Includes complications of the procedure that result in 
vascular injury due to introduction of ancillary devices 
(access catheters, sheaths, microcatheters, study 
device). These include the following: 
• 
Dissection: Physical separation of intima that 
results in exposure of internal arterial wall layers 
(media and/or adventitia) to blood. 
• 
Perforation: A tear or hole placed in a vascular 
structure of small nature, results in blood loss, 
but may not be as severe as a great vessel tear 
• 
Rupture: Rupture created entirely through the 
arterial wall causing significant amount of blood 
loss. 
• 
Vasospasm: Vasoconstriction observed during 
study procedure access of the aneurysm or 
treatment with study device. 
The vascular complications will be further classified as: 
o 
Intra-Cranial: Observed within the cerebral 
vessels (cerebral vasospasms) 
o 
Extra Cranial: Observed in neck vessels eg. 
external carotid artery 
o 
Peripheral: observed in the peripheral 
arteries e.g. femoral, radial, aortic etc. 
Visual Symptoms (Ipsilateral) 
All visual symptoms that appear as either a worsening 
from baseline or are new events from baseline and are 
presumed to be related to the study treatment in the 
absence of evidence of cerebral ischemia and not 
qualifying for ipsilateral cranial nerve palsies or 
neurological deficits 

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These will be categorized further in the following 
symptom classifications with one event denoted to a 
single symptom: 
• 
Blurred Vision 
• 
Scintillations (e.g., Flashes of Light) 
• 
Eye Floaters (temporary clumpy obstruction of 
vision) 
• 
Diplopia (double vision) 
• 
Retinal artery occlusion (evidence of retinal 
artery occlusion on funduscopic exam) 
• 
Visual disturbance, Not Otherwise Specified 
(NOS) 
In addition, where known a categorization of symptom 
frequency will be done into one of the followings: 
o 
Transient: Continuous symptoms resolving 
within the study period. 
o 
Permanent: Continuous symptoms persisting 
at the end of the study period. 
o 
Intermittent: Non-continuous symptoms 
appearing and disappearing within the study 
period. 

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3. Synopsis 
 
Title 
A Study of the Pipeline™ Vantage Embolization DeVice with Shield 
Technology™ for EndovAscular TreatmeNt of Wide-NeCked Intracranial 
AnEurysms 
Clinical Study Type 
Investigation Device Exemption (IDE) Study (Interventional) 
Product Name 
Pipeline™ Device Family with Shield Technology™ (referred to as Pipeline™ 
Vantage Embolization Device with Shield Technology™ in this CIP) 
Sponsor  
Micro Therapeutics, Inc. d/b/a ev3 Neurovascular (a wholly owned subsidiary 
of Medtronic) 
Indication under 
Investigation  
The Pipeline™ Vantage Embolization Device with Shield Technology™ is 
intended for endovascular treatment of adults (22 years of age or older) with 
wide-necked intracranial aneurysms located in the internal carotid artery (up 
to the terminus). 
Investigation 
Purpose 
The investigation purpose is to assess the safety and effectiveness of the 
Pipeline™ Vantage Embolization Device with Shield Technology™ in the 
treatment of intracranial aneurysms within the intended indication for use. 
Product Status 
Pipeline™ Vantage Embolization 
Device with Shield Technology™, 
investigational product in U.S. 
Primary Objective 
The primary objective of the study is to assess the safety and effectiveness of 
the Pipeline™ Vantage Embolization Device with Shield Technology™ in the 
treatment of intracranial aneurysms within the intended indication for use. 
Primary Study 
Endpoints 
Primary Effectiveness Endpoint: Incidence of complete aneurysm occlusion 
(Raymond Roy Scale Class 1) without significant parent artery stenosis (≤ 50%) 
or retreatment of the target aneurysm at 1-year post-procedure. 
 
Primary Safety Endpoint: Incidence of major stroke in the territory supplied by 
the treated artery or neurological death at 1-year post-procedure. 
Secondary Objective The secondary objective of the study is to assess the safety and effectiveness 
of the Pipeline™ Vantage Embolization Device with Shield Technology™ in the 
treatment of intracranial aneurysms within the intended indication for use. 
Secondary 
Endpoint(s) 
Effectiveness Outcome measures: 
1. Incidence of successful device implantation at the target site 
2. Incidence of complete aneurysm occlusion (Raymond Roy Class 1) at 1- 
and 3-years post-procedure 
3. Incidence of target aneurysm recurrence at 1- and 3-years post-
procedure 
 

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Safety Outcome measures: 
1. Incidence of major stroke in the territory supplied by the treated artery 
or neurological death at 2- and 3-years post-procedure 
2. Incidence of major stroke in the territory supplied by the treated artery 
or neurological death at 30 days post-procedure 
3. Incidence of delayed intraparenchymal hemorrhage >30 days post-
procedure through 1-year post-procedure 
4. Incidence of subjects with disabling strokes that have a mRS decline to 
a score of 3 or more (mRS ≥ 3) due to a stroke-related cause assessed 
at a minimum of 90 days post-stroke event at 1 year, 2 year, and 3 year 
post-procedure  
Study Design 
A prospective, global, multi-center, single-arm, IDE clinical study  
• 
Enrollment Duration: Approximately 1 year 
• 
Follow-up: 3 years 
• 
Total Study Duration: Approximately 4 years 
Sample Size 
Up to 140 subjects may be enrolled (consented) to ensure 100 evaluable 
subjects undergo attempted treatment with the Pipeline™ Vantage 
Embolization Device with Shield Technology™ at up to 30 sites, including up to 
25 sites in the U.S. and up to 5 sites outside U.S. (OUS).  The target sample size 
for this clinical investigation is 100 patients enrolled and treated and followed 
for safety events with the expectation of having follow-up imaging at 1-year 
post-procedure on a minimum of 80 patients.   
Inclusion/Exclusion 
Criteria 
Inclusion Criteria: 
Imaging Criteria (Core Lab Assessed) 
1. Subject has a target intracranial aneurysm located in the internal 
carotid artery (up to the terminus). 
2. Subject has a target intracranial aneurysm with an aneurysm neck 
≥4mm or a dome-to-neck ratio of < 2. 
3. Subject has a target intracranial aneurysm that has a parent vessel 
with diameter 1.5–5.0 mm distal/proximal to the target intracranial 
aneurysm. 
Clinical Criteria 
4. Subject (or subject’s legally authorized representative) has provided 
written informed consent using the IRB/REB and Medtronic approved 
Informed Consent Form and agrees to comply with protocol 
requirements. HIPAA/data protection authorization has been 

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provided and signed by the subject (or subject’s legally authorized 
representative). 
5. Age 22-80 years at the time of consent. 
6. Life expectancy ≥3 years 
7. Subject has a mRS ≤ 2 at baseline to be determined by a certified 
independent assessor at the site. 
8. Subject has already been selected for endovascular treatment of the 
target aneurysm.  
9. Subject’s last recorded P2Y12 reaction units (PRU) value is between 
≥60 and ≤200 prior to study procedure. For OUS sites, a 
Thromboelastogram (TEG) test may be carried out instead of the PRU 
test (depending on PRU test availability). In cases where TEG test is 
carried out, the subject should have a pre-procedure therapeutic 
ADP% between >30% to <90%. 
10. Subject has multiple increased risk factors for intracranial aneurysm 
rupture, including but not limited to, aneurysm morphology, smoking, 
hypertension, diabetes, age, prior and/or family history of rupture, 
and/or history of subarachnoid hemorrhage that may result in a 
benefit risk profile of endovascular treatment to outweigh the risks of 
intracranial aneurysm rupture during the subject’s expected lifetime if 
left untreated. 
Exclusion Criteria: 
Imaging Criteria (Core Lab Assessed) 
11. Subject has internal carotid artery bifurcation aneurysm. 
12. Aneurysms that arise from the Posterior Communicating Artery 
(PComm). 
13. The internal carotid artery aneurysms of the C7 segment will be 
excluded under the following conditions: 
a. Observed fetal posterior communicating artery (PComm) (A 
PComm of fetal origin is defined as a small, hypoplastic, or 
absent P1 segment of the posterior cerebral artery (PCA) with 
the PComm artery supplying a majority of blood flow to the 
P2 and higher order segments of the PCA) 
b. PComm overlapping with the aneurysm neck 
c. PComm branch arising from the dome of the aneurysm 
14. Subject has aneurysm arising from internal carotid artery but is 
primarily fed by posterior circulation (i.e., retrograde flow from the 
basilar artery) as confirmed by DSA 
Clinical Criteria 

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15. Subject requires treatment of another aneurysm (with another 
treatment modality) within the affected territory of the target 
aneurysm during the study period. 
16. Subject has received an intracranial implant (e.g. coils) in the area of 
the target intracranial aneurysm within the past 6 months prior to the 
study procedure. 
17. Subject has had a SAH and/or target aneurysm rupture in the past 30 
days prior to the study procedure. 
18. Subject has undergone a surgery including endovascular procedures 
in the last 30 days prior to the study procedure. 
19. Vessel characteristics (e.g. severe tortuosity, stenosis, morphology) 
that preclude safe endovascular access to the aneurysm to allow for 
necessary access to treat with the study device. 
20. Aneurysm vessel characteristics (e.g., parent vessel stenosis, irregular 
morphology) that would preclude the device from fully conforming to 
the parent vessel to reduce any risk of embolic complications, re-
treatment, or device movement. 
21. Subject has active vasospasm, malignant brain tumor or vascular 
malformation (e.g. arteriovascular malformation). 
22. History of major bleeding disorder (based on coagulation profile and 
platelet count) and/or subject presents with signs of active bleeding. 
23. Subject requires adjunctive device use (e.g. coils) during the index 
procedure.  
24. Subject has extradural target aneurysm <12mm which is not 
symptomatic or not exhibiting aneurysm growth (exception: unless it 
is a fusiform aneurysm <12 mm i.e., asymptomatic extradural fusiform 
aneurysms <12 mm can be included). 
25. Any known contraindication to treatment with the Pipeline™ Vantage 
Embolization Device with Shield Technology™, or use of antiplatelet 
therapy including: 
a. Active bacterial infection 
b. Contraindication to DAPT agents  
26. Pre-existing stent is in place in the parent artery at the target 
intracranial aneurysm location  
27. Platelet count < 100 x 103 cells/mm3 or known platelet dysfunction. 
28. The Investigator determines that the health of the subject or the 
validity of the study outcomes (e.g., high risk of neurologic events, 
conditions that may increase the chance of stroke) may be 
compromised by the subject’s enrollment. 

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29. Subject is pregnant or wishes to become pregnant during the first 
year of study participation. 
30. Subject is participating in another clinical trial at any time during the 
duration of the study that could confound the treatment or outcomes 
of this investigation. 
31. Subject with known allergy to platinum or cobalt chromium alloy 
(including the major elements platinum, cobalt, chromium, nickel or 
molybdenum). 
32. History of previous acute ischemic stroke 
33. Subject is unable to undergo DSA or CTA imaging at follow-up. 
Study Procedures 
and Assessments 
Treatment/Follow-up: 
The study will consist of the following study visits: 
• 
Baseline 
• 
Pre-Procedure 
• 
Post-Procedure 
• 
Discharge exam 
• 
30-day follow-up 
• 
180-day follow-up 
• 
1-year follow-up 
• 
2-year follow-up 
• 
3-year follow-up 
Eligible subjects will be treated with the Pipeline™ Vantage Embolization 
Device with Shield Technology™ per the Instructions For Use (IFU). 
 
All subjects will receive DAPT pre- and post-procedure as described in the 
protocol. 
 
A schedule of assessments to be performed at each study visit is listed in the 
table below:  

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 Statistics 
Primary Hypothesis for Evaluating Study Success 
The hypothesis for evaluating the primary safety endpoint will be evaluated 
according to the following 2 requirements: 
Requirement 1: The incidence of primary safety events must be ≤7%, and  
Requirement 2: The null hypothesis must be rejected in favor of the alternative: 
Ho: Incidence at 1-year post-procedure of major stroke and/or neurological 
death is ≥ 14.0% 
Ha: Incidence at 1-year post-procedure of major stroke and/or neurological 
death is < 14.0% 
Given the primary safety endpoint reported in PMA P100018 (PUFs) was 5.6%, 
an incidence of ≤7% for the primary safety endpoint would be considered 
clinically acceptable within the confines of a study of this general size. If the 
incidence of primary safety events is ≤7% and the upper bound of the 1-sided 
97.5% exact binomial confidence interval is <14%, the primary safety endpoint 
will have been met. 
 
The primary effectiveness endpoint is the incidence of complete aneurysm 
occlusion (Raymond Roy Scale Class 1) without significant parent artery 

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stenosis (≤ 50%) or retreatment of the target aneurysm at 1-year post-
procedure. The incidence will be summarized using counts and percentages; 
the 1-sided upper bound of the 97.5% confidence limit for the incidence will be 
evaluated relative to the a priori threshold of 50%. The hypothesis for 
evaluating the primary effectiveness endpoint is stated below: 
Ho: Incidence at 1-year post-procedure of complete aneurysm 
occlusion without retreatment or significant parent artery stenosis is ≤ 
50.0% 
Ha: Incidence at 1-year post-procedure of complete aneurysm 
occlusion without retreatment or significant parent artery stenosis is > 
50.0% 
The pre-specified threshold of 50% for effectiveness endpoint is based on the 
effectiveness threshold of the recent PREMIER study with the Pipeline™ Device. 
This threshold must be exceeded at a certain magnitude to reject the null 
hypothesis and merely serves a statistical boundary for analysis. If the upper 
bound of the 1-sided 97.5% exact binomial confidence interval is >50%, the 
primary effectiveness endpoint will have been met. 
 
 
Sample Size 
The target sample size for this clinical investigation is 100 patients enrolled and 
treated and followed for safety events with the expectation of having digital 
imagery at 1-year post-procedure on a minimum of 80 patients.  To calculate 
the sample size, simulations were prepared in SAS assuming an observed 
incidence in the ADVANCE IDE study of primary safety events ranging from 5.6% 
to 6.9%.  With 100 patients and an observed incidence of safety event from 
5.6% to 6.4%, the power exceeded 80%. Between the ranges of 6.5% to 6.9%, 
the power ranged from 79.8% to 74.7% for the primary safety endpoint and 
slightly below 80%.  Although the power is less than 80 when the incidence of 
safety events was 6.5% or higher, the power was still considered adequate 
when contrasted against the actual upper bound of the 1-sided 97.5% exact 
binomial confidence interval.  Specifically, if 7 of the 100 patients experience a 
primary safety event, the upper bound of the 1-sided 97.5% exact binomial 
confidence interval would be 13.89% and below the 14% threshold. 
For primary effectiveness endpoint, the power was estimated for an observed 
rate between 65% to 80% considering sample sizes from 80 to 100 patients.  
With a type 1 error rate of 2.5%, 100 patients would have 82.8% power to reject 
the null hypothesis if the observed incidence of complete aneurysm occlusion 
without parent artery stenosis or retreatment was 65%. Under the same 
scenario with 80 patients, the power would be 83.5% if the observed incidence 
of complete aneurysm occlusion without parent artery stenosis was 67%. To 

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ensure at least 95% power with 80 and 100 patients, the observed incidence of 
complete aneurysm occlusion without parent artery stenosis would need to be 
a minimum of 71% and 69%, respectively, which is relatively in-line with the 
previous results with the results from previous Pipeline studies. 
 
Statistical Analysis 
With the general exception of the tests comparing the response to an a priori 
threshold, all statistical tests will be 2-sided, performed at the 5% significance 
level. Baseline is defined as the last observation recorded prior to the study 
procedure. 
The primary effectiveness endpoint is the incidence of complete aneurysm 
occlusion (Raymond Roy Scale Class 1) without significant parent artery 
stenosis (≤ 50%) or retreatment of the target aneurysm at 1-year post-
procedure; the 1-sided lower bound of the 97.5% confidence limit for the 
incidence will be evaluated relative to the a priori threshold of 50%.  The 
primary presentation of the results for the ITT population will be based on the 
observed data with multiple imputation for missing endpoint data using SAS 
PROC MI. 
The primary safety endpoint is the incidence of major stroke in the territory 
supplied by the treated artery or neurological death recorded within 1 year of 
the study procedure. The incidence will be summarized using counts and 
percentages; the 1-sided upper bound of the 97.5% confidence limit for the 
incidence will be evaluated relative to the a priori threshold of 14%. 
 
 

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4. Introduction 
4.1. 
Background 
Intracranial aneurysms are common vascular abnormalities estimated to occur in 3-5% of the population.2-
6 Intracranial aneurysms can be classified according to size: small (<7 mm), medium (7-12mm), large (13-
24 mm), and giant (≥25 mm). In terms of aneurysm morphology, the majority are saccular and are 
classified into either of two anatomical locations: side-wall or bifurcation aneurysms. The neck of the 
aneurysm for both of these aneurysm subtypes can be either narrow (< 4 mm) or wide (≥ 4 mm).7-9 
Most intracranial aneurysms are asymptomatic until they rupture, which can occur suddenly and without 
warning, leading to cerebral bleeding or subarachnoid hemorrhage (SAH). SAH is a devastating 
complication with a reported case-fatality rate of up to 45%, leaving nearly half of its survivors functionally 
incapacitated with less than 5% good outcomes.1,10,11 Aneurysm characteristics including larger size, 
location (BasA bifurcation, vertebral/basilar artery, AcomA or PcomA), and morphology and shape 
(irregularity or lobulation, size ratio > 3 or aspect ratio > 1.6) have been shown to contribute to rupture 
risk.12-16 Other aneurysm-related factors that may impact the risk of rupture include aneurysm de novo 
formation on serial imaging, contralateral steno-occlusive vessel disease, and aneurysm multiplicity. In 
addition to aneurysm-related factors, several patient-related factors, such as prior individual history or 
familial history of SAH, hypertension, cigarette smoking, drug use, alcohol abuse, cardiac conditions 
(including atrial fibrillation, cardiac arrhythmias, congestive heart failure, and myocardial infarction), 
psychiatric disorders, and epilepsy have been shown to contribute to rupture risk. Risk of aneurysm 
rupture has also been shown to be associated with aneurysm growth.17-20 A meta-analysis conducted by 
Brinjinki et al. including 21 studies with 3,954 subjects examined the risk factors associated with aneurysm 
growth. The overall proportion of growing aneurysms was 3.0% per aneurysm-year, and aneurysm growth 
was associated with a rupture rate of 3.1% per year, compared with 0.1% per year for non-growing 
aneurysms (p < 0.01). Recent data suggests that aneurysmal growth is likely non-linear and occurs in 
episodes of instability and growth followed by periods of stability, which could add to the risk of rupture 
regardless of size.21 Given the high mortality rate and poor prognosis associated with ruptured intracranial 
aneurysms, the goal of aneurysm therapy is to reduce the incidence of spontaneous rupture or to alleviate 
symptoms of mass effect related to aneurysm growth. The anatomic goals of intracranial aneurysm 
treatment are 1) to completely isolate the aneurysm sac from the circulation (i.e. complete occlusion) 
and, 2) to restore the morphologic integrity of the parent artery.22 
In evaluating intracranial aneurysm treatment options, physicians commonly consider both surgical 
clipping and endovascular therapy, which differ in their ability to achieve complete occlusion. Surgical 
clipping of intracranial aneurysms is generally associated with good aneurysm occlusion, but high 
procedure-related mortality and morbidity rates. Endovascular treatment generally provides a safe and 
effective alternative to surgical treatment. Prospective controlled trials have demonstrated that 
endovascular coil embolization is associated with better outcomes compared to surgical clipping.23-27  

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In cases of wide-neck aneurysms, which are difficult to treat with coils alone, stent-assistance can be 
employed to prevent coil protrusion into the main vessel lumen. Stent-assisted coiling (SAC) uses 
conventional intracranial stents with low-metal-surface-area (high porosity), which are labeled as a 
humanitarian use device in the U.S.28 SAC is used to treat wide-neck aneurysms by the scaffold they 
provide and can provide better initial occlusion rates while sparing the parent artery lumen and decrease 
likelihood of recanalization by altering the intra-aneurysmal hemodynamics.28 
Although SAC of wide-necked aneurysms of various sizes represents a well-established and widely-applied 
treatment option, this treatment approach may be associated with sub-optimal long-term outcomes. In 
particular, SAC has shown diminished efficacy in the treatment of large and giant complex aneurysms, 
differing widely in terms of reported occlusion rates, ranging from 48-87.3%.28-34 Furthermore, despite 
achieving complete occlusion, coil compaction over time may lead to aneurysm recurrence, necessitating 
retreatment. In a systematic review by Shapiro et al. on 39 published studies including 1,517 subjects with 
various-sized aneurysms treated by stent-assisted coiling, complete aneurysm occlusion was achieved in 
61% of subjects at various follow-up times among studies.35 In the same review, aneurysm recanalization 
was reported in 14% of subjects.35 In other published literature on SAC for the treatment of aneurysms of 
various sizes, recanalization after treatment with coiling or SAC has been reported at rates between 16.8% 
and 59.1% for large/giant aneurysms36-41 and between 6.2% and 16.9% for small/medium aneurysms.42-47 
Recurrence rates as high as 16.9% in small/medium aneurysms and 59.1%48 in giant aneurysms after 
coiling alone, and as high as 10.5% for small/medium aneurysms after stent-assisted coiling have been 
reported in the literature.  
Complications following SAC of large and giant complex aneurysms include neurological morbidity, such 
as ischemic and hemorrhagic events. 28-34 Reported morbidity rates ranged from 0-9.4% and a mortality 
rates from 0-4.1%.28-34 Procedural and long-term outcomes across the studies evaluated indicate that the 
potential harms from coiling techniques include thromboembolic/stroke (1.4-8.7%) and hemorrhage (1.7-
6%). In the aforementioned systematic review by Shapiro et al., 9% of cases were confounded by technical 
stent-related issues, including 4% failure of deployment.35 The overall procedural complication rate was 
19%, with a peri-procedural mortality of 2.1%. Thromboembolic issues were most prevalent at close to 
10% while hemorrhagic complications occurred in 2.2% of cases–accounting for approximately 1% of all 
deaths. The authors concluded that next-generation endoluminal devices will likely expand the scope and 
effectiveness of endovascular aneurysm treatment.35  
Flow-diverting devices represent a paradigm shift in the endovascular treatment philosophy for 
intracranial aneurysms and act in a two-fold manner: 
(1) They divert flow away from the aneurysm sac, thereby inducing thrombosis within the sac and 
obviating the need for coil embolization; and 
(2) They facilitate reconstruction of the parent vessel by providing a scaffold for endothelialization.  

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Pipeline™ Flex Embolization Device flow diverter is currently indicated in the US for the endovascular 
treatment of adults (22 years of age or older) with large or giant wide-necked intracranial aneurysms (IAs) 
in the internal carotid artery from the petrous to the superior hypophyseal segments. The Pipeline™ Flex 
embolization device is also indicated for use in the internal carotid artery up to the terminus for the 
endovascular treatment of adults (22 years of age or older) with small and medium wide necked (neck 
width ≥ 4 mm or dome-to-neck ratio < 2) saccular or fusiform intracranial aneurysm (IAs) arising from a 
parent vessel with a diameter ≥ 2.0 mm and ≤ 5.0 mm. The Pipeline™ Embolization Device and Pipeline™ 
Flex Embolization Device consist of the same device implant. The main difference lies in the delivery 
system. The Pipeline™ Flex Embolization Device improves on the Pipeline™ Embolization Device delivery 
system via incorporation of a resheathing mechanism and the replacement of the Pipeline™ Embolization 
Device protective coil with polytetrafluoroethylene (PTFE) sleeves. The resheathing mechanism allows 
physicians to reposition and redeploy the Pipeline™ Flex Embolization Device and the PTFE sleeves 
improve the physician’s ability to release the implant.  
Published data on the Pipeline™ Embolization Device used to treat complex large/giant aneurysms show 
rates of 68-94.4% complete occlusion that remains persistent 2-3 years after the index procedure and 0-
13.9% associated morbidity and 0-6.9% mortality.49-55 The PREMIER study (Section 4.2.5) on the Pipeline™ 
Embolization Device and the Pipeline™ Flex Embolization Device included 119 (84.4%, 119/141) small 
aneurysms (< 7 mm) and 22 (15.6%, 22/141) medium aneurysms (7-12 mm). Through 1-year follow-up, 
81.9% (113/138) aneurysms had complete occlusion, none (0%; 0/138) had aneurysm recurrence and 
2.9% (4/139) had aneurysm retreatment; delayed intracerebral hemorrhage >30 days through 1-year 
post-procedure occurred in 0.73% of subjects and the overall mortality rate was 0.7% (1/141). These rates 
are similar to or better than those for conventional intracranial aneurysm treatment of surgery or 
coiling.38,56 Technical results of Pipeline™ Flex Embolization Device use show high procedural success (93-
100%).57-62 Additionally, the Pipeline™ Flex Embolization Device was associated with significant reductions 
in total procedure time, fluoroscopy time, patient radiation exposure, contrast usage, and rate of 
deployment failure compared with Pipeline™ Embolization Device. 
Even though the Pipeline™ Embolization Device and Pipeline™ Flex Embolization Device have been 
associated with high long-term complete aneurysm occlusion rates, low retreatment and no recurrence 
rates, one of the major concerns has been the associated ischemic complications (including 
thromboembolic complications) and stenosis.63,64 Thus, the next developmental modification to the 
Pipeline™ Device was adding the Shield Technology™ to the next generation device, Pipeline™ Flex 
Embolization Device with Shield Technology™. Shield Technology™ utilizes a phosphorylcholine (PC) 
surface modification to the existing implant combined with the Pipeline™ Flex Embolization Device 
delivery system. The Shield Technology™ surface modification applied to the implant is an inert, PC 
polymer material that is chemically bonded to the braid surface. The polymer is a chemically derived 
material, created to mimic the outer membrane of a human red blood cell. Shield Technology™ reduces 
the material thrombogenicity of the braid surface compared to the bare metal PFED implant based on 

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bench data with human platelets and plasma.65-68 In vitro assessment of PC-coated stainless steel 
demonstrated that it is resistant to fibrinogen adsorption, platelet activation, platelet adherence, and 
erythrocyte adherence.69,70 Platelet adherence and thrombosis are also inhibited on PC-coated stents 
implanted in peripheral arteries of rabbits, pigs, dogs, and baboons.69,71-73 The SHIELD OUS (Section 4.2.7) 
and PFLEX (Section 4.2.8) prospective, multi-centre, post-market studies were carried out to gather real-
world safety and effectiveness data of the Pipeline™ Flex Embolization Device with Shield Technology™. 
These studies, combined, gathered substantial real-world evidence on more than 250 subjects. Both 
SHIELD OUS and PFLEX studies achieved a high rate of complete aneurysm occlusion with the use of the 
Pipeline™ Flex Embolization Device with Shield Technology™ in the treatment of intracranial aneurysms. 
The incidence of major stroke, neurological death, and delayed intracerebral hemorrhage in both these 
studies were low. Therefore, results from the SHIELD OUS and PFLEX studies demonstrated that the 
Pipeline™ Flex Embolization Device with Shield Technology™ is effective and safe for the endovascular 
treatment of intracranial aneurysms (Section 4.2.7 and 4.2.8). 
The latest iteration of the Pipeline™ Embolization Device, the Pipeline™ Vantage Embolization Device with 
Shield Technology™ (herein after referred to as Pipeline™ Vantage), employs an enhanced version of the 
Pipeline™ Flex Embolization Device with Shield Technology™. Pipeline™ Vantage implant is a braided, 
multi-alloy, mesh cylinder woven from Drawn Filled Tubes (DFT) constructed from cobalt-chromium-
nickel (MP35N LT) that is filled with a platinum core. The implant is modified with an inert surface 
treatment (Shield Technology™) that incorporates a durable, non-reactive material specifically designed 
to mimic human red blood cell membrane. The surface treatment is primarily composed of a 
phosphorylcholine polymer (Lipidure®-NH01). Design enhancements to the braided implant (Section 
7.1.1) are intended to enhance radiopacity, delivery forces, distal, middle and proximal opening. The 
delivery system (Section 7.1.1.4) utilizes a single tapered core wire for improved one to one response, 
including a larger proximal portion for enhanced pushability. The newly designed Advanced Resheathing 
Mechanism (ARM) engages the pores of the braid to enable resheathing with enhanced reliability. Design 
enhancements to the delivery system are intended to enhance tactile feedback, delivery forces and 
include a low-profile delivery.  
For pre-clinical application, 9 published pre-clinical studies analyzed thrombogenicity, endothelialization, 
stenosis, and aneurysm occlusion for Pipeline™ Flex Embolization Device with Shield Technology™.74-82 
Three of these studies74,75,81 compared thrombogenicity of Pipeline™ Shield to other flow diverters such 
as  Pipeline™ Embolization Device (PED),75 Pipeline™ Flex,74,81 SILK+,74 P64,81 Derivo®,81 and Flow 
Redirection Endoluminal Device (FRED™)74,75 in vitro under varied antiplatelet regiments. These studies 
reported that the Pipeline™ Shield device led to significantly lower thrombin generation,74,81  platelet 
activation,81 aggregation,81 and deposition on device surface,75,9 and significantly lower fibrin 
accumulation75 than the other flow diverters studied, with or without antiplatelet therapy. These results 
provided clinically relevant evidence that the Shield Technology™ surface modification of endoluminal 
stents could be an effective method to mitigate thrombogenic complications associated with aneurysm 

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treatments. Further, 6 studies76-80,82 compared the Pipeline™ Shield device to the other flow diverters such 
as PED,76,77,79,82 Pipeline™ Flex,78,80 and FRED™82 using animal models. Under various single or dual 
antiplatelet therapy regimens, Pipeline™ Shield implantation was shown to be associated with less 
thrombus formation on the surface of the device,77,80,82 especially post-angioplasty.82 As compared to PED, 
in-stent stenosis was reduced in Pipeline™ Shield without DAPT76 and was reported as 0% with DAPT,76 
and neointimal hyperplasia was reduced without reducing aneurysm occlusion.79 At the same time, these 
studies demonstrated faster endothelium growth80 with more evenly distributed concentric neointimal 
formation,78 comparable neointimal volume (to other flow diverters),78,80 and earlier healing response78 
after the Pipeline™ Shield device implantation. Overall, the published in-vivo preclinical studies 
demonstrated that the Shield Technology™ resulted in reduced thrombus formation and in-stent stenosis; 
while demonstrating similar occlusion and faster and more uniform healing response as compared to the 
previous generations of PED and other flow diverters. 
4.2. 
Clinical Experience with the Pipeline™ device 
The clinical benefits achieved with the use of use of Pipeline™ Embolization Device have been consistently 
demonstrated in multiple clinical trials.49,50,52-54,83-88 Pipeline™ Embolization Device demonstrates high 
efficacy and a good safety profile in treating aneurysms of diverse morphology, ranging from small to 
more complex and difficult to treat aneurysms (e.g. large aneurysms, wide-neck aneurysms, or aneurysms 
with complex morphology).50,54,55,89-91 Clinical outcomes from 8 key studies on the Pipeline™ Device 
(including, Pipeline™ Embolization Device, Pipeline™ Flex Device, and Pipeline™ Flex with Shield 
Technology) have been summarized below. 
4.2.1. 
PITA: Pipeline for Intracranial treatment of Aneurysms 
The PITA study was the first prospective multi-center trial of a flow-diverting construct for the treatment 
of complex intracranial aneurysms. Thirty-one subjects with wide-necked (>4 mm) and unfavorable 
dome/neck ratios (<1.5 mm) and subjects with an intracranial aneurysm that had failed previous 
endovascular treatment were included. Of the 31 aneurysms, 65% were small (<10 mm) and the remaining 
35% were large and giant in size. In total, 46 of 47 Pipeline™ device braids were placed successfully 
(97.9%). In 30 out of 31 subjects, the entire neck of the targeted intracranial aneurysm was covered by 
the Pipeline™ device braid. Complete aneurysm occlusion was observed in 93.3% (28/30) subjects at 180 
days. Two subjects experienced a major peri-procedural stroke and no deaths occurred. 
4.2.2. 
PUFs: Pipeline™ Embolization Device for Uncoilable or Failed Aneurysms 
The PUFs study was a multi-center, prospective, single-arm trial to evaluate the safety and effectiveness 
of the Pipeline™ Embolization Device (PED) in complex large and giant intracranial aneurysms. One 
hundred seven subjects with large and giant unruptured wide-necked aneurysms in the petrous to the 
superior hypophyseal segment of the ICA were treated with the PED. The aneurysms measured ≥ 10 mm 
in diameter and had either a neck ≥ 4 mm or no discernable neck. A total of 104 subjects with 106 

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aneurysms were included in the primary effectiveness cohort and evaluated by an independent core lab. 
Of the 106 aneurysms, 78 demonstrated complete occlusion without major stenosis at 180 days (73.6%; 
95% posterior probability interval: 64.4%–81.0%). At one year, 86.8% (79/91) of the target aneurysms 
were completely occluded. This rate increased to 95.2% (59/62) complete occlusion at five years. There 
were no cases of aneurysm recurrence. The primary safety endpoint was the occurrence of major 
ipsilateral stroke or neurologic death at 180 days, which occurred in six of the 107 subjects (5.6%; 95% 
posterior probability interval: 2.6%–11.7%). At five year follow-up, and the rate of major ipsilateral stroke 
or neurologic death remained 5.6%.92  
4.2.3. 
IntrePED: International Retrospective Study of the Pipeline™ Embolization Device 
The IntrePED study was a retrospective global post-market study of subjects treated with the PED at 17 
centers worldwide.85,93 A total of 793 subjects with 906 aneurysms of various sizes and locations were 
included. The median follow-up period was 19.3 months with 89% subjects with greater than 1 year 
follow-up. The overall neurological morbidity rate was 7.4% (59/793) and the neurological mortality rate 
was 3.8% (30/793). The combined neurological morbidity and mortality rate was 8.4% (67/793). The 
combined neurological morbidity and mortality for the subset of subjects with unruptured aneurysms was 
lower at 7.5% (54/720). Data from the IntrePED study report the safety of the PED in the treatment of 
various intracranial aneurysms in a real-world clinical setting. 
4.2.4. 
ASPIRe: Aneurysm Study of Pipeline™ in an Observational Registry  
ASPIRe was a prospective, multi-center, single-arm, post-market registry of 191 intracranial aneurysm 
patients with 207 aneurysms from 28 worldwide centers who underwent PED treatment. The 207 
aneurysms in the study had a median follow-up duration of 6.6 months. The majority of aneurysms 
treated were saccular and overall average size of treated aneurysms was 14.5 mm. 
Neurological morbidity was 6.8% (13/191) and the neurologic mortality rate was 1.6% (3/191). The 
combined rate of neurological morbidity and mortality was 6.8% (13/19), with the most common major 
adverse event of interest being intracerebral hemorrhage (3.7%, 7/191) followed by ischemic stroke 
(1.6%, 3/191). Most of the major adverse events (6.3%, 12/191) occurred in the early post-operative phase 
within the first 30 days following PED treatment. 
Aneurysm occlusion was assessed by an independent core lab according to the Scale of Roy at last visit 
for all subjects with imaging follow-up of at least 6 months. The median follow-up duration was 7.8 
months and complete occlusion was reported in 75% of subjects (77/103). 
The ASPIRe registry, as a comprehensive evaluation of PED use in the real world, confirmed that the PED 
is safe when used for the treatment of intracranial aneurysms in routine clinical practice, reporting a 6.8% 
rate of associated major morbidity and neurological mortality. 

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4.2.5. 
PREMIER: Prospective Study on Embolization of Intracranial Aneurysms with the 
Pipeline™ Device 
PREMIER was the first prospective, multicenter trial to evaluate the use of the Pipeline™ device for the 
treatment of small and medium, unruptured aneurysms of the intracranial carotid and proximal vertebral 
artery. The study was conducted in 1 Canadian and 22 US centers.  
A total of 141 subjects with 141 target aneurysms were treated in the study; target aneurysm was defined 
as the largest aneurysm treated in the procedure. The majority of target aneurysms (96.5%, 136/141) 
were unruptured at the time of entry into the study. The target aneurysms were mostly located in the ICA 
(95.0%, 134/141), most of which were located in C6 (ophthalmic segment, 74.6%, 100/134) and C7 
(communicating segment, 14.2%, 19/134). Five percent (7/141) of aneurysms were located in the VA. The 
mean dome/neck ratio was 1.1±0.28 and the mean aneurysm size was 5.0±1.92 mm. Of the 141 target 
aneurysms, 119 (84.4%, 119/141) were small (< 7 mm) and 22 (15.6%, 22/141) were medium (7-12 mm) 
aneurysms. No large or giant aneurysms (≥13 mm) were included in the PREMIER Study.  
Subject follow-up rates were high, with 98.6% (139/141) of subjects completing the 1-year clinical follow-
up. Complete aneurysm occlusion without significant parent artery stenosis (≤ 50%) or retreatment of the 
target aneurysm 1-year post-procedure (primary effectiveness endpoint) occurred in 76.71% of subjects. 
Occurrence of major stroke in the territory supplied by the treated artery or neurological death at 1-year 
post-procedure (primary safety endpoint) occurred in 2.17% of subjects. A total of 81.9% (113/138) 
aneurysms had complete occlusion, none (0%; 0/138) had aneurysm recurrence and 2.9% (4/139) had 
aneurysm retreatment at the 1-year follow-up. There were no major strokes in the territory supplied by 
the treated artery or neurological death at 30 days post-procedure due to procedural complications. 
Delayed intracerebral hemorrhage >30 days through 1-year post-procedure occurred in 0.73% of subjects. 
The overall mortality rate was 0.7% (1/141). 
Overall, a high rate of complete aneurysm occlusion was achieved with the use of the Pipeline™ device in 
the treatment of small/medium-sized wide-necked aneurysms. The incidence of major stroke, 
neurological death, and delayed intracerebral hemorrhage in the PREMIER study were low. Therefore, 
results from the PREMIER Study demonstrated that the Pipeline™ device is effective and safe for the 
endovascular treatment of unruptured, small and medium, wide-necked intracranial aneurysms in the 
intracranial carotid and proximal vertebral artery. 
4.2.6. 
INSPIRE: Innovative Neurovascular Product Surveillance Registry 
INSPIRE is a neurovascular registry of patients treated for either intracranial aneurysms or large vessel 
occlusion-acute ischemic stroke (LVO-AIS) with a Medtronic market approved device. INSPIRE aims to 
continuously assess safety and measure effectiveness of market released neurovascular products. 
Additionally, the cumulatively collected high volume of patient data drives therapy evidence to support 
treatment paradigms in the rapidly evolving neurovascular therapy field. The objectives of the study are 

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to identify unforeseen adverse events and potential signals for emerging performance issues, characterize 
patient outcomes and patterns of product use, and determine predictors of performance and 
effectiveness. Study endpoints are specific to each device; and include safety endpoints adjudicated by 
Clinical Events Committee and effectiveness endpoints measured by an independent core laboratory. 
INSPIRE was launched in December 2016; and up to July 2019 includes 600 patients with intracranial 
aneurysms treated with the Pipeline™ Flex or Pipeline™ Shield flow diverting devices. Patients were 
enrolled from 30 neurointerventional centers across Europe, Asia, Australia, Latin America, Middle East 
and Russia. INSPIRE is the neurovascular arm of a larger global Medtronic Product Surveillance Registry 
(PSR) Platform which builds on more than 25 years of post-market clinical surveillance experience. 
4.2.7. 
SHIELD OUS: Pipeline™ Flex with Shield Technology Embolization- An International 
Multicenter Observational Post Market Study of treated Intra Cranial Aneurysms 
In the SHIELD Study, follow-up visits were not required by the Clinical Study Protocol and only conducted 
per standard of care at the investigational site. In the study population, 87.3% (178/204) subjects returned 
for the 30-day follow-up visit, 81.4% (166/204) subjects returned for the 3 month follow-up visit, 91.2% 
(186/204) subjects returned for the 6 month follow-up visit, and 83.8% (171/204) subjects returned for 
the 1 year follow-up visit. Complete aneurysm occlusion without significant parent artery stenosis (≤ 50%) 
or retreatment of the target aneurysm 1-year post-procedure (primary effectiveness endpoint) occurred 
in 71.67% of subjects. A total of 75.0% (141/188) subjects had complete target aneurysm occlusion, 0.0% 
(0/204) subjects had aneurysm recurrence and 2.0% (4/200) subjects had aneurysm retreatment through 
1-year follow-up; residual neck was seen in 4.8% (9/188) of subjects and residual aneurysm was seen in 
20.2% (38/188) of subjects. Through 1-year follow-up, majority of subjects (98.94%, 186/188) did not have 
significant stenosis, defined as >50% stenosis of the parent artery.  
The primary objective of the SHIELD Study was to assess the outcomes of the Pipeline™ Shield device in 
subjects undergoing treatment for intracranial aneurysms in a real-world, post-market setting. The SHIELD 
study, conducted in 21 sites outside the United States (OUS), which included European Union (EU), 
Australia and Israel, prospectively consented 205 subjects and attempted to treat a total of 204 target 
aneurysms in 204 subjects. The aneurysms were located in the parent arteries of the ICA (segments C1-
C7) (76.0%, 155/204), MCA (7.8%, 16/204), Vertebral Artery (6.4%, 13/204), Anterior Communicating 
Artery (5.9%, 12/204), and ACA (3.9%, 8/204). The majority of aneurysms were located in the ICA (76.0%, 
155/204), most of which were located in C6 (ophthalmic segment, 41.2%, 84/204) and C7 (communicating 
segment, 19.1%, 39/204). Of the 204 target aneurysms, 50.0% (102/204) were small (< 7 mm), 33.8% 
(69/204) were medium (7-12 mm), 13.7% (28/204) were large (13-24 mm), and 2.5% (5/204) were giant 
(≥ 25 mm). The majority of target aneurysms (81.4%,166/204) were never ruptured at the time of entry 
into the study, while previously ruptured target aneurysms were reported as acutely ruptured (< 30 days) 
in 1.5% (3/204) and as previously ruptured > 30 days in 16.7% (34/204); rupture status was not reported 
in the remaining 0.5% (1/204) of target aneurysms. Device deployment success on a subject level was 
observed in 98.0% (200/204) of subjects. 

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Occurrence of major stroke in the territory supplied by the treated artery or neurological death at 1-year 
post-procedure (primary safety endpoint) occurred in 3.23% of subjects. Major stroke in the territory 
supplied by the treated artery or neurological death at 30 days post-procedure due to procedural 
complications were observed in 2.9% (6/204) of subjects. No delayed intracerebral hemorrhage (>30 days 
to 1-year post-procedure) was observed (0.0%). Overall, the incidence of major stroke, neurological death, 
and delayed intracerebral hemorrhage in the SHIELD study was low. Through the 1-year follow-up, the 
rate for death was 1.0% (2/204) (same for neurological death), all stroke was 6.4% (13/204), disabling 
stroke as observed (including death) was 1.0% (2/200), and ICH was 4.4% (9/204). Summary of primary 
endpoints of SHIELD study is presented in Table 4-1. 
Table 4-1. Summary of Primary Endpoints of SHIELD Study 
Endpoints 
Rates 
2-sided 95% 
exact binomial 
confidence 
interval 
Primary Effectiveness Endpoint: Complete aneurysm occlusion (defined as Raymond-Roy grade 11) without significant 
parent artery stenosis (≤ 50%) or retreatment of the target aneurysm at 1-year post-procedure 
FAS# population (N=200) 
71.67% 
(64.95%,77.74%) 
ICA†-FAS population (N=149) 
75.30% 
(67.58%,81.99%) 
Primary Safety Endpoint: Occurrence of major stroke in the territory supplied by the treated artery or neurological death at 
1-year post-procedure 
ITT* population (N=204) 
3.23% 
(1.27%,6.68%) 
ICA† population (N=153) 
3.27% 
(1.07%,7.46%) 
*Intention to Treat (ITT) population includes all consented subjects in whom deployment of the Pipeline™ Shield device was attempted. For 
the ITT population, primary effectiveness endpoint analysis was based on Full Analysis Set (FAS) population and safety analysis was based on 
the ITT population. 
#Full Analysis Set (FAS) is defined as a subset of the ITT population including only those in whom the Pipeline™ Shield device was implanted. 
†Internal Carotid Artery population (ICA population) is defined as a subset of ITT population that included only those subjects in whom the 
Pipeline™ Shield device was implanted in the ICA (segments C2-C7). For the ICA population, primary effectiveness endpoint analysis was 
based on FAS (referred to as ICA-FAS) and safety analysis was based on the ICA population. 
Overall, a high rate of complete aneurysm occlusion was achieved with the use of the Pipeline™ Shield 
device in the treatment of intracranial aneurysms. The incidence of major stroke, neurological death, and 
delayed intracerebral hemorrhage in the SHIELD study were low. Therefore, results from the SHIELD study 
demonstrated that the Pipeline™ Shield device is effective and safe for the endovascular treatment of 
intracranial aneurysms. 
In summary, wide-neck aneurysms are poor candidates for endovascular treatment with coils. Along with 
the possibility of coil protrusion into the parent vessel, there are reportedly high rates of aneurysm 
recurrence or recanalization after treatment.7,94-96 Current evidence demonstrates that the Pipeline™ 
device meets the need for the treatment of wide-neck intracranial aneurysms and results in high complete 
occlusion rates, low recurrence rates and a favorable safety profile.  

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4.2.8. 
PFLEX: Pipeline™ Flex Embolization Device with Shield Technology™ Clinical Study 
The primary objective of the Pipeline™ Flex Embolization Device with Shield Technology™ Clinical Study 
or PFLEX Study was to assess the outcomes of the Pipeline™ Shield device in patients undergoing 
treatment for intracranial aneurysms in a real-world, post-market clinical setting. The PFLEX study was 
conducted in 7 European Union study centers which prospectively consented 58 subjects and attempted 
to treat a total of 50 target aneurysms in 50 subjects. Ninety-four percent (47/50) of target aneurysms 
were located in the intracranial ICA (C2 to C7 including the terminus), and 6.0% (3/50) of aneurysms were 
located in the vertebral artery. Most target aneurysms (48.0%, 24/50) were small (<7 mm), 30.0% (15/50) 
were medium (7- <13 mm), 20.0% (10/50) were large (13- <25 mm), and 2.0% (1/50) were giant aneurysms 
(≥25mm). Most subjects (88.0%, 44/50) had unruptured target aneurysms at the time of entry into the 
study, and 6 (12.0%, 6/50) subjects had previously ruptured aneurysms (>30 days) which were treated in 
this study. None of the subjects had previously ruptured aneurysms acutely (<30 days from the study). 
Device deployment success on a subject level was observed in 100.0% (50/50) of subjects. 
In the PFLEX Study, subject follow-up rates were high, with 6-month clinical follow-up data available for 
98.0% (49/50) and 1-year clinical follow-up data available for 98.0% (49/50) of subjects for analysis of 
safety endpoints. Complete aneurysm occlusion without significant parent artery stenosis (≤ 50%) or 
retreatment of the target aneurysm 1-year post-procedure (primary effectiveness endpoint) occurred in 
73.62% of subjects. A total of 78.7% (37/47) subjects had complete occlusion of their target aneurysms 
and none (0%) had aneurysm recurrence or retreatment through the 1-year follow-up; residual neck was 
seen in 4.3% (2/47) of subjects, and residual aneurysm was seen in 17.0% (8/47) of subjects. Through 1-
year follow-up, majority of subjects (95.7%, 45/47) did not have significant parent artery stenosis, defined 
as >50% stenosis of the parent artery.  
Occurrence of major stroke in the territory supplied by the treated artery or neurological death at 1-year 
post-procedure (primary safety endpoint) occurred in 0.0% of subjects. There were no major strokes in 
the territory supplied by the treated artery or neurological death at 30 days post-procedure due to 
procedural complications. There was no delayed intracerebral hemorrhage >30 days through 1-year post-
procedure (0.0%; 0/50). The overall mortality rate was 0.0% (0/50). Summary of primary endpoints of 
PFLEX study is presented in Table 4-2. 
Table 4-2. Summary of Primary Endpoints of PFLEX Study 
Endpoints 
Rates 
1-Sided 
97.5% Exact 
Binomial 
Confidence 
Interval 
Primary Effectiveness Endpoint: Complete aneurysm occlusion (defined as Raymond-Roy grade 11) without significant 
parent artery stenosis (≤ 50%) or retreatment of the target aneurysm at 1-year post-procedure 
ITT‡ population (N=50) 
73.62% 
59.39%* 
ICA# Population (N=47) 
74.23% 
59.24%* 

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Primary Safety Endpoint: Occurrence of major stroke in the territory supplied by the treated artery or neurological death at 
1-year post-procedure 
ITT‡ population (N=50) 
0.0% 
7.1%† 
ICA# population (N=47) 
0.0% 
7.5%† 
*Lower Bound of the Binomial Confidence Interval 
†Upper Bound of the Binomial Confidence Interval 
‡Intention to Treat (ITT) population included all consented subjects in whom deployment of the Pipeline™ Shield device was attempted.  
#Internal Carotid Artery Population (ICA Population) is defined as a subset of ITT population that included only those subjects in whom the 
Pipeline™ Shield device was implanted in the ICA (segments C2-C7 including the terminus). 
Overall, a high rate of complete aneurysm occlusion was achieved with the use of the Pipeline™ Shield 
device in the treatment of intracranial aneurysms. The incidence of major stroke, neurological death, and 
delayed intracerebral hemorrhage in the PFLEX study were low. Therefore, results from the PFLEX Study 
demonstrated that the Pipeline™ Shield device is effective and safe for the endovascular treatment of 
intracranial aneurysms.  
4.3. 
Purpose 
A Study of the Pipeline™ Vantage Embolization Device with Shield Technology™ for Endovascular 
Treatment of Wide-Necked Intracranial Aneurysms (ADVANCE Study) is a prospective, global, multi-
center, single-arm IDE study of the Pipeline™ Vantage  device for the treatment of adults (22 years of age 
or older) with wide-necked intracranial aneurysms located in the internal carotid artery (ICA) (up to the 
terminus). The primary purpose of the ADVANCE Study is to assess the safety and effectiveness of the 
Pipeline™ Vantage device in the treatment of unruptured intracranial aneurysms within the intended 
indication for use. The safety of the Pipeline™ Vantage will be assessed through incidence of major stroke 
in the territory supplied by the treated artery or neurological death at 1-year post-procedure. The 
effectiveness of the Pipeline™ Vantage will be assessed through incidence of complete aneurysm 
occlusion (Raymond Roy Scale Class 1) without significant parent artery stenosis (≤ 50%) or retreatment 
of the target aneurysm at 1-year post-procedure. Additional safety and effectiveness analyses will include 
incidence of major stroke in the territory supplied by the treated artery or neurological death at 2- and 3-
years post-procedure, incidence of major stroke in the territory supplied by the treated artery or 
neurological death at 30 days post-procedure, incidence of delayed intraparenchymal hemorrhage >30 
days post-procedure through 1-year post-procedure, incidence of subjects with disabling strokes that 
have a mRS decline to a score of 3 or more (mRS ≥ 3) due to a stroke-related cause assessed at a minimum 
of 90 days post-stroke event at 1 year, 2 year, and 3 year post-procedure, incidence of successful device 
implantation at the target site, incidence of complete aneurysm occlusion (Raymond Roy Class 1) at 1- 
and 3-years post-procedure, incidence of target aneurysm recurrence at 1- and 3-years post-procedure. 

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5. Objectives and Endpoints 
5.1. 
Objectives 
5.1.1. 
Primary Objective(s) 
The primary objective of this study is to assess the safety and effectiveness of the Pipeline™ Vantage 
Device in the treatment of intracranial aneurysms within the intended indication for use*. 
*The Pipeline™ Vantage Embolization Device with Shield Technology™ is intended for endovascular 
treatment of adults (22 years of age or older) with wide-necked intracranial aneurysms located in the 
internal carotid artery (up to the terminus).   
5.1.1.1. 
Primary Endpoints 
5.1.1.1.1. Primary Effectiveness Endpoint 
The following will be assessed for the primary effectiveness endpoint: 
Complete occlusion and parent artery stenosis will be adjudicated by the Imaging Core Laboratory. 
Retreatment will be assessed per site records. 
5.1.1.1.2. Primary Safety Endpoint 
The following will be assessed for the primary safety endpoint: 
• 
Incidence of major stroke in the territory supplied by the treated artery or neurological death at 1-
year post-procedure 
This endpoint will be adjudicated by the independent Clinical Events Committee (CEC). 
For the purposes of this study protocol, stroke is defined as a focal neurological deficit of presumed 
vascular origin persisting ≥24 hours from symptom onset and a neuro-imaging study or other quantitative 
study that does not indicate a different etiology. The 24-hour criterion is excluded if the subject undergoes 
cerebrovascular surgery or dies during the first 24 hours. 
The definition includes: 
• 
Subjects presenting with clinical signs and symptoms suggestive of SAH, intracerebral hemorrhage, or 
cerebral infarction. 
• 
Sudden loss or worsening of visual acuity due to retinal artery occlusion or retinal emboli. 
o Incidence of complete aneurysm occlusion (Raymond Roy Scale Class 1) without significant 
parent artery stenosis (≤ 50%) or retreatment of the target aneurysm at 1-year post-procedure. 

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The definition excludes: 
• 
Slowly progressive cranial nerve palsies or progressive visual field deficits due to continued aneurysm 
growth. 
• 
Stroke events in cases of blood disorder such as leukemia or external events such as trauma. 
Severity of stroke will be classified by the CEC as major or minor: 
• 
Major Stroke: A stroke, which is present for ≥24 hours and increases the NIHSS of the subject by ≥ 4. 
• 
Minor Stroke: A stroke, which is present for ≥24 hours and increases the NIHSS of the subject by ≤ 3. 
Disability status of the Stroke events will be assessed based on mRS assessment conducted at a minimum 
of 90 days post stroke event: 
• 
Disabling: (mRS with poor functional outcome i.e. ≥3 points) 
• 
Non-Disabling (mRS with good functional outcome 0-2 points) 
The following assessments are required to be performed (if hospitalized at the primary investigative 
site) or source documents obtained (if hospitalized at an outside hospital) for All Stroke Events: 
o NIHSS at time of Stroke presentation to the hospital 
o NIHSS at 24 hrs from the Stroke presentation 
o mRS assessment at a minimum of 90 days post-Stroke event 
o Any Imaging / imaging report available during Stroke hospitalization 
Neurological death is any death of a subject in which the primary cause of death is due to neurologic 
reasons. 
The following documents are to be obtained for all events that lead to Death: 
- 
Hospitalization Record (where available) 
- 
Autopsy Report (where available) 
- 
Death Certificate (where available) 
A PI note describing the last subject contact with detail of any assessments to be provided where Death 
Certificate is not available. 

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5.1.2. 
Secondary Objective(s) 
The secondary objective of this study is to assess the efficacy and safety of the Pipeline™ Vantage Device 
in the treatment of intracranial aneurysms within the intended indication for use. 
5.1.2.1. 
Secondary Endpoint(s) 
The following will be assessed for the effectiveness outcome measures: 
1. Incidence of successful device implantation at the target site 
2. Incidence of complete aneurysm occlusion (Raymond Roy Class 1) at 1- and 3-years post-
procedure 
3. Incidence of target aneurysm recurrence at 1- and 3-years post-procedure 
For the purposes of this study protocol, successful device implantation will be presented in terms of 
Procedural Technical Success and Device Technical Success. Procedure technical success is measured by 
the rate of successful implantation of the study device during the study index procedure at the target site 
regardless of the number of devices deployed and implanted at the target site. Device technical success 
is measured by the rate of successful study device implantation at the target site with the total number 
of devices attempted to be deployed. 
Successful device implantation and retreatment will be site reported. Aneurysm occlusion class, 
recurrence, and parent artery stenosis will be assessed by the independent Imaging Core Lab. 
The following will be assessed for the secondary safety endpoints: 
1. Incidence of major stroke in the territory supplied by the treated artery or neurological death at 
2- and 3-years post-procedure 
2. Incidence of major stroke in the territory supplied by the treated artery or neurological death at 
30 days post-procedure 
3. Incidence of delayed intraparenchymal hemorrhage >30 days post-procedure through 1-year 
post-procedure 
4. Incidence of subjects with disabling strokes that have a mRS decline to a score of 3 or more (mRS 
≥ 3) due to a stroke-related cause assessed at a minimum of 90 days post-stroke event at 1 year, 
2 year, and 3 year post-procedure 
The events comprising the safety endpoints will be adjudicated by the independent CEC. 

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6. Study Design 
The study is a prospective, global, multi-center, single-arm IDE clinical study evaluating the performance 
of the Pipeline™ Vantage Device. The Pipeline™ Vantage Device is investigational in the United States and 
Canada. 
6.1. 
Duration 
Subjects will actively participate for approximately 3 years. Study participation includes Baseline, Pre-
Procedure, Post-Procedure, Discharge exam, and follow-up visits at 30-day, 180-day, 1-year, 2-year and 
3-year. Enrollment will be approximately 1 year. The total study duration is expected to be approximately 
4 years. 
6.2. 
Rationale 
The Pipeline™ Embolization Device has been commercialized in the US since 2011 for the endovascular 
treatment of adults with large (≥ 10-24 mm) or giant (≥ 25 mm) wide-necked intracranial aneurysms in 
the ICA from the petrous to the superior hypophyseal segments. Over time, additional long-term data has 
been generated which further confirms the safety and effectiveness of the Pipeline™ Embolization Device 
for this indication. Additionally, outside the US, the Pipeline™ Embolization Device has been approved and 
commercialized since 2008 for endovascular embolization of cerebral aneurysms. 
The latest developmental modification to the Pipeline™ Embolization Device (PED) system is Pipeline™ 
Vantage Embolization Device with Shield Technology™. Pipeline™ Vantage utilizes the same 
phosphorylcholine (PC) surface treatment (Shield Technology™) as the Pipeline™ Flex Embolization 
Device with Shield Technology™. Additionally, the wire design and braid pattern are unchanged in 
Pipeline™ Vantage. However, there are some key enhancements in the Pipeline™ Vantage device. 
Pipeline™ Vantage implant has larger implant diameters and longer lengths, drawn filled tubes and 
decreased wire diameter as well as increased pore density (Section 7.1.1). These changes to the implant 
increase radiopacity, optimize deliverability and enhance the ability of the implant to open upon 
deployment. The Pipeline™ Vantage delivery system (Section 7.1.1.4) was designed to be compatible with 
0.021” inner diameter micro catheters for select sizes and also includes a new Advanced Resheathing 
Mechanism, Corewire-based Delivery System and Corewire Subassembly for improved reliability. The 
Shield Technology™ surface treatment applied to the implant is an inert, PC polymer material that is 
chemically bonded to the braid surface. The polymer is a chemically derived material, created to mimic 
the outer membrane of a human red blood cell. Shield Technology™ reduces the material thrombogenicity 
of the braid surface compared to the current bare metal Pipeline™ Embolization Device implant based on 
bench data with human platelets and plasma. 
Objective evidence on the safety and effectiveness of the Pipeline™ Vantage Device is best collected by 
conducting a prospective study with standardized follow-up evaluations. The use of an independent core 

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lab is uncommon in studies evaluating intracranial aneurysms despite evidence showing site reported 
data underestimates unfavorable angiographic appearance.97,98 Along with an independent core lab, the 
Pipeline™ Vantage Device trial will employ an independent Data Monitoring Committee (DMC) and an 
independent Clinical Events Committee (CEC) to assist in the oversight and analysis of the study data. 
Treatment with the Pipeline™ Vantage Device is expected to show high complete aneurysm occlusion 
rates and minimal safety events. 
The patient population proposed for enrollment in the study includes patients with a wide-neck 
intracranial aneurysm located in the internal carotid artery (up to the carotid terminus). The justification 
for the patient population and the single-arm study design is provided below. 
Small, Medium, Large, and Giant Wide-Necked Aneurysms 
Pipeline™ Flex Embolization Device flow diverter is currently indicated in the US for the endovascular 
treatment of adults (22 years of age or older) with large or giant wide-necked intracranial aneurysms (IAs) 
in the internal carotid artery from the petrous to the superior hypophyseal segments. The Pipeline™ Flex 
embolization device is also indicated for use in the internal carotid artery up to the terminus for the 
endovascular treatment of adults (22 years of age or older) with small and medium widenecked (neck 
width ≥ 4 mm or dome-to-neck ratio < 2) saccular or fusiform intracranial aneurysm (IAs) arising from a 
parent vessel with a diameter ≥ 2.0 mm and ≤ 5.0 mm. The device has shown high effectiveness and low 
complication rates for this indication.84 
In addition to evaluating large and giant wide-neck aneurysms, the proposed study also aims to include 
wide-neck aneurysms measuring <10mm. There is a lack of consensus in the literature and guidelines on 
whether small and medium size aneurysms should be treated. The natural course of untreated aneurysms 
of specific size ranges has not been clearly identified.99-103 Although several studies have reported a wide 
range of rupture rates over time for untreated small and medium size aneurysms of various locations; 
annual rupture rates for small and medium size aneurysms vary significantly up to a 20 fold difference 
(0.05% vs. 1.0%, annually).99,102-106 This most likely can be explained by the fact that in addition to 
aneurysm size, the risk of aneurysm rupture is attributed to various other factors, including aneurysm 
morphology, location, previous subarachnoid hemorrhage, and subject characteristics.100,105,107,108 
In the Small Unruptured Intracranial Aneurysm Verification (SUAVe) Study, patient age, aneurysm 
diameter ≥4 mm, hypertension, and aneurysm multiplicity were significant predictive factors for rupture 
of small aneurysms.108 The average annual risk of rupture for small aneurysms (<5 mm) in the study was 
0.54% overall, 0.34% for single aneurysms and 0.95% for multiple aneurysms (mean follow-up: 41 
months).108 Another study which followed the natural course of unruptured aneurysms with a mean size 
of 5.7 mm in 5720 patients reported a similar annual rupture rate to the SUAVe study at 0.95% (follow-
up: 3 months to 8 years). The annual rupture rates from both studies, however, may be an underestimate 

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due to possible selection bias. Data from patients who underwent surgical intervention were censored 
and some of these patients may have been at an increased risk for rupture.100,108 
Although the rupture rate for untreated unruptured small and medium aneurysms is low, it is also 
important to consider that the majority of unruptured intracranial aneurysms are small and medium in 
size. In the International Study of Unruptured Intracranial Aneurysms (ISUIA) study, out of 1692 untreated, 
1917 surgically treated, and 451 endovascularly treated subjects, 85%, 78%, and 58% of the subjects’ 
aneurysms were ≤12 mm in size, respectively. In a meta-analysis of 71 studies investigating the 
endovascular treatment of intracranial unruptured aneurysms, of the 2688 patients included, 75% of the 
patient’s aneurysms’ were < 10 mm in size. Furthermore, in recent randomized controlled trials in which 
bare metal coils were studied against alternative treatment options in hundreds of patients, both 
unruptured and ruptured aneurysms were included and the majority of patients treated had small and 
medium size aneurysms.14,109-112 
Data for ruptured aneurysms also supports the treatment of small and medium aneurysms. Many of the 
aneurysms that rupture are small or medium in size. In the International Subarachnoid Aneurysm Trial 
(ISAT), a landmark trial on the treatment of 2143 ruptured intracranial aneurysms, 92% of the ruptured 
aneurysms were ≤ 10 mm.27 Similarly, in the CLARITY study of ruptured aneurysms, 89.5% (700/782) of 
the subjects had an aneurysm ≤ 10 mm.113 Treatment of a ruptured aneurysm is critical in order to stop 
the bleeding and attempt to reduce the risk of potentially devastating complications. Since a significant 
majority of ruptured aneurysms reported in the literature appear to be small and medium in size, these 
findings support the fact that these aneurysms pose a considerable risk and warrant careful consideration 
for treatment.26,27,101,114 
Multiple publications demonstrate that these small and medium wide-necked aneurysms are commonly 
treated endovascularly with SAC.115-122 Although initial occlusion rates are good, the primary limitation of 
SAC is the inability to provide sustained long-term aneurysm occlusion. Aneurysm recurrence rates of up 
to 16% have been reported in the literature after SAC treatment of small and medium 
lAs.30,115,117,118,121,123,124 The presence of major aneurysm recurrence requires retreatment, which is 
evidenced by aneurysm retreatment rates of up to 10% for small and medium lAs.119,121-126 Therefore, an 
alternative approach for obtaining sustained aneurysm occlusion, such as flow diversion, is needed for 
small and medium wide-necked intracranial aneurysms. 
In the IntrePED trial, a post-market registry to evaluate the Pipeline™ Embolization Device in which all 
consecutive subjects treated with the Pipeline™ Embolization Device were required to be enrolled, more 
than half the aneurysms treated (473/896, 52.8%) were small (<10 mm).85,93 Combined neurologic 
morbidity and mortality for small unruptured anterior circulation aneurysms was 3.5% (11/311) and 0.0% 
(0/24) for small unruptured posterior circulation aneurysms. When specifically evaluating small (<10 mm) 
aneurysms located in the ICA, the rate of neurologic morbidity in ruptured and unruptured aneurysms 
was 4.1% (12/291), neurologic mortality was 1.4% (4/291) and the combined rate of neurologic morbidity 

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and mortality for unruptured aneurysms was 3.4% (9/268). The overall IntrePED study results show that 
intracranial aneurysms measuring less than 10 mm are treated frequently and are associated with low 
complication rates. 
Although there is some debate within the medical community regarding treatment of small and medium 
sized wide-neck aneurysms, it is clear from the literature that physicians worldwide treat a significant 
number small and medium aneurysms, both unruptured and ruptured. When deciding treatment 
approach, physicians take numerous factors into account in addition to aneurysm size, including age, 
aneurysm morphology, location, medical history and co-morbidities, previous SAH, and individual subject 
characteristics. After consideration of these factors, many times physicians conclude that the benefit of 
endovascular treatment outweighs the risk and subsequently treat these aneurysms. These cases 
demonstrate the need for endovascular treatment in a selected subject population and further, that these 
subjects may benefit from treatment with the Pipeline™ Vantage Device. 
It is also important to note that subjects with unruptured or ruptured (>30 days since occurrence) small 
and medium aneurysms proposed for enrollment in the current trial are those who have already been 
identified by their physician as being appropriate for endovascular treatment of their aneurysm. 
Investigators and subjects will first make the collective determination regarding the appropriateness of 
endovascular treatment based on their clinical expertise and experience. This will be the same process 
and decision that physicians, in consultation with subjects are currently performing when determining 
whether to treat subjects with small and medium aneurysms using endovascular coils. Only after the 
decision has been made by the physician and subject to treat the aneurysm through endovascular means, 
will the potential for enrollment into the proposed study be considered. 
The following inclusion criterion will be used as a treatment inclusion risk mitigation measure to ensure 
only those small aneurysm subjects who demonstrate an appropriate level of aneurysm rupture risk, will 
be enrolled into this study. “Subject has been already selected for endovascular treatment of the target 
aneurysm. If the target aneurysm measures ≤5mm, risk factors leading to the determination to treat the 
aneurysm must be identified.” 
Internal Carotid Artery (up to the terminus) 
Treatment with the Pipeline™ Flex Embolization Device is currently indicated in the U.S. for the 
endovascular treatment of adults (22 years of age or older) with large or giant wide-necked intracranial 
aneurysms (IAs) in the internal carotid artery from the petrous to the superior hypophyseal segments. The 
Pipeline™ Flex embolization device is also indicated for use in the internal carotid artery up to the terminus 
for the endovascular treatment of adults (22 years of age or older) with small and medium widenecked 
(neck width ≥ 4 mm or dome-to-neck ratio < 2) saccular or fusiform intracranial aneurysm (IAs) arising 
from a parent vessel with a diameter ≥ 2.0 mm and ≤ 5.0 mm. The proposed study aims to include 
intracranial aneurysms in the ICA up to the terminus. The majority of aneurysms in the IntrePED study 

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were located in the ICA (684/906, 75.5%) and ranged in size from small to giant (360 small, 272 large and 
45 giant aneurysms, respectively).85,93 The combined neurologic morbidity and mortality rate for subjects 
with unruptured ICA aneurysms <10mm was 3.4% (9/268) and the combined neurologic morbidity and 
mortality rate for subjects with unruptured ICA aneurysms ≥10mm was 9.5% (27/285). These rates 
demonstrate that the Pipeline™ Vantage Device can serve as a potentially safe treatment option for 
aneurysms of all sizes in the ICA (up to the terminus). Within this current study, the Pipeline™ Vantage 
Device for the treatment of unruptured or ruptured (>30 days since occurrence), wide-necked intracranial 
aneurysms located in the ICA (up to the terminus) will be investigated. 
Single- Arm Study Design 
The proposed study design is a single-arm trial. As with the evaluation of the Pipeline™ Embolization 
Device in the PUFs IDE study, a randomized controlled trial is not feasible for the evaluation of the 
Pipeline™ Vantage Device due to the lack of an appropriate control treatment for small/medium and 
large/giant wide-neck intracranial aneurysms. 
The target intracranial aneurysm population is likely to include many aneurysms that can be treated by 
Pipeline™ Vantage Device but not by any particular single alternative treatment. In the U.S., wide-neck 
aneurysms are most commonly treated with stent-assisted coiling.  Although intracranial stents are 
available, they are currently approved through a Humanitarian Device Exemption (HDE) and as such have 
only been proven to demonstrate safety and not effectiveness. Even the recent PMA approved stent, LVIS 
and LVIS Jr. showed relatively lower effectiveness outcomes with large/giant aneurysms (compared to 
small/medium aneurysms in the same study) (PMA 170013). As a result, stent-assisted coiling is not a 
feasible option for the control treatment. The use of coil embolization alone, is predicted to be infeasible 
in many subjects due to the wide-neck nature of the target aneurysms. 
As a result, the study design for the evaluation of the Pipeline™ Vantage Device is a prospective single-
arm trial. 
Conclusion 
In summary, intracranial aneurysms can potentially rupture and lead to serious complications with 
significantly poor outcomes. SAH resulting from aneurysmal rupture is associated with a high mortality 
rate of greater than 40%.1,10 In addition to large and giant aneurysms, which have rupture rates of 18.4% 
and 50%, small and medium aneurysms warrant consideration for treatment.99 The average size of 
ruptured intracranial aneurysms is approximately 6.6-6.8 mm. Small and medium wide-necked 
intracranial aneurysms are most commonly treated endovascularly with SAC, however, treatment 
outcomes are sub-optimal. Given the high long-term recanalization and retreatment rates reported with 
SAC, alternative options with sustained curative effects are necessary. Treatment with the Pipeline™ 
Embolization Device has demonstrated high rates of long-term complete occlusion, low rates of 
retreatment and low rates of adverse transient and persistent neurologic events in large and giant wide-

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necked intracranial aneurysms.54,55,85,93,127 Data collected in the lntrePED retrospective study and 
published literature suggests that the Pipeline™ Embolization Device could also be a possible treatment 
option for small and medium wide-necked intracranial aneurysms.85,93 
Thus, the aim of the present study is to assess the Pipeline™ Vantage Device beyond the present indication 
to include wide-neck intracranial aneurysms of all sizes in the ICA (up to the terminus). 

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7. Product Description 
7.1. 
General 
The device under investigation is the Pipeline™ Vantage Embolization Device with Shield Technology™ 
(Pipeline™ Vantage). 
Figure 7-1. Pipeline™ Vantage Embolization Device with Shield Technology™ Implant 
The Pipeline™ Vantage consists of a permanent implant (Figure 7-1) combined with a guidewire-based 
delivery system (Figure 7-2).  
.021” microcatheter compatible system 
 
.027” microcatheter compatible system 
Figure 7-2. Pipeline™ Vantage System 

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The Pipeline™ Vantage implant is a braided, multi-alloy, mesh cylinder woven from Drawn Filled Tubes 
(DFT). The DFT wires are constructed from a Cobalt-Chromium-Nickel (MP35N LT) that is filled with a 
platinum core. The woven wires of the device provide approximately 30% metal coverage of the arterial 
wall surface area. The Pipeline™ Vantage implant is designed for placement in a parent vessel across the 
neck of an intracranial aneurysm to disrupt pulsatile blood flow from the parent artery into the fundus 
and to serve as a scaffold upon which endothelial cells can grow. The expanded or unconstrained diameter 
of the Pipeline™ Vantage implant is 0.25 mm larger than the labeled diameter. The Pipeline™ Vantage 
Embolization Device includes a surface-modification referred to as Shield Technology™. 
The Pipeline™ Vantage implant is assembled on a guide-wire based delivery system and is supplied 
compressed inside an introducer sheath. The core wire subassembly of the delivery system consists of a 
stainless-steel core wire, a hypotube and a radiopaque proximal bumper to indicate the proximal end of 
the implant. The Pipeline™ Vantage implant is mounted at the distal portion of the core wire subassembly. 
During delivery, the proximal bumper advances the implant, which can be deployed either by forward 
motion of the delivery wire or by retracting the microcatheter. Advanced Resheathing Mechanism (ARM) 
is constructed from stainless steel components to allow the user to resheath the implant back into the 
microcatheter. A Platinum-Iridium restraint is located distal to the resheathing components and is termed 
the Resheathing Marker to indicate the resheathing limit for the implant. The Distal Protective 
Subassembly (DPS) is constructed from ePTFE and a Platinum/Tungsten coil to protect the distal portion 
of the implant while the device is advanced through the microcatheter.  
The hypotube is welded at the proximal and distal end to the core wire. The proximal bumper is welded 
to the core wire and the distal end of the hypotube. The tip coil, distal, and proximal solder joints are 
manufactured using tin-silver solder material. Refer to Figure 7-2 for assembled device drawings 
indicating overall dimensions and marker locations. The Pipeline™ Vantage implant is designed to be 
delivered through a compatible microcatheter with an inner diameter of 0.021” (0.53 mm) for implant 
diameters ≤3.50mm and inner diameter of  0.027” (0.69 mm) for implant diameters ≥3.50mm with a 
minimum length of 135 cm (Figure 7-2). 
The Pipeline™ Vantage device will be referred to as PED3-XXX-XXX-XX (the first three-digits signify 
catheter compatibility, the second three-digits refer to the braided implant labeled diameter, and the last 
two-digits represent the implant length at labeled diameter). The Pipeline™ Vantage will be available in 
the configurations as listed in Table 7-1. 
Table 7-1. Pipeline™ Vantage Embolization Device with Shield Technology™ Implant 
Legend:  
         Pipeline Vantage .021” 
         Pipeline Vantage .021” & 
.027” 
         Pipeline Vantage .027” 
Braided Implant Length (mm) 
-10 
-12 
-14 
-16 
-18 
-20 
-25 
-30 
-35 
-40 
-45 
-50 

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Braided Implant Diameters (mm) 
2.50 
PED3-021 -250 
48 
48 
48 
48 
48 
48 
 
 
The values listed 
indicate the total 
number of wires in the 
braided implant. 
2.75 
PED3-021-275 
48 
48 
48 
48 
48 
48 
 
 
3.00 
PED3-021-300 
48 
48 
48 
48 
48 
48 
48 
48 
3.25 
PED3-021-325 
48 
48 
48 
48 
48 
48 
48 
48 
3.50 
PED3-021-350 
48 
48 
48 
48 
48 
48 
48 
48 
48 
 
 
 
3.50 
PED3-027-350 
48 
48 
48 
48 
48 
48 
48 
48 
48 
 
 
 
4.00 
PED3-027-400 
64 
64 
64 
64 
64 
64 
64 
64 
64 
64 
 
 
4.50 
PED3-027-450 
64 
64 
64 
64 
64 
64 
64 
64 
64 
64 
 
 
5.00 
PED3-027-500 
64 
64 
64 
64 
64 
64 
64 
64 
64 
64 
 
 
5.50 
PED3-027-550 
64 
64 
64 
64 
64 
64 
64 
64 
64 
64 
64 
64 
6.00 
PED3-027-600 
64 
64 
64 
64 
64 
64 
64 
64 
64 
64 
64 
64 
The Pipeline™ Vantage device is similar to the FDA approved Pipeline™ Flex Embolization Device 
(P100018/S011). Similar to Pipeline™ Flex, the Pipeline™ Vantage implant is constructed from Cobalt-
Chromium-Nickel alloy and platinum material. No new alloys have been introduced in the manufacture of 
the Pipeline™ Vantage implant. Additionally, the Pipeline™ Vantage device has the same Shield 
Technology that was utilized in Pipeline™ Flex with Shield Technology™ Device. 
Shield Technology™ (same as Pipeline™ Flex Embolization Device with Shield Technology™) 
The Pipeline™ Vantage implant is treated with an inert surface modification (Shield Technology™) process. 
This is the same surface modification, applied via the same manufacturing (submerge) process, and 
composed of the same materials as previously submitted and characterized in the ADVANCE IDE 
(G170234). The Shield surface modification adds an inert, non-biodegradable phosphorylcholine (PC) 
polymer that is covalently bonded to the surface of the braided implant. The result is a layer only 3 
nanometers in thickness on the surface of the braid wire (the smallest braid wire itself has a thickness of 
22860 microns). In addition, the 3-nanometer thick layer is significantly smaller than 10 microns (10,000 
nanometers), which is the smallest collection size for particulate matter in injections per USP <788>. The 
surface modification is primarily composed of a Phosphorylcholine polymer (Lipidure®-NH01), The 
implant is also pretreated with (3-Glycidyloxypropyl) trimethoxysilane, which acts a coupling agent to 
covalently bond the Phosphorylcholine polymer to the implant.  Phosphorylcholine is an electrically 
neutral component of the outer membrane of red blood cells.  Because Phosphorylcholine is abundant on 
the surface of red blood cells, surface modification of a device with Phosphorylcholine physiologically 
mimics the cell membrane. In vitro assessments of Phosphorylcholine surface modified devices have 
demonstrated reduced material thrombogenicity. 

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Wire Design and Braid Pattern 
There has been no change to the fundamental braid pattern or wire design of the Pipeline™ Vantage 
implant when compared to the existing Pipeline™ Flex device.  Each implant diameter offered has a unique 
wire diameter combination of either two or three differently sized wires for optimized deliverability and 
deployment performance. All Pipeline™ Vantage implants are designed with a 1-over-2 under-2 braid 
pattern.  This is the same pattern utilized by the Pipeline™ Flex braid.  Wire diameter distribution and 
braid pattern is uniform throughout the device regardless of braid orientation or direction. The diagram 
in Figure 7-3 shows the wire diameter distribution for both 2- and 3-wire size configurations. The 1-over-
2-under-2 pattern can be observed by following the path of a single wire which passes over 2 consecutive 
wires then passes under the next 2 consecutive wires. 
Figure 7-3. Wire Design and Braid Pattern 
 
The key design modifications from the Pipeline™ Flex Embolization Device (Pipeline™ Flex) 
(P100018/S011) to Pipeline™ Vantage are detailed below. 
7.1.1. 
Key Design Modifications of the Pipeline™ Vantage compared to the Pipeline™ Flex 
Device 
The design enhancements implemented to the Pipeline™ Vantage implant are intended to optimize 
radiopacity, delivery and resheathing forces, proximal, distal opening, and middle opening. The impact of 
the design enhancement is most appropriately assessed through non-clinical bench testing such as 
implant opening, chronic outward force, fatigue, and metal coverage. 

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7.1.1.1. 
Larger Implant Diameter/Longer Length 
The Pipeline™ Vantage implant is offered in both larger diameters and longer lengths in comparison to 
the Pipeline™ Flex implant. The Pipeline™ Vantage implant is also offered in a 64-wire configuration (Table 
7-1).  
7.1.1.2. 
Drawn Filled Tubes/Wire Size 
Drawn Filled Tubes of the Pipeline™ Vantage Implant Increases Radiopacity (compared to Pipeline™ Flex) 
The currently approved Pipeline™ Flex Embolization Device (Pipeline™ Flex) Implant is a braided, multi-
alloy, mesh cylinder woven from a combination of distinct Cobalt-Chromium-Nickel and 
Platinum/Tungsten monofilaments. The Cobalt-Chromium-Nickel monofilaments provides mechanical 
benefits to the Pipeline™ Flex implant for shape retention which facilitates braid deployment. The 
Platinum/Tungsten monofilaments provides visual benefits to the Pipeline™ Flex implant for visualization 
under fluoroscopy.  
Figure 7-4. Cross sectional view of Drawn Filled Tubes (DFT) (Left), Drawn Filled Tubes (DFT) 
Visualization (Right) of the Pipeline™ Vantage Device 
In comparison, the Pipeline™ Vantage implant is a braided, multi-alloy, mesh cylinder woven from Drawn 
Filled Tubes (DFT). The DFT are cylindrical wires constructed from Cobalt-Chromium-Nickel alloy tube 
filled with a Platinum core. The outer element of the DFT is the same alloy as the Cobalt-Chromium-Nickel 
alloy used in the monofilaments in the Pipeline™ Flex implant. The inner element (or core) of the drawn 
filled tube is 99.95% Platinum (Figure 7-4). The Pipeline™ Flex Embolization Device Implant 
Platinum/Tungsten monofilaments are 92% Platinum and 8% Tungsten.  
Removal of the Platinum/Tungsten monofilaments optimizes the opening of the implant by incorporating 
the mechanical benefits of the cobalt-chromium-nickel alloy into all wires that comprise the braided mesh 
of the Pipeline™ Vantage device. The DFT wires also optimize the visual benefits of platinum by 
incorporating a 99.95% Platinum fill within all wires that comprise the braided mesh of the Pipeline™ 
Vantage.  Figure 7-4 depicts the Platinum core extending beyond the outer shell to distinguish the two 
metallic components; however, each of the alloys have the same termination point in the finished device.  
Cobalt-Chromium-Nickel 
Alloy (MP35NLT) 
Platinum Core 

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Decreased Wire Diameter of the Pipeline™ Vantage Implant Optimizes Deliverability (compared to 
Pipeline™ Flex) 
The Pipeline™ Vantage will be offered in diameter range of 2.50 to 6.00 mm in comparison to Pipeline™ 
Flex’s 2.50 to 5.00 mm. For each implant diameter offered, the average wire diameter has been reduced 
(Table 7-2). This reduction in wire diameter minimizes the crimped braid profile, reduces the effective 
wall thickness of the implant and optimizes the metal coverage. The reduction in wire diameter was 
engineered with the intent to enhance deliverability and promote the healing response once delivered. 
With the incorporation of Cobalt-Chromium-Nickel alloy into all wires of the braid by means of DFT, 
reduction in wire diameter was achieved with improved opening performance of the implant itself. The 
woven wires of the Pipeline™ Vantage implant provide approximately 30% metal coverage of the arterial 
wall. The reduction in wire diameter, increase in wire count (4.0-6.0mm braids), and optimized braid angle 
resulted in a marginal reduction in metal coverage, without sacrificing pore density.  
Table 7-2. Implant Wire Comparison of Pipeline™ Flex and Pipeline™ Vantage  
Labeled 
Implant 
Diameter 
(mm) 
Implant Wire Diameter (inches) 
Implant Braid Angle 
(degrees) 
FLEX 
VANTAGE 
FLEX 
VANTAGE 
2.50 
Wire 1 
24 x 0.0010” 
Wire 1 
24 x 0.0009” 
61° 
61° 
Wire 2 
24 x 0.0011” 
Wire 2 
24 x 0.0011” 
2.75 
Wire 1 
24 x 0.0010” 
Wire 1 
24 x 0.0009” 
58° 
58° 
Wire 2 
24 x 0.0011” 
Wire 2 
24 x 0.0011” 
3.00 
Wire 1 
24 x 0.0010” 
Wire 1 
24 x 0.0009” 
56° 
57° 
Wire 2 
24 x 0.0012” 
Wire 2 
24 x 0.0012” 
3.25 
Wire 1 
24 x 0.0011” 
Wire 1 
24 x 0.0010” 
53° 
54° 
Wire 2 
24 x 0.0012” 
Wire 2 
24 x 0.0012” 
3.50 
Wire 1 
24 x 0.0011” 
Wire 1 
24 x 0.0010” 
52° 
53° 
Wire 2 
24 x 0.0013” 
Wire 2 
24 x 0.0013” 
4.00 
Wire 1 
12 x 0.0011” 
Wire 1 
16 x 0.0009” 
48° 
55° 
Wire 2 
36 x 0.0013” 
Wire 2 
16 x 0.0010” 
N/A 
Wire 3 
32 x 0.0011” 
4.50 
Wire 1 
24 x 0.0012” 
Wire 1 
32 x 0.0010” 
45° 
52° 
Wire 2 
24 x 0.0014” 
Wire 2 
32 x 0.0012” 
5.00 
Wire 1 
12 x 0.0012” 
Wire 1 
32 x 0.0010” 
43° 
50° 
Wire 2 
12 x 0.0013” 
Wire 2 
32 x 0.0013” 
Wire 3 
24 x 0.0014” 
N/A 
5.50 
N/A 
Wire 1 
16 x 0.0010” 
N/A 
49° 
Wire 2 
16 x 0.0012” 
Wire 3 
32 x 0.0014” 
6.00 
N/A 
Wire 1 
32 x 0.0010” 
N/A 
48° 
Wire 2 
32 x 0.0015” 
 

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7.1.1.3. 
Wire Count (available in 48-wire and 64-wire configuration) 
The Pipeline™ Vantage implant will be offered in diameter range of 2.50 to 6.00 mm. To accommodate 
for the diameter range, the braided implant is offered in a 48-wire and a 64-wire configuration (Table 7-1). 
The 48-wire configuration is offered for braid diameters ≤3.5 mm and the 64-wire configuration is offered 
for braid diameters ≥4.0 mm. Whereas, the currently approved Pipeline™ Flex is available in the diameter 
range 2.50 to 5.00 mm and is only offered in a 48-wire configuration. The 64-wire configuration enhances 
the ability of the implant to open upon deployment from the delivery system.  
In addition to the 64-wire configuration, individual pore sizes were decreased while pore density was 
increased for the larger diameter implants (Figure 7-5 and Table 7-3). Pore density, which is defined as 
the number of pores per mm2 (pores/mm2) is considered to determine efficacy for flow diverters.128,129 
In Figure 7-5, the white diamonds represent pores and the black diamonds represent metal. The porosity 
of the two are identical at 50%. However, the image on the left has a higher pore density (sixteen-fold) 
than the image on the right. The concept of pore density (or pore size) is important for the biological 
response of the artery to the implant since pore density determines the properties of the scaffold over 
which cellular elements proliferate and populate.128 
Figure 7-5. Pore Density of the Pipeline™ Vantage Device (left) and the Pipeline™ Flex Device (right) 
 
Table 7-3. Implant Property Comparison of Pipeline™ Flex and Pipeline™ Vantage 
Labeled 
Implant 
Diameter 
Pore Density 
(pores/mm2) 
Metal Coverage (%) 
Average 
Wall 
Thickness (µm) 
Foreshortening 
(%) 
FLEX 
VANTAGE 
FLEX 
VANTAGE 
FLEX 
VANTAGE 
FLEX 
VANTAGE 
2.50 
33 
33 
30 
29 
53 
51 
48 
47 
2.75 
29 
29 
29 
27 
53 
51 
50 
49 
In the figure above, the white diamonds represent pores and the black diamonds represent metal. The porosity of the two 
are identical at 50%. However, the image on the left has a higher pore density (sixteen-fold) than the image on the right.  

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Labeled 
Implant 
Diameter 
Pore Density 
(pores/mm2) 
Metal Coverage (%) 
Average 
Wall 
Thickness (µm) 
Foreshortening 
(%) 
FLEX 
VANTAGE 
FLEX 
VANTAGE 
FLEX 
VANTAGE 
FLEX 
VANTAGE 
3.00 
26 
25 
28 
27 
56 
53 
52 
50 
3.25 
22 
22 
29 
27 
58 
56 
54 
53 
3.50 
20 
20 
29 
27 
61 
58 
56 
55 
4.00 
17 
26 
28 
27 
64 
52 
59 
53 
4.50 
14 
22 
27 
27 
66 
56 
61 
52 
5.00 
12 
18 
26 
26 
67 
58 
63 
51 
5.50 
N/A 
15 
N/A 
27 
N/A 
64 
N/A 
54 
6.00 
N/A 
13 
N/A 
25 
N/A 
64 
N/A 
58 
7.1.1.4. 
Pipeline™ Vantage Delivery System 
Similar to the Pipeline™ Flex, the Pipeline™ Vantage implant is mounted on a guide-wire based delivery 
system approximately 200 cm long and is supplied compressed inside an introducer sheath. The primary 
component remains a 304-stainless steel core wire that extends from the proximal end of the delivery 
system to the distal tip. Like that of Pipeline™ Flex, a spiral cut 304L stainless steel hypotube is mounted 
over the core wire and covered with a polytetrafluoroethylene (PTFE) jacket. The below design 
enhancements implemented to the Pipeline™ Vantage Delivery System are intended to enhance tactile 
feedback, deliverability, and include a low-profile delivery system to enable compatibility with micro 
catheters that have an inner diameter of 0.021” for delivering implants with a diameter of ≤3.50 mm. 
7.1.1.4.1. Corewire-based Delivery System 
The Pipeline™ Vantage Delivery System utilizes a single tapered core wire subassembly design, including 
a larger proximal portion for .027” microcatheter compatible sizes for enhanced pushability when 
compared to Pipeline™ Flex Embolization Device. In comparison, the existing Pipeline™ Flex delivery 
system uses separate proximal and distal core wires secured by the spiral cut hypotube. 
7.1.1.4.2. Advanced Resheathing Mechanism  
The Pipeline™ Vantage delivery system incorporates a newly designed Advanced Resheathing Mechanism 
(ARM) that allows the user to resheath the implant up to two times. The ARM is a stainless-steel 
subassembly that engages the pores of the braid with gear-like functionality to enable resheathing with 
enhanced reliability. During resheathing, the user holds the delivery wire and simultaneously advances 
the microcatheter to recapture the implant. The ARM secures the implant within the microcatheter to 
facilitate resheathing. In comparison, the existing Pipeline™ Flex Delivery System uses a friction based 
resheathing pad which exerts a constant radial force against the implant during both delivery and 
resheathing.  
7.1.1.4.3. Distal Protective Subassembly (DPS) 
The Pipeline™ Vantage delivery system also includes a Distal Protective Subassembly (DPS), like that of 
Pipeline Flex, which protects the distal portion of the implant while the device is advanced through a 

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microcatheter. The DPS is comprised of protective sleeves made from ePTFE and a Platinum-Tungsten 
coil. The sleeves are attached to the radiopaque coil to allow the DPS to be mounted over the distal 
portion of the core wire and cover the distal end of the Pipeline™ Vantage braid. The coil has been 
designed to be smaller in outer diameter compared to Pipeline™ Flex to enable compatibility with 0.021” 
microcatheters. 
7.1.1.4.4.  Corewire Subassembly  
The Pipeline™ Vantage Corewire Subassembly includes the core wire, spiral cut hypotube, and proximal 
bumper. PTFE shrink tubing covers the spiral cut hypotube and tapered section of the core wire to provide 
a smooth lubricious liner to facilitate navigation. The PTFE shrink tube length is longer for devices 
compatible with .021” microcatheter. The hypotube length and the overall length of the delivery system 
remains constant for all sizes. The implant is mounted on the distal portion of the core wire and is 
compressed inside an introducer sheath prior to delivery. The radiopaque proximal bumper is secured at 
the distal end of the hypotube to indicate the proximal end of the implant. During delivery, the proximal 
bumper advances the implant, which can be deployed either by forward motion of the delivery wire or by 
retracting the microcatheter. 
7.2. 
Manufacturer 
The manufacturer of the Pipeline™ Vantage Device is Micro Therapeutics, Inc. d/b/a ev3 Neurovascular (a 
wholly owned subsidiary of Medtronic) located at 9775 Toledo Way, Irvine, CA 92618, United States. 
7.3. 
Pre-clinical Summary 
7.3.1. 
Biocompatibility Summary 
Biocompatibility was conducted for the Pipeline™ Vantage Implant and Delivery System. The Pipeline™ 
Vantage Implant and Delivery System met the acceptance criteria specified per ISO 10993-1:2009 and FDA 
Guidance on the Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - 
Part 1: Evaluation and testing within a risk management issued on June 16, 2016. 
7.3.2. 
Animal Studies Summary 
7.3.2.1. 
7-Day Porcine Study Summary: 
Test report: D00026019 
Objective: Assess the acute inflammatory tissue response, thromboembolism, and endothelization of 
Pipeline™ Vantage as compared to Pipeline™ Flex and verify the conformance of the Pipeline Vantage 
Delivery system to established biocompatibility requirements. 
Number of animals & devices: Seven (7) animals were used in this study. One animal was excluded due 
to failure to meeting exclusion criteria per protocol. Six (6) animals were successfully implanted with two 
paired test and control braids (four devices per animal) in like vessels. 

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Endpoint: 7-day survival 
Procedure: The Pipeline™ Vantage Delivery System was tested in six porcine models by navigating the 
Pipeline™ Vantage Delivery System to the target location, unsheathing and resheathing the Pipeline™ 
Vantage Implant (a maximum of three times) followed by a 30-minute dwell time. Following the 30-minute 
dwell, the Pipeline™ Vantage Delivery System was removed and the 7-day survival time point began. 
Results:  
1. All animals survived to their designated 7-day survival time point. Study met the protocol specified 
acceptance criteria.  
2. No safety risks were identified with Pipeline™ Vantage when compared to Pipeline™ Flex and it was 
determined that there is a non-inferior difference of < 20% for Pipeline™ Vantage as compared to 
Pipeline™ Flex. 
Conclusion: The pathology findings of the study are supportive of an acceptable safety profile for all braids 
and delivery systems, with no safety concerns identified in the animal model. 
7.3.2.2. 
90-Day Porcine Study Summary 
Test report: D00026003 
Objective: Demonstrate the safety, efficacy, and usability of the of Pipeline™ Vantage as compared to 
Pipeline™ Flex at 90 days. 
Number of animals & devices: Six (6) animals were successfully implanted with two paired test and 
control braids (four devices per animal) in like vessels. 
Endpoint: 90-day survival 
Procedure: Six (6) animals were successfully implanted with two paired test and control braids (four 
devices per animal) in like vessels. 
Results:  
1. All animals survived to their designated time point. The study met the protocol specified acceptance 
criteria.  
2. No safety risks were identified with Pipeline™ Vantage when compared to Pipeline™ Flex and it was 
determined that there is a non-inferior difference of < 20% for the Pipeline™ Vantage as compared to 
Pipeline™ Flex.  
3. No significant acute and/or sub-acute complications from implantation to the 90-day survival time 
point were noted. 
Conclusion: Findings of the study support an acceptable safety profile for all braids and delivery systems, 
with no safety concerns identified in the animal model. 
7.3.2.3. 
90-Day Laprine (Rabbit) Study Summary: 
Test report: D00026006 

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Objective: Demonstrate the safety, efficacy, and usability of Pipeline™ Vantage as compared to Pipeline™ 
Flex at 90 days. 
Number of animals & devices: Thirty-six (36) animals had aneurysms created using elastase in the right 
carotid artery (one aneurysm per model) ~41-48 days prior to implantation. 
Endpoint: 90-day survival 
Procedure: Prior to the study, three animals died, leaving a total of thirty-three available. Throughout the 
study, three animals were omitted due to exclusion criteria (e.g. incorrect aneurysm formation). A single 
device was successfully implanted in the right brachiocephalic/right subclavian artery across the neck of 
the aneurysm in thirty animals as well as three devices successfully implanted across the ostia of lumbar 
arteries in the descending aorta. 
Results:  
1. The remaining twenty-nine animals survived to their designated survival time point.  
2. No safety risks were identified with Pipeline™ Vantage when compared to Pipeline™ Flex and it was 
determined that there is a non-inferior difference of < 20% for the Pipeline™ Vantage as compared to 
Pipeline™ Flex.  
3. No significant acute and/or sub-acute complications from implantation to the 90-day survival time 
point were noted. 
Conclusion: Findings of the study support an acceptable safety profile for all braids and delivery systems, 
with no safety concerns identified in the animal model. 
7.3.2.4. 
180-Day Laprine (Rabbit)Study Summary: 
Test report: D00026887 
Objective: Demonstrate the safety, efficacy, and usability of Pipeline™ Vantage as compared to Pipeline™ 
Flex at 180 days. 
Number of animals & devices: Thirty-six (36) animals had aneurysms created using elastase in the right 
carotid artery (one aneurysm per model) ~21-48 days prior to implantation. Two (2) of thirty-six (36) 
animals were intended as backup animals. Three (3) of thirty-four animals (were excluded following 
baseline imaging due to meeting protocol exclusion criteria. 
Endpoint: 180-day survival 
Procedure: Thirty-one (31) animals were implanted with the test or control devices were implanted in the 
right brachiocephalic/right subclavian artery (BCA/RSC) across the neck of an aneurysm of each animal. 
Of the 31 animals with test or control devices implanted, four (4) were excluded from the study. 
Results:  
1. Three animals died within 1-2 days post implant procedure and were most likely procedure related 
(unrelated to treatment or device).  

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2. One (1) animal was humanely euthanized on day 27 due to declining health (fractured left femur) and 
the cause of this finding was considered unrelated to the device.  
3. A total of twenty-seven (27) animals completed this study at the intended 180 time point.  
4. No safety risks were identified with Pipeline™ Vantage when compared to Pipeline™ Flex and it was 
determined that there is a non-inferior difference of < 20% for the Pipeline™ Vantage as compared to 
Pipeline™ Flex.  
5. No significant acute and/or sub-acute complications from implantation to the 180-day survival time 
point were noted.  
Conclusion: Findings of the study support an acceptable safety profile for all braids and delivery systems, 
with no safety concerns identified in the animal model. 
7.4. 
Packaging 
Pipeline™ Vantage is an investigational device. Pipeline™ Vantage is limited by Federal (or United States) 
law to investigational use and is labeled as such. 
Physicians using the device should follow the current IFU version at the site. 
7.5. 
Intended Population 
The Pipeline™ Vantage Embolization Device with Shield Technology™ is intended for endovascular 
treatment of adults (22 years of age or older) with wide-necked intracranial aneurysms located in the 
internal carotid artery (up to the terminus). 
7.6. 
Contraindications 
7.7. 
Product Training Requirements 
Pipeline™ Vantage should only be used by attending physicians trained in percutaneous, intravascular 
techniques and procedures at medical facilities with the appropriate fluoroscopic equipment. Fellows are 
not permitted to implant Pipeline™ Vantage or any other adjunctive device for the treatment of 
aneurysms during the study procedure. Physicians who participate in this study are responsible for 
implanting the study device and are required to self-attest to completing a minimum of 20 cases with 
Pipeline™ Flex Embolization Device. Prior to implantation of the Pipeline™ Vantage, implanting 
Investigator(s) will be trained on the CIP and IFU. 
o Patients with active bacterial infection 
o Patients in whom dual antiplatelet and/or anticoagulation therapy (aspirin and clopidogrel) is 
contraindicated. 
o Patients who have not received dual antiplatelet agents prior to the procedure. 
o Patients in whom the parent vessel size does not fall within the indicated range. 

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7.8. 
Product Accountability 
Pipeline™ Vantage is tracked by lot number and usage of all study devices will be recorded. All devices 
must be kept in a secured location with limited access complete accountability for each device must be 
maintained, including shipping, receiving and return of the devices. Any unused devices must be returned 
to Medtronic at the conclusion of the study or upon product expiration. 
 
 

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8. Selection of Subjects 
8.1. 
Study Population 
The study population will consist of subjects with unruptured or ruptured (>30 days since occurrence) 
wide-neck intracranial aneurysms in the ICA. 
For subjects with more than one aneurysm requiring treatment, the following guidance is to be followed 
for subjects to be enrolled in the study. 
• 
If more than one aneurysm can be covered by a single Pipeline™ Vantage Device, the largest 
aneurysm meeting study criteria will be designated the target aneurysm. For equal sized 
aneurysms, the Core Lab will designate the target aneurysm. Overlapping of Pipeline™ 
Vantage device (i.e., stacking of devices) to be allowed if the investigator determines that it is 
required to cover the target aneurysm neck adequately. A maximum of 3 Pipeline™ Vantage 
Devices may be stacked at any point in the arterial vessel. 
• 
Provided the subject has more than one aneurysm and all aneurysms requiring treatment 
cannot be covered by a single Pipeline™ Vantage Device (unless overlapping with devices is 
for covering the target aneurysm neck adequately), AND the non-target aneurysms are 
outside of the affected territory, the non-target aneurysms should be treated first. After 
waiting at least 30 days per exclusion, the subject may return for treatment of the target 
aneurysm in the study with the Pipeline™ Vantage Device. 
• 
If the subject has more than one aneurysm and all aneurysms requiring treatment cannot be 
covered by a single Pipeline™ Vantage Device (unless overlapping with devices is for covering 
the target aneurysm neck adequately), AND the non-target aneurysms is inside the affected 
territory of the target aneurysm, the subject is ineligible for this study per exclusion criterion. 
8.2. 
Subject Enrollment 
Subjects are considered enrolled in the study when the subject (or subject’s legally authorized 
representative) signs the Informed Consent Form. Each site will follow the same protocol, and no single 
site will be allowed to enroll more than 20% of the total subjects. 
8.3. 
Inclusion Criteria 
Subjects must meet all of the following Imaging (determined by the core lab) and Clinical inclusion criteria: 

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Imaging Criteria (Core Lab Assessed) 
1. Subject has a target intracranial aneurysm located in the internal carotid artery (up to the 
terminus). 
2. Subject has a target intracranial aneurysm with an aneurysm neck ≥4mm or a dome-to-neck 
ratio of < 2. 
3. Subject has a target intracranial aneurysm that has a parent vessel with diameter 1.5–5.0 mm 
distal/proximal to the target intracranial aneurysm. 
Clinical Criteria 
4. Subject (or subject’s legally authorized representative) has provided written informed consent 
using the IRB/REB and Medtronic approved Informed Consent Form and agrees to comply with 
protocol requirements. HIPAA/data protection authorization has been provided and signed by 
the subject (or subject’s legally authorized representative). 
5. Age 22-80 years at the time of consent. 
6. Life expectancy ≥3 years 
7. Subject has a mRS ≤ 2 at baseline to be determined by a certified independent assessor at the 
site 
8. Subject has already been selected for endovascular treatment of the target aneurysm.  
9. Subject’s last recorded P2Y12 reaction units (PRU) value is between ≥60 and ≤200 prior to study 
procedure. For OUS sites, a TEG test may be carried out instead of the PRU test (depending on 
PRU test availability). In cases where TEG test is carried out, the subject should have a pre-
procedure therapeutic ADP% between >30% to <90%. 
10. Subject has multiple increased risk factors for intracranial aneurysm rupture, including but not 
limited to, aneurysm morphology, smoking, hypertension, diabetes, age, prior and/or family 
history of rupture, and/or history of subarachnoid hemorrhage that may result in a benefit risk 
profile of endovascular treatment to outweigh the risks of intracranial aneurysm rupture during 
the subject’s expected lifetime if left untreated. 

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8.4. 
Exclusion Criteria 
The subject must not meet any of the following exclusion criteria: 
Imaging Criteria (Core Lab Assessed) 
11. Subject has internal carotid artery bifurcation aneurysm. 
12. Aneurysms that arise from the Posterior Communicating Artery (PComm). 
13. The internal carotid artery aneurysms of the C7 segment will be excluded under the following 
conditions: 
a. Observed fetal posterior communicating artery (PComm) (A PComm of fetal origin is 
defined as a small, hypoplastic, or absent P1 segment of the posterior cerebral artery 
(PCA) with the PComm artery supplying a majority of blood flow to the P2 and higher 
order segments of the PCA) 
b. PComm overlapping with the aneurysm neck 
c. PComm branch arising from the dome of the aneurysm 
14. Subject has aneurysm arising from internal carotid artery but is primarily fed by posterior 
circulation (i.e., retrograde flow from the basilar artery) as confirmed by DSA 
Clinical Criteria 
15. Subject requires treatment of another aneurysm (with another treatment modality) within the 
affected territory of the target aneurysm during the study period. 
16. Subject has received an intracranial implant (e.g. coils) in the area of the target intracranial 
aneurysm within the past 6 months prior to the study procedure. 
17. Subject has had a SAH and/or target aneurysm rupture in the past 30 days prior to the study 
procedure. 
18. Subject has undergone a surgery including endovascular procedures in the last 30 days prior to 
the study procedure. 
19. Vessel characteristics (e.g. severe tortuosity, stenosis, morphology) that preclude safe 
endovascular access to the aneurysm to allow for necessary access to treat with the study 
device. 

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20. Aneurysm vessel characteristics (e.g., parent vessel stenosis, irregular morphology) that would 
preclude the device from fully conforming to the parent vessel to reduce any risk of embolic 
complications, re-treatment, or device movement. 
21. Subject has active vasospasm, malignant brain tumor or vascular malformation (e.g. 
arteriovascular malformation). 
22. History of major bleeding disorder (based on coagulation profile and platelet count) and/or 
subject presents with signs of active bleeding. 
23. Subject requires adjunctive device use (e.g. coils) during the index procedure.  
24. Subject has extradural target aneurysm <12mm which is not symptomatic or not exhibiting 
aneurysm growth (exception: unless it is a fusiform aneurysm <12 mm i.e., asymptomatic 
extradural fusiform aneurysms <12 mm can be included). 
25. Any known contraindication to treatment with the Pipeline™ Vantage Embolization Device with 
Shield Technology™, or use of antiplatelet therapy including: 
d. Active bacterial infection 
e. Contraindication to DAPT agents  
26. Pre-existing stent is in place in the parent artery at the target intracranial aneurysm location. 
27. Platelet count < 100 x 103 cells/mm3 or known platelet dysfunction. 
28. The Investigator determines that the health of the subject or the validity of the study outcomes 
(e.g., high risk of neurologic events, conditions that may increase the chance of stroke) may be 
compromised by the subject’s enrollment. 
29. Subject is pregnant or wishes to become pregnant during the first year of study participation. 
30. Subject is participating in another clinical trial at any time during the duration of the study that 
could confound the treatment or outcomes of this investigation. 
31. Subject with known allergy to platinum or cobalt chromium alloy (including the major elements 
platinum, cobalt, chromium, nickel or molybdenum).  
32. History of previous acute ischemic stroke 
33. Subject is unable to undergo DSA or CTA imaging at follow-up. 

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9. Study Procedures 
9.1. 
Schedule of Events 
An overview of the assessments to be performed at each follow-up interval along with the required timing 
is provided in Table 9-1. Scheduled visits occurring outside of the specified date range will be considered 
clinical protocol deviations. After the clinical investigation has been completed, subjects will be followed 
according to standard of care. 
Table 9-1. Visit and Assessment Schedule 
 
Visits 
Baseline 
Procedure 
Discharge 
exam 
Follow-up 
 
Pre- 
(Day 0) 
Post- 
(Day 0) 
Day 1-7 
30-day 
180-day 
1-year 
2-year 
3-year 
Un-
scheduled 
Assessments 
Time  
Window 
-7 to 
 -30 days 
Day 0 
Day 0 
1-7 days 
±7  
days 
±30  
days 
± 56 
days 
± 56  
days 
± 56  
days 
 
Assess Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Risk Factors 
X1 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
 
X6 
 
 
 
 
X6 
X6 
X6 
 
WBC 
X10 
 
 
 
 
 
 
 
 
 
Platelet count 
X10 
 
 
 
 
 
 
 
 
 
Coagulation Profile (PT/aPTT) 
X10 
 
 
 
 
 
 
 
 
 
Platelet Reactivity Testing 
  
X7 
 
 
 
 
 
 
 
 
Protocol Specified Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DSA Imaging 
X2 
X9 
X 
 
 
X4 
X 
X3 
X3,4 
X4 
MRA 
 
 
 
 
 
 
X3 
X11 
X4 
CTA 
 
 
 
 
X11 
 
 
X11 
X4 
Modified Rankin Scale (mRS)  
 
X5 
 
X5 
X5 
X5 
X5 
X5 
X5 
X5,8 
NIH Stroke Scale 
 
X 
 
 
 
 
X 
 
 
X8 
Neurological Exam 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Assess Adverse Events  
X12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Risk factors to be assessed and collected for all subjects regardless of aneurysm size  
2 The baseline DSA, CTA OR MRA images must be taken no more than 90 calendar days prior to the procedure and core lab can use this for diagnostic or eligibility determination. Note that 
the pre-procedure exam for imaging would be with a DSA. 
3 If aneurysm is not occluded at 1 year or subsequent follow-up visits, DSA must be performed at 2- and 3- year follow-up. If child bearing potential woman becomes pregnant during the 
study, subject may obtain MRA without contrast instead of DSA. 
4 To be collected if conducted per standard of care 
5 mRS to be carried out by a certified independent assessor at the site. To become a certified independent assessor for mRS, the assessor should have passed a certification exam via 
online portal BlueCloud (or have evidence of a previous certification within the last 2 years). The assessor, once certified, will only be tasked with performing the mRS assessment for the 
trial and will have no other responsibilities or duties associated with the trial. 
6 Pregnancy test (serum or urine) only required for females of childbearing potential. Females who are surgically sterile or post-menopausal are not required to take a pregnancy test. At 
the 2- and 3- year follow-up, pregnancy test is only required for female subjects of childbearing potential that are undergoing DSA imaging.  
7 If PRU is found below 60 or above 200 on the day of the procedure, the procedure should be delayed until it is within therapeutic range. In such cases, baseline measurements should be 
repeated if the next procedure is scheduled >30 days from the initial baseline measurements. If procedure is performed <30 days from the initial baseline measurements, the PRU must 
be repeated, however, the baseline measurements may be repeated per standard of care at the treating hospital. For OUS sites, a TEG test may be carried out instead of the PRU test 
(depending on PRU test availability). In cases where TEG test is carried out, the subject should have a pre-procedure therapeutic ADP% between >30% to <90%.  If ADP% is <30% or >90% 
on the day of the procedure, the procedure should be delayed until it is within therapeutic range. In such cases, baseline measurements should be repeated if the next procedure is 
schedule >30 days from the initial baseline measurements. If procedure is performed <30 days from the initial baseline measurements, the TEG measurements must be repeated but the 
other baseline measurements may be repeated per standard of care at the treating hospital. Note: treating physicians should also assess if ARU testing is required to assess aspirin 
responsiveness based on subject condition and response (per standard of care) 
8 For stroke events, mRS should be performed minimum of 90 days post event and NIHSS should be performed at the time of event and 24 hours after event. 
9 DSA at pre-procedure to be used for final aneurysm measurements can be done any time prior to the index procedure 
10 Can be done any time prior to the index procedure 
11If DSA not collected per standard of care, subject must undergo CTA imaging. For follow-up images after the 1-year follow-up, under certain conditions, MRA imaging may be obtained 
instead of a DSA or CTA imaging e.g., subjects with iodine allergies, borderline renal function, pregnancy, or concerns over excessive radiation. The justification for using MRA over DSA or 
CTA should be captured in the case report form. Precaution: DSA or CTA imaging are preferred over MRA imaging due to the risk of reduced image quality (artifact) when attempting to 
visualize near or inside the implanted device with MRA imaging. Note that MRA should not be used for any follow-up imaging within 1-year 
12Assess adverse events after informed consent is signed. 

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An overview of the study procedures is shown in Figure 9-1 
 
*As permitted by the IRB/REB, de-identified images taken per standard of care may be sent to the core lab for screening committee review prior 
to informed consent. 
Baseline (7 to 30 days prior to procedure) 
Subject meets all eligibility criteria evaluated by standard of care assessments 
Screening Image Review* 
Core Laboratory reviews de-identified image (image must be within 90 days of 
procedure). 
Informed Consent (Point of Enrollment)  
Procedure (Day 0) (Puncture at the arterial access 
site)
Discharge Exam (Day 1 – 7) 
Pre-Screen Failure (Consent not Signed) 
Record on screening log. No entry should 
be made on eCRFs. 
180 Day Visit (±30 days)  
1 Year Visit (±56 days)  
Procedure (Day 0) 
Deploy PipelineTM Vantage Device to target 
aneurysm 
Pre-Procedure 
(On the day of Procedure) Subject meets all 
eligibility criteria evaluated by study-specific 
assessments  
2 Year Visit (±56 days)  
Figure 9-1. Overview of Study Procedures 
30 Day Visit (±7 days) 
3 Year Visit (±56 days)  
Collect 
adverse events 
Subjects Consented but Device not Attempted 
(Screen Failure) 
Subjects that are consented/enrolled in the study but 
do not undergo Pipeline™ Vantage device implant 
attempt i.e., puncture at the arterial access site (for 
not meeting eligibility criteria) should be exited from 
the study with the reason for exit recorded on eCRFs. 

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9.2. 
Baseline 
The baseline visit must occur 7 to 30 days prior to the procedure day. 
During baseline, the following assessments should be completed. 
• 
Inclusion/exclusion criteria assessment 
• 
Informed consent 
• 
Demographics: age, gender, ethnicity and race 
• 
Medical and surgical history 
• 
Risk factors, including aneurysm history; note that risk factors to be collected for all enrolled 
subjects regardless of the aneurysm size 
• 
Platelet count and WBC (can be done any time prior to index procedure) 
• 
Coagulation Profile (can be done any time prior to index procedure) 
• 
Protocol specified Medications 
• 
Record concomitant medications 
• 
DSA, CTA or MRA imaging (The baseline DSA, CTA or MRA images must be taken no more 
than 90 calendar days prior to the procedure) 
• 
Neurological Exam 
• 
Assessment of Adverse Events (Assess adverse events after informed consent is signed) 
This data will be collected in the electronic case report forms (eCRF) for all subjects enrolled and treated 
in the study. The de-identified images will be sent to the Core Lab for review. Enrolled subjects determined 
to be ineligible for the study prior to the puncture at the arterial access site on the day of the study 
procedure (Day 0), will only require the reason for the eligibility failure and study exit to be recorded in 
the eCRF. No further eCRFs are required. 
9.2.1. 
Baseline Imaging 
Baseline imaging (DSA, CTA, or MRA) must be taken within the 90 calendar days prior to the planned 
procedure date and core lab can use this for eligibility determination. As permitted by the IRB/REB, de-
identified images taken per standard of care may be sent to the core lab for screening committee review 
prior to informed consent.  

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At Screening, all of the following images shall be collected: 
• 
Imaging showing the aneurysm measurements 
Screening imaging to characterize the aneurysm must be reviewed and approved by the Core Lab. As 
permitted by the IRB/REB, de-identified images taken per standard of care may be submitted to the Core 
Lab prior to the subject (or subject’s legally authorized representative) signing the Informed Consent 
Form. 
9.2.2. 
Medical History 
Medical/surgical history and aneurysm specific history will be collected for all subjects at the time of 
enrollment and will include those conditions that are observed or self-reported by the subject at the 
baseline visit. Risk factors will be assessed and collected for all subjects regardless of aneurysm size. 
Aneurysm history and detailed symptoms and signs present at baseline shall be collected as medical 
history. Any worsening of these symptoms after the point of consent shall be collected as adverse events. 
9.2.3. 
Concomitant Medications 
Concomitant medications are to be collected starting at baseline and through the duration of the study 
which include: 
1) All medications the subject is on at the time of enrollment (consent) 
2) Medications received on the study procedure day (Day 0)–further detail regarding these 
medications is provided in Section 9.2.4 and 9.6 
3) Any new medications taken for intervention of study reportable events of interest 
4) Change in previously recorded concomitant medications after the study procedure (Day 0) 
through study exit 
9.2.4. 
Pre-Procedure Antiplatelet/Anticoagulation agents 
All protocol specified medications will be collected from the point of consent or from the first day of 
anticoagulation/antiplatelet treatment (whichever is earlier) through study exit. 
The following dose of antiplatelet agents will be given before treatment with the Pipeline™ Vantage 
Device as defined below. The DAPT regimen should be taken for a minimum of 5 consecutive days prior 
to the index procedure 
• 
Aspirin: 81-325 mg daily  
• 
P2Y12 Platelet Inhibitor: Only the following agents shall be utilized: 

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o Clopidogrel: 75–100 mg daily  
In situations where subjects are hypo-responders to Clopidogrel: 
 
Prasugrel (Only for subjects <75 years of age and should not be used in subjects 
with a history of TIA or stroke): 5-10 mg once daily 
Or 
 
Ticagrelor: 60-90 mg twice daily with a maximum daily dose of Aspirin not 
exceeding 100 mg 
The PRU value will be collected on eCRFs and treatment with the Pipeline™ Vantage Device can only be 
undertaken when PRU levels within therapeutic of ≥ 60 and ≤200 is achieved. If PRU is found below 60 or 
above 200 on the day of the procedure, the procedure should be delayed until it is within therapeutic 
range. In such cases, baseline PRU measurements must be repeated if the next procedure is scheduled 
>30 days from the initial baseline measurements. If procedure is performed <30 days from the initial 
baseline measurements, the PRU measurements must be repeated but the other baseline measurements 
may be repeated per standard of care at the treating hospital. For OUS sites, a TEG test may be carried 
out instead of the PRU test (depending on PRU test availability). In cases where TEG test is carried out, 
the subject should have a pre-procedure therapeutic ADP% between >30% to <90%.  If ADP% is <30% or 
>90% on the day of the procedure, the procedure should be delayed until it is within therapeutic range. 
In such cases, baseline measurements should be repeated if the next procedure is schedule >30 days from 
the initial baseline measurements. If procedure is performed <30 days from the initial baseline 
measurements, the TEG measurements must be repeated but the other baseline measurements may be 
repeated per standard of care at the treating hospital. 
Note: Treating physicians should also assess if ARU testing is required to assess aspirin responsiveness 
based on subject condition and response (per standard of care). 
9.3. 
Subject Consent 
Informed consent is defined as legally effective, documented confirmation of a subject’s (or their legally 
authorized representative’s) voluntary agreement to participate in a particular clinical investigation after 
information has been given to the subject on all aspects of the clinical investigation that are relevant to 
the subject’s decision to participate. 
Pre-screening (visit to collect standard of care assessments according to institution) may be permitted 
prior to informed consent. 
The Investigator(s) and/or staff delegated for this task are responsible for obtaining written informed 
consent and the HIPAA/data protection authorization from each potential subject before any study-

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specific procedures required by the clinical protocol are performed. Informed consent should be obtained 
in written format and using a form approved by the local IRB/REB and Medtronic. All subjects (or their 
legally authorized representative) must sign and date the Informed Consent Form and the HIPAA/data 
protection authorization prior to any procedures/tests that go beyond pre-screening assessments 
associated with the standard of care for subjects with intracranial aneurysms and before any study-related 
treatment assessments are administered and subject-related health information is entered into the study 
database. The Informed Consent Form and HIPAA/data protection authorization should be given to the 
subject (or their legally authorized representative) in a language he/she is able to read and understand. 
Prior to inclusion in the study, it is the responsibility of the Investigator and/or staff delegated to this task 
to give each subject (or subject’s legally authorized representative) full and adequate verbal and written 
information regarding the objective of this study and the confidentiality of the data collected. The process 
of obtaining informed consent must also be documented in the subject’s file. The original or a copy of the 
signed Informed Consent Form should be filed in the hospital/clinical chart or with the subject’s study 
documents. A copy of the consent and HIPAA/data protection authorization must be provided to the 
subject. 
A thorough explanation will be provided to the subject (or subject’s legally authorized representative) as 
to the nature and objectives of this study. Details of the study will be included according to country 
regulatory requirements which include but are not limited to the following: 
• 
Purpose of the study 
• 
Alternative treatments 
• 
Procedures of the study including the need to return for 30-day, 180-day, 1-year, 2-year, and 3-
year follow-up visits 
• 
Participation is voluntary, and there is no penalty for withdrawal 
• 
Potential risks and benefits of participation 
• 
Compensation and expenses to subject 
• 
Contact information to ask questions or voice concerns 
Medtronic will maintain the sample Informed Consent Form and all materials used to consent including 
the HIPAA/data protection authorization within the Trial Master File. 

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9.4. 
Pre-Procedure Assessment 
Subjects must undergo the device placement procedure within 30 calendar days of completion of all 
baseline assessment tests and procedures. On the day of the procedure and prior to treatment, the 
subject will again be evaluated and the following data shall be collected and recorded in the eCRF: 
• 
Inclusion/exclusion criteria assessment 
• 
Pregnancy test (Pregnancy test (serum or urine) only required for females of childbearing 
potential. Females who are surgically sterile or post-menopausal are not required to take a 
pregnancy test) 
• 
Platelet count (can be done any time prior to the procedure) 
• 
Platelet reactivity testing (If PRU is found below 60 or above 200 on the day of the 
procedure, the procedure should be delayed until it is within therapeutic range. In such 
cases, baseline measurements should be repeated if the next procedure is schedule >30 
days from the initial planned procedure. If procedure is performed <30 days from the initial 
planned procedure, the PRU measurements must be repeated but the other baseline 
measurements may be repeated per standard of care at the treating hospital). For OUS 
sites, a TEG test may be carried out instead of the PRU test (depending on PRU test 
availability). In cases where TEG test is carried out, the subject should have a pre-procedure 
therapeutic ADP% between >30% to <90%.  If ADP% is <30% or >90% on the day of the 
procedure, the procedure should be delayed until it is within therapeutic range. In such 
cases, baseline measurements should be repeated if the next procedure is schedule >30 
days from the initial baseline measurements. If procedure is performed <30 days from the 
initial baseline measurements, the TEG measurements must be repeated but the other 
baseline measurements may be repeated per standard of care at the treating hospital. 
• 
Record protocol specified medications 
• 
Record concomitant medications 
• 
DSA imaging for final aneurysm measurements 
• 
mRS assessment to be carried out by certified independent assessor at the site  
• 
NIHSS 
• 
Assessment of Adverse events of interest 
 

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9.5. 
Procedure 
Eligible subjects will be treated with the Pipeline™ Vantage Device per the IFU. During the procedure, 
Heparin should be administered as an anticoagulation agent. 
Note: The Investigator(s) should review and understand the complete CIP and IFU prior to performing any 
study implant placement in this clinical study. 
During or after the procedure, the following data shall be collected and recorded in the eCRF: 
• 
Procedure date and time 
• 
Primary interventionalist first and last name 
• 
Target aneurysm location and dimensions 
• 
Study device placement and resheathing information 
• 
Device implant success (yes/no)- per device used 
• 
Technical procedural success (per subject) 
• 
Subject’s radiation exposure (dose and fluoroscopy time)* 
• 
Volume of contrast used 
• 
Post-Pipeline™ Vantage Device implant aneurysm occlusion, device placement and 
aneurysm status 
• 
Procedural Complications 
• 
Record protocol specified anticoagulation medications 
• 
Record protocol specified DAPT 
• 
ACT: Record at the start, after heparin is given, and at the end of the procedure if collected 
per standard of care 
• 
Concomitant medications 
*Take all necessary precautions to limit X-ray radiation doses to patients and themselves by using 
sufficient shielding, reducing fluoroscopy times, and modifying X-ray technical factors where possible. 
Medications appropriate for general anesthesia will be administered using standard hospital practice. 
Capture all peri-procedural medications specific to the endovascular study procedure (e.g., anti-

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hypertensives, prophylactic antibiotics) on the eCRFs. Anesthetics and other standard of care medications 
for surgical procedures (e.g., saline, povidone-iodine antiseptic, etc.) do not need to be collected. 
Medications during treatment: 
Anesthetics: The subject will undergo the Pipeline™ Vantage placement under general anesthesia. 
Medications appropriate for general anesthesia will be administered using standard hospital practice. 
These are not required to be collected. 
Anticoagulants: Heparin use will be required during Pipeline™ Vantage placement with confirmation of 
anticoagulation via activated clotting time (ACT) prior to insertion of Pipeline™ Vantage. During the 
procedure, ACT values should be monitored per standard practice and heparin dose adjusted, as clinically 
appropriate. Heparin may be used up to 24 hours after procedure. If medically indicated, heparin use may 
be continued after 24 hours, but the Investigator must document the reason for the continued use. 
Heparin use (dose in ug/dl), frequency, start and stop dates will be collected. ACT values at the start of 
procedure, during procedure and at the end of procedure will be collected per standard of care. 
Other Procedural Medications: Any anti-thrombotic agents e.g., GPIIb3a inhibitors, Bivalirudin, Calcium 
Channel Blockers, Vasodilators, Antibiotics administered during the procedure shall be collected with their 
reason for use (prophylactic or for an AE intervention). 
9.5.1. 
Ancillary Devices 
Ancillary devices that may be required for the study procedure include, but are not limited to, access 
devices, intermediate support catheters, guidewires and microcatheters. Access devices, intermediate 
support catheters, and guidewires may be selected for use from FDA cleared devices as per Investigator 
preference and standard of care.  
The Pipeline™ Vantage implant is designed to be delivered through a compatible microcatheter of either 
0.021 inch (0.53 mm) or 0.027 inch (0.69 mm) inside diameter and minimum 135 cm in length. 
Compatibility testing with the Phenom™ 0.021” and 0.027” Microcatheter has been performed. Any 
compatible 0.021” and 0.027” microcatheter may be used but Phenom™ Microcatheter is recommended. 
Refer to the below table (Table 9-2) for microcatheter compatibility for each device size. 
Table 9-2. Size ranges: Pipeline™ Vantage Embolization Device with Shield Technology™ 
Labeled Diameter (mm) 
Compatible catheter inner diameter 
2.50 
0.021 inch (0.53 mm) 
2.75 
3.00 

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3.25 
3.50 
0.021 inch (0.53 mm) or 0.027 inch (0.69 mm) per 
product label 
4.00 
0.027 inch (0.69 mm) 
4.50 
5.00 
5.50 
6.00 
Ancillary Device Instructions: All endovascular devices are to be used in accordance with directions for 
use in the package insert approved by the FDA.  
The use of guide catheters and microcatheters will be documented in the eCRFs. 
9.5.2. 
Usage of Multiple Pipeline™ Vantage Devices 
Based on aneurysm and anatomical factors, if an investigator determines that multiple devices are 
required to cover the aneurysm neck adequately, an investigator may choose to deploy a maximum of 3 
Pipeline™ Vantage Devices that may be stacked at any point in the arterial vessel.  
9.5.3. 
Adjunctive Device Use 
Adjunctive devices are defined as devices (other than the Pipeline™ Vantage Device) that are used to treat 
the target aneurysm. 
Adjunctive device use (e.g. coils) is not allowed during the index procedure. Subjects that will require 
concomitant coiling should be excluded from the study (exclusion criteria). However, previous coiling 
failed subjects can be included. 
9.5.4. 
Day 0 Imaging 
At the beginning of the procedure prior to implantation, the following images shall be collected: 
• 
3-D DSA imaging pre-procedure to be used for final aneurysm measurements (if available) 
• 
Two planes showing the entire vascular territory (either complete hemisphere or full posterior 
circulation filmed in the early venous phase) 
• 
Views in the working projection with and without subtraction 
At the end of the procedure after implantation, the following images shall be collected: 

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• 
3D DSA imaging (if available) 
• 
Two planes showing the entire vascular territory (either complete hemisphere or full posterior 
circulation filmed in the early venous phase) 
• 
Views in the working projection with and without subtraction 
The Investigator or delegated study staff will submit procedural images to the core laboratory. The 
Investigator or delegated study staff will ensure that subject identifiers are removed from all submitted 
images. Image files/CDs should be labeled with the subject’s study ID number. 
9.5.5. 
Screen Failure 
Subjects that are consented/enrolled in the study but do not undergo Pipeline™ Vantage device implant 
attempt i.e., puncture at the arterial access site (for not meeting eligibility criteria) should be exited from 
the study with the reason for exit recorded on eCRFs. Baseline CRFs should also be recorded for Screen 
Failure subjects. 
9.5.6. 
No Treatment of an Eligible Subject with the Pipeline™ Vantage Device  
In the event that the subject was confirmed to be eligible for the study at baseline, signed informed 
consent, but the target intracranial aneurysm is not treated with the Pipeline™ Vantage Device at the 
initially scheduled procedure, the subject may be brought in later to undergo the Pipeline™ Vantage 
Device. In this case: 
1) In the event the subject does not meet protocol specified PRU value range (≥ 60 and ≤200) or TEG 
value range (>30% to <90%) on the day of the procedure, the procedure should be delayed (and 
no puncture at the arterial access site performed) until a protocol specified therapeutic range for 
PRU/TEG is achieved.  The day of the puncture at the arterial access site is considered day 0. 
2) In cases where PRU/TEG criteria is met and puncture at the arterial access site is performed, and 
the aneurysm is not able to be accessed or a study device unable to be deployed, the reasons of 
the inaccessibility of the aneurysm or study device failing to deploy (incomplete treatment) will 
be captured. Any alternate treatments if received will be captured. Such subjects will not be 
included in the per-protocol analysis. In cases where the subject is brought back at a later time 
and undergoes a second procedure with the study device, the date of the first intervention will 
be considered Day 0. The second intervention (if successful) will not be considered a retreatment. 
The subject must be brought back for the second intervention within 6 weeks of the initial 
attempted treatment. 

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9.6. 
Post-Placement Antiplatelet Agents 
The subject should be tested for antiplatelet response per standard of care and the appropriate dose of 
antiplatelet agents will be given after the Pipeline™ Vantage Device implant procedure as defined below. 
• 
Aspirin: At least 81 mg daily for a minimum of 6 months 
• 
P2Y12 Platelet Inhibitor: Daily for a minimum of 3 months. Only the following agents shall be 
utilized: 
Clopidogrel: At least 75 mg daily for a minimum of 3 months 
In situations where patients are hypo-responders to Clopidogrel: 
 
Prasugrel (Only for subjects <75 years of age and should not be used in subjects 
with a history of TIA or stroke): 5-10 mg once daily for a minimum of 3 months 
Or 
 
Ticagrelor: 60-90 mg twice daily with a maximum daily dose of Aspirin not 
exceeding 100 mg for a minimum of 3 months 
Note: Treating physicians should evaluate extending the DAPT regimen based on individual subject 
condition and response (per their standard of care) Dosing amount will be collected on eCRFs. 
9.7. 
Discharge Exam 
At day 7 or discharge (whichever is earlier), the following study assessments shall be performed: 
• 
Record protocol specified medications 
• 
Record concomitant medications 
• 
mRS to be carried out by a certified independent assessor at site 
• 
Full neurological exam and assessment of aneurysm symptoms (new, worsened, improved, 
stable) 
• 
Assessment of Adverse events 
Subject discharge disposition will be documented in the eCRFs. 

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9.8. 
Retreatment 
At the Investigator’s discretion, the target aneurysm may be retreated at any time during the study. The 
retreatment procedure can include any endovascular or surgical intervention including the implant of the 
Pipeline™ Vantage Device. In such situations, the date that the subject receives the initial Pipeline™ 
Vantage Device implant (and not the date of the retreatment) will be considered Day 0. 
Reason(s) for retreatment of aneurysm shall be documented: 
• 
Device Movement 
o Foreshortening (Peri-procedural or Delayed) 
o Migration 
• 
Aneurysm Growth 
• 
Aneurysm Rupture 
• 
Aneurysm Non-Occlusion 
• 
Insufficient Neck Coverage 
Type of Retreatment will be documented: 
• 
Planned 
• 
Unplanned 
A retreatment will be considered an “Unscheduled Visit” and subjects will be required to undergo the 
following study assessments: 
• 
Full neurological exam and assessment of aneurysm symptoms (new, worsened, improved, 
stable) 
• 
Record concomitant and protocol-specified medications 
• 
Imaging (per standard of care) 
• 
NIHSS  
• 
mRS assessment to be carried out by a certified independent assessor at site 
• 
Assessment of Adverse events 

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Data will be collected for all retreatment procedures in the Retreatment eCRFs. Retreatments should be 
reported as an SAE. 
9.9. 
Follow-up Evaluations 
Subjects that consented/enrolled and underwent a successful Pipeline™ Vantage Device implant will 
undergo in-clinic follow-up at 30 days, 180 days, 1 year, 2 years, and 3 years. Subjects that had a Pipeline™ 
Vantage device attempt but were not successfully implanted with the Pipeline™ Vantage device at the 
index procedure or subsequent attempts, will undergo in-clinic follow-up at 1 year. 
9.9.1. 
30-Day 
At day 30 post-procedure (± 7 days), the following study assessments shall be performed and recorded in 
the eCRFs: 
• 
Record protocol specified medications 
• 
Record concomitant medications 
• 
mRS assessment to be carried out by a certified independent assessor at site 
• 
Full Neurological Exam and assessment of aneurysm symptoms (new, improved, worsened, 
stable) 
• 
Assessment of Adverse events of interest 
9.9.2. 
180-Day 
At day 180 post-procedure (± 30 days), the following study assessments shall be performed and recorded 
in the eCRFs: 
• 
Record protocol specified medications 
• 
Record concomitant medications 
• 
DSA imaging, if done per standard of care; if DSA not performed per standard of care, 
subject must undergo CTA imaging. 
• 
mRS assessment to be carried out by a certified independent assessor at site 
• 
Full neurological exam and assessment of aneurysm symptoms (new, worsened, improved, 
stable) 
• 
Assessment of Adverse events of interest 

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9.9.3. 
1-Year 
At 1-year post-procedure (± 56 days), the following study assessments shall be performed and recorded 
in the eCRFs: 
• 
Pregnancy test (Pregnancy test (serum or urine) only required for females of childbearing 
potential. Females who are surgically sterile or post-menopausal are not required to take a 
pregnancy test) 
• 
Record protocol specified medications 
• 
Record concomitant medications 
• 
DSA imaging  
• 
mRS assessment to be carried out by a certified independent assessor at site 
• 
Full neurological exam and assessment of aneurysm symptoms (new, worsened, improved, 
stable) 
• 
NIHSS 
• 
Assessment of Adverse events of interest 
9.9.4. 
2-Year 
At 2-year post-procedure (± 56 days), the following study assessments shall be performed and recorded 
in the eCRFs: 
• 
mRS assessment to be carried out by a certified independent assessor at site 
• 
Pregnancy test (Pregnancy test (serum or urine) only required for females of childbearing 
potential. Females who are surgically sterile or post-menopausal are not required to take a 
pregnancy test). At the 2-year follow-up, pregnancy test is only required for female subjects 
of childbearing potential that are undergoing DSA imaging.   
• 
Record protocol specified medications 
• 
Record concomitant medications 
• 
If aneurysm is not occluded at 1 year or subsequent follow-up visits (per core lab 
assessment), DSA must be performed at 2-year follow-up. If child bearing potential woman 
becomes pregnant during the study, subject may obtain MRA without contrast instead of 
DSA. 

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• 
Full neurological exam and assessment of aneurysm symptoms (new, worsened, improved, 
stable) 
• 
Assessment of Adverse events of interest 
9.9.5. 
3-Year 
At 3-year post-procedure (± 56 days), the following study assessments shall be performed and recorded 
in the eCRFs: 
• 
Pregnancy test (Pregnancy test (serum or urine) only required for females of childbearing 
potential. Females who are surgically sterile or post-menopausal are not required to take a 
pregnancy test). At the 3-year follow-up, pregnancy test is only required for female subjects 
of childbearing potential that are undergoing DSA imaging.    
• 
Record protocol specified medications 
• 
Record concomitant medications 
• 
If aneurysm is not occluded at 1 year and subsequent follow-up visits (per core lab 
assessment), DSA must be performed at 3- year follow-up. Subjects with aneurysm 
occluded at 1 year and subsequent follow-up visits (per core lab assessment) to undergo 
DSA, if performed per standard of care; if DSA not collected per standard of care, subject 
must undergo CTA imaging. Under certain conditions, MRA imaging may be obtained 
instead of a DSA or CTA imaging e.g., subjects with iodine allergies, borderline renal 
function, pregnancy, or concerns over excessive radiation. The justification for using MRA 
over DSA or CTA should be captured in the case report form. Precaution: DSA or CTA imaging 
are preferred over MRA imaging due to the risk of reduced image quality (artifact) when 
attempting to visualize near or inside the implanted device with MRA imaging. 
• 
mRS assessment to be carried out by a certified independent assessor at site 
• 
Full neurological exam and assessment of aneurysm symptoms (new, worsened, improved, 
stable) 
• 
Assessment of Adverse events of interest 
9.9.6. 
Unscheduled Visits 
At unscheduled follow-up visit (any visit to the study site that is performed between the planned follow-
up visits) that occurs post-procedure through the 3-year visit, the following study assessments shall be 
performed and recorded in the eCRFs: 

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• 
Record protocol specified medications 
• 
Record concomitant medications 
• 
DSA imaging (collected if performed per standard of care) 
• 
Imaging of the treated aneurysm using CTA/MRA (collected if conducted per standard of 
care) 
• 
mRS (for stroke events, mRS should be performed at a minimum of 90 days post event) 
assessment to be carried out by a certified independent assessor at site  
• 
NIHSS (For stroke events, NIHSS should be performed at the time of event and 24 hours 
after event)* 
• 
Full neurological exam and assessment of aneurysm symptoms (new, worsened, 
improved, stable) 
• 
Assessment of Adverse events of interest  
*Note that for assessments not performed at study center, the medical charts need to be obtained and 
sent to Sponsor for CEC evaluation. 
9.10. Assessment of Effectiveness  
The methods and timing for assessing effectiveness parameters is seen in Table 9-1. 
9.11. Assessment of Safety 
The methods and timing for assessing safety parameters, including adverse events, is seen in Table 9-1. 
9.12. New Information 
Study subjects will be informed of new information that becomes available during the course of this study 
by their treating physician. Subjects will be notified, at a minimum, in accordance with the procedure of 
IRB/REB for providing updated information to clinical study subjects. 
9.13. Recording Data 
Study data will be collected using electronic case report forms and a 21 CFR Part 11-compliant electronic 
data capture system. The system allows the capability of data collection remotely through the internet so 
the participating clinical site personnel may log on to the system securely and enter the data. All subjects’ 
data collected in the system will be extensively verified through data validation programs, database 
integrity rules, and investigation-specific data entry conventions for data accuracy and logical 

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meaningfulness. Periodic analysis of all subjects’ collected data will be performed in order to examine the 
expected distributions of data and to identify outliers for possible data entry errors. 
The Investigator is responsible for reviewing all eCRF entries for completion and correctness. Changes in 
case report forms will be made electronically and the system used will keep an audit trail of changes. If 
necessary, an explanation for the change(s) may be provided. The Investigator will electronically approve 
all eCRF data. 
All study staff that enter data into eCRFs will undergo appropriate training for use of eCRFs. Further 
information regarding eCRF navigation and use may be found in the eCRF Completion Guidelines. 
9.14. Deviation Handling 
A protocol deviation is defined as an event where the Investigator or clinical study personnel did not 
conduct the study according to the clinical protocol. Protocol deviations will be reported to the Sponsor 
within the eCRF regardless of whether it was medically justifiable or taken to protect the subject in an 
emergency. 
Except under emergency circumstances to protect the rights, safety and well-being of human subjects, 
the clinical protocol will be followed as described. Subject-specific protocol deviations and non-subject-
specific protocol deviations must be reported. Investigators will also adhere to procedures for reporting 
protocol deviations to their IRB/REB in accordance with their specific IRB/REB reporting policies, timelines, 
and procedures. 
The Sponsor is responsible for analyzing deviations and assessing their significance. Protocol deviations 
will be routinely reviewed by the Sponsor study team. Where deviations occur, clinical sites are expected 
to implement preventative and corrective actions to prevent further protocol deviations. Clinical sites 
with a high rate of protocol deviations will be closely evaluated. If a clinical site demonstrates persistent 
protocol deviations, the clinical site may be prohibited from enrolling additional subjects, and in some 
cases, sponsor may terminate the Investigator’s participation in the study. If a study required assessment 
is missed, then it will be considered as a protocol deviation. 
9.15. Subject Withdrawal or Discontinuation 
Upon completion of the specified study follow-up, the subject will be exempt from further data collection. 
The subject will be seen by the treating physician according to standard of care following intracranial 
aneurysm treatment. 
Subjects may withdraw from the study at any time without penalty or loss of medical care, or they may 
be withdrawn at any time at the discretion of the Principal Investigator or Sponsor for safety or 
administrative reasons. Subjects that withdraw from the study will not be replaced. 

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9.15.1. 
Subject Withdrawal 
All enrolled subjects have the right to withdraw their consent at any time during this study. All data 
collected until the time of subject withdrawal will remain in the study database and will be used for 
analysis. If a subject is withdrawn from the clinical study, the reason for withdrawal shall be recorded in 
the eCRF and in the subject’s hospital record. 
Whenever possible, the clinical site staff should obtain written documentation from the subject who 
wishes to withdraw his/her consent for future follow-up visits. If the clinical site staff is unable to obtain 
written documentation, all information regarding the subject’s withdrawal must be recorded in the 
subject’s medical record. In addition, the appropriate eCRFs must be completed for the subject and clear 
documentation of the subject’s withdrawal should be provided to the Sponsor. 
9.15.2. 
Subject Discontinuation by Investigator 
An Investigator may discontinue a subject from the study, with or without the subject’s consent for any 
reason that may, in the Investigator’s opinion, negatively affect the well-being of the subject, subject non-
compliance, Sponsor decision due to early termination of the study, or if the IRB/REB or regulatory 
authority stops the study for any reason. If a subject is discontinued from the study, the Investigator will 
promptly inform the subject and Sponsor. 
9.15.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if the subject cannot be reached after a minimum of three 
(3) attempts to contact the subject for a follow-up visit. The clinical site must document a minimum of 
three (3) attempts, and the final documented attempt should be made via registered letter. 

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10.Risks and Benefits 
10.1. Potential Risks 
Residual risks from the risk management workbook (RMW15-0012_L) for Pipeline™ Vantage was analyzed 
to determine the potential clinical harms that may be associated with the use of the Pipeline™ Vantage 
device. Residual risks, as identified in the risk management work (RMW15-0012_L) are included in the 
below potential risks. Note that the Risk Management Workbook is a document that is continuously 
updated. The most current associated risks are also captured in the Instructions For Use (IFU), (P/N 
M993912ADOC2). Anticipated Adverse Events and Adverse Device Effects associated with use of the study 
device and the study procedure(s) include: 
Neurological Events 
of Interest 
An event of interest related to the target aneurysm clinical outcome and includes the 
following events of interest: 
Death 
Neurological Death 
Stroke* 
Major 
Minor 
ICH* 
Target Aneurysm Rupture 
Transient Ischemic Attack 
Cerebral Infarction 
Symptomatic 
Asymptomatic 
Target Aneurysm Retreatment 
Planned 
Unplanned 
Neurological Deficit (decline in mRS)* 
Focal 
Generalized 
Visual Symptoms*: 
Scintillations 
Blurred vision 
Floaters 
Diplopia 
Retinal Artery Occlusion 
Amaurosis Fugax 
Vision Loss 
Visual Field Deficit 
*Ipsilateral Territory: Presumed to be of the vascular origin of the treated vascular 
territory 

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Procedural Events of 
Interest 
Events representing the endovascular procedural complications of the study aneurysm 
treatment. Complications could be fatal or non-fatal, Serious or Non-Serious, Acute or 
Delayed. These include: 
Access Site Complications: 
Hematoma/hemorrhage 
Retroperitoneal  
Localized  
Pseudoaneurysm (PSA) 
Vessel occlusion 
Arteriovenous fistula (AVF) 
Deep Vein Thrombosis (DVT) 
Local neurogenic or nerve complications 
Pain 
Vascular Complications (Intra-Cranial or Extra Cranial): 
Dissection 
Perforation 
Rupture 
Vasospasms (vasoconstriction) 
Intracranial fistula formation 
Occlusion 
Thromboembolic Complications 
Distal Thromboembolic complication 
Anesthesia related complications 
Aspiration 
Hypertension 
Hypotension 
Contrast Related Complications: 
Burning Sensation 
Nausea 
Contrast Nephropathy 
Visual Impairment/Visual symptoms 
Excessive Radiation Complications: 
Skin reddening, 
Blisters and ulcers, 
Hair loss (alopecia) 
Cataracts 
Late appearing cancers 
Systemic complications: Infection, Shock, Arrhythmia 
 
  

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Device related 
Events of Interest  
Events representing complications of the study device or its use. These include fatal or 
non-fatal, serious or non-serious in nature: 
Device Thrombosis 
Parent Artery (In-Stent) Stenosis 
Incomplete Occlusion (At follow-up imaging) 
Mechanical Device Failures (Device Deficiencies) including but not limited to: 
o 
Incomplete Open 
o 
Failure to Open 
o 
Pushwire Separation issues 
o 
Loss of Device Integrity (fracture, fragmentation break) 
o 
Device- Catheter Interaction (excessive friction, trackability issues) 
o 
Device Foreign Body Reaction (Toxicity, Granuloma) 
o 
Device Movement 
 
Foreshortening (delayed) 
 
Migration 
 
DAPT Related Events 
of Interests 
Events representing complications of the use of Dual Antiplatelet Therapy. These include 
fatal or non-fatal, serious or non-serious in nature: 
Bleeding Complications (GUSTO) 
o 
Mild 
o 
Moderate 
o 
Severe 
Thrombocytopenia/Thrombotic thrombocytopenic purpura 
Nose bleeds (epistaxis) 
Allergic reaction to medications including angioedema 
Generalized Headache 
Dizziness 
Anemia 
Abnormal Liver and/or kidney function 
GI Symptoms: 
o 
Abdominal pain, 
o 
Nausea, 
o 
Vomiting 
o 
Indigestion 
o 
Gastritis/Gastric Ulcer 
Dyspnea 
Fatigue 
Arrhythmias/ventricular pause(s) 
Note: For comprehensive potential risks associated with dual antiplatelet therapy, please 
refer to the most current labelling for the specific antiplatelet drug e.g., Aspirin, Clopidogrel, 
Prasugrel, Ticagrelor 
10.2. Risk Mitigations 
Several safeguards are incorporated into the study to minimize subject risk. All pre-clinical device testing 
for the implantable braid and the single use delivery system are performed in accordance with regulations 
and recognized standards. All test results have passed the required specifications supporting reasonable 

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safety for this clinical product. 
At each investigational site, the study will be conducted under the direction of a qualified physician 
experienced with endovascular procedures including intracranial aneurysm repair and who will self-attest 
to completing a minimum of 20 Pipeline™ Flex Embolization Device cases. All participating investigators 
have experience conducting clinical research and have adequate personnel to assure compliance to the 
study protocol. 
Subjects will be monitored closely as part of the study to allow for detection of adverse events, should 
they be present. This, in turn, should allow for early treatment, if necessary. Personally identifying subject 
information will not be collected on eCRFs or other study-related documentation to be provided to the 
Sponsor. 
In addition, subjects must have pre-procedure P2Y12 reaction unit value (PRU) within therapeutic range of 
60 and 200 prior to undergoing procedure with the Pipeline™ Vantage Device. Pre-procedure P2Y12 
reaction unit value (PRU) has shown to predict perioperative thromboembolic and hemorrhagic 
complications. In a study involving 44 subject and 48 Pipeline™ Embolization Device (PED) procedures for 
cerebral aneurysm treatment, Delgado Almandoz et al. reported that a pre-procedure PRU value of <60 
or >240 (p=0.02) and a technically difficult procedure (p=0.04) were independent predictors of all 
perioperative thromboembolic and hemorrhagic complications after PED procedures. Inclusion criteria 
surrounding this optimal pre-procedural PRU value range is intended to minimize subject risk for 
procedural complications. Additionally, TEG was added for sites OUS where PRU test cannot be 
performed; based on the TEG test, pre-procedure ADP% between >30% and <90% has been used to 
evaluate adequate platelet reactivity.130 
All study data will be monitored by individual site and combined sites. Clinical outcomes of all study 
subjects will be routinely monitored by the Sponsor during the course of the study. Safety endpoint 
related events will be reviewed and adjudicated by an independent CEC and an independent DMC will 
provide oversight throughout the trial. In the event of unforeseen or increased risks to subjects 
encountered during the course of the study, the study may be suspended or terminated. 
10.3. Potential Benefits 
Endovascular coiling is a commonly prescribed intracranial aneurysm treatment due to its favorable safety 
and efficacy profile.27,131 However, the major limitations of this intracranial aneurysm treatment mode are 
risks for incomplete occlusion and aneurysm recurrence or recanalization.132,133 Large and giant complex 
intracranial aneurysms are even more susceptible to endovascular coiling failure with high rates of 
incomplete occlusion and subsequent recanalization.94 Even with the achievement of complete occlusion 
following coil embolization, lesions are subject to coil compaction leading to recurrence, continued 
surveillance, and often necessitate retreatment due to rupture risk. Finally, important subgroups of 
lesions including fusiform, wide-neck, dissecting, and other complex aneurysm configurations are 

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unsuitable or unsafe for embolization and/or conventional stenting. 
Since the introduction of the Pipeline™ Embolization Device, flow diverters have represented a shift in 
interventional aneurysm treatment from endoluminal based approaches to vessel reconstruction. The 
Pipeline™ device, when placed across the aneurysmal neck, redirects blood flow away from the aneurysm 
sac, leading to aneurysm thrombosis and occlusion. By disrupting the hemodynamic exchanges across the 
aneurysm neck and into the sac, the Pipeline™ implant addresses the diseased segment of the parent 
artery, allowing for neoendothelialization to occur, effectively excluding the aneurysm from the vessel 
wall.134-136 The occluded aneurysm decreases progressively in size, resulting in a restructuring of the local 
neurovasculature to its pre-aneurysm state. The curative and permanent outcomes of flow diversion 
treatment are thus a consequence of three potential mechanisms of action: (i) endovascular 
reconstruction of a segmentally diseased artery, (ii) flow reduction sufficient to induce thrombosis in the 
aneurysm sac, and (iii) biologic repair of the aneurysm neck by intimal growth. Finally, because the flow 
diverter’s mechanism of action is independent of aneurysm size, dome-to-neck ratio, or need for dense 
coil packing, flow diversion strategies seem particularly well-suited to wide-necked and fusiform 
aneurysms, for which no optimal endovascular and/or surgical alternative exists. In addition, since flow 
diverters are placed in the parent artery, they do not leave behind coil mass which may cause significant 
symptoms following treatment. Clinical trial results and findings from the published literature report 
Pipeline™ Embolization Device and Pipeline™ Flex Embolization Device technical success rates of 87-
100%.52,57-62,87 Complete aneurysm occlusion is commonly measured using the Raymond Roy Scale.1 
Arteriographic outcomes are divided into three categories in this scale: (1) complete occlusion, (2) residual 
neck, and (3) residual aneurysm.1 Pipeline™ Embolization Device treatment achieves up to approximately 
95% permanent aneurysm occlusion.49-55,87 Aneurysm obliteration has been shown to be maintained over 
long-term follow-up - further evidence of the high probability for patients to experience one or more 
major benefits following Pipeline™ Embolization Device treatment. 
The introduction of the Pipeline™ Vantage Device aims to further improve the safety and effectiveness 
profile of the device. The Shield Technology™ surface modification, based on phosphorylcholine (PC), aims 
to improve the biocompatibility and decrease the thrombogenicity of the Pipeline™ Vantage device while 
preserving the clinically proven design of the Pipeline™ implant. In vivo studies have shown that PC-coated 
stents implanted in the peripheral arteries inhibit platelet adherence and thrombosis in this specific 
application.69,71,72,137 Thus, it is anticipated that the benefits achieved from the Pipeline™ Flex Embolization 
Device should be at least maintained and perhaps improved with the use of Pipeline™ Vantage 
Embolization Device with Shield Technology™. 
10.4. Risk-Benefit Rationale 
The potential risks associated with the use of the Pipeline™ Vantage Device, based on risks observed with 
the Pipeline™ Embolization Device and Pipeline™ Flex Embolization Device, include ischemic 

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stroke,62,61,85,138,139,140,141 intracranial hemorrhage,52,53,142-146 neurological deficit,58 and death.33,50,51,53-
55,87,91,130,138,145,147-202 
Ischemic stroke with the Pipeline™ Embolization Device has ranged from 0.96% to 10.7%.52-
54,61,62,85,127,138,169,181,182,184,194,196,203-220 Thirty-three studies reporting clinical outcomes in ≥ 25 patients 
observed 230 ischemic stroke or cerebral infarction. Five studies did not report rate of ischemic stroke or 
cerebral infarction.205,209,212,220 One study reported ischemic stroke in one out of 59 patients.206 Three 
studies reported cerebral infarction in one of 50 patients,220 one of 40 patients,209 and two of 140 
patients.205 One study reported stroke in two of 110 patients.212 Overall, three of the studies that reported 
ischemic stroke reported that the events were procedure-related and one study reported an ischemic 
stroke that was device related.154,181,184,221,222 Considered the total patients captured in the relevant 
literature (9,121), the number of reported ischemic stroke events was low; thus the benefits of the use of 
the Pipeline™ device are expected to outweigh the risk. 
Pipeline™ Embolization Device studies have also reported intracranial hemorrhage (0.6% to 
12%).52,53,84,85,91,139,144,149,152,164,166,182,185,187,203-205,207,211,213,215,216,219,223-235 In their IntrePED sub-analysis, 
Brinjikji et al. investigated the risk factors for hemorrhagic complications with Pipeline™ Embolization 
Device treatment.236 Variables related to higher odds of intraparenchymal hemorrhage included 
treatment of ruptured aneurysms and use of more than 3 Pipeline™ Embolization Devices.236 The exact 
cause of intracranial hemorrhage with Pipeline™ Embolization Device use is unknown but possible 
explanations include use of DAPT and hemodynamic perturbations from flow diverter treatment.236 
Pipeline™ Embolization Device studies have also reported Neurological deficit/dysfunction. Thirty-six 
studies reporting clinical outcomes in ≥ 25 patients observe a total of 145 neurologic deficits/dysfunctions, 
with rates ranging from 0.3% to 15.4%.50,53,84,140,152,153,160,169,173,181,187,196,204,211,227,232,237-255 Six studies did not 
report rates for neurological deficits/dysfunction, but reported the number of cases, totaling 15 reported 
cases in 271 subjects. The number of reported neurological deficit/dysfunction was low; thus the benefits 
of the use of the Pipeline™ device are expected to outweigh the risk. 
Reported mortality with Pipeline™ Embolization Device use was 0.7% to 11.5% from 24 studies reporting 
clinical outcomes in ≥ 25 patients.52,53,85,127,144,149,150,164,169,175,182,187,205,210,213,215,219,224,225,228,229,233 A total of 
132 deaths were reported in these studies.52,53,85,127,144,149,150,164,169,175,182,187,205,210,213,215,219,224,225,228,229,233 
When taken into consideration with the rest of the published literature, out of the total patients captured 
in the literature, the number of reported deaths was low; thus the benefits of the use of Pipeline™ are 
expected to outweigh the risk. 
The risks associated with intracranial aneurysm treatment have to be balanced with the lifetime risk of 
rupture, patient life expectancy, and patient stress from the knowledge of the aneurysm and the 
possibility of rupture.256 When an intracranial aneurysm ruptures, the resulting SAH is life-threatening. 

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Subarachnoid hemorrhage from an aneurysm rupture is associated with 45% 30 day mortality and of the 
patients who survive, half experience morbidity.112,257 
Published data on the Pipeline™ Embolization Device and Pipeline™ Flex Embolization Device support its 
efficacy and safety in the treatment of small, medium, large, and giant wide-neck aneurysms in both the 
anterior and posterior circulation.52,55,59,61,84,85,166,258 The device currently has commercial approval in the 
US for large and giant wide-neck aneurysms and preliminary evidence with the Pipeline™ Embolization 
Device has shown that it can safely completely occlude small aneurysms. In a 100 patient study, Chalouhi 
et al. observed 72% (54/75) of small aneurysms were completely occluded (mean follow-up time: 6.3 
months).166 All patients achieved a favorable outcome at 7.3 month mean follow-up.136 Griessenhauer et 
al. treated 52 small paraophthalmic artery aneurysms and noted 81.5% (44/54) complete occlusion with 
a median follow-up of 11.5 months.259 There was no mortality or permanent visual deficit.259 Overall 
complete occlusion rates ranged from 72-86% at mean follow-ups of 4-6.3 months. Morbidity was 0-5% 
and mortality was 0-2.3% at mean follow-up of 4-7.3 months.33,160,166,259,260 Safety data from the IntrePED 
study reveal that of the 268 patients with unruptured intracranial aneurysms <10 mm located in the ICA 
up to the terminus, the combined neurological morbidity and mortality rate was 3.4%.85 
The published literature provides evidence that the risk-benefit ratio of the Pipeline™ Embolization Device 
and Pipeline™ Flex Embolization Device is acceptable. The clinical benefits achieved with the Pipeline™ 
Embolization Device and Pipeline™ Flex Embolization Device for the endovascular embolization of 
intracranial aneurysms is significant and outweighs the individual and overall residual risk associated with 
its use. Pipeline™ Vantage device should enhance the deliverability; and lower material thrombogenicity 
associated with the established Pipeline™ Flex Embolization Device based upon analogous thrombotic 
reductions seen in peripheral stent applications using PC surface modification. In addition, pre-clinical 
bench and animal testing of the Pipeline™ Vantage Device indicates non-inferiority to the established 
Pipeline™ Flex Embolization Device. 
The Pipeline™ Vantage Device consists of an improved version of the same Pipeline™ Flex Embolization 
Device implant with increased radiopacity and pore density. The delivery system of Pipeline™ Vantage 
was designed to be compatible with 0.021” inner diameter micro catheters for select sizes and also 
includes a new Advanced Resheathing Mechanism with enhanced reliability. Additionally, Pipeline™ 
Vantage has a phosphorylcholine polymer coating on the implant braid. Pipeline™ Vantage, Pipeline™ 
Shield, Pipeline™ and Pipeline™ Flex share substantial equivalence in terms of indication for use, structural 
composition, construction materials, manufacturing process, safety, and performance. In a prospective 
clinical study, Martinez-Galdamez et al. assessed peri-procedural outcomes and early safety outcomes 
associated with the use of Pipeline™ Shield for the treatment of unruptured aneurysms in 50 patients.217 
The device was successfully deployed in 98.1% of patients. Complete wall apposition was achieved 
immediately in 96% patients, with the aneurysm neck successfully covered in all patients. No major 
strokes or neurologic deaths were reported 30 days post-procedure. Retreatment was not required in any 

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of the patients. During the 30-day follow-up period, procedure-related, SAEs, including access site 
hematoma in one (2%) patient, carotid artery dissection in one (2%) patient, cerebral infarction in one 
(2%) patient, and nausea in two (4%) patients were reported. No morbidity or mortality were reported. 
Results from this study demonstrate that use of Pipeline™ Flex Embolization Device with Shield 
Technology™ was not associated with greater risk compared to Pipeline™ and Pipeline™ Flex. 
Collectively, based on the extensive data with previous generations of the Pipeline™ device, it is expected 
that the Pipeline™ Vantage device should provide a safe and effective treatment option for the treatment 
of patients with intracranial aneurysms. With the addition of the Shield Technology™, the potential to 
reduce material thrombogenicity improves upon the acceptable benefit-to-risk ratio that currently exists 
with the Pipeline™ Flex Embolization Device. Therefore, Medtronic considers the potential benefits of the 
Pipeline™ Vantage Device to outweigh the potential risks in the defined subject population. 

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11. Adverse Events and Device Deficiencies 
All adverse events (AEs) will be collected and evaluated from point of enrollment through study exit per 
the Schedule of Assessments for all subjects enrolled in the study. Adverse event status will be evaluated 
throughout the study.  
Investigators must obtain all information available to determine the causality, seriousness and outcome 
of the AE and to assess whether it meets the criteria for expedited reporting requiring notification to the 
Sponsor, and where applicable, regulatory agency(ies) and IRBs/REBs/Ethics Committees within the 
specified reporting timeframe per 21 CFR 812 or local regulations. Reported AEs shall be categorized by 
the site investigator when reporting to the sponsor using the definitions provided in Section 11.1 and 
11.3.  
Target Aneurysm related signs and symptoms that in the opinion of the Investigator existed prior to the 
point of puncture at the arterial access site on the day of the study procedure (Day 0) are not considered 
AEs (but will be collected as Medical History/ Risk Factors) unless the condition recurs after the subject 
has recovered from the pre-existing condition, or the condition worsens in severity, seriousness or 
frequency during the study.  
If the subject is enrolled and undergoes puncture at the arterial access site but an attempt to deploy the 
Pipeline™ Vantage Device is not made due to ineligibility of the subject for the study (e.g., inability to 
access the aneurysm or other exclusion criterion identified during the procedure) any adverse events or 
device deficiencies that occur are to be collected through subject’s study exit. 
All AEs, as well as their start dates, action taken, severity, causality assessment, seriousness and outcome 
should be documented in the subject’s medical records and in the eCRF.  
A list of foreseeable adverse events of the study is provided in Section 10.1. 
11.1. Adverse Event Definitions 
11.1.1. 
Adverse Event 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or other persons, whether or not related to the 
investigational medical device. (ISO 14155:2011 3.2) 
Note 1: This definition includes events related to the investigational medical device or the comparator. 
Note 2: This definition includes events related to the procedures involved. 

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Note 3: For users or other persons, this definition is restricted to events related to investigational medical 
devices. 
11.1.2. 
Serious Adverse Event 
 Adverse Event that 
a) Led to death, injury or permanent impairment to a body structure or a body function 
b) Led to a serious deterioration in the health of the subject, that either resulted in: 
a. A life-threatening illness or injury, or 
b. A permanent impairment of a body structure or a body function, or 
c. In-patient hospitalization or prolongation of existing hospitalization, or 
d. Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect (ISO 14155:2011 
3.37) 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without serious deterioration in health, is not considered a SAE. 
11.1.3. 
Adverse Device Event 
Adverse event related to the use of an investigational medical device. (ISO 14155:2011 3.1) The 
investigational medical device for this study is the Pipeline™ Vantage Device used during the study 
procedure (Day 0). 
Note 1: This definition includes any adverse events resulting from insufficiencies or inadequacies in the 
IFU, the deployment, implantation, installation, operation, or any malfunction of the investigational 
medical device. 
Note 2: This definition includes any event resulting from use error or intentional abnormal use of the 
investigational medical device. 
11.1.4. 
Serious Adverse Device Event 
Adverse device effect that has resulted in any of the consequences characteristic of a SAE. (ISO 
14155:2011 3.36) 

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11.1.5. 
Unanticipated Serious Adverse Device Event (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been identified 
in the current version of the risk analysis report. (ISO 14155:2011 3.42) 
Note: Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, severity 
or outcome has been identified in the risk analysis report. 
11.1.6. 
Unanticipated Adverse Device Event 
Serious adverse effect on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, 
or degree of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects. (21 CFR 812.3 (s)) 
11.1.7. 
Event Severity 
The severity of an adverse event is a qualitative judgment of the degree of intensity, as determined by the 
Principal Investigator or as reported by the subject. The severity of the AE should be evaluated according 
to the following scale: 
• 
Mild: No limitation of usual activities, no therapy or only symptomatic therapy required to treat 
the injury or illness. 
• 
Moderate: Some limitation of usual activities or specific therapy is required. 
• 
Severe: Inability to carry out usual activities, hospitalization, emergency treatment, life-
threatening events, or death. 
11.1.8. 
Causality Assessment of Events 
The relationship between the occurrence of each adverse event to the following will be assessed: 
• 
Use of the medical device for this study, Pipeline™ Vantage Device 
• 
 Index study procedure (on Day 0) involving initial application of the investigational medical device, 
and therefore not to any other procedures or treatments applied later during the clinical investigation 
(e.g., surgical procedures to treat SAEs). 
• 
Use of antiplatelet therapy. 

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The occurrence of each adverse event shall be assessed and categorized according to five different levels 
of causality for which the following definitions shall be used to assess the relationship of the adverse event 
to the investigational medical device, or index procedure, or use of DAPT: 
1. Not Related: 
Relationship to the device or procedures can be excluded when: 
• 
the event is not a known side effect of the product category the device belongs to or 
of similar devices and procedures; 
• 
the event has no temporal relationship with the use of the investigational device or 
the procedures; 
• 
the serious event does not follow a known response pattern to the medical device (if 
the response pattern is previously known) and is biologically implausible; 
• 
the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact on the serious event; 
• 
the event involves a body-site or an organ not expected to be affected by the device 
or procedure; 
• 
the event can be attributed to another cause (e.g. an underlying or concurrent 
illness/clinical condition, an effect of another device, drug, treatment or other risk 
factors); 
• 
the event does not depend on a false result given by the investigational device used 
for diagnosis*, when applicable [*If an investigational device gives an incorrect 
diagnosis, the subject might, for example, receive an unnecessary treatment and 
incur all the risks that accompany that treatment, or might be incorrectly diagnosed 
with a serious disease. In other cases, the subject might not receive an effective 
treatment (thereby missing out on the benefits that treatment would confer), or 
might not be diagnosed with the correct disease or condition]; 
• 
harms to the subject are not clearly due to use error; 
• 
In order to establish the non-relatedness, not all the criteria listed above might be 
met at the same time, depending on the type of device/procedures and the serious 
event. 

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2. Unlikely: 
The relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
3. Possible: 
The relationship with the use of the investigational device is weak but cannot be ruled out 
completely. Alternative causes are also possible (e.g., an underlying or concurrent 
illness/clinical condition or/and an effect of another device, drug or treatment). Cases were 
relatedness cannot be assessed or no information has been obtained should also be classified 
as possible. 
4. Probable: 
The relationship with the use of the investigational device seems relevant and/or the event 
cannot reasonably explain by another cause, but additional information may be obtained. 
5. Causal relationship: 
The adverse event is associated with the investigational device or with procedures beyond 
reasonable doubt when: 
• 
the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures; 
• 
the event has a temporal relationship with investigational device use/application or 
procedures; 
• 
the event involves a body-site or organ that: 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on: 
• 
the adverse event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
• 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 

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• 
other possible causes (e.g. an underlying or concurrent illness/clinical condition or/and 
an effect of another device, drug or treatment) have been adequately ruled out; 
• 
harm to the subject is due to error in use; 
• 
the event depends on a false result given by the investigational device used for diagnosis*, 
when applicable; 
• 
In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
The Investigators shall distinguish between the adverse events related to the investigational device and 
those related to the procedures (any procedure specific to the clinical investigation). 
An adverse event can be related both to procedures and the investigational device. 
Complications of procedures are considered not related if the said procedures would have been applied 
to the subjects in the absence of investigational device use/application. 
In some particular cases the event may be not adequately assessed because information is insufficient or 
contradictory and/or the data cannot be verified or supplemented. The Investigators will make the 
maximum effort to define and categorize the event and avoid these situations. Where the Sponsor 
remains uncertain about classifying the adverse event, it should not exclude the relatedness and 
classification of the event should be noted as “possible”. 
11.2. Reporting of Adverse Events 
The Investigator is required to report all reportable SAEs and UADE’s within 24 hours after first learning 
of the event to the Sponsor (Table 11-1).  In addition, where local country regulatory authorities specially 
require a more stringent definition or additional requirement, the local regulation should also be complied 
with. 
The primary method of reporting SAEs to the sponsor will be through the electronic study database on 
the Adverse Event eCRF. 
The primary method of reporting UADE’s is through SAE hotline email. 
If the database is unavailable or not accessible the Investigator may send the information to the SAE email 
hotline. 
The Investigator shall provide all requested supporting documentation for reported SAEs or AEs 
(blinded/de-identified as to subjects’ identity) through the SAE Hotline or to the monitor and/or clinical 
team via email as requested. The Investigator shall complete data entry in the study Electronic Data 

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Capture (EDC) database with the same information provided on the paper form as soon as the database 
becomes available. 
Table 11-1. Expedited Adverse Event and Device Specific Event Reporting Requirements     
SAEs / DD with SADE 
potential 
Investigator will notify Sponsor of all SAEs and Device Deficiencies with SADE 
potential within 24 hours of being aware of the event. 
Primary method of 
reporting 
Corresponding eCRF (e.g., Adverse Event CRF or Device Deficiency CRF) in 
study EDC database 
Sponsor 24 Hour 
SAE/UADE Hotline 
contact information: 
Email: 
 
To be used as back-up in event that database if unavailable or inaccessible 
within required reporting timeline or for reporting all UADE’s. 
 
As additional information becomes available, copies of source documentation which contain significant 
information related to the event such as operative reports, imaging studies, discharge notes and subject 
summaries etc. may be requested for a complete evaluation of the event by the sponsor or CEC. 
In regard to subject deaths, a de-identified copy of the death certificate and a de-identified copy of the 
autopsy report, if applicable, is to be sent to the Sponsor. Any other source documents related to the 
death should also be provided to the Sponsor and should be blinded/de-identified as to the subject’s 
identity. In the event that no source documents are available, the Investigator is requested to describe 
the circumstances of the subject’s death in a letter, e-mail or other written communication to the Sponsor. 
The Investigators are required to comply with their local Safety reporting requirements per their 
region/IRB/REB. 
UADEs/USADEs have expedited reporting requirements. UADEs must be reported by the Investigator to 
the Sponsor via email provided above within 24 hours and the reviewing IRB/REB per IRB/REB reporting 
requirement, but in no event later than 10 working days after the investigational site first learns of the 
event (CFR 812.150(a)(1)). 
11.3. Device Deficiency 
Device Deficiency is defined as inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance (ISO 14155:2011 3.15).  
Note that device deficiencies include malfunctions, use errors, and inadequate labeling. 

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All device deficiencies should be reported to the Sponsor on the DD eCRFs in a timely manner.  
Device Deficiencies that have the potential to cause a serious adverse device effect shall be reported to 
the sponsor within 24 hrs of site’s awareness of the event. 
These should be reported to the local competent authorities and IRBs/REBs as required per local 
requirements. 
When a DD is observed, every effort should be made to return the device and its packaging to the Sponsor 
in a timely manner. 
All Qualified Investigators must report product complaints to the sponsor (i.e., any Medtronic personnel) 
and Health Canada as required by governing law (i.e., Canada Medical Device Regulations 1998 (SOR/98-
282). 
 

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12. Data Review Committees 
To avoid and minimize bias, an independent CEC, Imaging Core Laboratory, and DMC will be in place to 
assess adverse events, occlusion and parent artery stenosis, and oversee the safety of the trial 
respectively. 
12.1. Clinical Events Committee 
A CEC shall be comprised of a minimum of three (3) physicians knowledgeable in the appropriate 
disciplines and medical specialties pertinent to the disease state being evaluated in this clinical study and 
will be responsible for an independent, objective and consistent review of AEs. 
Event level adjudications will be performed by a single CEC member for start and stop dates, seriousness, 
causality assessment, severity and outcomes for all adjudicable adverse events per CEC charter. 
The CEC will independently adjudicate each subject to pre-specified Events Of Interest (EOI) which include 
the primary endpoint, secondary safety endpoints, and pre-specified events of interest per Section 10.1. 
The CEC can request additional source documentation and any potential imaging obtained in support of 
the adverse event to assist with adjudication. 
12.2. Imaging Core Laboratory 
To objectively and consistently assess imaging data, an imaging protocol will be provided to the site. The 
imaging core laboratory will be responsible for the qualitative image analysis to determine aneurysm 
occlusion, parent artery stenosis, and discernible device movement. 
12.2.1. 
Screening Eligibility Review 
The core lab will be responsible for review of screening images to determine suitability for treatment in 
the study. In this role, the core lab will perform measurements to confirm the anatomical dimensions 
included in the eligibility criteria.  
The reviewing committee (Physician Screening Committee) will be responsible for determining subject 
eligibility in the study. Further details on the Physician Screening Committee will be provided in the core 
lab charter. 
12.2.2. 
Pre-Procedure Anatomy 
Baseline imaging will be reviewed to assess baseline aneurysm and parent artery characteristics. 

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12.2.3. 
Aneurysm Occlusion 
Post-procedure and follow-up angiograms will be reviewed to assess aneurysm occlusion according to the 
Raymond Roy Scale1 (Figure 12-1). 
 
Figure 12-1. Raymond Roy Scale for Grading Aneurysm Occlusion 
 
• 
Class 1: Complete Occlusion = Complete obliteration of the aneurysm 
• 
Class 2: Residual Neck = Persistence of any portion of the original defect of the arterial wall as 
seen on any singe projection, but without opacification of the aneurysmal sac 
• 
Class 3: Residual Aneurysm = Any opacification of the aneurysmal sac 
12.2.4. 
Parent Artery Stenosis 
Post-procedure angiograms will be reviewed to assess stenosis in the parent artery across the entire 
Pipeline™ Vantage Device implant. Vessel stenosis will be measured and judged according to the scale in 
Table 12-1 in cases, where paired imaging is available for DSA. If DSA is unavailable, flow limiting stenosis 
(> 50%) vs. non-flow limiting stenosis (≤50%) will be assessed by CTA images. 
Table 12-1. Stenosis Grading Scale 
Category Degree of Stenosis 
0 
1–25% 
1 
>25 – ≤50% 
2 
>50 – ≤75% 
3 
>75–100% 
12.3. Data Monitoring Committee 
The DMC will be an independent group that will serve as a data monitoring committee. The DMC will be 
comprised of representatives from multiple disciplines including but not limited to neurology, 

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biostatistics/epidemiology, neurosurgery and interventional neuroradiology that are independent of the 
clinical sites. 
In the safety monitoring role, this board shall provide recommendations to the Sponsor regarding in the 
conduct of the clinical study. The DMC will establish proposed safety monitoring criteria for the study and 
will establish and document any required analysis time points for assessing safety. The group will also 
establish a DMC Charter which will describe the DMC operating procedures. 
 

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13. Statistical Design and Methods 
13.1. General Principles 
A detailed statistical analysis plan (SAP) will be finalized prior to performing any analyses to expand upon 
the statistical methods presented below. Summary tables will summarize data for all subjects combined. 
All recorded data will be presented in the individual data listings sorted by site patient, and date of 
observation. 
13.2. Sample Size Determination 
The target sample size for this clinical investigation is 100 patients enrolled and treated and followed for 
safety events with the expectation of having digital imagery at 1-year post-procedure on a minimum of 
80 patients.   
Sample size estimation for the primary safety endpoint was initially based on recommendations by the 
FDA considering the precision of the estimates.  For the primary safety endpoint, the incidence of major 
stroke in the territory supplied by the treated artery or neurological death at 1 year, with an incidence as 
high as 8%, a sample size of 100 subjects will provide a precision of approximately ± 5.5%, which is 
considered to be reasonable.   
The basis for establishing the a priori threshold for the primary safety endpoint at 14% is rooted in the 
derivations presented in the table presented below, predicated on a population for analysis of 100 
patients (with up to 140 subjects enrolled).  Simulations were prepared in SAS assuming an observed 
incidence in the ADVANCE IDE study of primary safety events ranging from 5.6% to 6.9%.  Scenarios 1 
through 9 reveal a power greater than 80% (Table 13-1).   
Table 13-1. Estimated Power Over a Range of Possible Primary Safety Outcomes with 100 Patients (a 
priori threshold of 14%) 
Simulation 
Scenario 
a priori Threshold 
(proportion) 
Observed Incidence 
(proportion) 
Actual Type 1 Error Rate 
Power 
(percent) 
1 
0.14 
0.0560 
0.0492 
89.19 
2 
0.14 
0.0570 
0.0492 
88.29 
3 
0.14 
0.0580 
0.0492 
87.36 
4 
0.14 
0.0590 
0.0492 
86.38 
5 
0.14 
0.0600 
0.0492 
85.37 
6 
0.14 
0.0610 
0.0492 
84.32 
7 
0.14 
0.0620 
0.0492 
83.23 
8 
0.14 
0.0630 
0.0492 
82.11 
9 
0.14 
0.0640 
0.0492 
80.96 

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10 
0.14 
0.0650 
0.0492 
79.77 
11 
0.14 
0.0660 
0.0492 
78.55 
12 
0.14 
0.0670 
0.0492 
77.30 
13 
0.14 
0.0680 
0.0492 
76.02 
14 
0.14 
0.0690 
0.0492 
74.72 
 
Although the power is less than 80 when the incidence of safety events is 6.5% or higher, the power is still 
adequate when contrasted against the actual upper bound of the 1-sided 97.5% exact binomial confidence 
interval.  Specifically, if 7 of the 100 patients experience a primary safety event, the upper bound of the 
1-sided 97.5% exact binomial confidence interval would be 13.89% and below the 14% threshold. 
For the primary effectiveness endpoint, the power was estimated for an observed rate between 65% to 
80% considering sample sizes from 80 to 100 patients.  With a type 1 error rate of 2.5%, 100 patients 
would have 82.8% power to reject the null hypothesis if the observed incidence of complete aneurysm 
occlusion without parent artery stenosis was 65%.  Under the same scenario with 80 patients, the power 
would be 83.5% if the observed incidence of complete aneurysm occlusion without parent artery stenosis 
was 67%. To ensure at least 95% power with 80 and 100 patients, the observed incidence of complete 
aneurysm occlusion without parent artery stenosis or retreatment would need to be a minimum of 71% 
and 69%, respectively.  Requiring a minimum sample size of 100 patients with 95% power translates into 
a minimum incidence of complete aneurysm occlusion without parent artery stenosis of 69% which is in-
line with the previous results with the results from previous Pipeline studies.      
13.3. Analysis Populations 
To ensure adequate representation patient with large and giant aneurysms must be enrolled.  All primary 
and secondary endpoints will be analyzed both on an ITT and PP basis. All summarizations and tabulations 
will be conducted on the ITT population, defined below. 
Intent-To-Treat Population: All subjects who were consented and in whom deployment of the Pipeline™ 
Vantage Device was attempted (i.e., puncture at the arterial access site), independent of the procedure 
being completed successfully. 
Subject will not be considered part of the ITT population if the puncture at the arterial access site for 
deployment of Pipeline™ Vantage Device was not successful. If the puncture at the arterial access site for 
deployment of Pipeline™ Vantage Device was successful, the subject will be considered part of the ITT 
population. Consented subjects who withdraw consent prior to undergoing the study procedure or are 
found not to meet the inclusion/exclusion criteria prior to undergoing the study procedure, will not be 
included in the ITT population. 
The ITT population will be the primary population for all analyses. 

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The PP population defined below will be used for sensitivity analyses and to provide outcomes for subjects 
with observed data. 
Per-Protocol Population: Per-protocol population is ITT subjects excluding the following subjects: 
- 
Subjects with use of more than 1 treatment device (e.g., coils) other than Pipeline™ Vantage 
device during index procedure 
- 
Subjects with failed implantation of study device at index procedure 
- 
Subjects assessed as mRS ≥3 at baseline by independent and certified assessors 
13.4. Eligibility of Subjects, Exclusions, and Missing Data 
The number and proportion of subjects eligible for and compliant with each follow-up examination will 
be presented. Subjects who withdraw from the study will be tabulated with reasons for withdrawal.  
Missing data, which in this instance is defined as data that was not entered into the EDC system for 
analysis, may have an impact upon the interpretation of the trial data.   
The primary presentation of the results for the ITT population will be based on the observed data with 
multiple imputation for missing endpoint data using SAS PROC MI.  This procedure uses an iterative 
modeling approach to generate estimates for patients who withdraw prematurely, incorporating 
multivariate imputation by fully conditional specification (FCS) methods.  The discriminant function 
method will be used for classification variables.   With the function method of classification, the missing 
values will be imputed sequentially in the following order: age, gender, aneurysm diameter and location 
(ICA: yes or no).  Additional sensitivity analyses will also be conducted using the last observation and the 
post-procedure observation carried forward. A tipping point analysis will also be conducted. 
Rules for imputing a full date for interventions with incomplete or missing start-dates will be addressed 
in detail in the Statistical Analysis Plan. 
13.5. Justification of Pooling 
This study will be powered statistically based on the primary efficacy and safety endpoint.  To assess 
poolability of the data across study sites and other predefined factors that may affect outcome, a 
threshold of 0.10 will be used.  The testing strategy and exact model for analysis will be included in the 
Statistical Analysis Plan (SAP).  In summary, a generalized linear model will be used, specifying the 
dependent variable as dichotomous and the distribution as binomial.    The exact location of the aneurysm 
will be included in the class statement, provided each location has ≥2 patients.  Aneurysm size will be 
introduced into the model as a continuous variable.  Separately, aneurysm size will be examined around 
prespecified thresholds to determine if location is a significant predictor of outcome.  If clinical site, or 
any predefined factor is found to be a significant predictor of outcome (p<0.1), the factor will be retained 

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in the model and adjusted confidence intervals will be derived as a secondary examination of the primary 
endpoint. 
Small clinical sites (i.e., clinical sites that have less than 4 patients) will be identified and the following 
method will be used for combining the data.  Data from all small clinical sites will be combined to form a 
single clinical site in the evaluation of clinical site interaction effects.  Once combined, the pooled clinical 
site will remain as such for all analyses for which a clinical site interaction effect is determined.  If the 
pooled smaller clinical sites represent a single clinical site that has more than twice as many patients as 
the largest single clinical site, however less than 3 times as many patients, the small clinical sites will be 
ranked by size and then by clinical site number and divided into 2 pooled assignments using an alternating 
treatment sequence (ABABAB).  If the pooled smaller clinical sites represent a clinical site that has more 
than three times as many patients as the largest single clinical site, however less than 4 times as many 
patients, the small clinical sites will be ranked by size and divided into 3 pooled assignments using an 
alternating treatment sequence (ABCABCABC).  This methodology will be applied, based on the initial 
pooling of the smaller clinical sites. If the pooling of smaller clinical sites results in a pooled clinical site 
that still has less than 4 patients, the smallest clinical site that was not included in the pooling procedure 
will be included and the procedure repeated.   
13.6. Subgroup Analysis 
Sub-group analysis will be performed based on aneurysm location and size. Note that the subgroup 
analyses listed here are not independently powered and they are for exploratory purpose only. Statistical 
testing analogous to the above (Section 13.5) will be performed to assess poolability of these subgroups 
into the overall study results. The incidence for the primary efficacy and primary safety endpoints will be 
derived and summarized without adjustment for other factors. A secondary examination will be 
performed where aneurysm location and aneurysm size will serve as covariates in an adjusted model.  It 
is indeterminate if there will be sufficient power to discriminate across these 2 factors, given the 
enrollment into the study will not be controlled for either factor. A series of derived estimates will be 
generated for the primary efficacy and safety endpoints retaining aneurysm size and anatomical location 
as a secondary examination of the primary endpoint.  All factors and method of analysis will be clearly 
defined in the SAP. 
13.7. Interim Analysis 
No formal interim analyses are planned for the purpose of stopping this trial early for effectiveness. 
13.8. Statistical Analysis 
All statistical analyses will be done using the SAS System software, version 9.4 or later (SAS Institute Inc., 
SAS Campus Drive, Cary, North Carolina 27513, USA). 

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13.8.1. 
Demographics, Clinical Baseline and Procedure Characteristics 
Patient demographics, clinical history, risk factors, aneurysm characteristics, procedure characteristics, 
and outcome variables will be summarized using descriptive statistics for continuous variables (mean, 
standard deviation, number of observations, minimum and maximum) and frequency tables for discrete 
variables. 
13.8.2. 
Primary Endpoint Analysis 
13.8.2.1. Primary Effectiveness Endpoint 
The pre-specified threshold of 50% for effectiveness endpoint is based on the effectiveness threshold of 
the recent PREMIER study with the Pipeline™ Device. This threshold must be exceeded at a certain 
magnitude to reject the null hypothesis and merely serves a statistical boundary for analysis. If the upper 
bound of the 1-sided 97.5% exact binomial confidence interval is >50%, the primary effectiveness 
endpoint will have been met. 
To ensure at least 95% power with 80 and 100 patients, the observed incidence of complete aneurysm 
occlusion without parent artery stenosis or retreatment would need to be a minimum of 71% and 69%, 
respectively.  Requiring a minimum sample size of 100 patients with 95% power translates into a minimum 
incidence of complete aneurysm occlusion without parent artery stenosis of 69% which is relatively in-
line with the previous results with the results from previous Pipeline studies.      
The primary effectiveness endpoint is the incidence of complete aneurysm occlusion (Raymond Roy Scale 
Class 1) without significant parent artery stenosis (≤ 50%) or retreatment of the target aneurysm at 1-year 
post-procedure. The incidence will be summarized using counts and percentages; the 1-sided upper 
bound of the 97.5% confidence limit for the incidence will be evaluated relative to the a priori threshold 
of 50%. The hypothesis for evaluating the primary effectiveness endpoint is stated below: 
Ho: Incidence at 1-year post-procedure of complete aneurysm occlusion without retreatment or 
significant parent artery stenosis is ≤ 50.0% 
Ha: Incidence at 1-year post-procedure of complete aneurysm occlusion without retreatment or 
significant parent artery stenosis is > 50.0% 
If the upper bound of the 1-sided 97.5% exact binomial confidence interval is >50%, the primary 
effectiveness endpoint will have been met. 
All eligible patients will undergo follow-up at 12 months. 
13.8.2.2. Primary Safety Endpoint 
The primary safety endpoint is 1-year incidence of major stroke in the territory supplied by the treated 
artery or neurological death. The incidence will be summarized using counts and percentages; the 1-sided 

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upper bound of the 97.5% confidence limit for the incidence will be evaluated relative to the a priori safety 
threshold of 14%. Given the primary safety endpoint reported in PMA P100018 was 5.6%, an incidence of 
≤7% for the primary safety endpoint would be considered clinically acceptable within the confines of a 
study of this general size.  The hypothesis for evaluating the primary safety endpoint will be evaluated 
according to the following 2 requirements: 
Requirement 1: The incidence of primary safety events must be ≤7%, and  
Requirement 2: The null hypothesis must be rejected in favor of the alternative: 
Ho: Incidence at 1-year post-procedure of major stroke and/or neurological death is ≥ 14.0% 
Ha: Incidence at 1-year post-procedure of major stroke and/or neurological death is < 14.0% 
If the incidence of primary safety events is ≤7% and the upper bound of the 1-sided 97.5% exact binomial 
confidence interval is <14%, the primary safety endpoint will have been met. 
All eligible patients will undergo follow-up at 12 months. 
13.8.3. 
Secondary Endpoint Analysis 
All the secondary endpoints will be summarized using frequency tables presenting counts and 
percentages; no statistical testing will be performed against any preset thresholds for the secondary 
endpoints. The secondary endpoints include the following: 
The following will be assessed for the effectiveness outcome measures: 
1. Incidence of successful device implantation at the target site 
2. Incidence of complete aneurysm occlusion (Raymond Roy Class 1) at 1- and 3-years post-
procedure 
3. Incidence of target aneurysm recurrence at 1- and 3-years post-procedure 
The following will be assessed for the secondary safety endpoints: 
1. Incidence of major stroke in the territory supplied by the treated artery or neurological death at 
2- and 3-years post-procedure 
2. Incidence of major stroke in the territory supplied by the treated artery or neurological death at 
30 days post-procedure 
3. Incidence of delayed intraparenchymal hemorrhage >30 days post-procedure through 1-year 
post-procedure 

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4. Incidence of subjects with disabling strokes that have a mRS decline to a score of 3 or more (mRS 
≥ 3) due to a stroke-related cause assessed at a minimum of 90 days post-stroke event at 1 year, 
2 year, and 3 year post-procedure 
13.8.4. 
Adverse Events 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activity (MedDRA) 
system dictionary. 
CEC adjudicated data Tables to summarize the incidence rates will be created for each of the following 
groups: (At 1 year, 1- 2 years, and 2- 3 years) 
• 
Adverse events (non-Serious) related to intervention (Procedure, anti-platelet therapy (APT)), 
Causal, Probable 
• 
Serious adverse events related to Intervention (Procedure, APT)- Causal, Probable 
• 
Adverse device effects (Non-SAE Related to Study Device- causal, probable) 
• 
Serious adverse device effects (SAE Related to Study Device- causal, probable) 
• 
Unanticipated serious adverse device effects (USADE)/UADE 
• 
 Adverse events by severity (Mild, Moderate and Severe) related to Device, Procedure or APT 
(causal, probable) 
 
 

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14. Ethics 
14.1. Statement(s) of Compliance 
This clinical study will be conducted in compliance with 21 CFR 812, Canada Medical Device Regulations 
1998 (SOR/98-282), the latest version of the Declaration of Helsinki, laws and regional or national 
regulations of the countries in which the clinical study is conducted, including but not limited to local good 
clinical practice, data protection laws, the Clinical Investigation Agreement and the Clinical Investigation 
Plan. 
 
All principles of the Declaration of Helsinki will be implemented in this clinical study by means of the 
informed consent process, IRB/REB approval, study training, clinical trial registration, pre-clinical testing, 
risk-benefit assessment, publication policy, etc. 
 
The Sponsor will avoid improper influence on, or inducement of the subject, monitor, and Investigator(s) 
or other parties participating in, or contributing to, the clinical study by implementing the informed 
consent process, Clinical Investigation Agreements, or IRB/REB approval. 
14.2. Institutional Review Boards/Research Ethics Board 
The Sponsor and/or Investigator must submit this clinical protocol, subject Informed Consent Form and 
Investigator’s Brochure to the appropriate Institutional Review Board (IRB)/Research Ethics Board (REB) 
and is required to forward to the Sponsor a copy of the written and dated approval. 
The study (study number, clinical protocol title, and version), documents reviewed (e.g. clinical protocol, 
ICF, etc.) and the date of the review should be clearly stated on the written IRB/REB approval. In addition, 
the approval letter needs to be accompanied by an IRB/REB roster, letter of compliance, or other 
documentation to allow verification that the Investigator, other investigation site personnel, and/or 
Sponsor personnel are not members of the IRB/REB. If they are members of the IRB/REB, written 
documentation is required stating that he/she did not participate in the approval process. 
The study will not start at a clinical site and subjects will not be enrolled until a copy of written and dated 
IRB/REB approval has been received by the Sponsor. 
Any amendment or modification to the clinical protocol must be sent to the IRB/REB. The IRB/REB must 
also be informed of any event likely to affect the safety of subjects or the conduct of the study. 
If the IRB/REB imposes any additional requirements (e.g. safety reports, progress reports etc.), this will be 
followed, if appropriate. The Sponsor will prepare the required documents and send them to the 
Investigator for reporting to the IRB/REB. Investigators must inform the Sponsor of any change in status 
of the IRB/REB approval. If any action is taken by an IRB/REB with respect to the investigation, that 
information will be forwarded to the Sponsor by the respective Investigator. 
 

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The Informed Consent Form used by the Investigator for obtaining the subjects informed consent must 
be reviewed and approved by the Sponsor prior to submission to the appropriate IRB/REB for approval. 

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15. Study Administration 
15.1. Steering Committee 
A Steering Committee will oversee the conduct and scientific aspects of the study. A Steering Committee 
comprised of 1 chair and 4 study investigators knowledgeable in the appropriate disciplines and medical 
specialties pertinent to the disease state being evaluated in this clinical study will be responsible for 
providing expert medical guidance in the following roles: 
• 
Advising on the study design and scientific value of data collection 
• 
Monitoring the overall conduct and progress of the study 
• 
Providing guidance to clinical sites 
15.2. Clinical Site Selection 
The ADVANCE IDE will be conducted at up to 30 sites, including up to 25 sites in U.S. and up to 5 sites OUS.  
The Sponsor or representative of the Sponsor will assess each potential clinical site to ensure the Principal 
Investigator and his/her staff has the facilities and expertise required for the study. Clinical sites will be 
selected based upon a clinical site assessment, appropriate facilities, and the qualifications of the 
Investigator(s). Individual Investigators will be evaluated by the Sponsor based on experience with the 
intended procedure(s) and ability to conduct the study according to the clinical protocol. 
To participate, a clinical site must have the following: 
• 
Previous experience with clinical research 
• 
Commitment from the investigator to enroll only subjects meeting the study criteria 
• 
A study coordinator or study team member who can enter data and respond to queries 
• 
Willingness to adhere to all relevant Core Laboratory requirements 
• 
Willingness to perform necessary documentation (e.g., eCRF) 
• 
Willingness to sign and adhere to the Investigator Statement 
• 
Willingness to participate in investigator meetings as scheduled by Medtronic 
• 
Willingness to provide full access to subject electronic medical records, or to provide complete, 
certified copies of subject records for the duration of the subject’s study participation 

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Medtronic will maintain an updated list of principal investigators, investigation sites and associated 
IRBs/REBs, institutions and their scope of duties in the Trial Master File. 
15.3. Monitoring 
Medtronic, as the Sponsor, will be responsible for ensuring that adequate monitoring at each clinical site 
is completed to ensure protection of the rights of subjects, the safety of subjects, and the quality and 
integrity of the data collected and submitted in compliance with applicable regulations. Appropriately 
qualified and trained personnel appointed by the Sponsor will conduct monitoring at each clinical site at 
the start, during and at the closure of the clinical study per the Medtronic Standard Operating Procedures 
(SOPs) and the Clinical Monitoring Plan. Monitors for the clinical study will consist of Sponsor clinical staff 
and/or qualified contract services (e.g., CRO) appointed by the Sponsor. The primary contact for the 
clinical study will be the Clinical Study Manager and monitoring (Refer to the contact list). 
Study Monitors will conduct clinical site visits to ensure accuracy of data, timeliness of data submissions, 
adequate subject enrollment, investigational device accountability, compliance with applicable laws and 
regulations, compliance with the clinical protocol, compliance with the signed investigator agreement, 
and compliance with IRB/REB conditions and guidelines. Any non-compliance with these items that is not 
adequately addressed by the Principal Investigator/site staff is cause for the Sponsor to put the 
Investigator/site staff on probation or withdraw the Investigator/site staff from the study. Frequency of 
monitoring will be based upon enrollment, study duration, compliance, and any suspected inconsistency 
in data that requires investigation. 
All subject treatment, follow-up visits and phone conversations/interviews will be fully documented either 
on the source document or in the subject’s medical records. Information entered into the eCRFs will be 
verified against the source documents and subject’s medical records according to the monitoring plan. 
Additional subject medical record review may be required for AE adjudication. Source documents may be 
photocopied if required. The study Monitor will also check the Investigator Site File (ISF) to ensure that all 
study-related documents are current. 
Medtronic representatives or their agents may be present during the endovascular procedure. 
15.3.1. 
Direct Access to Source Data/Documents 
By participating in this research study, the Investigator agrees to permit monitoring and auditing by the 
Sponsor and/or its designee(s) and inspection by applicable regulatory authorities. The Investigator also 
agrees to allow the Sponsors CRAs/monitors/auditors/FDA investigators to have direct access to his/her 
original research-related study records (e.g. complete medical records, source documentation, and billing 
information) for review. The Principal Investigator(s), his/her delegate(s) and the study coordinator(s) 
shall be accessible to Sponsor field personnel and the Clinical Study Manager. This accessibility is of 
particular importance for reviewing data in the eCRFs. 

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15.3.2. 
Clinical Site Training 
Each clinical site will be trained to the investigational plan and any updates if applicable. Investigator/site 
personnel will undergo training prior to performing any study-related procedures (e.g., at a Site Initiation 
Visit or training meeting). All training must be documented. Existing clinical site personnel who have been 
delegated new tasks and new clinical site personnel will undergo training to the investigational plan, as 
appropriate. Training for Investigators and their site team is dependent on their delegated task(s) per 
Delegation Task List (DTL) Log. Investigators and their site team are to be trained to perform their 
delegated responsibilities prior to performing study-specific duties. 
15.3.3. 
Monitoring Reports 
After each monitoring visit, the monitor will send to the Principal Investigator an e-mail or letter 
summarizing the monitoring visit. A monitoring report will be sent to the Sponsor. The report will include 
the date of the monitoring visit, the clinical site name, the name of the monitor, the name of the 
Investigator, the names of other individuals present for the monitoring visit, items reviewed during the 
visit, findings, and any required follow-up. The Principal Investigator will be responsible for ensuring that 
follow-up action items requiring resolution at the clinical site are completed in an accurate and timely 
manner. 
15.3.4. 
Close-Out Visit 
Final close-out visits at the clinical sites will be conducted at the end of the study. The purpose of the final 
visit is to collect all outstanding study data documents, ensure that the Principal Investigator’s files are 
accurate and complete, review record retention requirements with the Principal Investigator, make a final 
accounting of all study supplies shipped to the Investigator/site, provide for appropriate disposition of 
any remaining supplies, and ensure that all applicable requirements are met for the study. 
15.4. Data Management 
Every effort will be made to ensure the accuracy and reliability of data including the selection of qualified 
Investigators and appropriate study centers, review of clinical protocol procedures with the Investigator 
and associated personnel before the study commences, and periodic onsite monitoring visits by the 
Sponsor as deemed appropriate by the Sponsor. Guidance for eCRF completion will be provided and 
reviewed with the study personnel prior to the start of the study. The Sponsor will review eCRFs for 
accuracy and completeness and any discrepancies will be resolved with the Investigator or designee, as 
appropriate. 
The Investigator must ensure accuracy, completeness and timeliness of the data reported in the eCRFs 
and in all other required reports. Data reported on the eCRFs which are derived from source documents 
must be consistent with the source documents and discrepancies need to be justified in a documented 
rationale, signed and dated by the Investigator, and filed in the subject medical file. 

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Only authorized persons can complete eCRFs. eCRFs shall be signed by Investigators as specified on the 
delegation log included in the ISF. 
The EDC system maintains an audit trail on entries, changes or corrections in the eCRFs. If a person is only 
authorized to complete eCRFs or to make changes to an already signed eCRF, the Investigator shall re-sign 
this eCRF. 
15.4.1. 
Data Quality Assurance 
ORACLE Clinical Remote Data Capture (OC/RDC) is the EDC system that will be deployed to support data 
collection for this study. Documentation pertinent to the use of the EDC system will be made available for 
use by appropriate clinical site personnel. All individuals who will be expected to use the EDC system will 
be given adequate training necessary to perform their assigned tasks as described in (21 CFR 11.10(i)). 
Training will be conducted by qualified individuals initially and on a continuing basis, as needed. 
15.4.2. 
Data Handling 
The Sponsor is responsible for compilation and verification of the study data, retention of the clinical study 
database, performance of statistical analyses, and preparation of the study reports. The Sponsor will 
ensure that the performance of Data Management activities occur in accordance with the study Data 
Management Plan. 
15.4.3. 
Data Ownership 
Rights, duties, and obligations regarding ownership of any ideas, concepts, inventions, or results, whether 
patentable or not, shall be in accordance with the terms and conditions set forth in the Clinical Study 
Agreement by and between the Institution and Sponsor. Unless otherwise expressly set forth in the 
Clinical Study Agreement, the Sponsor retains exclusive ownership of all data, results, reports, findings, 
discoveries and any other information collected during this study. The Sponsor reserves the right to use 
the data from the database in the present study. 
15.5. Compliance 
15.5.1. 
Sponsor Compliance 
The Sponsor is responsible for implementing and maintaining quality assurance and a quality control 
system to ensure that the data generated are recorded and reported in accordance with established 
procedures. The study will be organized, performed, and reported in compliance with this research clinical 
protocol, SOPs, applicable regulations and recognized standards and any additional requirements 
imposed by the IRB/REB or regulatory authority. 

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The Sponsor is responsible for obtaining and maintaining appropriate insurance policies for the clinical 
study. 
The Sponsor will secure an agreement with all parties to allow direct access to all study-related clinical 
sites, source documents, and reports for the purpose of monitoring and auditing by the Sponsor and/or 
its designee(s) and inspection by regulatory agencies. 
The Sponsor will apply quality control measures to all stages of data collection and handling to ensure 
reliability and accuracy. In addition, the Sponsor will confirm that the data are processed correctly. 
Data from eCRFs and other external data (i.e., core laboratory data) will be entered into a clinical database 
as specified in the data management plan. 
The clinical database will be reviewed and checked for omissions, apparent errors, and values requiring 
further clarification in accordance with the Data Management Plan. Data queries requiring clarification 
will be documented and returned to the clinical site for resolution. Only authorized personnel will make 
corrections to the clinical database, and all corrections will be documented in an audit trail. 
15.5.2. 
Investigator Compliance 
The Principal Investigator assumes full responsibility for performance of the research study in accordance 
with the Clinical Study Agreement, this clinical protocol, GCP, all regulatory requirements applicable to 
the jurisdictions in which the study is being conducted, and any additional requirements imposed by the 
IRB/REB. The Principal Investigator shall be responsible for the day-to-day conduct of the clinical 
investigation as well as for the safety and well-being of the human subjects involved in the clinical 
investigation. 
15.5.3. 
Onsite Audits 
Representatives of the Sponsor may visit the clinical site(s) to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. The purpose of an audit is to verify the adequate 
performance of the clinical study-related activities, independent of the employees involved in the clinical 
study. 
Similar auditing procedures may also be conducted by agents of any regulatory body reviewing the results 
of the study in support of a regulatory submission. The Investigator and/or institution shall permit the 
Sponsor and regulatory bodies (e.g., FDA) direct access to source data and documents, taking into account 
any restrictions due to local law, to perform clinical study-related monitoring, audits, IRB/REB review, and 
regulatory inspections. 
The Investigator should immediately notify the Sponsor if he/she has been contacted by a regulatory 
agency or IRB/REB concerning an upcoming inspection. 

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15.6. Confidentiality 
The Investigator and his/her study staff shall consider all information, results, discoveries; records 
accumulated, acquired, or deduced in the course of the study, other than that information to be disclosed 
by law, as confidential and shall not disclose any such results, discoveries, records to any third party 
without the Sponsor’s prior written consent. 
IRB/REB members have the same obligation of confidentiality. 
Protected Health Information of study subjects will be kept as confidential as possible in accordance with 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and any other data privacy laws 
as applicable. 
15.7. Liability 
The Sponsor is responsible for obtaining and maintaining appropriate insurance policies for the clinical 
study. 
15.8. CIP Amendments 
During the course of the study, an amendment to the clinical protocol may be necessary. Only the Sponsor 
is allowed to amend this clinical protocol. 
The Sponsor will submit any significant amendment to the Clinical Investigation Plan, including a 
justification for this amendment, to the appropriate regulatory authorities and to the Investigators to 
obtain approval from their IRB/REB. The Investigator will only implement the amendment after approval 
of the IRB/REB and regulatory authority, unless the modifications increase subject safety. Administrative 
amendments to the Clinical Investigation Plan will be submitted to the regulatory authorities and IRB/REB 
for notification. Furthermore, Investigators shall sign any approved amendment for agreement. The 
clinical sites will receive the following for their regulatory file, and if applicable, IRB/REB submission: 
• 
An updated clinical protocol 
• 
Changes to ICF template (if necessary) 
15.9. Record Retention 
The Investigator shall maintain all study documentation in his/her possession and/or control and institute 
measures to prevent accidental or premature destruction of any data and/or documents related to the 
study. 
The Investigator shall retain study documentation (the ISF, subject medical files and eCRFs) in accordance 
with local law and regulations during the study and for a minimum period of two (2) years (or longer if 

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local laws require) after the latter of the following two dates: The date on which the investigation is 
terminated or completed, or the date that the records are no longer required for purposes of supporting 
a premarket approval application or a notice of completion of a product development protocol. 
• 
The Sponsor will maintain all study documentation in its possession and/or contact and institute 
measures to prevent accidental or premature destruction of any data and/or documents related to 
the research study. 
• 
The Sponsor shall retain the study documentation in accordance with local law and regulations during 
the study and for a minimum period of two (2) years (or longer if local laws require) after the latter of 
the following two dates: The date on which the investigation is terminated or completed, or the date 
that the records are no longer required for purposes of supporting a premarket approval application 
or a notice of completion of a product development protocol. 
15.10. Publication and Use of Information 
The Sponsor intends to publish the results of this multi-center study. Individual Investigators are therefore 
asked to refrain from reporting results from their study participants prior to publication of the main multi-
center report. A Publication Committee will be formed and will be responsible for generating a Publication 
Plan. The Publication Plan will establish authorship criteria for publications for the study group based on 
the study conduct and compliance, contribution to the study design, management or enrollment, and 
willingness to accept the rights and responsibilities of an author. 
The Sponsor will enter the study into a public clinical trials repository such as ClinicalTrials.gov. 
Participating subjects will not be identified by name in any published reports about the clinical study. 
15.11. Suspension or Early Termination 
If the study is terminated prematurely or suspended (e.g. if information becomes available that the risk 
to study subject is higher than initially indicated), the Sponsor will promptly inform all clinical Investigators 
of the termination or suspension and the reason(s) for this. The Investigator shall then promptly inform 
the reviewing IRB/REB and provide the reasons(s) for the termination. If applicable, regulatory authorities 
will be informed. Enrolled subjects will be asked to complete all remaining study visits and the subject will 
then be seen by the treating physician according to standard of care following intracranial aneurysm 
treatment. 
The Sponsor, IRB/REB or Regulatory Authority may decide to suspend or prematurely terminate an 
investigation site (e.g. in case of expiring approval of the reviewing IRB/REB, non-compliance to the 
Clinical Investigation Plan or lack of enrollment). If an investigation site is suspended or prematurely 
terminated, the Sponsor shall promptly inform the Investigator(s) of the termination or suspension and 
the reason(s). The Investigator shall then promptly inform the reviewing IRB/REB. 

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225. 
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unruptured large and giant aneurysms. World neurosurgery. 2017. 
226. 
Brinjikji W, Kallmes DF, Cloft HJ, Lanzino G. Age-related outcomes following intracranial aneurysm 
treatment with the Pipeline Embolization Device: a subgroup analysis of the IntrePED registry. 
Journal of neurosurgery. 2016;124(6):1726-1730. 
227. 
Burrows A, Brinjikji W, Puffer R, Cloft H, Kallmes D, Lanzino G. Flow diversion for ophthalmic artery 
aneurysms. American Journal of Neuroradiology. 2016;37(10):1866-1869. 
228. 
Burrows AM, Cloft H, Kallmes DF, Lanzino G. Periprocedural and mid-term technical and clinical 
events after flow diversion for intracranial aneurysms. J Neurointerv Surg. 2014. 
229. 
Chalouhi N, Tjoumakaris S, Gonzalez L, et al. Spontaneous delayed migration/shortening of the 
pipeline embolization device: report of 5 cases. American Journal of Neuroradiology. 
2013;34(12):2326-2330. 
230. 
Di Maria F, Pistocchi S, Clarençon F, et al. Flow diversion versus standard endovascular techniques 
for the treatment of unruptured carotid-ophthalmic aneurysms. American Journal of 
Neuroradiology. 2015;36(12):2325-2330. 
231. 
Griessenauer CJ, Shallwani H, Adeeb N, et al. Conscious Sedation Versus General Anesthesia for 
the Treatment of Cerebral Aneurysms with Flow Diversion: A Matched Cohort Study. World 
neurosurgery. 2017;102:1-5. 
232. 
Patel A, Miller TR, Shivashankar R, Jindal G, Gandhi D. Early angiographic signs of acute thrombus 
formation following cerebral aneurysm treatment with the Pipeline embolization device. Journal 
of neurointerventional surgery. 2016:neurintsurg-2016-012701. 
233. 
Petr O, Brinjikji W, Cloft H, Kallmes D, Lanzino G. Current trends and results of endovascular 
treatment of unruptured intracranial aneurysms at a single institution in the flow-diverter era. 
American Journal of Neuroradiology. 2016;37(6):1106-1113. 
234. 
Tomasello A, Romero N, Aixut S, et al. Endovascular treatment of intracraneal aneurysm with 
pipeline embolization device: experience in four centres in Barcelona. Neurological research. 
2016;38(5):381-388. 
235. 
Tsang ACO, Fung AMY, Tsang FCP, Leung GKK, Lee R, Lui WM. Failure of flow diverter treatment 
of intracranial aneurysms related to the fetal-type posterior communicating artery. 
Neurointervention. 2015;10(2):60-66. 
236. 
Brinjikji W, Lanzino G, Cloft HJ, Siddiqui AH, Kallmes DF. Risk Factors for Hemorrhagic 
Complications following Pipeline Embolization Device Treatment of Intracranial Aneurysms: 
Results from the International Retrospective Study of the Pipeline Embolization Device. AJNR Am 
J Neuroradiol. 2015. 
237. 
Briganti F, Napoli M, Tortora F, et al. Italian multicenter experience with flow-diverter devices for 
intracranial unruptured aneurysm treatment with periprocedural complications—a retrospective 
data analysis. Neuroradiology. 2012:1-8. 
238. 
Brinjikji W, Kallmes DF, Cloft HJ, Lanzino G. Age-related outcomes following intracranial aneurysm 
treatment with the Pipeline Embolization Device: a subgroup analysis of the IntrePED registry. J 
Neurosurg. 2016;124(6):1726-1730. 

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Brinjikji W, Kallmes DF, Cloft HJ, Lanzino G. Patency of the anterior choroidal artery after flow-
diversion treatment of internal carotid artery aneurysms. American Journal of Neuroradiology. 
2015;36(3):537-541. 
240. 
Di Maria F, Pistocchi S, Clarencon F, et al. Flow Diversion versus Standard Endovascular Techniques 
for the Treatment of Unruptured Carotid-Ophthalmic Aneurysms. AJNR Am J Neuroradiol. 
2015;36(12):2325-2330. 
241. 
Durst CR, Starke RM, Clopton D, et al. Endovascular treatment of ophthalmic artery aneurysms: 
ophthalmic artery patency following flow diversion versus coil embolization. J Neurointerv Surg. 
2015. 
242. 
Griessenauer CJ, Ogilvy CS, Foreman PM, et al. Pipeline Embolization Device for Small Intracranial 
Aneurysms: Evaluation of Safety and Efficacy in a Multicenter Cohort. Neurosurgery. 2016. 
243. 
Griessenauer CJ, Ogilvy CS, Foreman PM, et al. Pipeline Embolization Device for small 
paraophthalmic artery aneurysms with an emphasis on the anatomical relationship of ophthalmic 
artery origin and aneurysm. Journal of neurosurgery. 2016:1-8. 
244. 
Kallmes DF, Hanel R, Lopes D, et al. International retrospective study of the pipeline embolization 
device: a multicenter aneurysm treatment study. American Journal of Neuroradiology. 
2015;36(1):108-115. 
245. 
McTaggart RA, Choudhri OA, Marcellus ML, et al. Use of thromboelastography to tailor dual-
antiplatelet therapy in patients undergoing treatment of intracranial aneurysms with the Pipeline 
embolization device. Journal of NeuroInterventional Surgery. 2015;7(6):425-430. 
246. 
Park MS, Kilburg C, Taussky P, et al. Pipeline Embolization Device with or without Adjunctive Coil 
Embolization: Analysis of Complications from the IntrePED Registry. AJNR Am J Neuroradiol. 
2016;37(6):1127-1131. 
247. 
Sahlein DH, Fouladvand M, Becske T, et al. Neuroophthalmological outcomes associated with use 
of the Pipeline Embolization Device: analysis of the PUFS trial results. Journal of neurosurgery. 
2015;123(4):897-905. 
248. 
Becske T, Potts MB, Shapiro M, et al. Pipeline for uncoilable or failed aneurysms: 3-year follow-up 
results. Journal of neurosurgery. 2016:1-8. 
249. 
Kabbasch C, Mpotsaris A, Behme D, Dorn F, Stavrinou P, Liebig T. Pipeline Embolization Device for 
Treatment of Intracranial Aneurysms—The More, the Better? A Single-center Retrospective 
Observational Study. Journal of vascular and interventional neurology. 2016;9(2):14. 
250. 
Phillips T, Wenderoth J, Phatouros C, et al. Safety of the pipeline embolization device in treatment 
of posterior circulation aneurysms. American Journal of Neuroradiology. 2012;33(7):1225-1231. 
251. 
Roy AK, Grossberg JA, Osbun JW, et al. Carotid cavernous fistula after Pipeline placement: a single-
center experience and review of the literature. Journal of neurointerventional surgery. 
2016:neurintsurg-2016-012586. 
252. 
Martinez-Galdamez M, Lamin SM, Lagios KG, et al. Periprocedural outcomes and early safety with 
the use of the Pipeline Flex Embolization Device with Shield Technology for unruptured 
intracranial aneurysms: preliminary results from a prospective clinical study. Journal of 
Neurointerventional Surgery. 2017;20:20. 
253. 
Le EJ, Miller T, Serulle Y, Shivashankar R, Jindal G, Gandhi D. Use of Pipeline Flex is associated with 
reduced fluoroscopy time, procedure time, and technical failure compared with the first-
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254. 
Adeeb N, Griessenauer CJ, Foreman PM, et al. Comparison of stent-assisted coil embolization and 
Pipeline embolization device for endovascular treatment of ophthalmic segment aneurysms: a 
multicenter cohort study. World neurosurgery. 2017;27:27. 
255. 
Griessenauer CJMD, Piske RLMD, Baccin CEMD, et al. Flow Diverters for Treatment of 160 
Ophthalmic Segment Aneurysms: Evaluation of Safety and Efficacy in a Multicenter Cohort. 
Neurosurgery. 2017;80(5):726-732. 
256. 
Murayama Y, Takao H, Ishibashi T, et al. Risk Analysis of Unruptured Intracranial Aneurysms: 
Prospective 10-Year Cohort Study. Stroke; a journal of cerebral circulation. 2016;47(2):365-371. 
257. 
Dolati P, Pittman D, Morrish WF, Wong J, Sutherland GR. The Frequency of Subarachnoid 
Hemorrhage from Very Small Cerebral Aneurysms (< 5 mm): A Population-Based Study. Cureus. 
2015;7(6):e279. 
258. 
Albuquerque FC, Park MS, Abla AA, Crowley RW, Ducruet AF, McDougall CG. A reappraisal of the 
Pipeline embolization device for the treatment of posterior circulation aneurysms. J Neurointerv 
Surg. 2014. 
259. 
Griessenauer CJ, Ogilvy CS, Foreman PM, et al. Pipeline Embolization Device for small 
paraophthalmic artery aneurysms with an emphasis on the anatomical relationship of ophthalmic 
artery origin and aneurysm. Journal of neurosurgery. 2016:1-8. 
260. 
Puri AS, Massari F, Asai T, et al. Safety, efficacy, and short-term follow-up of the use of Pipeline 
Embolization Device in small (<2.5mm) cerebral vessels for aneurysm treatment: single institution 
experience. Neuroradiology. 2016;58(3):267-275. 
261. 
Simon S, Koyama T, Cheng J, Mericle R. Incidence of clipping and coiling procedures: aneurysm 
treatment of Medicare patients, 1996-2006. AANS Neurosurgeon. 2011;20(1):16-31. 
262. 
Brinjikji W, Rabinstein AA, Lanzino G, Kallmes DF, Cloft HJ. Effect of age on outcomes of treatment 
of unruptured cerebral aneurysms: a study of the National Inpatient Sample 2001–2008. Stroke; 
a journal of cerebral circulation. 2011;42(5):1320-1324. 
263. 
Jalbert JJ, Isaacs AJ, Kamel H, Sedrakyan A. Clipping and Coiling of Unruptured Intracranial 
Aneurysms Among Medicare Beneficiaries, 2000 to 2010. Stroke; a journal of cerebral circulation. 
2015;46(9):2452-2457. 
 
 

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17. Version History 
Version 
Summary of Changes 
Author(s)/Title 
Rev A 
Not Applicable, New Document 
 Medical Writing 
Manager 
Rev B 
Changes to Schedule of Events based on FDA 
Feedback 
 Medical Writing 
Manager 
Rev C 
See table below “Changes in Rev C”. 
 Medical Writer 
 
Changes in Rev C 
Sections Affected 
Change in the Protocol 
Rationale 
Section 4.3, Section 
5.1.1, 
Throughout the CIP 
Addition of primary 
effectiveness endpoint to 
the study 
Pipeline™ Vantage, a new generation 
Pipeline™ device, is being studied under 
IDE G170234. Thus, the study is being 
modified to be an effectiveness and safety 
study. 
Section 13 
Changes to sample size and 
statistical considerations 
Addition of primary effectiveness endpoint 
to the study required changes to Statistical 
Design and Methods section. 
Cover page, Section 
14.2 and section 11.2 
Addition of Local Sponsor – 
Canada and Health Canada 
specific requirements 
including ethics committee. 
ADVANCE study will have centers in 
Canada and therefore Local Sponsor and 
ethics committee were updated to comply 
with Health Canada regulations. 
Glossary and Table 9-1 mRS certified independent 
assessor 
mRS certified independent assessor 
defined and certification requirements 
specified 
Throughout the CIP 
“Groin puncture” changed to 
“puncture at arterial access 
site” 
CIP modified to ensure access to arterial 
vasculature is site-neutral 
Throughout the CIP, 
specifically Section 7 
Pipeline™ Shield device 
replaced with Pipeline™ 
Vantage device 
Pipeline™ Vantage, a new generation 
Pipeline™ device, is being studied under 
IDE G170234. 
Throughout the CIP 
Any mention of 
“recanalization” with respect 
to the study changed to 
“recurrence” 
Consistent and uniform usage of a single 
term “recurrence” to describe initial 
complete aneurysmal occlusion followed 
by incomplete occlusion at follow-up 
exam. 

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Section 4 
Added additional 
information about clinical 
experience with Pipeline™ 
group of devices 
Background section modified to provide 
additional data regarding the use of 
Pipeline™ group of devices 
Section 6.2 
Study rationale 
Study rationale modified since Pipeline™ 
Vantage, a new generation Pipeline™ 
device, is being studied under IDE 
G170234. 
Section 10.1 
Potential Risks 
Potential Risks revised as per comments 
by FDA. 
Section 11.2 
Reporting of adverse events 
Adverse events can be reported 
electronically as well. 
Section 12.2.4 
Stenosis grading scale 
 
 
Changed to “CTA” from 
“MRA” imaging 
Since there is a separate category for “no 
stenosis”, 1st category of grading scale 
begins at 1-25%. 
Revision as per comments by FDA. 
Section 9 (Table 9-1, 
Sections 9.2.4, 9.6, 
9.9.2, 9.9.6) 
Visit and Assessment 
Schedule table, 180-day 
imaging and follow-up visits 
Defined the timepoint from which 
assessment of adverse events will begin 
and revisions as per comments by FDA. 
Cover page 
Sponsor changed from 
“Medtronic Neurovascular” 
to “Micro Therapeutics, Inc. 
d/b/a ev3 Neurovascular (a 
wholly owned subsidiary of 
Medtronic)” 
Micro Therapeutics, Inc. d/b/a ev3 
Neurovascular (a wholly owned subsidiary 
of Medtronic) manufactures the Pipeline™ 
Vantage device. 
Section 15.6 
Added text 
Added language for compliance with data 
privacy laws. 
Section 8.4 
Exclusion criteria 
In the exclusion criteria, one criterion was 
split into two for more clarity. 
As per comments by FDA, added exclusion 
criteria #20 and #33 and added 
clarifications to the exclusion criteria #13. 
Section 9.9 
1-year follow up 
 
 
 
Clarification was added to ensure clinical 
follow up for subjects with failed device 
implant. 
 

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2-year and 3-year follow up 
evaluations 
Clarification was added regarding 
pregnancy test for 2-year and 3-year 
follow-up visits. 
Section 15.1 
Steering committee 
Change made to align with Steering 
committee charter 
Section 7.7 and 10.2 
Requirement for Physicians 
Clarified that physicians who are 
responsible for implanting the study 
device, Pipeline™ Vantage, need to self-
attest to having completed a minimum of 
20 cases with Pipeline™ Flex Embolization 
Device.  
Section 9.5.1, Table 9-
2 
Ancillary devices’ details 
Added Table 9-2 that provides compatible 
microcatheter sizes for Pipeline™ Vantage. 
Also, added text regarding ancillary 
devices in general. 
Section 12.2.1 
Physician Screening 
Committee 
Added that Physician Screening 
Committee will be responsible for 
determining subject eligibility in the study. 
Section 15.2 
Site selection requirement  
Removed physician-specific requirement 
from the list of requirements for clinical 
sites. 
Appendix Section 18.1 Center for Medicare and 
Medicaid Services (CMS) IDE 
Study Criteria added 
Evidence provided regarding effect on 
Medicare beneficiaries 
 

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18. Appendices 
18.1. Appendix I: Center for Medicare and Medicaid Services (CMS) IDE Study Criteria 
Medicare beneficiaries may be affected by the device. Given the increasing percentage of the U.S. 
population that will qualify for Medicare in the coming decade as well as the four times higher prevalence 
of intracranial aneurysms among older adults, the trend toward an increasing number of endovascular 
procedures is very likely to continue.261 Between 1996 and 2006, endovascular treatment of cerebral 
aneurysms increased from 20.1% to 67.0% per Medicare CPT codes.261 In the PUFs study (Section 4.2.2) a 
total of 26.7% (30/114) of subjects enrolled were > 65 years old. This percentage is consistent with a study 
by Brinjikji et al262 which found that between 2001 and 2008, from among the 34,054 patients >50 years 
old who underwent coiling of intracranial aneurysms, 29.3% (9,987) were > 65 years old. The rate of 
Medicare beneficiaries undergoing coiling in cases of unruptured intracranial aneurysm increased almost 
15-fold between 2000 and 2010.263 Study results are expected to be generalizable within the Medicare 
beneficiary population based on the prevalence of unruptured intracranial aneurysm in patients age 65 
and older.