A Prospective, Multi-center, Single Arm Study to Evaluate the Safety and Effectiveness of the CODMAN ENTERPRISE® Vascular Reconstruction Device and Delivery System When Used in Conjunction With Endovascular Coil Embolization in the Treatment of Wide-necked Saccular Intracranial Aneurysms
Phase: NA
Conditions: Intracranial Aneurysm
Sponsor: Cerenovus, Part of DePuy Synthes Products, Inc.

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 1 of 121 
 
 
 
 
 
 
 
A Prospective, Multi-center, Single Arm Study to Evaluate the Safety and 
Effectiveness of the CODMAN ENTERPRISE® Vascular Reconstruction Device and 
Delivery System when Used in Conjunction with Endovascular Coil Embolization 
in the Treatment of Wide-necked Saccular Intracranial Aneurysms 
 
 
 
This investigational protocol contains confidential information for use by the 
principal investigators and their designated representatives participating in this 
clinical investigation.  It should be held confidential and maintained in a secure 
location. It should not be copied or made available for review by any 
unauthorized person or firm. 
 
 
 
Cerenovus 
33 Technology Drive 
Irvine, CA, U.S.A. 92618 
Tel: + 1.888.783.7723 
 
 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 2 of 121 
A Prospective, Multi-center, Single Arm Study to Evaluate the Safety and Effectiveness of 
the CODMAN ENTERPRISE® Vascular Reconstruction Device and Delivery System when 
Used in Conjunction with Endovascular Coil Embolization in the Treatment of Wide-
necked Saccular Intracranial Aneurysms 
 
PROTOCOL SIGNATURE PAGE  
 
I have read this protocol and agree to conduct this clinical investigation in accordance with the design and 
specific provisions outlined herein. I understand the protocol, and I understand I am solely responsible to 
ensure the investigation is conducted in accordance with Good Clinical Practices, applicable FDA 
regulations, local regulations, the Declaration of Helsinki, the signed agreement with the Sponsor, and with 
the protocol outlined herein. I will conduct this study as outlined therein and will make reasonable effort to 
complete the study within the time period designated by the Sponsor.    
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who will 
assist in the conduct of this study. I will discuss this material with them to ensure they are fully informed 
regarding the device and the conduct of the study.  
I will fulfill the requirements of my Institutional Review Board (IRB), or other oversight committee, to ensure 
complete and continual oversight of this clinical investigation. I will use an Informed Consent Document 
approved by the Sponsor and my reviewing IRB.  
I agree to report all information or data in accordance with the protocol and, in particular, I agree to report 
any serious adverse events as defined in this protocol to the Sponsor and my reviewing IRB.  I agree to 
permit the Sponsor, FDA, or other regulatory authority access to all records relating to the clinical 
investigation, whether paper-based or electronic data capture. 
The below signature confirms I have read and understood this clinical investigational protocol and its 
associated amendments or attachments, and will accept respective revisions or amendments provided by 
the Sponsor. 
Investigational product for this study will be sent to: 
 
Name of Institution: 
 
 
 
 
 
 
 
 
 
 
Attention/title:   
 
 
 
 
 
 
 
 
 
 
Address:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone:  
 
 
 
 
 
 
 
 
 
 
 
Fax:  
 
 
 
 
 
 
 
 
 
 
 
 
Email:   
 
 
 
 
 
 
 
 
 
 
 
 
I, and any sub-investigator(s) participating in this study under my supervision as Principal Investigator (PI), 
will conduct this protocol implant procedure and all follow-up procedures, including angiography, 
at the hospital/institution listed below: 
 
Name of Institution: 
 
 
 
 
 
 
 
 
 
 
Address:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Subjects must return to the institution listed above for all related follow-up visits, 
assessments and procedure. 
 
 
 
 
 
 
 
 
 
 
/ 
/ 
 
Principal Investigator’s  
Principal Investigator’s   
 Day / Month / Year 
 
Printed Name 
 
 
Signature 
 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 3 of 121 
 
TABLE OF CONTENTS  
 
PROTOCOL SIGNATURE PAGE ...................................................................... 2 
TABLE OF CONTENTS ..................................................................................... 3 
OVERVIEW OF STUDY PROTOCOL ............................................................... 8 
LIST OF ABBREVIATIONS ............................................................................. 21 
1.0 INTRODUCTION ....................................................................................... 23 
1.1. Literature Summary and Background ...................................................... 23 
1.1.1 Background ............................................................................................. 23 
1.1.2 Pathophysiology of Aneurysms ............................................................... 23 
1.1.3 Treatment Options for Intracranial Saccular Aneurysms ......................... 26 
1.2. Investigational (Study) Device Description ............................................... 28 
1.3. Previous Codman Sponsored Clinical Studies ......................................... 29 
1.3.1 Feasibility studies:  United States and Europe ........................................ 29 
1.3.2 Feasibility study:  Argentina .................................................................... 32 
1.3.3 Study of ENTERPRISE in the Japanese Clinical Setting ........................ 33 
1.3.4 Sunrise Registry: European Post Market Surveillance ............................ 33 
1.4. Commercial Approval of ENTERPRISE ................................................... 34 
2.0 STUDY OBJECTIVES ............................................................................. 35 
3.0 STUDY DESIGN ...................................................................................... 35 
3.1 General Design .......................................................................................... 35 
3.2 Study Endpoints ......................................................................................... 37 
3.2.1 Primary Effectiveness Endpoint .............................................................. 37 
3.2.2 Primary Safety Endpoints ....................................................................... 37 
3.2.3 Secondary Effectiveness Endpoints ........................................................ 38 
3.2.4   Secondary Safety Endpoints ................................................................. 39 
3.2.5   Ancillary Endpoint ................................................................................. 41 
3.2.6   Safety Follow-up for Subjects with Adverse Events of Special Interest 41 
4.0 ELIGIBILITY OF SUBJECTS, EXCLUSIONS AND REMOVAL OF 
SUBJECTS .............................................................................................. 41 
4.1 Criteria for Eligibility ................................................................................... 42 
4.1.1 General Inclusion Criteria ........................................................................ 42 
4.1.2 General Exclusion Criteria ....................................................................... 43 
4.1.3 Angiographic Inclusion Criteria ................................................................ 45 
4.1.4 Angiographic Exclusion Criteria .............................................................. 45 
4.2 Early Withdrawal of Subjects ..................................................................... 46 
4.2.1 Withdrawal Criteria .................................................................................. 46 
5 STUDY DEVICE ............................................................................................ 46 
5.1 ENTERPRISE Investigational (Study) Device Description ......................... 46 
5.2 ENTERPRISE Instructions for Use (IFU) ................................................... 53 
5.2.1 ENTERPRISE General Use and Study Protocol ...................................... 53 
5.3 ENTERPRISE Packaging .......................................................................... 54 
5.4 ENTERPRISE Receiving, Storage, Dispensing and Return ...................... 54 
5.4.1 Receipt and Accountability of Study Device ............................................ 55 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 4 of 121 
5.4.2  Storage of Study Device ......................................................................... 55 
5.4.3 Dispensing of Study Device ..................................................................... 55 
5.4.4 Return or Destruction of Study Device ..................................................... 55 
6 STUDY PROCEDURES ................................................................................ 56 
6.1 Screening/Baseline .................................................................................... 56 
6.1.1 Screening Procedures ............................................................................ 56 
6.1.2 Subject Numbering ................................................................................. 57 
6.1.3 Baseline Medication and Assessments ................................................... 57 
6.2 Procedure .................................................................................................. 58 
6.2.1 Indications for Use – Study Device ......................................................... 59 
6.2.2 Index Procedure ...................................................................................... 59 
6.2.3 Embolic Devices ..................................................................................... 60 
6.2.4 Procedure Assessments ......................................................................... 60 
6.2.5 Pre & Post Procedural Medications ........................................................ 60 
6.3 Follow-up ................................................................................................. 61 
6.3.1 Follow-up of Angiographic Screening Failures ........................................ 61 
6.3.2 Follow-up After Stroke or Suspected Stroke (Unscheduled Visit) ........... 62 
6.3.3 Post-Procedure through Hospital Discharge ........................................... 62 
6.3.4 Thirty-Day Follow-up (Telephone Interview) ........................................... 63 
6.3.5   6 Month Follow-up (Clinic Visit & Angiogram) ....................................... 63 
6.3.6 12 Month Follow-up (Clinic Visit & Angiogram) ........................................ 64 
6.3.7   18 Month Follow-up (Telephone Interview) ........................................... 65 
6.3.8   24 Month Follow-up (Clinic Visit & MRA or Angiogram) ........................ 65 
6.3.7 Safety Follow-up (Subjects with Adverse Events of Special Interest) ...... 66 
6.4 Placement of Second ENTERPRISE Stent ................................................ 66 
6.5 Retreatment of the Target Aneurysm ......................................................... 67 
6.6   Unscheduled Angiogram .......................................................................... 67 
6.7 Summary of Follow-up Schedule and Time Windows .............................. 67 
7 CORE LABORATORY .................................................................................. 68 
8 CONCOMITANT MEDICATIONS .................................................................. 68 
8.1 Pre-procedure – elective procedures ......................................................... 68 
8.2 Pre-procedure – emergency procedures ..... Error! Bookmark not defined. 
8.3 Intra-procedure .......................................................................................... 68 
8.4 Post-procedure .......................................................................................... 69 
9 STATISTICAL METHODS ............................................................................ 69 
9.1 Study Design ............................................................................................. 69 
9.2 Treatment Assignment ............................................................................... 69 
9.3 Levels of Significance ................................................................................ 70 
9.4 Interval Windows ........................................................................................ 70 
Study Interval Windows [days or hours, as indicated] ...................................... 70 
-14 to 0 ............................................................................................................. 70 
Within 12 hours prior to procedure ................................................................... 70 
Within 12 hours after procedure ....................................................................... 70 
12 to 36 hours after procedure ......................................................................... 70 
16 to 44 days after procedure .......................................................................... 70 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 5 of 121 
92 to 212 days after procedure ........................................................................ 70 
320 to 410 days after procedure ...................................................................... 71 
457 to 592 days after procedure ...................................................................... 71 
685 to 775 days after procedure ...................................................................... 71 
9.5 Handling of Missing Data ........................................................................... 71 
9.6 Primary and Secondary Endpoints ............................................................. 71 
9.7 Hypotheses ................................................................................................ 75 
9.8 Analysis Sets ............................................................................................. 76 
9.9 Dataset Flow Diagram ............................................................................... 78 
9.10 Analysis Plan ........................................................................................... 82 
9.10.1 General Considerations ........................................................................ 82 
9.10.2 Subject Disposition ............................................................................... 82 
9.10.3 Aneurysm and Procedure Characteristics ............................................. 82 
9.10.4 Analysis of Angiographic Screening Failures ........................................ 83 
9.10.5 Analysis of Primary and Secondary Endpoints ..................................... 83 
9.10.6 Supplemental Safety Follow-up Report on Continued Follow-up Subjects
 84 
9.10.7 Subgroup Analyses ............................................................................... 84 
9.11 Plans for Interim Analysis ........................................................................ 84 
10 SAFETY AND ADVERSE EVENTS ............................................................ 86 
10.1 Adverse Events/Complications ................................................................ 86 
10.1.1 Potential or Anticipated Adverse Events/Complications - ENTERPRISE
 86 
10.1.2 Adverse Event Definitions ..................................................................... 87 
10.1.3 Adverse Event Severity and Causal Relationship Ratings .................... 89 
10.2 Unanticipated Adverse Device Effects ..................................................... 90 
10.3 Management of Post-procedure Symptoms ............................................. 90 
10.4 Subject Death .......................................................................................... 91 
10.5 Adverse Event Reporting Period .............................................................. 91 
10.5.1 Adverse Event Reporting for Angiographic Screening Failure .............. 91 
10.5.2 Adverse Event Reporting for Entered Subjects ..................................... 91 
10.6 Recording Adverse Event Information ..................................................... 91 
10.7 Device Product Complaints, Failures, and Device Malfunctions .............. 92 
10.8 Reporting of Adverse Events and Study Device Product Complaints and 
Device Malfunctions ................................................................................. 92 
10.8.1 Follow-up of Unresolved Adverse Events ............................................. 93 
10.9 Medical Monitoring ................................................................................... 94 
10.9.1 Clinical Events Committee .................................................................... 94 
10.9.2 Data and Safety Monitoring Board ........................................................ 94 
11 QUALITY CONTROL AND QUALITY ASSURANCE .................................. 94 
11.1 Organizational Preparations .................................................................... 94 
11.2 Training .................................................................................................... 94 
11.3 Case Report Forms .................................................................................. 94 
11.4 Monitoring and Source Data Verification .................................................. 95 
11.5 Data Management ................................................................................... 96 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 6 of 121 
11.6 Securing Compliance ............................................................................... 96 
11.7 On-Site Audits .......................................................................................... 96 
12 ETHICS AND REGULATORY CONSIDERATIONS ................................... 96 
12.1 Institutional Review Board (IRB) .............................................................. 96 
12.2 Informed Consent .................................................................................... 97 
12.3 Confidentiality .......................................................................................... 98 
12.4 Insurance ................................................................................................. 98 
13 RECORD KEEPING ................................................................................... 98 
13.1 Study Initiation ......................................................................................... 98 
13.2 Retention of Records ............................................................................... 99 
14 REPORTS ................................................................................................ 100 
14.1 Investigators Final Report ...................................................................... 100 
15 END OF STUDY ....................................................................................... 100 
15.1 Planned End .......................................................................................... 100 
15.2 Premature End ....................................................................................... 100 
15.3 Termination of Center by Sponsor ......................................................... 100 
15.4 Resumption of Terminated Studies ........................................................ 101 
16 PUBLICATION .......................................................................................... 101 
17 REFERENCES ......................................................................................... 102 
19 APPENDICES ........................................................................................... 108 
APPENDIX 1: STUDY DEFINTIONS ............................................................. 109 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 7 of 121 
 
Summary of Figures and Tables 
 
Table 1: Summary of Study Procedures and Assessments .......................................... 20 
Table 2: CODMAN ENTERPRISE Stent Sizes and Parent Vessel Diameter ................ 47 
Table 3: Follow-up visits: Schedule & Time Windows ................................................... 67 
Table 4: Report requirements of adverse events, product complaint and device 
malfunctioning ............................................................................................................... 93 
 
 
Figure 1: Expanded Stent .............................................................................................. 47 
Figure 2:  CODMAN ENTERPRISE Vascular Reconstruction Device and Delivery 
System .......................................................................................................................... 49 
Figure 3:  Enterprise Stent With Distal Tip and Without Distal Tip ................................ 50 
Figure 4: Dataset Flow Diagram for Enrolled Subjects .................................................. 79 
 
 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 8 of 121 
 
OVERVIEW OF STUDY PROTOCOL 
 
Title of Study: 
A Prospective, Multi-center, Single Arm Study to Evaluate 
the 
Safety 
and 
Effectiveness 
of 
the 
CODMAN 
ENTERPRISE® Vascular Reconstruction Device and 
Delivery 
System 
when 
Used 
in 
Conjunction 
with 
Endovascular Coil Embolization in the Treatment of Wide-
necked Saccular Intracranial Aneurysms 
 
Study Devices: 
CODMAN  ENTERPRISE® Vascular Reconstruction Device 
and Delivery System (CODMAN ENTERPRISE) and 
CODMAN ENTERPRISE® 2 Vascular Reconstruction 
Device (ENTERPRISE 2), hereafter referred to as 
ENTERPRISE. 
 
Comparator Device: 
 
This is a single arm study with no comparator device.  
 
 
Study Sponsor:  
Cerenovus 
33 Technology Drive 
Irvine, CA, U.S.A. 92618 
 
Study Objectives: 
The primary objectives of the study are to evaluate the 
safety (as assessed by rates of major ipsilateral stroke 
and/or death and in-stent stenosis) and effectiveness (as 
assessed by the rate of complete angiographic occlusion) 
of 
ENTERPRISE 
when 
used 
in 
conjunction 
with 
endovascular coil embolization of unruptured wide-neck 
intracranial saccular anterior circulation aneurysms in a 
prospective, multi-center, single-arm clinical study. 
 
Secondary effectiveness objectives include the evaluation 
of 
treatment 
outcomes 
for 
subjects 
treated 
with 
ENTERPRISE in the acute (procedure and immediate post-
procedure time frames) and follow-up phases of patient 
management.   
 
Secondary safety objectives include the evaluation of 
adverse safety outcomes for subjects treated with 
ENTERPRISE from the start of the procedure through the 
end of study participation (12 months or premature 
discontinuation of study participation).    
 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 9 of 121 
In addition, the rates of stent movement and migration in 
ENTERPRISE-treated subjects will be described. 
 
Study Design: 
This is a prospective, multi-center, single arm, clinical study 
to 
evaluate 
the 
safety 
and 
effectiveness 
of 
the 
ENTERPRISE stent when used in conjunction with 
endovascular coil embolization in the treatment of 
unruptured wide-neck, intracranial, saccular anterior 
circulation aneurysms (≤ 10 mm)  arising from a parent 
vessel with a diameter of ≥ 2.5 mm and ≤ 4 mm.  A group 
sequential design will be utilized in which one primary 
endpoint interim analysis will be conducted after N=160 
subjects have been enrolled and followed through 6 months 
post-procedure, to determine if the study should stop early 
for futility or a tentative determination of success; enrollment 
will pause after these 160 subjects have been enrolled. If 
the stopping rule is met for the trial to stop early for tentative 
success, a final confirmatory analysis will be conducted 
when all subjects have reached 12 months post-procedure.  
If the trial is not terminated early for futility or tentative 
success, then enrollment will continue up to a full enrollment 
sample size of N=320, and a final analysis will be conducted 
when all subjects have reached 12 months post-procedure.  
 
An analysis will be conducted to support a marketing 
application after all subjects have reached 12 months post-
procedure. The remaining data out to 24 months post-
procedure will be submitted as a post-approval study (PAS) 
report once all subjects have completed their 24 month 
follow-up. 
 
 
 
Sample Size: 
A group sequential design will be utilized in which N=160 
subjects are enrolled and followed for a minimum of 6 
months post-procedure, at which time an interim analysis 
will be conducted to determine whether or not to terminate 
the study early for futility or a tentative determination of 
success.  If the trial is not terminated early for futility or 
tentative success, then enrollment will resume to a 
maximum enrolled sample size of N=320 (including the 
original N=160).  Subjects who are enrolled but who are 
found to be ineligible for treatment with ENTERPRISE at the 
time of the pre-procedure angiogram will be replaced.  
Subjects in whom treatment with ENTERPRISE is 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 10 of 121 
attempted 
but 
who 
discontinue 
study 
participation 
prematurely will not be replaced.   
 
Number of Sites: 
 
Up to 25 institutions in the United States               
 
Study Population: 
 
 
 
 
Subjects with an unruptured wide-neck, intracranial 
saccular anterior circulation aneurysm (≤ 10 mm), arising 
from a parent vessel with a diameter of ≥ 2.5 mm and ≤ 4 
mm, will be eligible for the study. Wide-necked is defined as 
having a neck width ≥ 4 mm or a dome-to-neck ratio < 2.  
Only one wide-necked aneurysm will be treated for each 
subject during the index procedure.  
 
Study Procedures: 
The study evaluation time points include:  
1. Screening/Baseline 
2. Procedure/Treatment Period 
3. Hospital Discharge 
4. Thirty Day Follow-up (Telephone Interview) 
5. 6 Month Follow-up (Clinic Visit & Angiogram) 
6. 12 Month Follow-up (Clinic Visit & Angiogram),  
7. 18 Month Follow-up (Telephone Interview) 
8. 24 Month Follow-up  (Clinic Visit plus MRA or 
angiogram) 
 
Primary Effectiveness 
Endpoint: 
 
Rate of Complete Aneurysm Occlusion (RCAO) 
according to the Raymond Scale: 
The primary effectiveness endpoint is the rate of complete 
aneurysm occlusion (RCAO) at 12 months post-procedure 
according to the Raymond Scale as assessed by the 
Independent 
Core 
Laboratory. 
Complete 
aneurysm 
occlusion is defined as an aneurysm in which a score of 1 
(complete obliteration) is achieved on the Raymond Scale 
at the relevant post-procedure angiogram, without 
additional procedures for treatment of the aneurysm since 
the index procedure. Subjects who are retreated 
(retreatment includes staged procedures) prior to the 12 
month post-procedure follow-up visit will be considered not 
to have achieved complete aneurysm occlusion for the 
purpose of the primary endpoint analysis.   
 
The primary endpoint analysis will be to demonstrate that 
the RCAO is significantly greater than a performance goal 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 11 of 121 
(PG) of 35%.  The primary endpoint null and alternative 
hypotheses are: 
Null hypothesis Ho: RCAO ≤ 35%  
Alternative hypothesis HA: RCAO > 35% 
This analysis will be conducted on the modified intent-to-
treat (MITT) population of subjects (subjects who are found 
to be eligible for treatment with ENTEPRISE at the time of 
the pre-procedure angiographic assessment, and in whom 
treatment is attempted).  A supportive analysis will be 
conducted on the PP population. 
Note:  The study will be deemed to be a success if this 
primary efficacy endpoint null hypothesis (on the MITT 
population with data from all sites combined) is rejected in 
favor of the alternative hypothesis.   
 
Primary Safety  
Endpoints: 
 
There are two primary safety endpoints: Major Ipsilateral 
Stroke and/or Death at 12 months post-procedure and In-
stenosis at 12 months post-procedure.    
 
The analyses of these safety endpoints will be conducted 
on the MITT population.  Supportive analyses will be 
conducted on the PP population. 
        
Incidence of Major Ipsilateral Stroke and/or Death: 
The incidence of a major ipsilateral stroke and/or death will 
be evaluated from the start of the index procedure until 
completion of the 12 month follow-up. A major ipsilateral 
stroke is defined as a new neurological event which is 
ipsilateral and in the vascular distribution territory of the 
stenting procedure and that results in an increase of ≥ 4 on 
the National Institute of Health Stroke Scale (NIHSS) as 
compared to baseline and persists for greater than 24 
hours. 
 
For a successful evaluation of this endpoint, the upper 
confidence limit of a 2-sided 95% confidence interval for the 
proportion of subjects who experience major ipsilateral 
stroke and/or death through 12 months post-procedure will 
be less than 25%.  
 
Incidence of In-stent Stenosis:  

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 12 of 121 
The percentage of stents in which stenosis is assessed 
angiographically, at or prior to 12 months post-procedure 
will be evaluated.  Stenosis is defined as greater than 50% 
narrowing of the vessel within the ENTERPRISE stent or 
within 10 mm of either end of the stent (i.e., in-stent 
stenosis). 
 
For a successful evaluation of this endpoint, the upper 
confidence limit of a 2-sided 95% confidence interval for the 
rate of in-stent stenosis at or prior to 12 months post-
procedure will be less than 15%. 
 
Secondary 
Effectiveness 
Endpoints: 
The following secondary effectiveness endpoints have been 
defined.  Observed rates will be described for both the MITT 
and PP populations. All angiographic imaging results will be 
based upon assessments by the independent Core 
Laboratory.  A subject who is retreated (retreatment 
includes staged procedures) is considered to be a treatment 
failure for endpoints based on angiographic imaging. 
 
a) Procedure Success Rate: 
The procedure success rate is defined to be the 
percentage of aneurysms in which coil mass position is 
maintained within the sac with parent artery patency, 
without additional procedures for treatment of the 
aneurysm since the index procedure. The procedure 
success rate will be summarized immediately post-
treatment (acute), and at the 6 and 12 month follow-up 
assessments.   
 
b) Complete Aneurysm Occlusion as per the Raymond 
Scale:   
The percentage of aneurysms in which a score of 1 
(complete obliteration) is achieved on the Raymond 
Scale immediately post-procedure (acute) and at the 6 
and 12 month follow-up angiographic assessments, 
respectively, will be evaluated.   
 
c) Complete/Partial Aneurysm Occlusion as per the 
Raymond Scale:   
The percentage of aneurysms in which a score of 1 
(complete obliteration) or 2 (residual neck) is achieved 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 13 of 121 
on the Raymond Scale immediately post-procedure 
(acute), and at the 6 and 12 month follow-up 
angiographic assessments will be evaluated.   
 
d)   Percent Aneurysm Occlusion: 
The percentage of aneurysms with occlusion of 100%, 
90%-99%, 70-89%, 50-69%, 25-49%, or <25% occlusion 
in accordance with Consensus Grades 0-5, respectively, 
will be summarized immediately post-procedure (acute), 
and at the 6 and 12 month follow-up, respectively.   
 
e)   Recanalization Rate:  
The percentage of aneurysms in which recanalization is 
documented at any time up to and including the 12 
month follow-up visit, will be evaluated.  Recanalization 
will be defined as an increase in aneurysm filling as 
compared to the previous study-specified angiographic 
assessment, resulting in a change in (i.e., worsening of) 
the Raymond classification.  Changes in Raymond 
Scale will be classified as stable, improved, or 
recanalized based on the follow-up angiograms. 
Percentages of aneurysms falling into each of the 
categories will be presented.   
 
f) Retreatment Rate:   
The percentage of target aneurysms that are retreated 
at any time up to and including the 12 month follow-up 
visit will be evaluated. Retreatment will be defined as 
any additional treatment of the target aneurysm after the 
index 
procedure 
(retreatment 
includes 
staged 
procedures), or an additional procedure (regardless of 
whether retreatment is by surgery or endovascular 
treatment) due to recanalization, rupture or bleeding.  
 
Secondary Safety 
Endpoints: 
 
 
 
The evaluation of the rate of new neurological deficits 
(increase in mRS > 2 from baseline not related to stroke or 
death) at 12 months will be a pre-specified, powered 
analysis.  All other secondary endpoints will be presented 
as a group to better characterize the ENTERPRISE stenting 
procedure. 
 
Unless otherwise stated, these secondary safety analyses 
will be conducted on the MITT population.   

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 14 of 121 
 
 
a) Rate of New Neurological Deficits per the Modified 
Rankin Scale (mRS): 
Observed scores on the Modified Rankin Scale will be 
presented at baseline (pre-procedure) and follow-up (30 
days, 6 and 12 months post-procedure).  The number 
and percentage of subjects who have an increase in 
mRS > 2 from baseline not related to stroke or death will 
also be presented for each follow-up time point.   
The evaluation of the rate of new neurological deficits at 
12 months post-procedure will be a pre-specified, 
powered analysis.  For a successful evaluation of this 
endpoint, the upper confidence limit of a 2-sided 95% 
confidence interval for the rate of subjects with a new 
neurological deficit will be less than 15%.  The analysis 
of new neurological deficits will exclude subjects who 
had a stroke or who died from the time of the index 
procedure to the time of the evaluation. 
 
b) NIH Stroke Scale (NIHSS) Total Score: 
The NIHSS Total Score evaluations will be summarized 
at baseline (pre-procedure) and follow-up (6 and 12 
months post-procedure); change from baseline at 6 and 
12 months will also be summarized.  The percentage of 
subjects who show a worsening from baseline (increase 
of 4 points or more) will also be presented.   
Observed scores and change from baseline will also be 
presented for NIHSS excluding scores on the aphasia 
subscale.   
 
c)  Adverse Events and Clinical Complications:  
Adverse 
Events 
(AEs), 
including 
complications 
associated with an untoward medical occurrence, from 
the start of the index procedure until completion of the 12 
month follow-up will be coded using the MedDRA system 
and summarized with frequencies. Serious adverse 
events (SAEs), device- or procedure-related AEs, 
unanticipated adverse device effects (UADEs) and 
deaths will be presented.    
 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 15 of 121 
AEs will be presented for the following study periods: 1) 
peri-procedure – i.e., from the start of the procedure until 
24 hours post-procedure; and, 2) through 12 month 
follow-up – i.e., from 24 hours post-procedure through 
the 12 month visit or premature termination. 
 
d)  Reduced TICI Flow:  
The percentage of target aneurysms in which a new 
occurrence of unintentional and persistent reduced TICI 
flow (TICI score of 0 or 1) is observed at the target vessel 
during the index procedure as a result of a mechanical 
obstruction such as dissection or luminal thrombus will 
be evaluated. 
 
e)  Bleeding Complications: 
The number and percentage of subjects who experience 
a procedure-related hemorrhagic event which requires 
any of the following will be evaluated:  blood transfusion, 
surgical 
intervention, 
a 
new 
hospitalization, 
or 
lengthening of hospital stay.  The complications of 
hematoma requiring treatment (i.e., a hematoma > 5 cm 
in diameter occurring at the access site) and 
retroperitoneal bleeding will be reported as hemorrhagic 
events.   
 
f)  In-stent Stenosis (Acute, and 6 Months):  
The percentage of aneurysms in which in-stent stenosis 
is documented immediately post-procedure (acute), and 
up to and including 6 months post-procedure, will be 
evaluated.   
Acute in-stent stenosis will be further characterized by 
whether it results from vasospasm, and whether or not 
the vasospasm was responsive to medication. 
 
g)  Thrombosis:  
The percentage of aneurysms in which thrombosis is 
documented up to and including 6 and 12 months post-
procedure will be evaluated.  Thrombosis is defined as 
in-stent thrombosis.   
 
Ancillary Endpoint 
Stent Movement/Migration: 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 16 of 121 
Incidence of stent movement and/or migration from the start 
of the index procedure until completion of the 12 month 
follow-up 
 
Safety Follow-up 
through 24 months 
post-procedure 
Subjects will be followed through 24 months post-
procedure, and their outcomes will be summarized in a 
supplemental safety follow-up report:  
• All adverse events 
• Rupture of the index aneurysm beyond 24 hours 
post-treatment 
• Major ipsilateral stroke more than 1 month post-
treatment  
• Ipsilateral parenchymal hemorrhage more than 1 
month post-treatment  
 
 
Sample Size 
Determination: 
Both primary effectiveness and primary safety endpoint 
analyses will be conducted on the MITT population, where 
subjects with missing data at the time of endpoint analysis 
will be imputed as last observation carried forward (LOCF).  
Hence all subjects in the MITT population with post-
procedure data are deemed to be evaluable for the purpose 
of MITT analyses.  Subjects who receive the device but in 
whom there is no post-procedure data will be treated as 
failures for the primary effectiveness analysis; subjects who 
do not receive the device because of treatment failure due 
to reasons associated with the device will also be treated as 
failures.  Subjects with no post-procedure endpoint data 
upon which to base a LOCF imputation will be excluded 
from the primary safety endpoint analyses; it is anticipated 
that fewer than 7% of MITT subjects will be excluded from 
either primary effectiveness or primary safety endpoint 
analyses.  Subjects who are enrolled but who are found to 
be ineligible for treatment with ENTERPRISE at the time of 
the pre-procedure angiogram will be replaced.  Subjects in 
whom treatment with ENTERPRISE is attempted but who 
discontinue study participation prematurely will not be 
replaced.   
 
The study design is a group sequential design, wherein after 
N=160 subjects have been enrolled, treated, and followed 
for a minimum of 6 months post-procedure, an interim 
analysis will be conducted to determine whether or not to 
terminate the study early for futility or tentative success.  

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 17 of 121 
The study will terminate early for tentative success if the 
unadjusted 2-sided normal approximation p-value for 
testing the primary effectiveness endpoint (RCAO vs. the 
PG of 35%) is less than 0.031, and will terminate early for 
futility if this p-value is greater than 0.358.  If the stopping 
rule is met for the trial to stop early for tentative success, a 
final confirmatory analysis will be conducted when all 
subjects have reached 12 months post-procedure; a p-
value threshold of 0.031 will be used for this final 
confirmatory analysis.  If neither of these interim analysis 
criteria for stopping the trial early is met, or if the 
confirmatory analysis for early success is not satisfied, then 
enrollment will commence until a total sample of N=320 
subjects have been enrolled (including the original N=160), 
and all subjects will be followed for a minimum of 12 months 
post-procedure at which time the final primary endpoint 
analysis will be conducted.  In this final primary endpoint 
analysis, the study will be deemed to be successful if the 
unadjusted 2-sided normal approximation p-value for 
testing the primary effectiveness endpoint (RCAO vs. the 
PG of 35%) is less than 0.031.   
 
The statistical power to stop early for success at the interim 
analysis is approximately 79% if the true RCAO is 47% in 
the general population and there are at least 150 evaluable 
MITT subjects (with post-procedure data) for this interim 
analysis.  The statistical power at the final endpoint (if the 
study continues to full enrollment) is 87.7% if the rate of 
complete occlusion in the general population is 44% and 
there are 300 evaluable MITT subjects (with post-procedure 
data) for this final analysis.  With the group-sequential 
design of this study and the specified interim and final 
analyses for the primary endpoint, including the sample 
sizes at which analyses will be conducted and the p-value 
thresholds for determining study success in the respective 
analyses, the overall probability of a Type 1 error in this 
study (α, 2-sided) is maintained below 0.05.    
 
There are two primary safety endpoints with formal 
hypotheses that will be tested, and the following are 
estimates of statistical power for each of these respective 
endpoints at the time of the interim analysis.  For each 
respective endpoint, the purpose of the hypothesis test is to 
ensure that the 2-sided 95% upper confidence limit for the 
estimate is less than a stated performance goal for the 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 18 of 121 
endpoint.  The performance goal, expected outcome, and 
estimated statistical power based upon a sample size of 
N=150 evaluable subjects (with post-procedure data) are 
provided for each respective endpoint.   
 
a) Major ipsilateral stroke/death at 12 months: 
• Performance 
goal 
= 
25%. 
The 
upper 
confidence limit of a 2-sided 95% confidence 
interval for the proportion of subjects who 
experience major ipsilateral stroke and/or 
death through 12 months post-procedure will 
be observed to be less than 25%.    
• Expected rate of major ipsilateral stroke and/or 
death is not greater than 14%. 
• Statistical power ≥ 92.5%. 
 
b) In-stent Stenosis at 12 months 
• Objective performance criterion = 15%. The 
upper confidence limit of a 2-sided 95% 
confidence interval for the rate of in-stent 
stenosis will be observed to be less than 15%.  
• Anticipated rate of in-stent stenosis is not 
greater than 6%. 
• Statistical power = 95.5%. 
 
 
Enrollment Start Date, 
Enrollment Phase and 
Follow-up Schedule:
 
 
  
The study is expected to start Q3 2015. The initial 
enrollment phase is expected to take 48 months.  A 6-month 
pause in enrollment will occur after 160 subjects have been 
enrolled for an interim analysis to be conducted to 
determine if the study should stop early for futility or 
tentative success.  If the trial is not terminated early, then 
enrollment will continue up to a full enrollment of 320 
subjects, which is anticipated to take an additional 12 
months.  
 
Subjects will be followed through 24 months with 
assessments at discharge, 30 days, 6 months, 12 months, 
18 months and 24 months with a follow-up angiography 
(digital subtraction angiography) being performed at 6, 12  
and 24 months for all subjects.   
 
If a subject experiences indications that in-stent stenosis or 
delayed hydrocephalus is occurring, additional follow-up 

 
           
 
 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 19 of 121 
may be required, including MRI or CT at the Investigator’s 
discretion. 
  

 
          

 
CONFIDENTIAL 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 20 of 121 
6&+('8/(2)(9(176
7DEOH6XPPDU\RI6WXG\3URFHGXUHVDQG$VVHVVPHQWV
$VVHVVPHQWV
6FUHHQLQJ%DVHOLQH
WRGD\V
3UHWUHDWPHQW
GD\
,QWUDSURFHGXUH
GD\
3RVWWUHDWPHQW
GD\
$QJLRJUDSKLF
6FUHHQLQJ)DLOXUH
GD\
+RVSLWDOGLVFKDUJH
'D\V
GD\V
0RQWKV
GD\V
0RQWKV
GD\V
0RQWKV
GD\V
0RQWKV
GD\V
6WURNHRU6XVSHFWHG
6WURNH
6WXG\DSSURYHGLQIRUPHG
FRQVHQW
;










0HGLFDOKLVWRU\
;











&OLQLFDODVVHVVPHQW	
SK\VLFDOH[DP
;




;

;
;

;

1,+6WURNH6FDOH6FRUH
1,+66
;
;
;
;
;
;
0RGLILHG5DQNLQ6FDOHP56
;




;
;
;
;
;
;
;
&OLQLFDOQHXURORJLFDO
HYDOXDWLRQ
;




;
;
;
;
;
;

+XQWDQG+HVV6FDOH++6
IRUVXEDUDFKQRLGKHPRUUKDJH





;

;
;

;

9LWDO6LJQV
;
;

;
;
;

;
;

;

5HOHYDQWSULRUDQG
FRQFRPLWDQWPHGLFDWLRQV
;




;
;
;
;
;
;

6HUXPFUHDWLQLQH
;











3UHJQDQF\WHVW
;











,QGH[3URFHGXUH


;









3URFHGXUDO0HGLFDWLRQV

;
;
;
;







,PDJLQJ












&7RU05,SHUIRUPHG
ZLWKLQ \HDUV
;











$QJLRJUDP
;
;
;
;
;


;
;

;

05,05$RU$QJLRJUDP










;

05,IRU6WURNH6XVSHFWHG
6WURNHZLWKLQKUV











;
5HFRUGRIDGYHUVHHYHQWV

;
;
;
;
;
;
;
;
;
;
5HFRUGRISURWRFROGHYLDWLRQ
;
;
;
;
;
;
;
;
;
;
;
5HFRUGGHYLFH
PDOIXQFWLRQSURGXFW
FRPSODLQW

;
;
;

;
;
;
;
;
;

(QGRI6WXG\RFFXUULQJRQFH
DWDQ\WLPHSRLQW

;
;
;
;
;
;
;
;
;
;

$WWRKRXUVDIWHUHQGRIWKHLQGH[SURFHGXUH
3URFHGXUDODQGUHOHYDQWFRQFRPLWDQWPHGLFDWLRQVLQFOXGH$QWLWKURPERWLFLQFOXGLQJDQWLSODWHOHWDQWLFRDJXODQWDQGILEULQRO\WLFVLQKLELWRUVRI$'3LQGXFHGSODWHOHWDJJUHJDWLRQ,,E,,,D,QKLELWRU
YDVRDFWLYHPHGLFDWLRQVFRQWUDVWDQGPHGLFDWLRQDVVRFLDWHGZLWK$(V
)RUIHPDOHVRIFKLOGEHDULQJSRWHQWLDODVDVVHVVHGSHULQYHVWLJDWRU
$VQHHGHG
&ROOHFWDWWKHLQGH[SURFHGXUHDQGDQ\VXEVHTXHQWSURFHGXUHVLIDSSOLFDEOH
$VVHVVIRUVWURNHRUVXVSHFWHGVWURNHDWHDFKYLVLW:LWKLQKRXUVRIV\PSWRPVRQVHWFRQGXFW05,,I,QYHVWLJDWRUGRHVQ¶WOHDUQRIHYHQWZLWKLQKRXUVFRQGXFW05,LPPHGLDWHO\DVZHOODVP56
DQG1,+66GD\IROORZXSZLQGRZGD\VUHTXLUHGLQWKHHYHQWRIFRQILUPHGVWURNHFRPSOHWHP56DQG1,+66
05,05$RUDQJLRJUDPWRDVVHVVIRULQVWHQWVWHQRVLVWKURPERVLVDQGK\GURFHSKDOXVRULIDQDQJLRJUDPLVSHUIRUPHGWKHQDOVRREWDLQ05,RU&7WRDVVHVVIRUK\GURFHSKDOXVDQJLRJUDPPXVWEH
SHUIRUPHGLIDQ\VWHQWRUFRLOVDUHQRW05$05,FRPSDWLEOH
2EWDLQDQD[LDO&7RU05,RIWKHVXEMHFWSHUIRUPHGZLWKLQWKHODVW\HDUVSURYLGHGWKDWWKH&7RU05,ZDVQRWSHUIRUPHGEHIRUHWKHVXEMHFW
VWKELUWKGD\WKDWVKRZVWKHRUELWDODQDWRP\7KH
&705,VKRXOGFRQWDLQDYDOLGFHQWLPHWHUPDUNHUDQGEHXSORDGHGWR,PDJH0DQDJHPHQW9HQGRU
,IWKHVXEMHFWVLJQHGWKHVWXG\LQIRUPHGFRQVHQWEXWPHHWVDQ\RIWKHDQJLRJUDSKLFH[FOXVLRQWKHVXEMHFWLVFRQVLGHUHGDQDQJLRJUDSKLFVFUHHQLQJIDLOXUH$6)DQGPD\QRWFRQWLQXHLQWKHVWXG\
&RPSOHWHGSRVWWUHDWPHQWDIWHUWUHDWPHQWZLWKVWHQWFRLOVSULRUWRHQGRISURFHGXUH
8QVFKHGXOHGDQJLRJUDPVDUHWKRVHQRWUHTXLUHGIRUWKHVWXG\,IQHHGHGWKH\VKRXOGEHSHUIRUPHGXVLQJWKHVDPHRUWKRJRQDOYLHZVXVHGGXULQJWKHLQGH[SURFHGXUHDQGVXEPLWWHGWRWKHFRUHODE
%DVHOLQHDQJLRJUDSK\HLWKHU&7$RUDQJLRJUDPZLWKLQGD\V

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 21 of 121 
LIST OF ABBREVIATIONS 
 
ADE 
ADP 
ADPKD 
AE 
ACT 
APTT 
ASA 
ASF 
AVM 
CFR 
CI 
CF 
CRA 
CRF 
CT 
CTA 
DS 
DSA 
DW 
eCRF 
EDC 
EDNRA 
EVT 
FDA 
GCP 
GI 
HDE 
HHS 
HUD 
ICES 
IFU 
INR 
IRB 
IVRS 
ITT 
LAR 
LOCF 
LR 
MI 
MITT 
MRA 
MRI 
mRS 
NIH 
NIHSS 
NiTi 
OR 
PP 
PTFE 
PSF 
QCA 
RCAO 
Adverse Device Effect 
Adenosine Diphosphate 
Autosomal Dominant Polycystic Kidney 
Adverse Event 
Activated Clotting Time 
Activated Partial Thromboplastin Time 
Aspirin 
Angiographic Screening Failures 
Arteriovenous Malformation 
Code of Federal Regulations 
Confidence Interval 
Continued Follow-up 
Clinical Research Associate 
Case Report Form 
Computed Tomography 
Computed Tomography Angiography 
Delivery System 
Digital Subtraction Angiography 
Delivery Wire 
Electronic Case Report Forms 
Electronic Data Collection 
Endothelin Receptor Type A 
Endovascular Treatment 
Food and Drug Administration (United States) 
Good Clinical Practice 
Gastrointestinal 
Humanitarian Device Exemption 
Hunt and Hess Scale 
Humanitarian Use Device 
Interstate Collaboration of Stent Coiling 
Instructions For Use 
International Normalized Ratio 
Institutional Review Board (United States) 
Interactive Voice Response System 
Intent-to-Treat 
Legal Authorized Representative 
Last Observation Carried Forward 
Logistic Regression 
Myocardial Infarction 
Modified Intent-to-Treat 
Magnetic Resonance Angiography 
Magnetic Resonance Imaging 
Modified Rankin Scale 
National Institute of Health 
National Institute of Health Stroke Scale 
Nitinol 
Odds Ratio 
Per Protocol  
Polymeric Tube 
Preliminary Screen Fail 
Standard Quantitative Angiography 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 22 of 121 
SAC 
SAE 
SAH 
SAP 
SAS 
SDV 
TICI 
UADE 
UIA 
US 
VRD 
WBC 
Rate of Complete Aneurysm Occlusion according to the Raymond Scale 
Stent-Assisted Coiling 
Serious Adverse Event 
Subarachnoid Hemorrhage 
Statistical Analysis Plan 
Statistical Analysis Software 
Source Data Verification 
Thrombolysis in Cerebral Infarction 
Unanticipated Adverse Device Effect 
Unruptured intracranial aneurysms 
United States 
Vascular Reconstruction Device 
White Blood Cell 
 
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 23 of 121 
1.0 INTRODUCTION 
 
1.1.  Literature Summary and Background  
 
1.1.1 Background 
 
Intracranial saccular aneurysms are common acquired lesions. Imaging 
studies have reported frequencies of 0.5% to 2%, while autopsy studies have 
reported frequencies of 1% to 9% (Burns et al., 2009a). Findings from an 
analysis of 68 prevalence studies reporting data from 83 study populations 
showed an overall prevalence of intracranial saccular aneurysms of 3.2% 
(Vlak, 2011). Findings from imaging studies in which arteriography and MRI 
were used suggest that the frequency of intracranial saccular aneurysms in 
the general population is 0.5–3% (Winn, 1983; Atkinson, 1989). In a 
European population-based prevalence study (Vernooij et al., 2007), about 
1.8% of adult participants had an aneurysm detected on screening MRI. In 
a cross-sectional study in China (Li et al., 2013), 7% of adults between the 
ages of 35 and 75 years had an aneurysm detected on widespread 
screening with brain magnetic resonance angiography (MRA). In Norway, 
the prevalence of intracranial saccular aneurysms on MRA was 1.9% and 
the incidence of subarachnoid hemorrhage in the same population was 16.4 
per 100 000 person-years (Müller et al., 2013).  
 
The inherent threat of unruptured intracranial aneurysms (UIAs) is rupture 
and subsequent subarachnoid hemorrhage (SAH). Studies of aneurysmal 
SAH, which accounts for around 80% of non-traumatic SAH, have reported 
1-month case mortality rates as high as 30% to 50% (Burns et al., 2009b; 
Broderick et al., 1993; Fogelholm et al., 1993); these devastating outcomes 
are still extraordinary. Poor neurologic and functional outcomes among 
patients whom have suffered SAH are due to initial hemorrhage, early 
rebleeding, and delayed cerebral ischemia resulting from cerebral 
vasospasm, microvascular dysfunction, and complex neuronal-glial 
interactions (Laskowitz and Kolls, 2010). The overall economic effect is 
substantial; data from the late 1970s and 1980s suggest that lifetime costs 
of management exceed US$500 million annually in the USA (Wiebers et al., 
1992). 
 
Intracranial saccular aneurysms have to be considered as an important 
disease due to the severe morbidity and mortality associated with SAH that 
result from rupture of cerebral aneurysms. The most important objective of 
the treatment is to prevent rupture or rebleeding by isolating an aneurysm 
from the normal blood circulation without narrowing the parent vessel 
 
1.1.2 Pathophysiology of Aneurysms 
 
An intracranial aneurysm is a focal bulging in the wall of an artery in the brain 
that results from a weakening of the internal muscular layer of a blood vessel. 
Due to certain histopathologic and hemodynamic factors, aneurysms most 
commonly occur in arteries that supply blood to the brain.  

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 24 of 121 
 
Several risk factors affecting both aneurysm formation/growth and risk of 
rupture have been identified: aneurysm shape and location, gender, age, 
family history, genetic conditions, cigarette smoking, hypertension, and 
alcohol and drugs consumption.  
 
Intracranial aneurysms are classified as saccular, fusiform, or dissecting. 
Nearly 90 percent are saccular aneurysms. Intracranial saccular aneurysms 
are responsible for most of the morbidity and mortality caused by SAH 
(Yong-Zhong and van Halphen, 1990). 
 
Intracranial saccular aneurysms occur primarily in proximal arterial 
bifurcations in the circle of Willis, and 85% of these lesions are located in the 
anterior circulation (Kassel et al., 1990) including the following sites: the 
internal carotid artery sidewall and bifurcation, the anterior communicating 
artery to anterior cerebral artery junction, the middle cerebral artery branch 
points and the ophthalmic artery origin. In the posterior vertebrobasilar 
distribution, the most common locations include the tip of the basilar artery, 
the superior cerebellar artery branch from the basilar artery, the anterior 
inferior cerebellar artery branch from the basilar artery, and the posterior 
inferior cerebellar artery branch from the vertebral artery. About 20% of 
patients have more than one aneurysm (Rinne et al., 1994). 
 
Unruptured intracranial aneurysms are more common in women than in 
men, with a 3:1 ratio of women to men with aneurysms in a large cohort 
(Chason and Hindman, 1958; ISUIA, 1998). Unruptured intracranial 
aneurysms are also more common in elderly people (Inagawa and Hirano, 
1990) and are uncommon in children (Meyer et al., 1989; Storrs et al., 1982). 
 
Occurrence of Intracranial saccular aneurysms is increased in some 
inherited disorders compared with the general population. Autosomal 
dominant polycystic kidney (ADPKD) disease is the most common inherited 
disorder associated with intracranial saccular aneurysm (Chapman et al., 
1992; Gibbs et al., 2004; Mariani et al., 1999; Schievink 1997). In this 
disease, the risk of aneurysm detection is higher when other family members 
have had brain aneurysm (Mariani et al., 1999) and with increasing age; the 
overall prevalence is about 10% (Chapman et al., 1992). Other inherited 
disorders that have been associated with brain aneurysm include multiple 
endocrine neoplasia type I (Schievink, 1998), hereditary hemorrhagic 
telangiectasia (Maher et al., 2001), Ehlers-Danlos syndrome type IV 
(Edwards and Taylor, 1969), Marfan’s syndrome (Schievink 1999), and 
neurofibromatosis type I (Schievink et al., 2005), although the overall 
frequency of association of these disorders with unruptured intracranial 
saccular aneurysms rather than fusiform aneurysms is uncertain. Increased 
occurrence of brain aneurysm has also been associated with moyamoya 
disease 
(Yasargil 
and 
Smith, 
1976), 
intracranial 
arteriovenous 
malformations (Brown et al., 1990), sickle-cell disease (Batjer et al., 1991), 
systemic lupus erythematosus (Nagayama et al., 1991), fibromuscular 
dysplasia (Palubinskas et al., 1966), and coarctation of the aorta (Connolly 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 25 of 121 
et al., 2003). Overall, among all unruptured intracranial aneurysms detected, 
the proportion that is associated with these disorders is low (ISUIA, 1998; 
Wiebers et al., 2003). 
 
The specific genetic abnormality associated with intracranial saccular 
aneurysm formation is not clear, but a large meta-analysis (Alg et al., 2013) 
of genetic studies identified 19 single nucleotide polymorphisms associated 
with sporadic intracranial aneurysm. The strongest associations were found 
on chromosome 9 within the CDKN2B antisense inhibitor gene, on 
chromosome 8 near the SOX17 transcription regulator gene, and on 
chromosome 4 near the EDNRA gene (Alg et al., 2013; Foroud et al., 2012). 
Findings from a meta-analysis of the Familial Intracranial Aneurysm cohort 
(Foroud et al., 2012) showed significance for single nucleotide 
polymorphisms on chromosome 9p and supported an association between 
intracranial aneurysm and single nucleotide polymorphisms in SOX17 on 
chromosome 8q. About 20% of patients with an aneurysm or subarachnoid 
hemorrhage will report a family history of these diagnoses (Kissela et al., 
2002). However, not all cases of familial aneurysm are necessarily genetic 
in cause; some represent a co-occurring familial history of hypertension or a 
higher occurrence of smoking in members of a family. In families with two or 
more members affected with intracranial saccular aneurysm or subarachnoid 
hemorrhage, there is an increased occurrence of these disorders in first-
degree and possibly second-degree relatives of those with either diagnosis. 
The mean age of subarachnoid hemorrhage is younger in familial than in 
non-familial cases (Bromberg 1995) and the overall outcome is often poorer 
(Bromberg et al., 1995). The overall occurrence of unruptured intracranial 
aneurysm or subarachnoid hemorrhage in the relatives of someone affected 
with subarachnoid hemorrhage is available from population-based data. In 
one such study of patients with subarachnoid hemorrhage (Kissela et al., 
2002), 9.4% of patients had a first-degree relative with subarachnoid 
hemorrhage or intracranial aneurysm and 14% had a second-degree relative 
with these diagnoses. In a screening study of the relatives of 193 patients 
with subarachnoid hemorrhage aged 20–70 years (Magnetic Resonance 
Angiography in Relatives of Patients with Subarachnoid Hemorrhage Study 
Group, 1999; Raaymakers, 1999) 4% of screened first-degree relatives had 
an unruptured intracranial aneurysm on MRA and subsequent intra-arterial 
angiography.  
 
Several treatable risk factors seem to increase the occurrence of aneurysms 
including cigarette smoking (Juvela et al., 1993; Shiue et al., 2012) and 
hypertension (Shiue et al., 2012; Knekt et al., 1991; Longstreth et al., 1992). 
Findings from some studies that assessed risk factors for subarachnoid 
hemorrhage suggested that heavy alcohol use (Shiue et al., 2012; 
Longstreth et al., 1992; Klatsky et al., 1989) increases the risk of 
subarachnoid hemorrhage. Drugs containing high dose oestrogen increase 
the risk of subarachnoid hemorrhage, but the risk might be lower with drugs 
containing low-dose oestrogen (Bonita, 1986; Longstreth et al., 1994; 
Johnston et al., 1998). Cocaine use has been associated with subarachnoid 
hemorrhage in young people (Broderick et al., 2003). Finally, low body-mass 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 26 of 121 
index has been associated with increased risk of subarachnoid hemorrhage, 
but the cause of this is unclear (Zacharia et al., 2010). 
 
1.1.3 Treatment Options for Intracranial Saccular Aneurysms 
 
The most appropriate treatment option for any UIAs is that which provides 
an optimal balance of procedural safety and long-term efficacy based on 
patient and aneurysm characteristics. Currently, there are two available 
options for treating UIAs, microsurgical clipping and endovascular coiling. 
 
Traditionally, surgical clipping has been viewed as being highly efficacious, 
but carrying greater risk due to the neurological complications associated 
with open neurosurgery. Efficacy of this treatment is illustrated by a study 
performed between 1998 and 2001 that explored the need for cerebral 
angiography following surgery for saccular aneurysms. Of the 315 surgically 
clipped UIAs in this study, 287 were completely occluded, a 91% complete 
occlusion rate (Kivisaari et al., 2004). On the other hand, safety concerns 
associated with surgical treatment are shown in a report analyzing data from 
twenty-one single-center and eight multicenter studies of surgical clipping 
from 1991 to 2003 (Lee and Kolls, 2005). In this study, mortality rates ranged 
from 0% to 6.9%. The same study found the adverse outcome rate (AOR) to 
range between 0% and 25.1% with a cumulative AOR of 17.8%. The largest 
multicenter study of UIAs at the time, the ISUIA (International Study of 
Unruptured Intracranial Aneurysms), aimed to characterize the natural 
history of unruptured aneurysms. One of the goals of the prospective branch 
of the ISUIA was to obtain a more comprehensive assessment of the surgical 
risks of aneurysm clipping. Among the 1917 patients who underwent surgical 
clipping, the study found a 1-year mortality rate of 2.3% and a 1-year 
morbidity rate of 12.1%. The study also found that increasing aneurysmal 
size and patient age as well as location in the posterior circulation 
(particularly basilar tip and posterior communication artery) are indicators of 
poor outcome following surgical treatment (Wiebers et al., 2003). 
Consequently, older patients with large, posterior circulation aneurysms are 
most likely better candidates for endovascular treatment. 
 
More recent studies are showing that refinement of microsurgical technique 
is leading to safer, more efficacious treatment of UIAs. One study followed a 
series of 450 aneurysms treated with surgical clipping by one neurosurgeon 
immediately upon completion of neurosurgery training. With 6-month 
morbidity and mortality rates of 1.06% and 0.27%, respectively, it is clear 
that, given proper mentorship and resources prevailing neurosurgeons can 
achieve acceptable results when treating UIAs surgically (Nussbaum et al., 
2007). 
 
Since its conception and implementation about two decades ago (Guglielmi 
et al., 1991a; Guglielmi et al., 1991b), endovascular coil embolization has 
become a primary treatment in the management of unruptured intracranial 
saccular aneurysms. In many institutions worldwide, endovascular coiling 
has become the preferred treatment for unruptured intracranial saccular 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 27 of 121 
aneurysms for which intervention is indicated (Moyle and Patel, 2010). To 
confirm the notion that endovascular procedures provide a safe alternative 
for treating unruptured intracranial saccular aneurysms, many studies have 
investigated the morbidity and mortality rates of patients who underwent 
endovascular coiling. As part of the prospective branch of the ISUIA, 451 
patients were chosen to undergo endovascular coiling. Among these 
patients, there was a 1-year surgery-related mortality rate of 3.1% and a 1-
year morbidity rate of 9.5% (Wiebers et al., 2003). A year later, Lanterna et 
al. (2004) analyzed thirty studies of endovascular coiling, published between 
1990 and 2002, and revealed case-fatality and permanent morbidity rates of 
0.6% and 7.0%, respectively. To appreciate the effect of advancing 
technology and technical refinement, the investigators divided the 
publications by midyear of the study and found that studies before 1995 
reported a morbidity rate of 8.6%, while the morbidity rate of studies after 
1995 had dropped to 4.5% (Lanterna et al., 2004). Another more recent 
meta-analysis performed by Naggara et al. (2010) looked at similar studies 
performed in 17 different countries from 2003 to 2008 and found unfavorable 
outcomes occurred at a rate of 4.8%. Ultimately, these data do seem to 
indicate that endovascular coiling provides a safe alternative to clipping by 
imparting lower complication rates upon patients. 
 
While endovascular treatment of unruptured intracranial saccular aneurysms 
is now widely used, certain aneurysmal morphologies and anatomical 
features, particularly a wide neck, render some aneurysms technically 
difficult to treat endovascularly. To facilitate endovascular coiling of 
aneurysms with broad necks, Moret et al. (1997) extended a previously 
utilized temporary balloon inflation technique to the treatment of unruptured 
intracranial saccular aneurysms  and named it balloon remodeling. One part 
of the ATENA (Analysis of Treatment by Endovascular Approach of 
Nonruptured Aneurysms) Study explored the safety of the balloon 
remodeling technique. The morbidity and mortality rates of UIAs treated with 
balloon remodeling were 2.3% and 1.4%, respectively, compared to 2.2% 
and 0.9% for those receiving standard endovascular coiling, a difference 
which was not statistically significant (Pierot et al., 2009). In terms of efficacy, 
a review comparing aneurysms treated with balloon remodeling versus 
standard endovascular treatment, in studies published from 1997 to 2006, 
revealed significantly higher initial and follow-up aneurysm occlusion rates 
for those aneurysms treated with balloon remodeling (Shapiro et al., 2008). 
 
Another adjunctive therapy for wide-neck UIAs is microcatheter-delivered 
stenting. The hope among neurosurgeons is that stent-assisted coil 
embolization (SAC) may improve long-term durability and effectiveness by 
minimizing herniation and increasing packing density (Gounis et al., 2010). 
After establishing procedural safety and periprocedural effectiveness 
(Fiorella et al., 2004), Sedat et al. (2009) reported that long-term complete 
aneurysmal occlusion occurred in 71% of patients, with aneurysmal regrowth 
in 4 out of 38 patients at first angiographic follow-up and no regrowth in any 
other follow-ups. In order to value the safety and efficacy of SAC, the 
Interstate Collaboration of Stent Coiling (ICES) was conducted. Data on 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 28 of 121 
consecutive patients treated with Enterprise stent-assisted coiling of 
ruptured and unruptured aneurysms from 9 high-volume neurointerventional 
centers was compiled. Initial results of the ICES study concluded that this 
technique was helpful for treatment of unruptured intracranial aneurysms but 
not ruptured intracranial aneurysms and produced morbidity and mortality 
rates of 2.8% and 2.0%, respectively (Mocco et al., 2009). The final report of 
the ICES study, which then encompassed 229 SAC-treated aneurysms with 
a mean follow-up of 655.7 days, reported that 59% of aneurysms 
demonstrated complete occlusion and 81% had≥90% aneurysm occlusion, 
illustrating that SAC is a viable option for wide-neck aneurysms (Fargen et 
al., 2012).  
 
Even though the ICES trial provides valuable information on stent-assisted 
coiling in general, a monitored trial evaluating the safety and efficacy of 
Enterprise assisted coiling in the treatment of intracranial, unruptured, wide-
necked aneurysms has not been conducted up to date. This study is 
designed to evaluate the safety and effectiveness of ENTERPRISE when 
used in conjunction with endovascular coil embolization of unruptured wide-
necked saccular intracranial aneurysms in a prospective, single arm clinical 
study. 
 
 
1.2.  Investigational (Study) Device Description  
 
1.2.1 CODMAN ENTERPRISE® Vascular Reconstruction Device 
 
The CODMAN ENTERPRISE® Vascular Reconstruction Device (CODMAN 
ENTERPRISE) is intended for use in the neurovasculature with embolic coils 
to provide treatment to a population of intracranial aneurysms where 
aneurysm geometry alone cannot support embolic coils. This aneurysm 
geometry, known as the wide-necked aneurysm, does not naturally support 
a coil mass. The wide-neck aneurysm is defined as having a neck width ≥ 4 
mm or a dome-to-neck ratio < 2. The stent serves the specific purpose of 
supporting a coil mass in a scenario where the shape of the aneurysm does 
not do so naturally, by providing a scaffold to prevent coil protrusion into the 
parent vessel lumen. 
 
The CODMAN ENTERPRISE consists of a nitinol stent pre-loaded on a 
delivery wire and constrained within an introducer that facilitates transfer of 
the stent into a microcatheter. The recapturable and repositionable stent 
bridges and reconstructs the neck of an aneurysm from within the lumen of 
a parent artery in the neurovasculature in order to support embolic coils 
deployed into the aneurysm. The stent is also coated with Parylene C, an 
insulating polymer that enhances the stent’s resistance to corrosion caused 
by dissimilar metal contact between nitinol and platinum/tungsten embolic 
coils. The delivery wire is used to advance and subsequently deploy and 
release the stent into the neurovasculature. 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 29 of 121 
1.2.2 CODMAN ENTERPRISE® 2 Vascular Reconstruction Device 
 
The CODMAN ENTERPRISE VRD System and ENTERPRISE 2 VRD 
System serve the specific purpose of supporting a coil mass in a scenario 
where the shape of the aneurysm does not do so naturally, by providing a 
scaffold to prevent coil protrusion into the parent vessel lumen.  The 
ENTERPRISE 2 VRD System incorporates several minor modifications, 
bench top testing showed that it met or exceeded the same acceptance 
criteria as the ENTERPRISE VRD System.     
 
The modifications are further described in Section 5.1.2.  There is no change 
to the intended use as a result of the modifications.  
 
1.3. Previous Codman Sponsored Clinical Studies 
 
1.3.1 Feasibility studies:  United States and Europe  
 
Cordis Neurovascular/Codman Neuro, Inc., conducted two multi-center, 
prospective, non-randomized, feasibility studies evaluating the CODMAN 
ENTERPRISE® Vascular Reconstruction Device (stent) and Delivery 
System.  The CODMAN ENTERPRISE stent size 4.5 X 22 mm was used in 
both of these studies. One study was conducted in Europe at three medical 
institutions and the other was conducted in the United States at five medical 
institutions.  Both studies were conducted according to local regulatory 
requirements and in accordance with the principles of the Declaration of 
Helsinki as enforced at the time the study was conducted. 
 
The studies demonstrated the safety and probable benefit of the CODMAN 
ENTERPRISE® Vascular Reconstruction Device and Delivery System to 
facilitate endovascular coil embolization of wide neck saccular or fusiform 
intracranial aneurysms.  The studies involved a more rigorous design than 
studies involving the use of stents to treat intracranial aneurysms currently 
found in the literature.  Notable study design features include the use of an 
independent Clinical Events Committee (CEC), the use of an independent 
angiographic core lab, independent neurological assessment, and collection 
of all adverse events, whether or not related to the device or procedure, 
confirmed via routine study monitoring. 
 
European Data 
The European clinical study began with the first implant on 19 December 
2003.  Thirty-one subjects were enrolled into the study.  The database was 
closed on 01 February 2006.   
 
Baseline data were collected on 31 subjects who enrolled into the study, 
which received the CODMAN ENTERPRISE stent and were followed 
through six months.  The majority (87.1%) of the subjects was female, and 
the average age was 54.5 years.  A medical history of hypertension was 
reported in 38.7% of the subjects enrolled and 25.8% had endocrine / 
metabolic disease. The most commonly reported neurological event was 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 30 of 121 
subarachnoid hemorrhage (38.7%) and 16.1% had a history of cranial nerve 
palsy and pounding / pulsatile headache.  Fourteen subjects (45.2%) had 
undergone a prior intracranial embolization procedure for their cerebral 
aneurysm.  
     
All serious adverse events were reviewed and adjudicated by the 
independent Clinical Events Committee.  Six subjects (16.1%) experienced 
one or more device or procedure related serious adverse events.  Eighteen 
subjects experienced 25 adverse events that were judged by the site to be 
at least possibly related to the device or procedure.  The majority of these 
events occurred within 30 days.  Neurological assessments included NIH 
Stroke score, modified Rankin score and clinical neurological examination.  
Most subjects experienced no change or improved neurological assessment 
ratings from pre-procedure to six months. 
 
The mean NIH Stroke score was 0.3 pre-procedure and was 0.3 at six 
months.  The majority of subjects (96.8%) were rated Grade 0 or Grade 1 on 
the modified Rankin scale pre-procedure, and 96.7% of subjects were Grade 
0 or Grade 1 at six months (a Rankin scale of “0” indicates no neurological 
disability).   
 
Angiographic measurements were performed by an angiographic core lab. 
At pre-procedure, the mean aneurysm dome height and width was 6.3 mm 
and 7.0 mm, respectively.  The mean neck width was 4.8 mm, and mean 
dome width-to-neck ratio was 1.47.  The mean proximal/distal diameter of 
the parent vessel pre-procedure was 3.1/2.8, and 2.8/2.5 at six months.   
 
The technical success measures were also assessed using the angiographic 
core lab.  Successful stent placement angiographically assessed 
immediately post-procedure was 96.8%. Successful stent placement was 
defined as stable stent placement with complete coverage across the 
aneurysm neck and parent artery patency, while satisfactory coil mass 
position was defined as stent maintains coil position within the sac with 
parent artery patency.  Procedural success, defined as successful stent 
placement with satisfactory coil mass position without occurrence of 
procedural serious adverse events, was 90.0%.  Maintenance of coil mass 
position was 96.7% at six months.  The mean percent aneurysm occlusion 
post-procedure was 93.0% and 93.9% at six months. 
 
United States Data 
The US clinical study includes data on subjects enrolled between 22 June 
2004 and 12 October 2004.  Subjects were followed for six months.  The 
database was closed on 13 July 2005.   
 
Baseline data were presented on 30 subjects who enrolled into the study 
and on 28 subjects who received the CODMAN ENTERPRISE stent and 
followed through six months.  Two subjects were enrolled into the study but 
did 
not 
receive 
the 
device 
due 
to 
pre-procedure 
angiographic 
disqualification.  In one case, the parent vessel was too large in diameter 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 31 of 121 
and in the other, the aneurysm neck was too wide.  The majority (76.7%) of 
the subjects was female, and the average age was 57.8 years.  A medical 
history of hypertension was reported in 66.7% of the subjects enrolled and 
40.0% had cardiovascular disease. The most commonly reported 
neurological event was pounding/pulsatile headache (43.3%) and 26.7% 
had a history of Altered Mental Status.  Five subjects (16.7%) had previously 
suffered a subarachnoid hemorrhage, and 23.3% of the subjects had 
undergone a prior intracranial embolization procedure for their cerebral 
aneurysm.  
 
All serious adverse events were reviewed and adjudicated by the Clinical 
Events Committee.  Seven subjects (25%) experienced one or more device 
or procedure related serious adverse events.  One subject died as a result 
of an intracerebral hemorrhage post-operatively.  This death was classified 
as secondary to the presenting intracerebral hemorrhage. Eighteen subjects 
experienced 47 other adverse events that were judged to be at least possibly 
related to the device or procedure.  The majority of these events occurred 
within 30 days.    
 
Neurological assessments included NIH Stroke score, modified Rankin 
score and clinical neurological examination.  Most subjects experienced no 
change or improved neurological assessment ratings from pre-procedure to 
six months. 
 
The mean NIH Stroke score was 1.4 pre-procedure and was 0.3 at six 
months.  This indicates that there was benefit for both neurological and 
overall clinical improvement following treatment, since an NIH stroke scale 
core of “0” is an indication of being completely normal.  The majority of 
subjects (75.9%) were rated Grade 0 or Grade 1 on the modified Rankin 
scale pre-procedure, and 80.7% of subjects were Grade 0 or Grade 1 at six 
months (a Rankin scale of “0” indicates no neurological disability).   
 
Angiographic measurements were made by an angiographic core lab. At 
pre-procedure, the mean aneurysm dome height and width was 8.2 mm and 
8.6 mm, respectively.  The mean neck width was 5.3 mm, and mean dome 
width-to-neck ratio was 1.43.  The mean proximal/distal diameter of the 
parent vessel pre-procedure was 3.4/3.0, and 3.3/2.9 at six months.   
 
The technical success measures were also assessed using the angiographic 
core lab.  Successful stent placement with satisfactory coil mass position 
assessed immediately post-procedure was 100%.  Successful stent 
placement was defined as stable stent placement with complete coverage 
across the aneurysm neck and parent artery patency, while satisfactory coil 
mass position was defined as stent maintains coil position within the sac with 
parent artery patency.  Maintenance of coil mass position was 95.8% at six 
months.    The mean post-procedure percent aneurysm occlusion was 
87.9%, and improving to 92.0% at six months.   
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 32 of 121 
 
1.3.2 Feasibility study:  Argentina 
 
A Feasibility Study of the Codman Neurovascular Self Expanding Stent 
System in Intracranial Arteries was conducted in Argentina. This was a 
prospective, single-arm, single-center study sponsored by Codman Neuro. 
The study was completed 09 March 2009.  
 
The purpose of the study was to assess both effectiveness and safety.  The 
CODMAN ENTERPRISE stent size 4.5 X 22 mm was used in this study. The 
two components of the effectiveness evaluation include: 
 
a) 
Technical feasibility 
For all subjects with a deployed stent: 
• Successful stent placement/coil mass position angiographically 
assessed immediately post-procedure, and 
• Evaluation of the percent occlusion assessed immediately post-
procedure and at six months after treatment.  
  
b) 
Clinical/neurological outcome 
For all subjects with a deployed stent, clinical/neurological outcome 
using independent neurological evaluations (NIH Stroke Scale, 
Modified 
Rankin Scale) by independent, qualified personnel 
immediately after the procedure, at discharge, at thirty days and six 
months after treatment compared to the baseline evaluation. 
 
Safety 
 
Adverse Events (AEs) 
For all enrolled subjects, incidence of AEs assessed immediately following 
the pre-procedure angiogram through hospital discharge. 
For subjects with a deployed stent, incidence of AEs assessed immediately 
following the pre-procedure angiogram through hospital discharge, at thirty 
days and six months after treatment. 
 
Results: 
Ten (10) subjects were enrolled, all of whom were entered into the study and 
evaluable at the 6 month follow-up. 
 
Effectiveness: 
This study demonstrated the technical feasibility of the CODMAN 
ENTERPRISE system for the treatment of wide-necked intracranial 
aneurysms. Stable stent placement with complete neck coverage and parent 
artery patency post-procedure was observed in 9/10 (90%) subjects; since 
due to poor angiographic image quality the Core Lab was unable to confirm 
stable stent placement immediately post-procedure and therefore this one 
subject was reported not to have stable stent placement immediately post-
procedure.  Immediately post-procedure and at the 6 month follow-up, the 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 33 of 121 
stent was reported to maintain coil mass position within the aneurysm sac 
with parent artery patency in 10/10 (100%) subjects. 
The mean post-procedure aneurysm occlusion was 86.8%, and improved to 
88.8% at six months. 
 
 
Safety: 
 
The CODMAN ENTERPRISE system was demonstrated to be safe for the 
treatment of wide-necked aneurysm in this study population.   Only 3 SAEs 
were reported in 3 subjects, and no SAEs were reported to be related to the 
device. There were no deaths and no event caused the stenting/coiling 
procedure to be discontinued.   
 
1.3.3 Study of ENTERPRISE in the Japanese Clinical Setting 
 
Johnson & Johnson Medical Company in Japan conducted a multicenter, 
single-arm study evaluating the CODMAN ENTERPRISE® Vascular 
Reconstruction Device.  The study period was November 2007 through 
October 2008. 
 
Since the probable benefit and safety of CODMAN ENTERPRISE had 
already been demonstrated in clinical studies in the United States and 
European countries, and since no device with similar functions of those to 
ENTERPRSISE was commercially available, Japan conducted the study to 
evaluate the applicability of CODMAN ENTERPRISE assisted procedure in 
the Japanese clinical setting.  In this study, procedural success was the 
primary endpoint in patients with a non-ruptured intracranial wide-neck 
(defined as a neck width ≥ 4 mm or a dome-to-neck ratio < 2) saccular 
aneurysm with a greatest diameter of at least 10 mm that is refractory to 
surgeries (e.g., clipping) or coil-only embolization.  Four stent sizes were 
used in the study (4.5 mm x 14 mm, 4.5 mm x 22 mm, 4.5 mm x 28 mm, or 
4.5 mm x 37 mm) according to lesion findings.  Fifteen (15) patients were 
enrolled and reported on in the study submission to the Shonin.  It was 
approved in Japan on 08 January 2010 under the product name CODMAN 
ENTERPRISE Stent. 
 
1.3.4 Sunrise Registry: European Post Market Surveillance  
 
The Sunrise Registry is a multicenter, prospective, observational registry to 
evaluate the safety and performance of the CODMAN ENTERPRISE 
System in routine clinical practice.  
This study demonstrates the safety and performance of the CODMAN 
ENTERPRISE System to facilitate endovascular coil embolization of wide 
neck saccular intracranial aneurysms.  The study design featured the use of 
an angiographic core lab as well as study monitoring.  
 
One hundred and nine (109) Subjects were enrolled in 15 centers (1 center 
in Australia and 14 centers in Europe) where the CODMAN ENTERPRISE 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 34 of 121 
System is approved for commercial use. Three subjects who did not give 
consent prior to data entry are omitted from analysis (consent forms were 
signed after the procedure had been performed). One subject did not receive 
treatment and was excluded as well.  
 
Data is presented on 105 subjects who were enrolled into the study and 
signed informed consent before stent placement. Per protocol, the study 
period for each subject was 6 months.  The majority (71.6%) of the subjects 
was female, and the average age was 55.3 years.  A medical history of 
hypertension was reported in 36.2% of the subjects enrolled and 3.8% had 
cardiovascular disease. The most commonly reported neurological event at 
baseline was TIA/CVA (20.0%), and 17.1% had a history of recurrent 
headaches. At baseline, 34.3% of the subjects had undergone a prior 
intracranial embolization procedure or clipping for their cerebral aneurysm.  
     
All serious adverse events were adjudicated by the participating 
investigators. Based on the adjudication, two subjects experienced a device- 
or procedure-related serious adverse event for an estimated rate of 1.9%. 
Seventeen subjects (16.2%) experienced 17 at least possibly device or 
procedure adverse events (including the two SAEs reported above). The 
majority (70.6%) of these events occurred before hospital discharge.  
 
Angiographic measurements were made by an angiographic core lab. At 
pre-procedure, the mean aneurysm dome height and width was 7.8 mm and 
6.9 mm, respectively.  The mean neck width was 4.9 mm. The mean 
proximal/distal diameter of the parent vessel pre-procedure was 3.6/3.3.  
 
The technical success measures were also assessed using the angiographic 
core lab.  Successful intracranial device placement (defined as stable 
CODMAN ENTERPRISE placement with complete coverage of the 
aneurysm neck and parent artery patency) was achieved in 85.7% of the 
cases. Satisfactory coil mass position (defined as CODMAN ENTERPRISE 
maintains coil position within the sac with parent artery patency as defined 
angiographically) was 83.5% immediately post-procedure and 83.3% at six 
months. Complete aneurysm occlusion was achieved in 20.2% of cases 
immediately post-procedure and in 58.2% of the subjects with 6 months 
follow-up. 
 
 
1.4. Commercial Approval of ENTERPRISE  
 
"Conformité Européene" (CE-mark): 
Outside of the United States (U.S.), the CODMAN ENTERPRISE® Vascular 
Reconstruction 
Device 
and Delivery 
System 
and 
the CODMAN 
ENTERPRISE® 2 Vascular Reconstruction Device are released by meeting 
the European medical device regulations for use with occlusive devices in 
the treatment of intracranial aneurysms.  
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 35 of 121 
Humanitarian Use Device (HUD) approved through Humanitarian    
Device Exemption (HDE) No. H060001:   
In the United States, the CODMAN ENTERPRISE® Vascular Reconstruction 
Device and Delivery System and the CODMAN ENTERPRISE® 2 Vascular 
Reconstruction Device are authorized by the Federal Law for use with 
embolic coils for the treatment of wide-neck, intracranial, saccular or fusiform 
aneurysms arising from a parent vessel with a diameter of ≥ 2.5 mm and ≤ 
4 mm.  Wide neck is defined as having a neck width ≥ 4 mm or a dome-to-
neck ratio < 2.  
 
Japanese Government: 
In January 2010, Johnson & Johnson Medical Company in Japan received 
SHONIN approval from Japan’s Ministry of Health, Labor and Welfare to 
market the CODMAN ENTERPRISE® Vascular Reconstruction Device and 
Delivery System in Japan. 
 
 
2.0 STUDY OBJECTIVES 
 
The primary objectives of the study are to evaluate the safety (as assessed 
by rates of major ipsilateral stroke and/or death and in-stent stenosis) and 
effectiveness (as measured by the rate of complete angiographic occlusion) 
of ENTERPRISE when used in conjunction with endovascular coil 
embolization of unruptured wide-neck, intracranial, saccular anterior 
circulation aneurysms (≤ 10 mm) in a prospective, multi-center, single arm 
clinical study.   
 
Secondary effectiveness objectives include the evaluation of treatment 
outcomes for subjects treated with ENTERPRISE in the acute (procedure 
and immediate post-procedure time frames) and follow-up phases of patient 
management.   
 
Secondary safety objectives include the evaluation of adverse safety 
outcomes for subjects treated with ENTERPRISE from the start of the 
procedure through the end of study participation (12 months or premature 
discontinuation of study participation).    
 
In addition, the rates of stent movement and migration will be described. 
 
 
3.0 STUDY DESIGN 
 
3.1 General Design 
 
This is a prospective, single arm, multicenter clinical study to evaluate the 
safety and effectiveness of the ENTERPRISE stent when used in conjunction 
with endovascular coil embolization in the treatment of unruptured wide-neck, 
saccular anterior circulation intracranial aneurysms (≤ 10 mm) arising from a 
parent vessel with a diameter of ≥ 2.5 mm and ≤ 4 mm. 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 36 of 121 
 
This study will be conducted at a maximum of 25 centers in the United States 
(US).  The study will be registered and results will be reported to the U.S. 
database maintained by the United States National Institutes of Health (NIH) 
on the United States National Library of Medicine’s (“NLM”) website 
www.clinicaltrials.gov under Title VIII of the Food and Drug Administration Act 
of 2007 (“FDAAA”).  
 
It is anticipated that fewer than 15% of entered subjects will be unevaluable at 
the 12 month follow-up visit due to loss to follow-up and/or missing primary 
angiographic occlusion or safety data.  However, subjects with missing data 
at the time of endpoint analysis will have primary effectiveness and primary 
safety endpoint data imputed as last observation carried forward (LOCF). 
Subjects who receive the device but in whom there is no post-procedure data 
will be treated as failures for the primary effectiveness analysis; subjects who 
do not receive the device because of treatment failure due to reasons 
associated with the device will also be treated as failures.  Subjects with no 
post-procedure endpoint data upon which to base a LOCF imputation will be 
excluded from the primary safety endpoint analyses; it is anticipated that fewer 
than 7% of MITT subjects will be excluded from either primary effectiveness 
or primary safety endpoint analyses.  Thus, although the primary endpoint 
analyses will be in the Modified Intent to Treat (MITT) population for primary 
effectiveness and safety endpoints, up to 320 subjects will be enrolled to 
achieve approximately 300 subjects with post-procedure data in the MITT 
population. A group sequential design will be employed in which one primary 
endpoint interim analysis will be conducted after N=160 subjects have been 
enrolled and followed through 6 months post-procedure, to determine if the 
study should stop early for futility or tentative success; it is anticipated that 
there will be at least N=150 subjects with post-procedure data in the MITT 
population for this analysis.  If the stopping rule is met for the trial to stop early 
for tentative success, a final confirmatory analysis will be conducted when all 
subjects have reached 12 months post-procedure.  If the trial is not terminated 
early for futility or tentative success, then enrollment will continue up to the full 
enrollment sample size of N=320.   
 
Patients who experience an AE of Special Interest and who have an MRS >2 
at any clinical evaluation will be followed through 24 months post-procedure.   
 
An independent core laboratory will perform the quantitative analysis for the 
primary and secondary effectiveness endpoints, as well as for subjects where 
the 12 month angiogram is an endpoint assessment.  A medical monitor will 
adjudicate the relationship of AEs to the device, procedure, and/or underlying 
disease in accordance with the definitions specified within this protocol.    
 
 
 
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 37 of 121 
3.2 Study Endpoints  
 
 3.2.1 Primary Effectiveness Endpoint 
 
• The primary effectiveness endpoint is the Rate of Complete 
Aneurysm Occlusion (RCAO) at 12 months post-procedure 
according to the Raymond Scale as assessed by the 
Independent Core Laboratory.   
 
Complete aneurysm occlusion is defined as an aneurysm in which a 
score of 1 (complete obliteration) is achieved on the Raymond Scale at 
the relevant post-procedure angiogram, without additional procedures 
for treatment of the aneurysm since the index procedure. Subjects who 
are retreated (retreatment includes staged procedures) prior to the 12 
month post-procedure follow-up visit will be considered not to have 
achieved complete aneurysm occlusion for the purpose of the primary 
endpoint analysis.   
 
The primary endpoint analysis will be to demonstrate that the RCAO is 
significantly greater than a performance goal (PG) of 35%.  The primary 
endpoint null and alternative hypotheses are: 
Null hypothesis Ho: RCAO ≤ 35%  
Alternative hypothesis HA: RCAO > 35% 
This analysis will be conducted on the modified intent-to-treat (MITT) 
population of subjects (subjects who are found to be eligible for 
treatment with ENTEPRISE at the time of the pre-procedure 
angiographic assessment, and in whom treatment is attempted).  A 
supportive analysis will be conducted on the PP population. 
 
Note:  The study will be deemed to be a success if this primary efficacy 
endpoint null hypothesis (on the MITT population with data from all sites 
combined) is rejected in favor of the alternative hypothesis.   
 
3.2.2 Primary Safety Endpoints 
 
There are two primary safety endpoints: the of rate of Major Ipsilateral 
Stroke and/or Death at 12 months post-procedure and In-stent Stenosis 
at 12 months post-procedure.   
 
The analyses of these safety endpoints will be conducted on the MITT 
population. Supportive analyses will be conducted on the PP population. 
 
 
3.2.2.1 Incidence of Major Ipsilateral Stroke and/or Death 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 38 of 121 
The incidence of a major ipsilateral stroke and/or death will be evaluated 
from the start of the index procedure until completion of the 12 month 
follow-up. A major ipsilateral stroke is defined as a new neurological 
event which is ipsilateral and in the vascular distribution territory of the 
stenting procedure and that results in an increase of ≥ 4 on the National 
Institute of Health Stroke Scale (NIHSS) as compared to baseline and 
persists for greater than 24 hours.  
 
For a successful evaluation of this endpoint, the upper confidence limit 
of a 2-sided 95% confidence interval for the proportion of subjects who 
experience major ipsilateral stroke and/or death through 12 months 
post-procedure will be less than 25%. 
 
3.2.2.2 Incidence of In-Stent Stenosis 
 
The percentage of aneurysms in which in-stent stenosis is assessed 
angiographically, at or prior to 12 months post-procedure will be 
evaluated.  In-stent stenosis is defined as greater than 50% narrowing 
of the vessel within the ENTERPRISE stent or within 10 mm of either 
end of the stent (i.e., in-stent stenosis). 
 
For a successful evaluation of this endpoint, the upper confidence limit 
of a 2-sided 95% confidence interval for the rate of stenosis at or prior 
to 12 months post-procedure will be less than 15%. 
 
3.2.3 Secondary Effectiveness Endpoints 
The following secondary effectiveness endpoints have been defined.  
Observed rates will be described for both the MITT and PP populations; 
All angiographic imaging results will be based upon assessments by the 
independent Core Laboratory.  A subject who is retreated (retreatment 
includes staged procedures) is considered to be a treatment failure for 
endpoints based on angiographic imaging. 
 
3.2.3.1 Procedure Success Rate 
The procedure success rate is defined to be the percentage of 
aneurysms in which coil mass position is maintained within the sac with 
parent artery patency, without additional procedures for treatment of the 
aneurysm since the index procedure. The procedure success rate will 
be summarized immediately post-treatment (acute), and at the 6 and 12 
month follow-up assessments.   
 
3.2.3.2 Complete Aneurysm Occlusion as per the Raymond Scale 
The percentage of aneurysms in which a score of 1 (complete 
obliteration) is achieved on the Raymond Scale immediately post-
procedure (acute) and at the 6 and 12 month follow-up 
angiographic assessments, respectively, will be evaluated.  

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 39 of 121 
 
3.2.3.3 Complete/Partial Aneurysm Occlusion as per the Raymond 
Scale 
The percentage of aneurysms in which a score of 1 (complete 
obliteration) or 2 (residual neck) is achieved on the Raymond 
Scale immediately post-procedure (acute), and at the 6, and 12 
month follow-up angiographic assessments will be evaluated.   
 
3.2.3.4 Percent Aneurysm Occlusion 
The percentage of aneurysms with occlusion of 100%, 90%-
99%, 70-89%, 50-69%, 25-49%, or <25% occlusion in 
accordance with Consensus Grades 0-5, respectively, will be 
summarized immediately post-procedure (acute), and at the 6 
and 12 month follow-up, respectively.   
 
3.2.3.5 Recanalization Rate 
The percentage of aneurysms in which recanalization is 
documented at any time up to and including the 12 month follow-
up visit, will be evaluated.  Recanalization will be defined as an 
increase in aneurysm filling as compared to the previous study-
specified angiographic assessment, resulting in a change in (i.e., 
worsening of) the Raymond classification.  Changes in Raymond 
Scale will be classified as stable, improved, or recanalized based 
on the follow-up angiograms. Percentages of aneurysms falling 
into each of the categories will be presented.   
 
3.2.3.6 Retreatment Rate 
The percentage of target aneurysms that are retreated at any 
time up to and including the 12 month follow-up visit will be 
evaluated. Retreatment will be defined as any additional 
treatment of the target aneurysm after the index procedure 
(retreatment includes staged procedures), or an additional 
procedure (regardless of whether retreatment is by surgery or 
endovascular treatment) due to recanalization, rupture or 
bleeding.  
 
3.2.4   Secondary Safety Endpoints 
 
The evaluation of the rate of new neurological deficits (increase in mRS 
> 2 from baseline not related to stroke or death) at 12 months will be a 
pre-specified, powered analysis.  All other secondary endpoints will be 
presented as a group to better characterize the ENTERPRISE stenting 
procedure. 
 
Unless otherwise stated, these secondary safety analyses will be 
conducted on the MITT population.   
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 40 of 121 
3.2.4.1 Rate of New Neurological Deficits as per the Modified 
Rankin Scale (mRS) 
Observed scores on the Modified Rankin Scale will be presented 
at baseline (pre-procedure) and follow-up (30 days, 6 and 12 
months post-procedure).  The number and percentage of 
subjects who have an increase in mRS > 2 from baseline not 
related to stroke or death will also be presented for each follow-
up time point.   
 
3.2.4.2 NIH Stroke Scale (NIHSS) Total Score 
The NIHSS Total Score evaluations will be summarized at 
baseline (pre-procedure) and follow-up (6 and 12 months post-
procedure); change from baseline at 6 and 12 months will also 
be summarized.  The percentage of subjects who show a 
worsening from baseline (increase of 4 points or more) will also 
be presented.  Observed scores and change from baseline will 
also be presented for NIHSS excluding scores on the aphasia 
subscale.   
 
3.2.4.3 Adverse Events and Clinical Complications 
 
Adverse Events (AEs), including complications associated with 
an untoward medical occurrence, from the start of the index 
procedure until completion of the 12 month follow-up will be 
coded using the MedDRA system and summarized with 
frequencies. Serious adverse events (SAEs), device- or 
procedure-related AEs, unanticipated adverse device effects 
(UADEs) and deaths will be presented.    
 
AEs will be presented for the following study periods: 1) peri-
procedure – i.e., from the start of the procedure until 24 hours 
post-procedure; and, 2) through 12 month follow-up – i.e., from 
24 hours post-procedure through the 12 month visit or premature 
termination. 
 
3.2.4.4 Reduced TICI Flow 
The percentage of target aneurysms in which a new occurrence 
of unintentional and persistent reduced TICI flow (TICI score of 
0 or 1) is observed at the target vessel during the index 
procedure as a result of a mechanical obstruction such as 
dissection or luminal thrombus will be evaluated. 
 
3.2.4.5 Bleeding Complications 
The number and percentage of subjects who experience a 
procedure-related hemorrhagic event which requires any of the 
following will be evaluated:  blood transfusion, surgical 
intervention, a new hospitalization, or lengthening of hospital 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 41 of 121 
stay.  The complications of hematoma requiring treatment (i.e., 
a hematoma > 5 cm in diameter occurring at the access site) and 
retroperitoneal bleeding will be reported as hemorrhagic events. 
 
3.2.4.6 In-stent Stenosis (Acute, and 6 Months)  
The percentage of aneurysms in which in-stent stenosis is 
documented immediately post-procedure (acute), and up to and 
including 6 months post-procedure, will be evaluated.   
Acute in-stent stenosis will be further characterized by whether 
it results from vasospasm, and whether or not the vasospasm 
was responsive to medication. 
 
3.2.4.7 Thrombosis  
The percentage of aneurysms in which thrombosis is 
documented up to and including 6 and 12 months post-
procedure will be evaluated.  Thrombosis is defined as in-stent 
thrombosis.   
 
3.2.5   Ancillary Endpoint 
3.2.5.1 Stent Movement/Migration  
Incidence of stent movement and/or migration from the start of the 
index procedure until completion of the 12 month follow-up 
 
3.2.6  Safety Follow-up through 24 months post-procedure  
Subjects who experience any of the following AEs of Special Interest 
and who have an MRS > 2 at any clinical evaluation will be followed 
through 24 months post-procedure, and their outcomes will be 
summarized in a supplemental safety follow-up report:  
 All adverse events 
 Rupture of the index aneurysm beyond 24 hours post-
treatment 
 Major ipsilateral stroke more than 1 month post-treatment  
 Ipsilateral parenchymal hemorrhage more than 1 month 
post-treatment  
 
 
4.0 ELIGIBILITY OF SUBJECTS, EXCLUSIONS AND REMOVAL OF SUBJECTS  
 
Subjects eligible for initial study screening are subjects who present with unruptured 
wide-neck, intracranial, saccular anterior circulation aneurysms and who are judged 
to be candidates for stenting.  Every effort will be made to establish eligibility of the 
participants prior to enrollment. 
 
Subjects who agree to voluntarily sign a study informed consent will be considered 
“enrolled” in the study, and will comprise the subject populations for this study.  

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 42 of 121 
Enrolled subjects who meet all of the general inclusion criteria and none of the 
general exclusion criteria described in this protocol will proceed with confirmation of 
angiographic inclusion/exclusion criteria.  
 
Pre-treatment angiography performed during the index procedure will be utilized for 
final assessment of angiographic eligibility criteria. Subjects, who meet all of the 
general and angiographic inclusion/exclusion criteria, including the requirement for 
only one aneurysm to be treated, may be treated with ENTERPRISE. Subjects will 
be “entered” in the study (if the intent is to proceed with stent deployment) at the time 
of the start of the index procedure as defined in this protocol (see definitions).   All 
subjects entered will be evaluated, regardless of sequence of treatment that ensues.  
 
Subjects who are enrolled but not entered due to angiographic ineligibility resulting 
from either a pre-procedure angiogram or a pre-treatment angiogram will be 
considered an Angiographic Screening Failure (ASF) and will be followed for the 
period 72 hours following the end of the angiogram, or until discharge, whichever 
comes first, or to resolution of any adverse event, whichever is longer, and then will 
be discontinued from the study. 
 
All subjects “entered” in the study are considered follow-up eligible and will be 
required to adhere to the follow-up schedule outlined in this protocol. Subjects who 
withdrew consent after treatment will be followed until the time of their withdrawal.   
Subjects who receive a retreatment of the study aneurysm will be followed for safety 
until the completion of their 24 month follow-up or premature study termination.  
These aneurysms will not be assessed for effectiveness beyond the retreatment. 
 
Subjects who were determined by the investigator to meet the angiographic eligibility 
criteria, and received treatment with ENTERPRISE, but upon core lab review do not 
meet these criteria will be included in the effectiveness analysis in the Modified Intent-
to-Treat population.  However, the subject will be excluded from the Per Protocol 
population.   
 
4.1 Criteria for Eligibility 
 
4.1.1 General Inclusion Criteria 
 
Prior to entry in this study, candidates must meet ALL of the following 
criteria: 
 
1. Subject is 21 to 70 years, inclusive. 
 
2. Subject whose target aneurysm is an unruptured wide-neck, 
intracranial, saccular anterior circulation aneurysm (≤ 10 mm) 
arising from a parent vessel with a diameter of ≥ 2.5 mm and ≤ 4 
mm who is referred for endovascular treatment.  Wide-necked is 
defined as width ≥ 4 mm or a dome-to-neck ratio < 2. 
i. For aneurysms < 5mm, subject must have another factor 
that increases the risk of rupture, specifically: 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 43 of 121 
1. Aneurysm is irregular in shape (e.g. multi—
lobulated/with daughter sac) 
2. Interval increase in aneurysm size 
3. Subject with history of subarachnoid hemorrhage 
(non-target aneurysm) 
4. Subject with 2 first degree relatives with history of 
aneurysmal SAH 
 
3. Subject whose target aneurysm is located in the anterior circulation. 
 
4. Subject understands the nature of the procedure and provides 
voluntary written informed consent prior to the treatment.  
 
5. Subject is willing to comply with specified follow-up evaluation and 
is willing to return to the investigational site for the thirty day, 6 
month and 12 month, 18 month and 24 month follow-up evaluations. 
 
4.1.2 General Exclusion Criteria 
 
Candidates must be excluded from this study if ANY of the following 
criteria are met: 
 
1. A planned staged procedure (a staged procedure is a procedure 
where entire treatment with the device (e.g., coils/stents) is 
completed over separate sessions). 
 
2. Currently enrolled in another investigational device or drug study 
that has not reached the primary endpoint or that clinically interferes 
with the current study endpoints. 
  
3. Two or more aneurysms (> 2 mm) in associated distribution. 
 
4. More than 2 aneurysms (> 2 mm) total, previously treated or 
untreated.  
 
5. Target aneurysm that has been previously treated  
 
6. A non-target intracranial aneurysm expected to require treatment 
during the 12 month follow-up period. 
 
7. A previous neuro-interventional or neuro-surgical procedure of any 
kind within 30 days prior to the study procedure. 
  
8. A ruptured aneurysm. 
 
9. Mycotic, fusiform or dissecting aneurysm. 
 
10. Arteriovenous malformation (AVM) in the territory of the target 
aneurysm. 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 44 of 121 
 
11. A Barthel Index < 80 from baseline condition not secondary to index 
aneurysm. 
 
12. An intracranial mass (tumor, abscess, or other infection). 
 
13. Dementia.  
 
14. Admission platelet <50,000 or any known hemorrhagic diathesis, 
coagulation deficiency, or on oral anticoagulant therapy with an INR 
>3.0 
 
15. A serum creatinine level > 2.5 mg/dL within 14 days prior to index 
procedure which the investigator determines restricts the use of 
contrast agents. 
 
16. Known hypersensitivity/allergies or contraindication to aspirin,  
bivalirudin, clopidogrel or ticlopidine, cobalt, nitinol metal, nickel, or 
sensitivity to contrast media, which cannot be adequately pre-
medicated or subject unable/unwilling to undergo therapy. 
 
17. Cannot receive heparin during the study procedure. 
 
18. A previously implanted intracranial stent associated with the 
symptomatic distribution within the past 12 weeks. 
 
19. A previously implanted carotid stent associated with the 
symptomatic distribution within the past 12 weeks. 
 
20. Evidence of an acute myocardial infarction (MI) within 31 days of 
the intended study procedure. 
 
21. Currently has uncontrolled atrial fibrillation or known cardiac 
disorders likely to be associated with cardioembolic symptoms. 
 
22. Females who are currently pregnant or intend to become pregnant 
during the study. 
 
23. Patients with ongoing treatment of cancer or any patient who does 
not have a 5 year life expectancy from congestive heart failure, renal 
failure or other significant medical problems.  
 
24. A history of stroke, cerebrovascular accident or transient ischemic 
attack in the last 6 months. 
 
25. Active peptic ulcer or active gastrointestinal (GI) bleeding. 
 
26. Otherwise determined by the investigator to be medically unsuitable 
for participation in this study.  

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 45 of 121 
 
27. A prisoner. 
 
28. Evidence of active infection (WBC >10x109 /L) 
 
29. Target aneurysm is an extradural aneurysm(s) 
 
30. Current substance-abuse /illicit drug use 
 
4.1.3 Angiographic Inclusion Criteria 
 
Candidates must meet ALL of the following criteria: 
 
1. An unruptured wide-neck, intracranial, saccular anterior circulation 
aneurysm  
(target aneurysm)  
 
2. Aneurysm size is ≤ 10 mm. 
i.  For aneurysms < 5mm, subject must have another factor 
that increases the risk of rupture, specifically: 
1. Aneurysm is irregular in shape (e.g. multi—
lobulated/with daughter sac) 
2. Interval increase in aneurysm size 
3. Subject with history of subarachnoid hemorrhage 
(non-target aneurysm) 
4. Subject with 2 first degree relatives with history of 
aneurysmal SAH 
 
3. Target aneurysm for the study treatment arises from a parent vessel 
with a diameter of ≥ 2.5 mm and ≤ 4 mm. 
 
4. A wide-necked aneurysm. Wide-necked is defined as width ≥ 4 
mm or a dome-to-neck ratio < 2. 
 
4.1.4 Angiographic Exclusion Criteria  
 
Candidates must be excluded if ANY of the following criteria are met: 
 
1. Angiogram demonstrates that the target aneurysm is not 
appropriate for endovascular treatment (i.e.: severe intracranial 
vessel tortuosity or stenosis, intracranial vasospasm not responsive 
to medical therapy). 
 
2. Aneurysm is expected to require more than one stent. 
 
 
3. Aneurysm will or may be treated with a Hydrocoil(s) (the use of all 
other polymer coils is not an exclusion criteria). 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 46 of 121 
 
4.2 Early Withdrawal of Subjects  
 
4.2.1 Withdrawal Criteria 
 
A subject can stop his or her participation by withdrawing his/her 
consent or when he/she is no longer able to participate in the study. 
Withdrawing consent will not result in any penalty whatsoever for the 
subject. Further treatment will be performed according to local practice. 
In case of a device-related or procedural-related adverse event that 
occurred as a result of participating in this study, the subject will be 
treated according to local practice.  
 
The data of the subject who withdraws his/her informed consent will not 
be discarded, and will be used in the final analysis of the study, unless 
the subject specifically requests that the data not be used.  
 
If a subject decides to withdraw from the study, he/she may do so at 
any time.  However, the reason for discontinuation must be recorded in 
the source documentation and on the CRF.  Possible reasons for 
premature discontinuation may include, but are not limited to, the 
following: 
 
• Subject decides to withdraw from the study 
• Investigator decides to withdraw subject from the study 
• Lost to follow-up:  after three attempts to reach the subject by 
telephone have failed, a certified letter will be sent to the subject. 
The subject will be considered lost to follow-up if this communication 
is unsuccessful. 
 
 
5 STUDY DEVICE 
 
5.1 ENTERPRISE Investigational (Study) Device Description 
 
5.1.1 CODMAN ENTERPRISE® Vascular Reconstruction Device 
 
The CODMAN ENTERPRISE® Vascular Reconstruction Device and Delivery 
System (may be referred to as ENTERPRISE) is comprised of a self- 
expandable stent pre-loaded in a delivery system.  The delivery system is 
composed of an introducer and a delivery wire.  The self-expanding stent is 
pre-loaded on the delivery system inside the introducer.  
The CODMAN ENTERPRISE Vascular Reconstruction Device and Delivery 
System is available in 2 versions. A first version with a 12 mm radio opaque 
tip at the distal part of the delivey wire, and a second version without the12 
mm radio opaque tip at the distal part of the delivery wire (referred as “no-
tip”).   
 
Stent: 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 47 of 121 
 
The stent is the implantable segment of the system.  It has a tubular mesh 
structure, which is laser-cut from a Nickel Titanium (NiTi) hypotube.  The 
proximal and distal ends of the stent are flared and are designed to enhance 
apposition of the implanted stent to the wall of the vessel. Once exposed to 
body temperature and upon release from the microcatheter constraint into 
vessels with smaller diameters than that of the stent, it expands to the vessel 
lumen diameter.  In its expanded shape, the stent creates a proprietary, 
highly flexible, closed-cell structure that provides support for coils inside the 
aneurysm.  The stent’s pattern provides the flexibility necessary to navigate 
the tortuous neurovasculature as well as sufficient radial strength and 
adequate cell size to provide reliable embolic coil support.  Refer to Figure 
1. 
 
The stent has radiopaque markers on 4 struts at either end of the device.  
This allows the physician to visualize the device in vivo under fluoroscopy.  
The markers are mechanically attached to the struts and covered with an 
adhesive.  The adhesive enhances the marker-strut bond and creates a 
smooth, continuous surface.  The stent and markers are covered with an 
insulating polymer.   
 
                                 
Figure 1: Expanded Stent 
 
              
 
 
Refer to Table 2 for a list of stent sizes. 
 
 
Table 2: CODMAN ENTERPRISE Stent Sizes and Parent Vessel Diameter   
 
Unconstrained 
Target Expanded 
Stent Diameter 
(mm) 
Unconstrained 
Target Stent 
Length (mm) 
Lumen Diameter 
of Vessel Treated 
(mm) 
4.5 
14 
2.5 – 4 
4.5 
22 
2.5  - 4 
4.5 
28 
2.5  - 4 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 48 of 121 
4.5 
37 
2.5  - 4 
 
 
Delivery System: 
 
As previously stated, the delivery system of the CODMAN ENTERPRISE 
Vascular Reconstruction Device and Delivery System is comprised of an 
introducer and a delivery wire. The CODMAN ENTERPRISE Vascular 
Reconstruction Device and Delivery System is available in 2 versions. A first 
version with a 12mm radio opaque tip at the distal part of the delivery wire, 
and a second version without the12mm radio opaque tip at the distal part of 
the delivery wire (referred as “no-tip”).   
 
The No distal tip delivery wire configuration has the same materials as the 
Enterprise with the 12mm distal tip delivery wire configuration. Refer to 
Figure 2. 
 
Introducer: 
 
The introducer consists of a polymeric tube (PTFE) .021″ inner diameter, 
with a tapered distal end.  Its inner diameter matches that of the 
microcatheter and the taper angle and diameter match corresponding 
parameters of the microcatheter hub.  The introducer is designed to protect 
the stent from damage and, when properly positioned in the microcatheter 
hub, creates an uninterrupted passage for the stent during its transition from 
the introducer into the microcatheter.  
 
Delivery Wire: 
 
The delivery wire (DW) is made of a Nitinol corewire that tapers down from 
the proximal to the distal end. The tapering of the corewire provides different 
stiffness zones along its length, stiffest at the proximal end and most flexible 
at the distal tip in order to facilitate navigation into the distal 
neurovasculature.   
 
For the Enterprise with the 12 mm distal tip delivery wire configuration, the 
distal section of the delivery wire has three radiopaque zones. They are 
created by platinum/tungsten coils soldered (95% Sn / 5% Ag solder alloy) 
to the corewire.  Each of the three radiopaque zones is of a specific length 
with gaps between them designed to serve different functions.  These 
radiopaque zones are referred to as the proximal marker, stent positioning 
marker and the distal marker of the delivery wire.  A stent retraction bump is 
located between the proximal marker and the stent positioning marker. 
Grinding the Nitinol corewire to a larger diameter than the adjacent corewire 
creates the stent retraction bump.  The space between the proximal stent 
marker of the delivery wire and the stent retraction bump is referred to as the 
stent marker engagement gap. The proximal stent markers rest within this 
gap, which engages the stent with the delivery wire as long as the stent is 
compressed within the lumen of the introducer or microcatheter.  The gap 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 49 of 121 
between the distal and stent positioning markers of the delivery wire is 
referred to as the resting gap. The distal stent markers reside over the resting 
gap of the delivery wire.  
 
The Enterprise “No-Tip” delivery wire configuration has the same materials 
as the Enterprise, but without the 12mm distal tip on the delivery wire.   
 
 
                                                    Note: Items are not drawn to scale. 
 
Figure 2:  CODMAN ENTERPRISE Vascular Reconstruction Device and 
Delivery System 
 
A: 
Introducer 
B: 
Proximal delivery wire 
C: 
Proximal marker of delivery wire 
D: 
Stent marker engagement gap 
E: 
Proximal stent markers 
F: 
Stent retraction bump 
G: 
Stent positioning marker of delivery wire 
H: 
Recapture limit point 
I: 
Stent body 
J: 
Distal stent markers 
K: 
Resting gap 
L:  
Distal marker of delivery wire (Not applicable for the Enterprise No-Tip 
configuration) 
 
 
The Enterprise stent is also available in a No Distal Tip configuration (Figure 
3).  This configuration eliminates the 12mm tip segment which will allow 
physicians to place stents in vasculature where additional distal stability is 
not required or desired (e.g., severe distal tortuosity, small distal diameter 
tapering vessels of the presence of perforator vessels that may be impacted 
by the distal coil.  
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 50 of 121 
 
 
 
 
Figure 3:  Enterprise Stent With Distal Tip and Without Distal Tip 
 
 
Principles of Operations: 
 
As described above, the proximal stent markers are engaged in the delivery 
wire stent marker engagement gap between the proximal markers of the 
delivery wire and the stent retraction bump and rest within the constraint of the 
microcatheter lumen.  Within the constraint of the microcatheter lumen, this 
mechanical interlocking of the stent marker engagement gap, located between 
the proximal marker and the stent retraction bump, gives the physician the 
ability to deploy, retract, and reposition the stent.  During deployment, the 
distal end of the delivery wire proximal marker pushes the proximal end of the 
stent markers.  During retraction, the proximal end of the delivery wire stent 
retraction bump pulls against the distal end of the proximal stent markers. 
 
The stent is advanced through the microcatheter to the intended location.  The 
delivery wire’s stent positioning marker is positioned in the desired location 
across the neck of the aneurysm.  Once accurate placement is confirmed, the 
microcatheter is slowly retracted while the delivery wire is held in place.  As 
the stent exits the tip of the microcatheter, it expands and takes the shape of 
the vasculature.  The stent may be re-sheathed until the position at which the 
recapture limit point is aligned with the distal end of the distal microcatheter 
marker band.  Once the proximal markers of the stent exit the tip of the 
microcatheter, the stent is fully deployed into the vessel. 
 
 
 
5.1.2 CODMAN ENTERPRISE® 2 Vascular Reconstruction Device 
 
The 
modifications 
to 
the 
CODMAN 
ENTERPRISE 
Vascular 
Reconstruction Device are described below. Table 3 provides 
additional information on the similarities and differences between the 
two devices. 
 
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 51 of 121 
All changes are applicable to the CODMAN ENTERPRISE  2 Vascular 
Reconstruction Device only and do not impact the current Codman 
Enterprise Vascular Reconstruction Device and Delivery System. 
 
Design Changes 
 
• The outer diameter (OD) of the stent (unconstrained) was expanded from 
4.5 mm to 5 mm to improve stent wall apposition; 
 
• The tantalum Coil Marker was replaced by a platinum 92%-tungsten 8% 
(PtW8) alloy marker band to improve stent marker radiopacity; 
 
• The marker retention feature on the stent crowns was modified to 
accommodate the new marker bands; 
 
• The nominal engagement gap diameter of the delivery wire assembly was 
increased minimally to increase the robustness of the delivery wire; 
 
• The minimum engagement gap length of the delivery wire assembly was  
increased minimally to accommodate new marker retention feature; 
 
• The corewire engagement gap length was increased minimally and a 
change was made to ensure a flatter joint surface on the distal end of the 
proximal coil distal joint, improving stent insertion; 
 
• Flushing holes were added to the Introducer to facilitate ease of use. 
 
Table 3: Similarities and differences between Enterprise and the Enterprise 2 
 
 
Component 
ENTERPRISE 
VRD 
ENTERPRISE 2 VRD 
Design Modifications 
ENTERPRISE 2 VRD 
Process Modifications 
Stent Assembly 
Stent 
50.8% Nickel / 
49.2% Titanium 
(Nitinol) 
No change 
• Use of a new cutting laser 
• Low oxide tubing with a new 
mechanical polishing step 
• Addition of an etching 
solution 
• Modification to the 
electropolishing solution 
and parameters. 
• Modification in heat 
treatment steps. 
• Passivation step and a new 
constraining fixture added. 
Radiopaque 
Stent Markers 
Tantalum  R05400 
92% Platinum, 8% Tungsten 
Changed from wound coils to 
solid marker bands 
UV Curable 
Adhesive (for 
Stent Marker 
attachment) 
Dymax Adhesive 
1128A-M-VT 
No change 
Added crimping process for 
marker bands 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 52 of 121 
 
Component 
ENTERPRISE 
VRD 
ENTERPRISE 2 VRD 
Design Modifications 
ENTERPRISE 2 VRD 
Process Modifications 
Stent Coating 
 
Parylene-C 
 
No change 
 
None 
 
Delivery Wire Assembly 
Corewire 
50.8%Nickel / 
49.2% Titanium 
(Nitinol) 
No change 
See below for Delivery Wire 
dimensional modifications: 
Corewire 
Engagement 
gap length 
0.058 + 0.007 / - 
0.003 
0.068 + 0.007/-  
0.003 
No change, same grinding 
process 
Corewire 
Engagement 
Gap (EG) OD 
Increase 
0.0033 +/- 0.0003 
0.0036 +/- 0.0003 
No change, same grinding 
process 
Constant 
ground section 
between EG 
and distal coil 
marker 
0.0033 +/- 0.0003 
(1)1 
0.0032 +.0007 / -
.0002 (2)2 
0.00345 +/- 0.00045 
No change, same grinding 
process 
Corewire 
Surface finish 
No Requirement 
Requirement 
No process change; inspection 
added to monitor surface finish 
Distal Marker 
(coil) 
92% Platinum / 
8% Tungsten 
No change 
No change 
Stent 
Positioning 
Marker (coil) 
92% Platinum / 
8% Tungsten 
No change 
No change 
Proximal 
Marker (coil) 
92% Platinum / 
8% Tungsten 
No change 
No change 
Solder/Flux 
(for Delivery 
Wire Marker 
attachment) 
Solder: EutecRod 
157 (95% Sn, 5% 
Ag, Cadmium 
free) 
Flux: Indalloy flux 
#2 
No change 
Removed buffing of the 
proximal coil distal join 
Delivery Wire 
Engagement 
Gap Length 
0.045” Min 
0.050” Min 
Placement of proximal delivery 
wire marker 
 
Delivery Wire –
Solder Station 
and Ultrasonic 
Bath 
Operations 
performed in 
Clean Room 
Building 340 
Operations to be performed 
in Clean Room in Building 
304 with other 
ENTERPRISE 
manufacturing 
A duplicate solder station and 
ultrasonic bath were 
purchased and qualified in 
order to move these 
operations from Building 340 
to the clean room located in 
Building 304 within the same 
LRM facility, thus consolidating 
all ENTERPRISE 2 operations 
into Building 304. 
Introducer 
Introducer 
Natural PTFE 
Same material but with the 
addition of flushing holes 
The taper and punch hole 
operations are performed by a 
new vendor. 
Final 
Assay 
Final Inspection 
Fixture constrains 
introducer only 
Fixture constrains introducer 
and delivery wire 
simultaneously 
Final inspection fixture 
changed; inspection process 
did not change 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 53 of 121 
 
Component 
ENTERPRISE 
VRD 
ENTERPRISE 2 VRD 
Design Modifications 
ENTERPRISE 2 VRD 
Process Modifications 
Stent  
Design 
Closed cell, 
flared ends, 4-
cell design 
 
Closed cell, flared 
ends, 4-cell 
design, 4.5mm 
unconstrained 
Closed cell, flared ends, 4-
cell design, 5.0mm 
unconstrained; dogbone 
features to accommodate 
new markers 
 
See item 1 
Packaging 
Hoop 
HDPE 
No change 
No change 
Cavity Clips 
60% HDPE / 
40% LDPE 
No change 
No change 
Wire Retention   
Clip 
TPV 8271-75 
No change 
No change 
Pouch 
Perfecseal 35721-
K Nylon to Du 
Pont 1073B Tyvek 
coated  with 
BB2000 
No change 
No change 
Carton 
Paperboard 
Same material as current, 
modified graphics 
No change 
 
 
Table 4: CODMAN ENTERPRISE  2 Stent Sizes and Parent Vessel Diameter   
 
Unconstrained 
Target Expanded 
Stent Diameter 
(mm) 
Unconstrained 
Target Stent 
Length (mm) 
Lumen Diameter 
of Vessel Treated 
(mm) 
5.0 
16 
2.5 – 4 
5.0 
23 
2.5  - 4 
5.0 
30 
2.5  - 4 
5.0 
39 
2.5  - 4 
 
 
 
5.2 ENTERPRISE Instructions for Use (IFU) 
 
5.2.1 ENTERPRISE General Use and Study Protocol  
 
The CODMAN ENTERPRISE® Vascular Reconstruction Device and 
Delivery System is currently approved under a Humanitarian Device 
Exemption as a Humanitarian Use Device in the United States.  Only 
ENTERPRISE devices that are specifically packaged and labeled for 
this clinical study are allowed to be used to treat subjects entered under 
this study protocol. There is no change to the instructions for use as 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 54 of 121 
a result of the modifications to the CODMAN ENTERPRISE Vascular 
Reconstruction Device. 
 
 
[NOTE: Per the protocol, subjects are only expected to have one 
ENTERPRISE stent implanted, however, if it becomes necessary 
to place an additional stent(s) during the Index Procedure:  
 
• ENTERPRISE IDE stent should be used if placed in the 
target aneurysm 
• ENTERPRISE HDE stent should be used if placed in a non-
target aneurysm]   
 
The investigator should follow the study specific Instructions for Use 
(IFU) that is packaged with the ENTERPRISE study device for general 
information, and follow the inclusion/exclusion criteria and procedures 
as outlined in this study protocol. 
 
5.3 ENTERPRISE Packaging  
  
The ENTERPRISE Device is protected by the dispenser hoop and extension 
tube. The loaded dispenser hoop is packaged in the primary and the 
secondary packaging components, comprised of the Nylon/Tyvek® pouch 
and the carton respectively. The carton will be a solid white carton sealed 
with the closure label.   The white carton is used to distinguish the clinical 
trial units it from the bronze carton of the current product.    
 
The No-Tip configuration packaging will employ red pigmented dispenser 
clips and a Tyvek tag to help the user identify the product. The Tyvek tag is 
attached to the dispenser hoop with one of the red clips and has a printed 
image of the No-Tip design, as well as the words “No Distal Tip” on a red 
background.  
 
Product labeling includes inner and outer product information labels.  
Temperature monitoring labels are used to indicate exposure of the product 
to temperatures exceeding 60°C. Prior to introducing the CODMAN 
ENTERPRISE Stent into the sterile field, observe the temperature exposure 
indicator label found on the product’s inner pouch. The acceptance criterion 
for the product is delineated by the graphic below the indicator label with the 
green check mark. The reject criterion for the label is delineated by the 
graphics marked with a red “X”. Do not use if the temperature exposure 
indicator mirrors the reject criterion graphics, as the constrained stent 
diameter may have been compromised by exposure to high temperature. 
The inner pouch and unit carton will also include an Investigational Device 
Sticker to identify it as clinical trial inventory.   
. 
 
5.4 ENTERPRISE Receiving, Storage, Dispensing and Return 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 55 of 121 
5.4.1 Receipt and Accountability of Study Device  
 
The investigator is responsible for device accountability at the study 
site. 
 
The investigator may assign some of the investigator’s duties for device 
accountability at the study site to an appropriate staff member.  This 
staff member must be listed on the Study Personnel Authorization 
Form. 
 
The investigator should maintain a record that documents receipt of 
study device at the study site, the inventory at the site, administration 
to each subject, and return to the Sponsor and submit the required 
forms to the study monitor. These records include dates, quantities, lot 
numbers, expiration dates, and the unique code numbers assigned to 
the investigational device and study subjects. Study devices must be 
recorded on the Investigational Device Disposition Log.  For any 
investigational devices destroyed at the site, the date, mode and 
method of destruction along with the name of the person destroying the 
device must be recorded.  
 
5.4.2  Storage of Study Device  
 
All study devices must be stored in a locked storage facility to which 
only the investigator, or designated assistants, will have access. 
 
 
5.4.3 Dispensing of Study Device   
 
The investigator agrees not to supply the investigational device(s) to 
any person except those named as sub-investigators on the study 
personnel authorization form. The investigator must ensure that the 
investigational devices are used only in accordance with the IFU and 
study protocol. 
 
5.4.4 Return or Destruction of Study Device  
 
Unused investigational devices being reclaimed for excess inventory, 
following study completion or due to product expiration, damage, or 
defect should be returned to Sponsor or designee.   
 
For unopened sterile device/product being returned for excess 
inventory, study completion and product expiration, the investigator 
must complete the Sterile Returned Clinical Device Form.  The 
investigator must notify the Sponsor or designee prior to shipment and 
return the device to the address printed on the Sterile Returned Clinical 
Device Form. 
 
For device malfunctions and product complaints, the device should be 
kept at the site until the Sponsor provides instructions for return of the 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 56 of 121 
device to the analysis lab.  Non-sterile devices will be returned to Crum 
Glenn (CG) Laboratories, 1410 Southtown Drive, Granbury, TX 76048. 
The investigator must notify the Sponsor or designee of device 
malfunction and product complaints with 10 business days of 
knowledge.  
 
 
6 STUDY PROCEDURES 
 
6.1 Screening/Baseline 
  
6.1.1 Screening and Enrollment Procedures  
 
Investigators will be encouraged to screen consecutive subjects who, 
in the Investigator’s judgment are candidates for stenting, as they 
present for treatment of wide-necked aneurysms, thus decreasing the 
risk of selection bias in this study. All subjects who are screened for the 
study will be entered on a screening eCRF.  Subjects who are screened 
will be assigned an identification number (see Section 6.1.2, Subject  
Identification).  The screening eCRF will include age, gender, race and 
ethnicity.  If the subject is not enrolled (the subject is enrolled in the 
study at the time they sign the study informed consent), the reason will 
be recorded on the screening eCRF.  
 
Subjects who meet all of the general inclusion criteria and none of the 
general exclusion criteria described in this protocol will be asked to 
participate in the study.  If the subject declines to participate, or if the 
investigator decides that the subject will not be asked to participate, 
then the reason must be documented on the study screening eCRF.   
 
The benefits and risks of the study will be explained and voluntary 
written informed consent must be obtained from all subjects. The study 
informed consent should be signed as close to the index procedure as 
possible, but must be signed prior to any study-specific tests or 
procedures that are not routine standard of care. Pre-treatment 
angiography will be performed at the start of the index procedure for 
the final determination of anatomic and angiographic eligibility. The 
subject is enrolled in the study at the time they sign the study informed 
consent.  The initial angiogram used to assess angiographic eligibility 
may or may not be at the same time as the index procedure. A pre-
procedure angiography may be performed up to 90 days prior to the 
index procedure (The pre-procedure angiographic inclusion/exclusion 
criteria can be taken from either a CTA angiogram or an angiogram).  
 
If the subject signed the study informed consent, but meets any of the 
angiographic exclusion criteria as the screening procedure progresses, 
the subject is considered an angiographic screening failure (ASF) and 
may not continue in the study.  For ASF subjects, the signed informed 
consent must be filed and all eCRF up to and including the 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 57 of 121 
Investigator’s angiographic assessment must be completed and 
entered in the database along with the reason why the subject was not 
eligible to participate in the study.  Any AEs that occurred from the time 
written consent was obtained through the period 72 hours following the 
end of the angiogram or until discharge, whichever comes first, must 
be documented.  If any adverse event has not resolved by the 72-hour 
safety evaluation or discharge, follow-up must continue up to 30 
additional days until resolution of the adverse event or the Investigator 
documents in the subject’s medical record that a stable clinical endpoint 
has been reached, or that the subject’s status is not associated with the 
device or procedure.  After the safety evaluation has been conducted, 
the ASF subject will be discontinued from the study.  
 
Subjects 
who 
meet 
all 
of 
the 
general 
and 
angiographic 
inclusion/exclusion criteria will actually be “entered” in the study (if the 
intent is to proceed with stent deployment) at the time of the start of the 
index procedure as defined in this protocol (see definitions) and pre-
treatment angiogram confirms subject still meets angiographic eligibility 
criteria.    
 
6.1.2 Subject Numbering 
 
Subjects who are screened for the study will be assigned an 
identification number (subject study number).  The first two digits 
assigned represent the site identification; this is followed by a hyphen, 
and three subsequent digits which represent the sequential 
identification.  For example, ID: 10-001 would represent the first subject 
screened at site 10.  If a subject is screened for the study but is not 
enrolled, the site will document the reason for not signing the consent. 
 
At the time the subject is enrolled (signs the study informed consent), 
the five digit identification number (subject study number) is also 
maintained for these subjects.  The first two digits assigned represent 
the site identification; this is followed by a hyphen, and three 
subsequent digits which represent the sequential enrollment number.  
For example, ID: 01-005 would represent the fifth subject at site 01.  
 
Subjects who are enrolled but who are found to be ineligible for 
treatment with ENTERPRISE at the time of the pre-procedure 
angiogram will be replaced.  Subjects in whom treatment with 
ENTERPRISE is attempted but who discontinue study participation 
prematurely will not be replaced. 
 
6.1.3 Baseline Medication and Assessments 
 
The following pre-procedure medications are a requirement of this 
protocol. Confirmation of correct antiplatelet therapy prior to the 
procedure must be documented. If confirmation of the correct 
antiplatelet therapy is not available, the procedure should be delayed. 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 58 of 121 
 
• Aspirin (ASA):  At least 81 mg/day for a minimum of 7 days prior to 
the procedure  
 
• P2Y12 Platelet Inhibitor:  Daily for a minimum of 7 days prior to the 
procedure     
 
All patients must have platelet reactivity testing performed.  Record 
the test results in the applicable eCRF. 
 
The following baseline data must be collected for all subjects prior to 
the treatment procedure (within 14 days prior to index procedure).  Note 
that the study informed consent must be signed prior to any study 
protocol required assessments or procedures that are not routine 
standard of care by the investigation. 
 
Neurological assessments and subject interview: 
(Within 14 days prior to index procedure) 
 
• Medical History 
• Clinical Assessment/Physical Exam/Vital Signs 
o Within 14 days prior to the index procedure, and during the index 
procedure (both pre-treatment and immediately post-treatment) 
• Relevant prior medications: indicate all antithrombotic (including anti-
platelets, anticoagulants, and fibrinolytics) and inhibitors of ADP-
induced platelet aggregation medications the subject has taken 
within14 days prior to index procedure: 
• Neurological evaluations performed by qualified personnel. Included 
as part of this examination are the NIH Stroke Scale Score (NIHSS), 
Modified Rankin Scale (mRS), and clinical neurological evaluations.   
 
Clinical Laboratory Tests:  
(Within 14 days prior to index procedure) 
 
 
• Serum creatinine   
 
CT or MRI 
 
• Obtain an axial CT or MRI of the patient (performed within the last 10 
years provided that the CT or MRI was not performed before the 
subject's 20th birthday) that shows the orbital anatomy of the skull. 
The CT/MRI should contain a valid centimeter marker and upload to 
Image Management Vendor (to be used for calibrating images). The 
CT/MRI scans are needed only for calibration and will not need 
interpretation. 
 
 
6.2 Procedure  
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 59 of 121 
6.2.1 Indications for Use – Study Device 
 
The CODMAN ENTERPRISE Vascular Reconstruction Device and 
Delivery System is intended for use with embolic coils for the treatment 
of unruptured wide-neck, intracranial, saccular anterior circulation 
aneurysms (≤ 10 mm) arising from a parent vessel with a diameter of 
≥ 2.5 mm and ≤ 4 mm.  Wide-neck is defined as having a neck width ≥ 
4 mm or a dome-to-neck ratio < 2. The device must be used according 
to the Instructions for Use packaged with the study device, the study 
protocol inclusion and exclusion criteria, and the study procedures 
outlined in this study protocol. 
   
6.2.2 Index Procedure 
 
For the ENTERPRISE Device see accompanying IFU for complete 
instructions including warnings and precautions, on intracranial stent 
preparation and usage.  The index procedure (pre-treatment, intra-
procedure, and immediate post-treatment of the index), 6 month and 
12 month follow-up, any unscheduled and any pre-retreatment 
angiograms must be performed according to the study Core Lab 
Manual.  Per the study protocol, the stenting and coiling must both be 
performed during the index procedure, and the embolization coils must 
be placed after the stent is deployed.  Staged procedures are not 
allowed under this study protocol.  If it becomes medically necessary to 
stage the stenting and coiling procedures this will be considered a 
treatment failure. 
 
General Overview for ENTERPRISE Stent-Assisted Coiling 
When delivering the stent under fluoroscopic visualization, the 
interventionist must slowly advance the delivery system to deploy the 
stent (See IFU for complete directions for use). Do not recapture the 
stent more than once.  Optimal expansion requires the stent to be in full 
contact with the artery wall, with the stent internal diameter matching 
the vessel diameter. Stent wall contact should be verified through 
routine angiography. The interventionist must fully cover the entire 
aneurysm with the stent, allowing for adequate stent coverage into 
healthy tissue proximal and distal to the lesion (to maintain a minimum 
of 5 mm on either side of aneurysm neck).  All efforts should be taken 
to assure that the stent is completely apposed to the vessel wall. Once 
the stent has been deployed, using the best orthogonal catheter 
arteriographic projections profiling the aneurysm relative to the parent 
artery, three orthogonal plane images of the stented artery must be 
obtained for independent core laboratory review.  For size calculations 
using planar projections, sizing markers must be placed on both sides 
of the head due to the significant magnification that occurs. 
 
After the stent has been deployed, remove and discard the delivery 
system.  Verify that the stent has remained patent and properly 
positioned. After completing the procedure, withdraw and discard all 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 60 of 121 
applicable accessory devices. The embolization coils must be placed 
after the stent is deployed, during the index procedure. 
 
6.2.3 Embolic Devices 
 
For the embolic device, refer to the enclosed labeling packaged with 
the embolic coils. 
 
Embolization Coils: The embolization coils must be placed after the 
stent is deployed, during the index procedure. The protocol does not 
allow the use of Hydrocoils (the use of all other polymer coils, except 
Hydrocoils, are allowed).  Any subject in whom a Hydrocoil is implanted 
will be considered a protocol deviation.   
 
6.2.4 Procedure Assessments  
 
(This is applicable to the index procedure as well as any other 
subsequent procedures) 
 
Start/End of Procedure: 
 
The following definitions apply to the index procedure.  
 
• The start of the procedure is the time the femoral artery is 
accessed. 
• The end of the procedure is the time the guiding catheter is 
removed from the subject. 
 
Procedural Study Assessments: 
• Procedural medications 
• Event assessment during index procedure (pre-treatment, intra-
procedure, and post-treatment), i.e. adverse events, protocol 
deviations, device malfunction/product complaint 
• Angiogram 
o Upload or send the pre-treatment, intra-procedure, and post-
treatment images to the study Image Management System 
 
6.2.5 Procedural Medications 
 
Procedural Medications: 
Procedural medications administered in the pre-procedural, intra-
procedural, and immediate post-procedural timeframes will be recorded 
on the eCRF. Procedure medications will include, antithrombotic, 
(including anti-platelet, anticoagulant, and fibrinolytics), and inhibitors 
of 
ADP-induced 
platelet 
aggregation 
medications 
that 
were 
administered within 7 days prior to the start of the procedure (femoral 
artery access) and up to and including 24 hours after end of the 
procedure (time guiding catheter is removed from the subject).  
Additionally, please indicate all vasoactive medications and contrast 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 61 of 121 
that were administered intra-procedurally until the end of the index 
procedure. 
 
Post-Procedural Medications: 
Medications administered 24 hours after end of the index procedure will 
be recorded on the eCRF.  Post-procedural medications will include all 
antithrombotics (including anti-platelet, anticoagulant, and fibrinolytics), 
and inhibitors of ADP-induced platelet aggregation medications. 
 
The following post-index procedure medications are a requirement of 
this protocol.  
 
• ASA (at least 81 mg/day) must be continued for a minimum of 12 
months. 
• P2Y12 Platelet Inhibitor must be taken daily for a minimum of 3 
months 
 
Please refer to Section 8 for further information concerning concomitant 
medications.  
 
6.3 Follow-up 
 
6.3.1 Follow-up of Angiographic Screening Failures 
 
An angiographic screening failure is any subject who signed the study 
informed consent but meets any of the angiographic exclusion criteria 
as the screening procedure progresses. These subjects will not be 
entered in the study and will be followed for the period 72 hours following 
the end of the angiographic procedure to determine study angiographic 
eligibility or until discharge, whichever comes first.  Any AEs that occur 
during this period must be documented.  If any AE has not resolved by 
the 72-hour safety evaluation or discharge, follow-up must continue until 
resolution of the adverse event, after which they will be discontinued 
from the study. 
 
For angiographic screening failures: 
 
• Complete and enter onto Screening Log the reason why the subject 
was not eligible to participate in the study 
• File the signed informed consent  
• Complete and enter into database all eCRF up to and including the 
Investigator’s angiographic assessment, these forms shall include: 
o Screening/Baseline  
o Pre-Procedure 
Angiography 
(and 
Pre-Treatment 
Angiography, if applicable) 
o Study Completion 
o Protocol Deviations, as applicable  
o Adverse Events, as applicable 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 62 of 121 
 Complete and entered in the Adverse Event (AE) 
eCRF any AEs that occurred from the time the study 
informed consent was signed through the period 72 
hours following the end of the angiographic procedure 
to determine study angiographic eligibility, or until 
discharge, whichever comes first, or to resolution of 
any adverse event, whichever is longer. 
 
6.3.2 Follow-up After Stroke or Suspected Stroke (Unscheduled Visit) 
 
If a subject experiences a stroke, or if there is any suspicion of a stroke, 
the subject needs to have an MRI completed within a time window of 24 
hours after symptom(s) onset. 
 
Additionally, if the subject experiences a stroke they will need to return 
to visit the investigator 30 days (window 16 - 44 days) after the stroke 
for a neurological assessment to include, at a minimum, a modified 
Rankin Score (mRS) assessment and the National Institute of Health 
Stroke Scale (NIHSS). 
 
In the event, that the subject experienced a stroke but the investigator 
did not learn about the stroke at the time it occurred, and thus an MRI 
was not done within 24 hours of the stroke, then site must obtain an MRI 
immediately upon learning of the stroke, as well perform the modified 
Rankin Score (mRS) assessment and the National Institute of Health 
Stroke Scale (NIHSS). 
 
6.3.3 Post-Procedure through Hospital Discharge  
 
All subjects entered into the study will undergo the following tests or 
procedures while in the hospital. 
 
Assessment and subject interview 
 
• Vital Signs (Blood pressure, Heart Rate, and Respirations) 
o Immediately Post-Treatment 
o Hospital discharge 
• Relevant 
Concomitant 
Medications 
(daily): 
indicate 
all 
antithrombotics (including anti-platelets, anticoagulants, and 
fibrinolytics), and inhibitors of ADP-induced platelet aggregation 
medications that were administered after 24 hours post-procedure 
through hospital discharge.  
• Neurological assessment and evaluations performed by qualified 
personnel at 12-36 hours after end of procedure (removal of the guiding 
catheter from the subject). Included as part of this examination are the 
NIH Stroke Scale Score, Modified Rankin Scale, clinical neurological 
evaluation, and if applicable, the Hunt and Hess Scale (HHS) for 
subarachnoid hemorrhage   

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 63 of 121 
• Event assessment (daily) as applicable (i.e. adverse events, protocol 
deviations, device malfunction/product complaint).  
 
6.3.4  Thirty-Day Follow-up (Telephone Interview) 
 
 
The thirty-day follow-up visit must occur between 16 days to 44 days 
from the date of the index procedure and may be conducted via 
telephone. 
 
All subjects entered into the study will be followed for adverse event 
assessment at thirty days.  
 
All subjects entered into the study will be submitted to the following 
interview about their health condition and medications: 
 
Subject interview 
 
• Relevant Concomitant Medications (daily since hospital discharge): 
indicate any antithrombotics (including anti-platelets, anticoagulants, 
and fibrinolytics) and inhibitors of ADP-induced platelet aggregation 
medications administered more than 24 hours post-procedure 
through end of study participation.  
• Neurological evaluation performed by qualified personnel.  Included 
as part of this examination is the Modified Rankin Scale.  
• Event assessment (since discharge evaluation) (i.e., adverse  
events, protocol deviations, device malfunction/product complaint) 
 
6.3.5   6 Month Follow-up (Clinic Visit & Angiogram) 
 
The 6 month follow-up visit must occur between 92 days and 212 days 
from the date of the index procedure. 
 
All subjects entered into the study will be followed for adverse event 
assessment at 6 months post-procedure.  
 
The 6 month follow-up evaluations must be performed at the 
investigational site.  All subjects entered into the study will be submitted 
to the following: 
 
Assessment and subject interview 
 
• Vital Signs (Blood pressure, Heart Rate, and Respirations) 
• Relevant Concomitant Medications (daily since 30 day follow-up):  
Indicate any antithrombotics (including anti-platelets, anticoagulants, 
and fibrinolytics) and inhibitors of ADP-induced platelet aggregation 
medications administered more than 24 hours post-procedure 
through end of study participation. 
• Clinical Assessment and Physical Exam 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 64 of 121 
• Neurological assessment and evaluations performed by qualified 
personnel.  Included as part of this examination are the NIH Stroke 
Scale Score, Modified Rankin Scale, clinical neurological evaluation, 
and, if applicable, the Hunt and Hess Scale (HHS) for subarachnoid 
hemorrhage   
• Event assessment (since 30 day follow-up) (i.e., adverse events, 
protocol deviations, device malfunction/product complaint) 
• Angiogram  
o Upload or send the follow-up angiogram images to the 
study Image Management System 
o The 6 month follow-up angiogram shall be performed 
using the same orthogonal views as used during the 
index procedure, and according to the study Core Lab 
Manual. 
 
6.3.6 12 Month Follow-up (Clinic Visit & Angiogram) 
 
The 12 month follow-up must occur between 320 days and 410 days 
from the date of the index procedure. 
 
All subjects entered into the study will be followed for adverse event 
assessment at 12 months.  
  
The 12 month follow-up evaluations must be performed at the 
investigational site.  All subjects entered into the study will be submitted 
to the following: 
 
Assessment and subject interview 
 
 
• Vital Signs (Blood Pressure, Heart Rate, and Respirations) 
• Relevant Concomitant Medications (since 6 month follow-up): 
indicate any antithrombotics (including anti-platelets, anticoagulants, 
and fibrinolytics) and inhibitors of ADP-induced platelet aggregation 
medications administered more than 24 hours post-procedure 
through end of study participation.  
• Clinical Assessment and Physical Exam 
• Neurological assessment and evaluation performed by qualified 
personnel.  Included as part of this examination are the NIH Stroke 
Scale Score, Modified Rankin Scale, clinical neurological evaluation, 
and, if applicable, the Hunt and Hess Scale (HHS) for subarachnoid 
hemorrhage.  
• Event assessment (since 6 month follow-up) (i.e., adverse events, 
protocol deviations, device malfunction/product complaint) 
• Angiogram  
o Upload or send the follow-up angiogram images to the 
study Image Management System 
o The 12 month follow-up angiogram shall be performed 
using the same orthogonal views as used during the 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 65 of 121 
index procedure, and according to the study Core Lab 
Manual. 
 
6.3.7   18 Month Follow-up (Telephone Interview)  
 
The 18 month follow-up visit telephone interview must occur between 
457 days and 592 days from the date of the index stenting procedure. 
 
The 18 month follow-up evaluations may be conducted via a telephone 
interview.  All subjects entered into the study will be submitted to the 
following: 
 
Subject interview 
 
• Relevant Concomitant Medications (since 12 month follow-up): 
indicate any antithrombotics (including anti-platelets, anticoagulants, 
and fibrinolytics) and inhibitors of ADP-induced platelet aggregation 
medications administered more than 24 hours post-procedure 
through end of study participation.  
• Neurological evaluations performed by qualified personnel.  Included 
as part of this examination is the Modified Rankin Scale.   
• Event assessment (since 12 month follow-up) (i.e. adverse events, 
protocol deviations, device malfunction/product complaint) 
 
6.3.8   24 Month Follow-up (Clinic Visit & MRA or Angiogram) 
 
The 24 month follow-up visit must occur between 685 days and 775 
days from the date of the index stenting procedure. 
 
The 24 month follow-up evaluations must be performed at the 
investigational site.  All subjects entered into the study will be 
submitted to the following: 
 
 
Assessment and subject interview 
 
• Vital Signs (Blood pressure, Heart Rate, and Respirations) 
• Relevant Concomitant Medications (since 18 month follow-up): 
indicate any antithrombotics (including anti-platelets, anticoagulants, 
and fibrinolytics) and inhibitors of ADP-induced platelet aggregation 
medications administered more than 24 hours post-procedure 
through end of study participation 
• Neurological evaluations performed by qualified personnel.  Included 
as part of this examination are the NIH Stroke Scale Score, Modified 
Rankin Scale, clinical neurological evaluation, and, if applicable, the 
Hunt and Hess Scale (HHS) for subarachnoid hemorrhage   
• MRI/MRA or angiogram (an angiogram must be performed if any 
stent or coils are not MRA/MRI compatible) to assess for in-stent 
stenosis, thrombosis and hydrocephalus, or if an angiogram is 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 66 of 121 
performed to assess for in-stent stenosis and thrombosis, then also 
obtain MRI or CT to assess for hydrocephalus)  
• Event assessment (since 18 month follow-up) (i.e. adverse events, 
protocol deviations, device malfunction/product complaint) 
 
 
Following the 24 month study visit, the subject will be discharged from 
the study.  However, if the investigator determines there are indications 
of delayed hydrocephalus or in-stent stenosis occurring, additional 
follow-up may be required, including MRI or CT at the Investigator’s 
discretion. If this should this occur the investigator will determine the 
additional follow-up required at that time and inform the study sponsor.   
 
If a subject presents with an adverse event at the 24 month follow-up, 
he/she will receive appropriate treatment for that condition.  If the 
subject’s condition precludes him or her from undergoing any 24 month 
evaluation specified by the protocol, the subject would be discharged 
from the study after the Investigator documents in the subject’s medical 
record that a stable clinical endpoint has been reached, or that the 
subject’s status is not associated with the device or procedure. 
 
Subjects entered into the study will be considered eligible for follow-up 
unless they have died or withdrawn their consent to be contacted.  The 
study center will review the follow-up requirements with the subject to 
help ensure compliance with the follow-up schedule.  Telephone 
numbers should be obtained from the subject to ensure the ability to 
contact him or her at the required follow-up times.  These phone 
numbers should include all home numbers, work numbers and primary 
physician numbers.  A phone number of a relative or friend should also 
be requested.  
 
6.3.7 Safety Follow-up (Subjects with Adverse Events of Special 
Interest)  
 
All subjects entered into the study who experience any adverse event 
of special interest and who have an MRS > 2 at any clinical evaluation 
will be followed through 24 months post-procedure, and their outcomes 
will be summarized in a supplemental safety follow-up report.  
Adverse Events of Special Interest include:   
• rupture of the index aneurysm beyond 24 hours post-treatment 
• major ipsilateral stroke more than 1 month post-treatment  
• ipsilateral parenchymal hemorrhage more than 1 month post-
treatment  
• device migration at the 6 month angiogram 
 
 
6.4 Placement of Second ENTERPRISE Stent 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 67 of 121 
Per the study protocol inclusion and exclusion criteria, subjects are only expected 
to have one ENTERPRISE stent implanted.  However, if upon initiating the index 
procedure, the Investigator deems it necessary to place an additional stent(s), 
the investigator must use an ENTERPRISE IDE stent.  Placement of an 
additional stent(s) will be considered a protocol deviation.  
 
• ENTERPRISE IDE stent should be used if placed in the 
target aneurysm 
• ENTERPRISE HDE stent should be used if placed in a non-
target aneurysm]   
 
 
6.5 Retreatment of the Target Aneurysm 
 
Retreatment in this study protocol, regardless whether by surgery or 
endovascular treatment, is defined as any additional treatment of the target 
aneurysm after the index procedure due to recanalization, rupture or bleeding, 
or as part of a staged procedure.    
 
6.6   Unscheduled Angiogram 
 
If a subject undergoes an angiogram that is not required as part of this study 
protocol, it is considered an unscheduled angiogram.  If a subject has an 
unscheduled angiogram, it should be performed using the same orthogonal 
views as used during the index embolization procedure, and according to the 
study Core Lab Manual.  The angiogram images should be uploaded or sent to 
the study Image Management System. 
 
6.7 Summary of Follow-up Schedule and Time Windows  
 
Table 5: Follow-up visits: Schedule & Time Windows   
Follow-up Visit 
Time Window 
(days) 
Timeframe 
30 days* 
16 - 44   
days after index procedure 
6 month 
92 - 212   
days after index procedure 
12 month 
320 - 410  
days after index procedure 
18 month* 
457 - 592  
days after index procedure 
24 month 
685 - 775  
days after index procedure 
Stroke or 
suspected 
stroke  visit 
16 - 44 
days after stroke or suspected 
stroke** 
* May be a Telephone Visit 
** If a subject experiences a stroke, or if there is any suspicion of a stroke, the subject needs to have an 
MRI completed within a time window of 24 hours after symptom(s) onset.  In the event, that the subject 
experienced a stroke but the investigator did not learn about the stroke at the time it occurred, and thus 
an MRI was not done within 24 hours of the stroke, then site must obtain an MRI immediately upon 
learning of the stroke,  as well perform the modified Rankin Score (mRS) assessment and the National 
Institute of Health Stroke Scale (NIHSS). 
 
All follow-up assessments will be performed at the specified times indicated 
unless a subject suffers an adverse event that prevents evaluation.  Under these 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 68 of 121 
circumstances, only clinically indicated assessments will be performed at the 
discretion of the attending physician.  
 
 
7 CORE LABORATORY 
 
An independent core laboratory will perform the quantitative angiographic 
measurements for the primary and secondary effectiveness endpoints and the 24 
month follow up using the Raymond scale assessment.  These measurements 
will be performed by an independent reader.  
 
All subjects are to have procedural angiograms (at pre-treatment, intra-procedure, 
and immediate post-treatment), as well as 6 and 12 and (if applicable) 24 month 
angiograms.  The angiograms need to be performed according to the study Core 
Lab Manual.  Standard quantitative angiography (QCA) acquisition procedures 
will be followed for QCA analysis.  All angiographies must provide angiograms 
that are suitable for quantitative analysis, based on optimal orthogonal catheter 
arteriographic projections.  Refer to the study Core Laboratory Manual for further 
angiographic methods and requirements. 
 
 
8 CONCOMITANT MEDICATIONS  
 
The following concomitant medications are a requirement of this protocol. 
Regardless of the therapy administered, the concomitant medication(s) will be 
documented on the eCRF.  
 
8.1 Pre-procedure Medications 
 
• Aspirin (ASA): At least 81 mg/day for a minimum of 7 days prior to the 
procedure  
• P2Y12 Platelet Inhibitor: Daily for a minimum of 7 days prior to the 
procedure     
 
Note: Confirmation of correct antiplatelet therapy prior to the procedure  
must be documented; If not available, the procedure should be delayed. 
 
8.2 Intra-procedure  
 
• General anesthesia is required for the procedure. 
 
• Heparin:  A bolus of intravenous heparin will be given that is weight 
adjusted to maintain the activated clotting time (ACT) near 250-300 
seconds throughout the procedure.  If a GP IIb-IIIa Inhibitor (Reopro or 
Integrilin) is given during the procedure, then the ACT should be 
maintained at less than 220 to minimize the risk of bleeding.  GP IIb-IIIa 
Inhibitors should not be given if the subject has a recent history (less than 
30 days) of hemorrhage.  It is required that the ACT be checked during 
the procedure at intervals of no longer than 60 minutes, as well as at the 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 69 of 121 
end of the procedure to verify conformity with this requirement.  It is 
recommended to discontinue heparin at the end of the procedure and the 
arterial sheath removed after the ACT has returned to < 140 seconds. 
 
The use of vascular closure devices is recommended, but sheath removal 
on the day following the procedure is acceptable. 
 
8.3 Post-procedure  
 
The following post-procedure medications are required per this protocol.  
 
• ASA (at least 81 mg/day) must be continued for a minimum of 12 
months. 
 
• P2Y12 Platelet Inhibitor must be taken daily for a minimum of 3 months. 
 
 
9 STATISTICAL METHODS  
 
The following sections provide a general description of the statistical plan for the 
analysis of study data.  A separate Statistical Analysis Plan (SAP) document that 
provides greater detail on data derivations and the analyses to be performed will be 
developed prior to the planned interim analysis.  The SAP will reflect the protocol and 
any amendments that have been implemented at the time the SAP is finalized.  Any 
deviations from the final SAP will be noted in the final clinical summary report. 
 
9.1 Study Design 
This is a prospective, multi-center, single arm, clinical study to evaluate the 
safety and effectiveness of the ENTERPRISE stent when used in conjunction 
with endovascular coil embolization in the treatment of unruptured  wide-neck, 
intracranial, saccular anterior circulation aneurysms (≤ 10 mm) arising from a 
parent vessel with a diameter of ≥ 2.5 mm and ≤ 4 mm.  A group sequential 
design will be utilized in which one primary endpoint interim analysis will be 
conducted after N=160 subjects have been enrolled and followed through 6 
months post-procedure. Enrollment will pause after these 160 subjects have 
been enrolled and will not resume until after the interim analysis has been 
conducted.  The purpose of the interim analysis will be to determine whether 
or not to terminate the trial early for futility or tentative success.  If the stopping 
rule is met for the trial to stop early for tentative success, a final confirmatory 
analysis will be conducted when all subjects have reached 12 months post-
procedure.  If the trial is not terminated early for futility or tentative success, 
then enrollment will continue up to a full enrollment sample size of N=320.  
After all 320 subjects have reached 12 months post-procedure, a final analysis 
will be conducted.     
 
9.2 Treatment Assignment 
 
This is a single arm study; all subjects will be treated with the CODMAN 
ENTERPRISE device.   

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 70 of 121 
 
9.3 Levels of Significance 
 
A 2-sided alpha of 0.05 will be used for statistical testing and confidence 
intervals unless otherwise noted.  There will be no adjustment to p-values or 
alpha levels for testing primary safety, secondary effectiveness, or secondary 
safety endpoints.   
 
A primary efficacy endpoint interim analysis will be conducted to determine 
whether or not to stop the trial early for futility or tentative success.  This 
analysis will be based solely on the primary efficacy endpoint, and will be 
conducted after N=160 subjects have been enrolled and have reached 6 
months post-procedure.  In this interim analysis, the two-sided unadjusted p-
value threshold for stopping the trial early for success will be 0.031.  If the 
stopping rule is met for the trial to stop early for tentative success, a final 
confirmatory analysis will be conducted when all subjects have reached 12 
months post-procedure; a p-value threshold of 0.031 will be used for this final 
confirmatory analysis.  If this early stopping rule is not met, then enrollment 
will commence until the total sample of N=320 subjects have been enrolled 
(including the original N=160).  The final endpoint analysis with all be 
conducted with a 2-sided p-value threshold of 0.031 for determining study 
success. These p-value thresholds have been established in order to maintain 
an overall 2-side alpha (probability of a Type 1 error) below 0.05 for the primary 
endpoint.    
 
9.4 Interval Windows 
The baseline/screening evaluation is to be done between14 days prior to the 
procedure and the day of the index procedure, which is considered to be day 
0.  The immediate pre-procedure evaluation (which includes angiographic 
assessment) and immediate post-procedure assessment will be considered 
within window if they occur within 12 hours (before and after, respectively) of 
the start of the index procedure (groin stick).  The assessment at hospital 
discharge will occur between 12 and 36 hours after the start of the index 
procedure.  The 30 day, 6 month, 12 month, 18 month and 24 month 
assessments will occur in the time intervals (days) indicated in the following 
table: 
 
 
Study Interval Windows [days or hours, as indicated] 
Baseline/Screening 
-14 to 0 
Immediate Pre-Procedure 
Within 12 hours prior to procedure 
Index Procedure 
Day 0 
Immediate Post-Procedure 
Within 12 hours after procedure 
Hospital Discharge 
12 to 36 hours after procedure 
30 Days 
16 to 44 days after procedure 
6 Months 
92 to 212 days after procedure 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 71 of 121 
12 Months 
320 to 410 days after procedure 
18 Months 
457 to 592 days after procedure 
24 Months 
685 to 775 days after procedure 
 
9.5 Handling of Missing Data 
Primary effectiveness and primary safety endpoint analyses will be conducted 
on the modified intent-to-treat (MITT) population, where subjects with missing 
data at the time of endpoint analysis will be imputed as last observation carried 
forward (LOCF); see Section 9.8 for analysis set definitions. Note that the 
immediate post-procedure evaluation will be utilized in this LOCF methodology 
if this is the last observation on file.  MITT subjects who receive the device but 
in whom there is no post-procedure data will be treated as failures for the 
purpose of the primary effectiveness endpoint analysis; these subjects will be 
excluded from all other endpoint analyses. Subjects who do not receive the 
device because of treatment failure due to reasons associated with the device 
will also be treated as failures for the primary effectiveness endpoint analysis; 
these subjects will be excluded from all other endpoint analyses.  MITT 
subjects who do not receive the device because of an intra-operative surgeon 
decision based on patient anatomy (e.g. vessel tortuosity) will be treated as 
missing (and not as failures) in all endpoint analyses, including the primary 
effectiveness and primary safety endpoint analysis.   
 
All subjects who have died prior to an evaluation will have a mRS score of 6 
imputed for that time point for analysis purposes.   
 
All other analyses based upon MITT or PP population data will be based upon 
actual data, with no data imputation.  
 
9.6 Primary and Secondary Endpoints 
 
Primary Endpoint  
 
Efficacy: 
The primary effectiveness endpoint is the rate of complete aneurysm occlusion 
(RCAO) at 12 months post-procedure according to the Raymond Scale as 
assessed by the Independent Core Laboratory. 
   
Complete aneurysm occlusion is defined as an aneurysm in which a score of 
1 (complete obliteration) is achieved on the Raymond Scale at the relevant 
post-procedure angiogram, without additional procedures for treatment of the 
aneurysm since the index procedure. Subjects who are retreated (retreatment 
includes staged procedures) prior to the 12 month post-procedure follow-up 
visit will be considered not to have achieved complete aneurysm occlusion for 
the purpose of the primary endpoint analysis. 
 
Safety: 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 72 of 121 
There are two primary safety endpoints: The incidence of Major Ipsilateral 
Stroke and/or Death at 12 months post-procedure and the incidence of In-
stent stenosis at 12 months post-procedure.    
 
Incidence of Major Ipsilateral Stroke and/or Death: 
Major ipsilateral stroke and/or death will be evaluated from the start of 
the index procedure until completion of the 12 month follow-up. A major 
ipsilateral stroke is defined as a new neurological event which is 
ipsilateral and in the vascular distribution territory of the stenting 
procedure and that results in an increase of ≥ 4 on the National Institute 
of Health Stroke Scale (NIHSS) as compared to baseline and persists for 
greater than 24 hours. 
 
Incidence of In-Stent Stenosis:  
In-stent stenosis at or prior to 12 months post-procedure will be assessed 
angiographically.  In-stent stenosis is defined as greater than 50% 
narrowing of the vessel within the ENTERPRISE stent or within 10 mm 
of either end of the stent. 
 
Secondary Endpoints 
 
Secondary Effectiveness Endpoints:  
 
Procedure Success:  Procedure Success is defined as the percentage 
of aneurysms in which coil mass position is maintained within the sac 
with parent artery patency, without additional procedures for treatment 
of the aneurysm since the index procedure. Procedure success will be 
summarized immediately post-treatment (acute), and at the 6 and 12 
month follow-up assessments. 
 
Acute and 6 Month Complete Aneurysm Occlusion as per the 
Raymond Scale:  The percentage of aneurysms in which a score of 1 
(complete obliteration) is achieved on the Raymond Scale immediately 
post-procedure (acute) and at the 6 month follow-up angiographic 
assessments, respectively, will be evaluated.   
 
Complete/Partial Aneurysm Occlusion as per the Raymond Scale:  
The percentage of aneurysms in which a score of 1 (complete 
obliteration) or 2 (residual neck) is achieved on the Raymond Scale 
immediately post-procedure (acute), and at the 6, and 12 month follow-
up angiographic assessments will be evaluated. 
 
Percent Aneurysm Occlusion:  The percentage of aneurysms with 
occlusion of 100%, 90%-99%, 70-89%, 50-69%, 25-49%, or <25% 
occlusion in accordance with Consensus Grades 0-5, respectively, will 
be summarized immediately post-procedure (acute), and at 6 and 12 
month follow-up, respectively. 
 
Recanalization Rate:  

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 73 of 121 
The percentage of aneurysms in which recanalization is documented at 
any time up to and including the 12 month follow-up visit, will be 
evaluated.  Recanalization will be defined as an increase in aneurysm 
filling as compared to the previous study-specified angiographic 
assessment, resulting in a change in (i.e., worsening of) the Raymond 
classification.  Changes in Raymond Scale will be classified as stable, 
improved, or recanalized based on the follow-up angiograms. 
Percentages of aneurysms falling into each of the categories will be 
presented. 
 
Retreatment Rate:   
The percentage of target aneurysms that are retreated at any time up 
to and including the 12 month follow-up visit will be evaluated. 
Retreatment will be defined as any additional treatment of the target 
aneurysm after the index procedure (retreatment includes staged 
procedures), and (regardless of whether retreatment is by surgery or 
endovascular treatment) due to recanalization, rupture or bleeding. 
 
Secondary Safety Endpoints:  
 
Rate of New Neurological Deficits per the Modified Rankin Scale 
(mRS):  Observed scores on the Modified Rankin Scale will be 
presented at baseline (pre-procedure) and follow-up (30 days, 6 and 12 
months post-procedure).  Subjects who have died at the prior to an 
evaluation will have an mRS score of 6 imputed for that time point for 
analysis purposes.   
 
The number and percentage of subjects who have an increase in mRS 
> 2 from baseline not related to stroke or death will also be presented 
for each follow-up time point.   
 
NIH Stroke Scale (NIHSS) Total Score:  NIHSS Total Score 
evaluations will be summarized at baseline (pre-procedure) and follow-
up (6 and 12 months post-procedure); change from baseline at 6 and 
12 months will also be summarized.  The percentage of subjects who 
show a worsening from baseline (increase of 4 points or more) will also 
be presented.   
 
Observed scores and change from baseline will also be presented for 
NIHSS excluding scores on the aphasia subscale. 
 
Adverse Events and Clinical Complications:  
Adverse Events (AEs), including complications associated with an 
untoward medical occurrence, from the start of the index procedure 
until completion of the 12 month follow-up will be coded using the 
MedDRA system and summarized with frequencies. Serious adverse 
events (SAEs), device- or procedure-related AEs, unanticipated 
adverse device effects (UADEs) and deaths will be presented.    
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 74 of 121 
AEs will be presented for the following study periods: 1) peri-procedure 
– i.e., from the start of the procedure until 24 hours post-procedure; 
and, 2) through 12 month follow-up – i.e., from 24 hours post-procedure 
through the 12 month visit or premature termination 
 
Reduced TICI Flow:  
 
The percentage of target aneurysms in which a new occurrence of 
unintentional and persistent reduced TICI flow (TICI score of 0 or 1) is 
observed at the target vessel during the index procedure as a result of 
a mechanical obstruction such as dissection or luminal thrombus will 
be evaluated. 
 
 
Bleeding Complications: 
 
The number and percentage of subjects who experience a procedure-
related hemorrhagic event which requires any of the following will be 
evaluated: 
 
blood 
transfusion, 
surgical 
intervention, 
a 
new 
hospitalization, or lengthening of hospital stay.  The complications of 
hematoma requiring treatment (i.e., a hematoma > 5 cm in diameter 
occurring at the access site) and retroperitoneal bleeding will be 
reported as hemorrhagic events. 
 
In-Stent Stenosis (Acute, and 6 Months):  
The percentage of aneurysms in which in-stent stenosis is documented 
immediately post-procedure (acute), and up to and including 6 months 
post-procedure, will be evaluated.   
 
Acute in-stent stenosis will be further characterized by whether it results 
from vasospasm, and whether or not the vasospasm was responsive to 
medication. 
 
Thrombosis:  
 
The percentage of aneurysms in which thrombosis is documented up 
to and including 6 and 12 months post-procedure will be evaluated.  
Thrombosis is defined as in-stent thrombosis. 
 
Ancillary Endpoints 
 
Stent Movement/Migration:  Incidence of stent movement and/or 
migration from the start of the index procedure until completion of the 
12 month follow-up 
 
Follow-up through 24 months:  Subjects will be followed through 24 
months post-procedure, and their outcomes will be summarized in a 
supplemental safety follow-up report:  

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 75 of 121 
• All adverse events through 24 months post-procedure 
• rupture of the index aneurysm beyond 24 hours post-treatment 
• major ipsilateral stroke more than 1 month post-treatment  
• ipsilateral parenchymal hemorrhage more than 1 month post-
treatment  
 
Note: Although a supplemental safety report will be written to 
summarize safety outcomes through 24 months, there are no formal 
primary or secondary endpoints regarding outcomes at this time-point.  
  
9.7 Hypotheses 
 
Primary Efficacy Endpoint: Rate of Complete Occlusion (RCAO) 
according to the Raymond Scale 
The primary efficacy endpoint analysis will be to demonstrate that the 
RCAO is significantly greater than a performance goal (PG) of 35%.  
The null and alternative hypotheses for this endpoint are as follows: 
Null hypothesis Ho: RCAO ≤ 35%  
Alternative hypothesis HA: RCAO > 35% 
Decision Criterion:  The decision will be made to reject the null 
hypotheses Ho and conclude the alternative hypothesis HA either of the 
following occur: 
1. At the interim analysis (when the first N=160 enrolled subjects 
have reached a minimum of 6 months post-operatively), the 
unadjusted 2-sided normal approximation p-value for testing 
the primary effectiveness endpoint (RCAO vs. the PG of 35%) 
is less than 0.031.  The conclusion of this analysis will be a 
tentative conclusion; if this stopping rule for tentative success 
is met, a final confirmatory analysis will be conducted when all 
subjects have reached 12 months post-procedure, and a p-
value threshold of 0.031 will be used for this final confirmatory 
analysis.    
2. At the final analysis when all N=320 subjects have been 
followed for a minimum of 12 months post-procedure, the 
unadjusted 2-sided normal approximation p-value for testing 
the primary effectiveness endpoint (RCAO vs. the PG of 35%) 
is less than 0.031. 
This primary efficacy endpoint analysis will be conducted on the 
MITT population.   
 
Note:  The study will be deemed to be a success if this primary efficacy 
endpoint null hypothesis (on the MITT population with data from all 
sites combined) is rejected in favor of the alternative hypothesis.   
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 76 of 121 
Primary Safety Endpoint: Incidence of Major Ipsilateral Stroke 
and/or Death 
For a successful evaluation of this endpoint, the upper confidence limit 
of a 2-sided 95% confidence interval for the proportion of subjects who 
experience major ipsilateral stroke and/or death through 12 months 
post-procedure will be less than 25% (regardless of whether this 
analysis is conducted at the interim analysis with N=160 subjects at 6 
months follow-up or the final analysis with N=320 subjects at 12 months 
follow-up).  The null and alternative hypotheses for this endpoint are as 
follows: 
Null Hypothesis Ho: pMajor Sroke/Death  ≥ 25%  
Alternative Hypothesis HA: pMajor Sroke/Death  < 25% 
where pMajor Sroke/Death represents the proportion of subjects in the 
treatment population who experience major ipsilateral stroke/death. 
 
Decision Criterion:  The null hypothesis will be rejected and the 
alternative hypothesis will be concluded if the upper confidence limit of 
a 2-sided 95% confidence limit (normal approximation) is less than 
25%. 
 
Primary Safety Endpoint: Incidence of In-Stent Stenosis 
For a successful evaluation of this endpoint, the upper confidence limit 
of a 2-sided 95% confidence interval for the rate of in-stent stenosis will 
be observed to be less than 15% (regardless of whether this analysis 
is conducted at the interim analysis with N=160 subjects at 6 months 
follow-up or the final analysis with N=320 subjects at 12 months follow-
up).  The null and alternative hypotheses for this endpoint are as 
follows: 
 
Null Hypothesis Ho: pStenosis  ≥ 15%  
Alternative Hypothesis HA: pStenosis  < 15% 
where pStenosis represents the proportion of subjects in the treatment 
population who experience in-stent stenosis. 
 
Decision Criterion: The null hypothesis will be rejected and the 
alternative hypothesis will be concluded if the upper confidence limit of 
a 2-sided 95% confidence limit (normal approximation) is less than 
15%. 
 
 
9.8 Analysis Sets 
The following analysis sets have been defined for this study: a Preliminary 
Screen Fail (PSF) analysis set, an Intent-to-Treat (ITT) analysis set, an 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 77 of 121 
Angiographic Screen Fail (ASF) analysis set, a Modified Intent-to-Treat (MITT) 
analysis set, a Per Protocol (PP) analysis set, and a Continued Follow-up (CF) 
analysis set.  The primary effectiveness, primary safety, and all secondary 
endpoint analyses will be carried out on available data in the MITT analysis 
set; supportive analyses of certain endpoints will be carried out on the PP 
analysis set.  Interim analyses for early stopping are based on available data 
in the MITT analysis set.  Demographic summaries will be provided for all 
analysis sets; a brief safety summary will be provided for the ASF analysis set.  
Clinical outcomes and safety summaries will be provided for the MITT, PP, 
and CF analysis sets, as specified for the various endpoint analyses, 
respectively.    
 
PSF Analysis Set 
The PSF analysis set consist of screening log data for all patients who 
are determined to be ineligible for the study based upon the initial 
screening information (including information from a preliminary 
angiographic assessment, which is distinct from the pre-treatment 
angiographic assessment at the time of the index procedure).  
 
ITT Analysis Set   
The ITT analysis set consists of all subjects who are consented 
(enrolled) into the study.  Note that at the time of consent, a screening 
angiographic assessment will have taken place to facilitate an initial 
determination regarding study treatment eligibility.    
 
ASF Analysis Set 
Angiographic Screen Fail Subjects are comprised of all ITT analysis set 
subjects who are determined to be ineligible for treatment at the time of 
the pre-procedure angiographic evaluation (which is more thorough 
than the screening angiographic assessment upon which treatment 
eligibility was initially determined).  These subjects are not treated with 
the ENTERPRISE device due to a failure to meet all angiographic 
eligibility criteria.  Angiographic Fail Subjects will be followed for 72 
hours following the end of the pre-procedure angiogram, or until 
hospital discharge, or to resolution of any adverse event, whichever is 
longer.   
 
MITT Analysis Set   
The MITT analysis set consists of all ITT subjects who meet all pre-
procedure angiographic eligibility criteria, and in whom treatment with 
the Enterprise device is attempted.   

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 78 of 121 
 
PP Analysis Set 
The PP analysis set is a subset of the MITT analysis set that includes 
all subjects who meet the following criteria:  
• there are no clinically meaningful deviations from the protocol 
eligibility criteria,  
• the subject receives  treatment with the Enterprise device, 
• the subject has either a 6 month or a 12 month angiographic 
assessment.  
 
 CF Analysis Set 
The CF analysis set is a subset of the MITT analysis set that is 
comprised of all subjects who are followed through 24 months post-
procedure. 
 
  
  9.9 Dataset Flow Diagram 
A detailed account of all subjects who are consented (enrolled) will be 
presented in a dataset flow diagram to display the analysis datasets, 
beginning with the set of enrolled subjects and explicitly listing the subjects 
with distinguishing reasons for exclusion from the other datasets. A 
template of this dataset flow diagram is given in Figure 3 below. 
 
 
 
 
 
 
 
 
 
 
 
 
ITT Analysis Set 
N= (Total Sample Size) 
All Enrolled Subjects 
ASF Analysis Set 
N= (Total Number of ASF Subjects) 
List all Subject Numbers and Reasons for 
Angiographic Ineligibility
minus 
PSF Analysis Set 
N= (Total Number Screened as Ineligible) 
Tallies of Reasons for Ineligibility

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 79 of 121 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4: Dataset Flow Diagram for Enrolled Subjects 
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 80 of 121 
True RCAO in 
the Patient 
Population 
Overall Power to 
demonstrate 
Primary Efficacy 
(at Interim or Full 
Enrollment)  
Probability of 
Stopping Early 
for Success 
(Interim 
Analysis) 
Probability of 
Study Success at 
Full Enrollment if 
Not Stopped at 
Interim Analysis 
Probability of 
Stopping Early 
for Futility 
(Interim 
Analysis) 
0.35 
2.70% 
1.40% 
2.90% 
60.80% 
0.37 
10.60% 
4.60% 
12.40% 
54.80% 
0.4 
41.40% 
18.00% 
40.90% 
32.20% 
0.42 
68.10% 
33.90% 
62.60% 
17.60% 
0.43 
79.10% 
43.30% 
72.10% 
12.10% 
0.44 
87.70% 
53.20% 
80.50% 
8.00% 
0.45 
93.30% 
62.70% 
86.90% 
4.90% 
0.46 
96.80% 
71.70% 
91.80% 
2.90% 
0.47 
98.60% 
79.30% 
95.00% 
1.60% 
0.5 
99.90% 
93.90% 
99.30% 
0.20% 
 
 
An estimate of the overall Type 1 error rate for this study design can be 
seen in the first row of this table, where the true RCAO in the patient 
population is equal to the performance goal of 35% for the Primary 
Efficacy Endpoint; this estimated Type 1 error rate is 2.7% (2-sided), 
which is below 5%.  An estimate of overall statistical power is 87.7% if 
the true RCAO is 44% in the patient population, and the likelihood of 
stopping early for tentative study success is approximately 79.3% if the 
RCAO in the patient population is 47%.  The likelihood of stopping early 
for futility is approximately 54.8% if the RCAO in the patient population 
is 37%.   
 
 
There are two primary and secondary safety endpoints with formal 
hypotheses that will be tested, and the following are estimates of 
statistical power for each of these respective endpoints at the time of 
the interim analysis.  For each respective endpoint, the purpose of the 
hypothesis test is to ensure that the 2-sided 95% upper confidence limit 
for the estimate is less than a stated performance goal for the endpoint.  
The performance goal, expected outcome, and estimated statistical 
power based upon a sample size of N=150 evaluable subjects (with 
post-procedure data) are provided for each respective endpoint.   
 
 
Statistical Power for Primary Safety Endpoints 
Primary Safety Endpoint: Incidence of Major Ipsilateral Stroke 
and/or Death 
For a successful evaluation of this endpoint, the upper confidence limit 
of a 2-sided 95% confidence interval for the proportion of subjects who 
experience major ipsilateral stroke and/or death through 12 months 
post-procedure will be less than 25% (regardless of whether this 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 81 of 121 
analysis is conducted at the interim analysis with N=160 subjects at 6 
months follow-up or the final analysis with N=320 subjects at 12 months 
follow-up).  The anticipated rate of major ipsilateral stroke and/or death 
in the population is not greater than 14%, so it is estimated that the 
statistical power to demonstrate this endpoint with a sample size of 
N=150 evaluable subjects (MITT subjects with post-procedure data) is 
approximately 92.5%.  This power estimate was calculated with the 
following SAS code:  
 
 
 
SAS Code for Power Estimation:  
Incidence of Major Ipsilateral Stroke and/or Death 
 
 
 
 
 
 
 
 
 
 
 
Primary Safety Endpoint: Incidence of In-Stent Stenosis 
For a successful evaluation of this endpoint, the upper confidence limit 
of a 2-sided 95% confidence interval for the rate of in-stent stenosis will 
be observed to be less than 15% (regardless of whether this analysis 
is conducted at the interim analysis with N=160 subjects at 6 months 
follow-up or the final analysis with N=320 subjects at 12 months follow-
up).  The anticipated rate of in-stent stenosis at 12 months in the 
population is not greater than 6%, so it is estimated that the statistical 
power to demonstrate this endpoint with a sample size of N=150 
evaluable subjects (MITT subjects with post-procedure data) is 
approximately 95.5%.  This power estimate was calculated with the 
following SAS code:  
 
SAS Code for Power Estimation:  
Incidence of In-stent Stenosis 
 
 
 
 
 
   
 
 
proc power; 
   onesamplefreq test=z method=normal 
      nullproportion = 0.25 
      proportion = .14 
        alpha = 0.05 
        sides = 2 
      ntotal = 150 
      power = .; 
      title 'z Test, uses null proportion for 
variance estimate'; 
run; 
proc power; 
   onesamplefreq test=z method=normal 
      nullproportion = 0.15 
      proportion = .06 
        alpha = 0.05 
        sides = 2 
      ntotal = 150 
      power = .; 
      title 'z Test, uses null proportion for 
variance estimate'; 
run; 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 82 of 121 
 
 
 
9.10 Analysis Plan 
 
9.10.1 General Considerations 
 
All statistical processing will be performed using SAS® Version 9.2 or 
higher, unless otherwise noted. A separate Statistical Analysis Plan 
(SAP) document that provides greater detail on data derivations and 
the analyses to be performed will be developed prior to the planned 
interim analysis. 
 
Summary tables will be provided for subject demographics and 
baseline variables for each dataset which has been defined.  
Effectiveness and safety endpoints will be summarized at each 
protocol-specified evaluation.  Endpoint analyses will be conducted on 
pooled data from all sites.  In addition, endpoint data will be presented 
by investigator/site; sites having fewer than 6 subjects will be pooled to 
comprise one group of all small sites..  For the primary effectiveness 
and primary safety endpoints, the homogeneity of study endpoint data 
will be assessed with a chi-square test of proportions across sites.       
 
Descriptive statistics for continuous variables will include number of 
subjects, mean, standard deviation, median, minimum, and maximum.  
Descriptive statistics for dichotomous/categorical variables will include 
number and percent of subjects.   
 
A 2-sided alpha of 0.05 will be used for statistical testing and confidence 
intervals unless otherwise noted.  Detail on the level of significance for 
testing the primary endpoint analysis in this group sequential design is 
addressed in Section 10.3 (Levels of Significance).   
 
9.10.2 Subject Disposition 
 
All subjects who are screened or enrolled (consented) into the study 
will be accounted for in Subject Disposition, overall and by study site; 
see section 10.8 (Analysis Sets). 
 
9.10.3 Aneurysm and Procedure Characteristics 
 
For aneurysms in which an ENTERPRISE procedure is attempted, 
baseline characteristics to be summarized will include presenting 
symptom and results of the pre-procedure treatment cerebral 
angiogram – i.e., parent vessel diameter (distal and proximal), percent 
occlusion, aneurysm location, aneurysm shape, dome height, neck 
width, dome-to-neck ratio.  Where the aneurysm is located at a distal 
vessel bifurcation, the number of vessels with a bifurcation will be 
reported; measurements of the parent vessel diameter will be taken in 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 83 of 121 
both distal vessels and summarized by the total number of distal 
vessels.  A summary of aneurysm characteristics will be presented 
overall and by study site.  
 
The following data will be summarized for the index procedure: 
• the number of procedures (index), attempted and successful 
• the number and duration of procedures to treat the target aneurysm 
(treatment with  stenting and coiling) 
• the number of stent recaptures 
• total index procedure duration from time the femoral artery is 
accessed until the time the guiding catheter is removed from the 
subject,  
• procedure technique to include catheter type and technique, guide 
wire type, guiding catheter type, adjunctive techniques 
• number, size, diameter, length and type of coils deployed into the 
target aneurysm. 
 
In addition, procedure resource utilization will be described for the 
following parameters:   
• contrast use, in particular, the amount of contrast used 
• fluoroscopy time 
• length of in-patient hospital stay – i.e. days from the date of the index 
procedure to the hospital discharge date  
• re-hospitalization or prolongation of hospitalization 
• number of days in each hospital ward/floor   
• discharge location of the subject 
• total number of days in the hospital and days in each hospital 
ward/floor  
 
9.10.4 Analysis of Angiographic Screening Failures 
Data will be collected from the time of consent through a 72-hour safety 
evaluation or hospital discharge (whichever comes first) or, in the case 
of an AE that has not resolved by 72 hours post-angiogram or 
discharge, the resolution of the AE.  Demographics, baseline subject 
and aneurysm characteristics, procedural and safety data will be listed 
and summarized separately from the other analysis populations.  
 
9.10.5 Analysis of Primary and Secondary Endpoints  
 
Primary effectiveness and primary safety endpoint analyses will be 
conducted on the modified intent-to-treat (MITT) population, where 
subjects with missing data at the time of endpoint analysis will be 
imputed as last observation carried forward (LOCF); some MITT 
subjects who receive the device but in whom there is no post-
procedure data will also be included in the primary effectiveness 
endpoint analysis as failures; see section 9.5 on the handling of 
missing data.  Subjects with no post-procedure endpoint data upon 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 84 of 121 
which to base a LOCF imputation will be excluded from all other 
analyses.   
 
All subjects who have died prior to an evaluation will have an mRS 
score of 6 imputed for that time point for analysis purposes.   
 
All other analyses based upon MITT or PP population data will be 
based upon actual data, with no data imputation.  
 
Supportive analyses the Primary effectiveness and primary safety 
endpoint analyses will be conducted on the.   
 
All secondary efficacy endpoints will be summarized on both the MITT 
and PP analysis sets.  All secondary safety endpoints will be 
summarized on the MITT analysis set.   
 
9.10.6 Supplemental Safety Follow-up Report on Continued Follow-up 
Subjects  
 
A supplemental safety follow-up report will be written to summarize 
safety outcomes for CF subjects  through the 2 year follow-up 
evaluation.  There are no formal primary or secondary endpoints 
regarding these outcomes.   
 
9.10.7 Subgroup Analyses   
 
Data summaries of the primary safety and effectiveness endpoints and the 
secondary safety endpoint regarding increase in mRS at 12 months post-
procedure will be presented for the ITT and PP populations, as 
appropriate, in the following subgroups:  
 
• study site 
• gender  
• age category (21-39, 40-49, 50-59, 60-69, and 70-80 years).   
• subject has any (1 or more) Hydrocoil implanted vs no Hydrocoil 
implanted. 
 
9.11 Plans for Interim Analysis 
 
This study is a group sequential design in which one primary endpoint interim 
analysis will be conducted after N=160 subjects have been enrolled and 
followed through 6 months post-procedure. The purpose of the interim 
analysis will be to determine whether or not to terminate the trial early for futility 
or tentative success.  This analysis will be a test of the primary efficacy 
endpoint only, and will be conducted after N=160 subjects have been enrolled 
and have reached 6 months post-procedure.  LOCF imputation methodology 
will be utilized for subjects who do not have 12 month post-procedure data, so 
that 6 month primary endpoint data will serve as a surrogate for 12 month data 
for subjects who have not yet reached 12 months post-procedure.   

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 85 of 121 
 
The trial will stop early and will be deemed to be tentatively successful if the 
two-sided unadjusted p-value for this primary efficacy endpoint analysis is 
below 0.031.  If the stopping rule is met for the trial to stop early for tentative 
success, a final confirmatory analysis will be conducted when all subjects have 
reached 12 months post-procedure; a p-value threshold of 0.031 will be used 
for this final confirmatory analysis.  The trial will stop early for futility and it will 
be decided that the study would not have been successful even if the study 
would have continued to an enrollment of N=320 if the two-sided unadjusted 
p-value for this primary efficacy endpoint analysis is above 0.358.  If neither of 
these criteria are met, or if the confirmatory analysis for early success is not 
satisfied, then enrollment will commence until the total sample of N=320 
subjects have been enrolled (including the original N=160), and the final 
endpoint analysis will be conducted after all 320 subjects have reached 12 
months post-procedure.  In the case that the study continues to a full 
enrollment of N=320, the study will be deemed to be a success if the two-sided 
unadjusted p-value for the final primary efficacy endpoint analysis is below 
0.031.    
 
If a decision is made to stop the trial early for either futility or tentative success, 
follow-up will continue through 12 months post-procedure for all enrolled 
subjects. Further details of this planned interim analysis are provided in 
sections 9.1 (Study Design), 9.3 (Levels of Significance), 9.7 (Hypotheses), 
and 9.9 (Sample Size Justification).      
 
The interim analysis for determining whether to stop the trial early for futility or 
tentative success will be conducted by the sponsor, and will be carried out on 
the MITT dataset.   
 
There are no other planned interim analyses for the purpose of stopping the 
trial early.  In addition to the annual progress report, interim reports will be 
provided to the FDA every four months (or an additional two interim reports) 
in effort to provide regular assessments of the progress and safety of the 
study. 
 
A study report will be filed for evaluation of the primary endpoint after all 
subjects have completed their 12 Month follow-up visit or prematurely 
terminated study participation prior to 12 months post-procedure.  The 
remaining data out to 24 months post-procedure will be submitted as a post-
approval study (PAS) report once all subjects have completed their 24 Month 
follow-up visit or prematurely terminated study participation prior to 24 months 
post-procedure.  No adjustment for multiplicity is proposed since the primary 
analysis will be the analysis at 12 months post-procedure. 
 
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 86 of 121 
10 SAFETY AND ADVERSE EVENTS 
 
10.1 Adverse Events/Complications 
 
10.1.1 Potential or Anticipated Adverse Events/Complications - 
ENTERPRISE 
 
The study is designed to minimize potential risks and complications in 
the subjects.  However the following adverse events associated with 
intracranial catheterization or intracranial stent placement have been 
identified as possible (anticipated) adverse events associated with the 
use of the CODMAN ENTERPRISE® Vascular Reconstruction Device 
and Delivery System or with the procedure:  
 
• Allergic reaction including, but not limited to, contrast, Nitinol 
metal and medications  
• Aneurysm Bleed or Rebleed 
• Aneurysm recanalization or regrowth 
• Arm cramps 
• Arrhythmia 
• Arteriovenous fistula  
• Cerebral edema  
• Cerebral infarct 
• Coil migration or prolapse into normal vessel adjacent to 
aneurysm  
• Cold hands and feet 
• Confusion 
• Cranial nerve II deficit 
• Cranial nerve palsy 
• Death   
• Deployment Difficulty 
• Dissection  
• Edema 
• Emboli (air, tissue or thrombotic) 
• Emergent neurosurgery 
• Eyes fixed unable to focus 
• Facial numbness 
• Failure to deliver stent 
• Fever 
• Floaters, blurry vision  
• Fracture of delivery wire 
• Groin Hemorrhage 
• Headache 
• Hip pain 
• Incomplete aneurysm occlusion 
• Infection 
• Infection at insertion site 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 87 of 121 
• Insertion site hematoma / bleeding 
• Injury to normal vessels or tissue 
• Intracerebral hemorrhage 
• Ischemia  
• Laboratory abnormality 
• Left, right-sided weakness 
• Mid, low back pain 
• Myocardial Infarction 
• Nausea  
• Neck pain 
• Neurological deficits  
• Not feeling right 
• Occlusion of side branch 
• Pain at insertion site 
• Panic attack 
• Perforation 
• Pseudoaneurysm 
• Radiation effects that include alopecia, cataracts, tissue burns 
ranging in severity from skin reddening to ulcers and delayed 
neoplasia1  
• Renal failure 
• Retroperitoneal Hematoma  
• Rupture, vessel or aneurysm 
• Stenosis of stented segment  
• Seizures 
• Stent migration / embolization 
• Stent thrombosis / occlusion 
• Stroke  
• Total occlusion of treated segment 
• Transient elevation or decrease in blood pressure 
• Transient ischemic attack 
• Upset stomach 
• Vasospasm 
• Vessel thrombosis 
• Visual field decrease 
 
10.1.2 Adverse Event Definitions 
 
An Adverse Event is any untoward medical occurrence in a study 
subject, and which does not necessarily have a causal relationship with 
the product or treatment; any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of the study 
devices, whether or not considered related to the devices. A preexisting 
                                                 
 
1 Radiation risk increases with exposure time and can be reduced by limiting exposure by using 
sufficient shielding, reducing fluoroscopy times, and modifying X-ray technical factors where 
possible. 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 88 of 121 
condition should not be reported as an adverse event unless the 
condition worsens or episodes increase in frequency during the 
adverse event reporting period. 
 
An Adverse Device Effect (ADE) is a device-related Adverse Event.   
 
A Serious Adverse Event (SAE) is any significant adverse experience, 
including those that may be either life-threatening or involving 
permanent or long term injuries but excluding injuries that are non-life-
threatening and/or that are temporary and reasonably reversible. A 
Serious Adverse Event includes any of the following events that may or 
may not be considered related to the device;  
• Results in Death, 
• Is life-threatening, 
• Requires inpatient hospitalization or prolongation of existing 
hospitalization, 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
 
Serious Adverse Events may or may not be related to the device.   
 
An Unanticipated Adverse Device Effect (UADE) is defined as 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 
problem associated with a device that affects the rights, safety, or 
welfare of study subjects may also be considered UADEs.  
 
All Adverse Events, Adverse Device Effects, Serious Adverse Events, 
and Unanticipated Adverse Device Effect must be recorded, as 
applicable, on the eCRF.  
 
Note:  
 
• Recanalization is not considered an adverse event since this is not an 
untoward medical occurrence to the subject, but rather an anticipated 
occurrence in the evolution of aneurysms 
 
• Adverse events include abnormalities in physiological testing or 
physical examination that require clinical intervention or further 
investigation. 
 
• Subjects should be encouraged to report AEs spontaneously or in 
response to general, non-directed questioning (e.g. “how has your 
health been since the last visit?”).  Any time during the clinical 
investigation, the subject may volunteer information that resembles an 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 89 of 121 
AE.  If it is determined that an AE has occurred, the investigator should 
obtain all the information required to complete the AE form. 
 
 
 
10.1.3 Adverse Event Severity and Causal Relationship Ratings  
 
The Investigator will record the nature, severity, treatment and outcome of 
the AE, and will determine the relationship to device, procedure or underlying 
disease.  This classification of the event determines the reporting procedures 
to be followed.  The sponsor may upgrade the classification as required for 
reporting purposes. 
 
For purposes of this protocol, the following definitions will apply. 
 
Adverse Event Severity Rating 
The following categories of adverse event severity are to be used: 
 
• Mild:  
Awareness of sign or symptom that does not interfere 
with the subject’s usual activity or is transient, resolved 
without treatment and with no sequelae, 
• Moderate: Interferes, but does not hinder, the subject’s usual   
activity and/or may require treatment, 
• Severe:  
Symptom(s) causing severe discomfort and significant 
impact on the subject’s usual activity and requires 
treatment or intervention. 
 
Causal Relationship Rating 
 
The causal relationship to study device, study procedure, and 
underlying disease will be evaluated as follows: 
 
• Definitely Related: The adverse event is clearly related to the test 
product. 
 
• Probably Related: The adverse event is temporally associated and 
plausibly related to the product/procedure but there are also potential 
alternative explanations, though the alternatives are not likely. 
 
 
• Possibly Related: The adverse event may be related, scientifically 
plausible, but there are also alternative explanations. 
 
• Unlikely Related: The adverse event is doubtfully related. 
 
• Not Related: The adverse event is clearly not related. The adverse 
event is most plausibly explained by the subject’s underlying medical 
condition or their concomitant therapy, or the adverse event has no 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 90 of 121 
plausible relationship to study treatment, or the adverse event has 
no plausible biological relationship to the study treatment. 
 
 
10.2 Unanticipated Adverse Device Effects   
 
The investigator shall submit to the Sponsor a report of any unanticipated 
adverse device effect (UADE) occurring during the investigation as soon as 
possible but no later than 72 hours after the investigator first learns of the 
effect.  Additionally, if a UADE occurs in a device other than the study device 
(ENTERPRISE), follow FDA and manufacturer’s instructions for reporting 
the UADE. 
 
Unanticipated adverse device effects are defined as 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 problem associated with a 
device that affects the rights, safety, or welfare of study subjects may also 
be considered UADEs.  
 
If the Sponsor determines that an unanticipated adverse device effect 
presents an unreasonable risk to subjects, all or parts of investigations 
presenting that risk will be terminated as soon as possible.  Termination will 
occur not later than five working days after the Sponsor makes this 
determination and not later than fifteen working days after the Sponsor first 
receives notice of the effect. 
 
 
10.3 Management of Post-procedure Symptoms   
 
If clinical symptoms deteriorate, the subject must be seen and assessed by 
the study investigator immediately. This does not exclude the subject from 
the study and follow-up should continue. All subjects entered into the study 
remain in the study until the 24 month  post procedure study follow-up visit 
has been reached. 
 
If a subject presents with an adverse event at the 24 month  study visit, 
he/she will receive appropriate treatment for that condition.  If the subject’s 
condition precludes him or her from undergoing any 24 month  evaluation 
specified by the protocol, the subject would be discharged from the study 
after the Investigator documents in the subject’s medical record that a stable 
clinical endpoint has been reached, or that the subject’s status is not 
associated with the device or procedure. 
 
Following the 24 month study visit, the subject will be discharged from the 
study.  However, if at the 24 month  study visit the investigator determines 
there are indications of delayed hydrocephalus or in-stent stenosis 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 91 of 121 
occurring, additional follow-up may be required, including MRI or CT at the 
Investigator’s discretion.  If this occurs, the investigator will determine the 
additional follow-up required at that time and inform the study sponsor. 
 
10.4 Subject Death  
 
Subject death during the investigation must be reported to the Sponsor as 
soon as possible but no later than 72 hours of the investigator’s knowledge 
of the death.  Notification of death must include a brief statement of the 
pertinent details and be signed by the investigator.  A copy of the death 
records, death certificates and an autopsy report (if performed) must be sent 
to the Sponsor. 
 
 
10.5 Adverse Event Reporting Period   
 
10.5.1 Adverse Event Reporting for Angiographic Screening Failure 
 
Any subject, who had an angiogram, but was not entered, will be 
followed for the period 72 hours following the end of the angiographic 
procedure to determine study angiographic eligibility, or until discharge, 
whichever comes first, or to resolution of any adverse event, whichever 
is longer.  Any AEs that occurred from the time written consent was 
obtained through the period described must be entered into the eCRF 
database. 
 
 
10.5.2 Adverse Event Reporting for Entered Subjects 
 
The adverse event reporting period for this study begins at the time the 
study informed consent is signed and ends at the twenty-four month 
follow-up unless noted otherwise in Section 11.3.  Adverse events that 
occur in subjects during the adverse event reporting period must be 
entered into the eCRF database.  All required treatments and outcomes 
of the adverse event must be recorded. 
 
 
10.6 Recording Adverse Event Information   
 
The investigator is to report all directly observed adverse events and all 
adverse events spontaneously reported by the subject via eCRF. In addition, 
each subject in the study will be questioned about adverse events on the day 
of hospital discharge, and at thirty (30) days, six (6) months, twelve (12), 
eighteen (18) months, and twenty-four (24) month follow-ups after the index 
procedure.  All required treatments and outcomes of the adverse event must 
be recorded. 
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 92 of 121 
10.7 Device Product Complaints, Failures, and Device Malfunctions 
 
All study device/product complaints, failures, and malfunctions (with or 
without an associated adverse event), must be documented on the 
appropriate eCRFs, and reported to the Sponsor within 10 business days. 
Another study device may be used.  If the study device is not implanted it 
must be retained at the site until the Sponsor provides directions on how to 
return the device for analysis.  
 
A study device has malfunctioned if it meets the following definition: The 
failure of a device to meet its performance specifications or otherwise 
perform as intended.  Performance specifications include all claims made on 
the labeling for the device. The intended performance of a device refers to 
the intended use for which the device is labeled or marketed.   
 
A product complaint is defined as: Any written, electronic or oral 
communication that alleges deficiencies related to the identity, quality, 
durability, reliability, safety, effectiveness or performance of a device.  
 
If a device other than the study device (ENTERPRISE Investigational 
Device) malfunctioned, follow the manufacturer’s instructions, and do not 
report as a product complaint on the eCRF and/or do not complete the study 
Device Malfunction eCRF. 
 
 
10.8 Reporting of Adverse Events and Study Device Product Complaints 
and Device Malfunctions 
 
As noted in the Table 6,  a serious adverse event is to be reported 
immediately via eCRF but no later than 72 hours after knowledge of the 
event.  
 
It is the responsibility of the investigators to inform their Institutional Review 
Board (IRB) of Adverse Events, Serious Adverse Events, Unanticipated 
Adverse Device Effects, and Device Malfunctions/Deviations as required by 
their IRB procedure and country law. The sponsor is responsible for sending 
information on the unanticipated adverse device effect to the regulatory 
authorities.  In the instance of death a copy of the death certificate or other 
relevant documentation (autopsy report) should be provided. If an autopsy 
is performed, a copy of the autopsy report may be requested and sent to the 
regulatory authorities, if required. 
 
If the ENTERPRISE device does not perform as expected, but is without any 
adverse event, the investigator must document on the appropriate eCRFs, 
and notify the Sponsor within 10 business days. If the study device is not 
implanted it must be retained at the site until the Sponsor provides 
instructions on the return process.   
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 93 of 121 
If a serious adverse event is related to the performance of the study device, 
the Sponsor must be notified immediately via eCRF immediately but no later 
than 72 hours after knowledge of the event. If the study device was not 
implanted it must be retained at the site until the Sponsor provides 
instructions on the return process.   
   
Non-Serious adverse events are to be reported via eCRF within 10 days of 
learning of the event.  
 
If a device other than the study investigational ENTERPRISE stent 
malfunctioned, follow the manufacturer’s instructions, and do not report as a 
product complaint on the eCRF and/or do not complete the study Device 
Malfunction eCRF. 
 
 
Table 6: Report requirements of adverse events, product complaint and 
device malfunctioning 
 
 
Classification 
 
Reporting time 
 
Type of report 
Death 
Notify Sponsor as soon as 
possible but no later than 72 
hours of learning of event. 
Notify IRB as required 
eCRF 
Unanticipated Adverse 
Device Effects (UADE) 
Notify Sponsor as soon as 
possible but no later than 72 
hours of learning of event. 
Notify IRB as required 
eCRF  
Serious Adverse Events 
(whether related to the 
performance of the study 
device or not) 
Notify Sponsor as soon as 
possible but no later than 72 
hours of learning of event. 
Notify IRB as required 
eCRF 
Non-serious Adverse 
Events 
Notify Sponsor within 10 
business days of learning of 
event. Notify IRB as required 
eCRF 
Study Device Product 
Complaint or Device 
Malfunction 
With or Without  
Adverse Event 
Notify Sponsor within 10 
business days of learning of 
event. Notify IRB as required  
eCRF  
 
 
10.8.1 Follow-up of Unresolved Adverse Events    
 
 All adverse events should be followed until they are resolved or the   
 subject’s participation in the study ends.  
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 94 of 121 
10.9 Medical Monitoring 
 
10.9.1 Clinical Events Committee   
 
An independent Clinical Events Committee (CEC) will review and 
adjudicate   the relationship of AEs to the device, procedure and/or 
underlying disease.  The CEC’s determinations of relationship are 
those that will be used in the safety analysis.  
 
10.9.2 Data and Safety Monitoring Board 
 
An independent Data and Safety Monitoring Board (DSMB) will be 
responsible for monitoring the accumulated interim data as the study 
progresses to ensure patient safety. All safety review procedures will 
be established and agreed upon in the DSMB Charter prior to 
enrollment of the first subject. 
 
Once the study begins, the DSMB will meet periodically to review 
safety data. The DSMB may request more frequent meetings if 
necessary to fulfill its charge.  
 
 
11 QUALITY CONTROL AND QUALITY ASSURANCE  
 
11.1 Organizational Preparations 
 
A site visit will be performed by the Sponsor or their designee prior to the 
start of the study to review the study protocol in detail and ensure the 
availability of appropriately trained personnel to conduct the study according 
to Good Clinical Practices (GCP) procedures.  This protocol will be 
conducted under the principles described in the Declaration of Helsinki and 
the Code of Federal Regulations. 
 
11.2 Training 
 
In order to provide for safe use of the CODMAN ENTERPRISE® Vascular 
Reconstruction Device and Delivery System, the primary concern in operator 
selection for this study is adequate experience, commitment to safety, and 
consistency in adherence to the clinical protocol.  Therefore, the 
investigators selected to participate will be neurointerventionalists who, by 
virtue of their experience and training, are accomplished in stent placement 
in intracranial arteries.   
 
 
11.3 Case Report Forms    
 
Electronic Case Report Forms (eCRFs) in an electronic data collection 
(EDC) system will be used to collect all subject data during the study.  

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 95 of 121 
Detailed description of the eCRF components and eCRF completion 
instructions are included in the Manual of Operations.  
 
eCRFs must be fully completed for each subject and, signed electronically, 
in a timely manner so that they are available for review in the EDC system 
by Sponsor appointed monitors.  
 
 
Data Reporting  
 
The Principal Investigator, or an individual designated by him/her, is 
responsible for recording all data from the study on the eCRFs supplied by 
the Sponsor in the EDC system.   
 
The Principal Investigator is required to electronically sign the eCRFs on the 
appropriate page(s) to verify that he/she has reviewed the entered data. 
 
A Sponsor appointed monitor will verify completed eCRFs in the EDC system 
at regular intervals throughout the study.  To this end, the Principal 
Investigator must permit inspection of the study files, and subject medical 
records by Sponsor appointed monitors and authorized government 
agencies. 
 
ENTERPRISE device accountability and usage will be recorded on the 
Device Accountability Log which will be supplied to the investigator. Subject 
specific information will also be collected in the subject’s eCRFs. 
 
11.4 Monitoring and Source Data Verification  
 
The purpose of monitoring the study is to verify that the rights and well-being 
of subjects are protected, that the reported study data are accurate, 
complete, and verifiable from source documents and that the conduct of the 
study is in compliance.  Ongoing site monitoring will be conducted by the 
Sponsor or designees to ensure compliance to Good Clinical Practices, 
Code of Federal Regulations, the protocol and applicable laws and/or 
regulatory requirements.  
 
The investigator and his/her staff will be expected to cooperate with the study 
responsible clinical research associate (CRA) (may also be referred to as 
Study Monitor) and to be available during at least a portion of the monitoring 
visits to answer questions and to provide any missing information. 
 
Source data verification (SDV) is an essential element to ensure accuracy 
and credibility of the data and conclusions derived from clinical 
investigations. All electronic Case Report Forms will be reviewed for 
completeness and clarity by the Study Monitor.  Entries on the eCRF are 
verified using the original documents of SDV such as subject files, informed 
consent forms signed by subjects, device accountability forms, and original 
recordings from automated instruments, X-ray films, laboratory notes, etc. 
whereby subject privacy is to be respected. 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 96 of 121 
 
Missing or unclear data shall be supplied or clarified as necessary 
throughout the study.  The Sponsor or designee may request further 
documentation such as physician and/or radiology suite procedure notes 
when adverse events are observed and reported. 
 
Clinical site personnel will perform primary data collection based on source-
documented hospital chart reviews.   
 
11.5 Data Management 
 
 
Clinical site personnel will enter data into electronic case report forms in the 
EDC system provided by the Sponsor for study data collection.  The Sponsor 
or designee will be responsible for confirming the overall integrity of the data.  
 
11.6 Securing Compliance   
 
If it is discovered that an investigator is not complying with the signed 
agreement, the protocol, GCP requirements, the requirements of the Code 
of Federal Regulations or other applicable regulations, or any conditions of 
approval imposed by the reviewing IRB or regulatory authorities, Codman 
Neuro is required to promptly either secure compliance or discontinue 
shipments of the device to the investigator and terminate the investigator’s 
participation in the investigation.  Codman Neuro will also require the 
investigator to dispose of or return the device, unless this action would 
jeopardize the rights, safety or welfare of a subject. 
 
11.7 On-Site Audits  
 
A trained and properly authorized employee of the Sponsor or designee, as 
well as regulatory authorities may request access to all study records, 
including source documents, for inspection and copying.   
 
 
12 ETHICS AND REGULATORY CONSIDERATIONS  
 
12.1 Institutional Review Board (IRB) 
 
The protocol and informed consent must be submitted to the appropriate IRB 
and other requirements per country law, and written approval must be 
obtained and submitted to the Sponsor prior to enrolling any subjects. 
 
The investigator will promptly report to the IRB all changes in research activity 
and all unanticipated problems involving risks to human subjects or others, 
and will not make any changes in the research without IRB approval, except 
when necessary to eliminate immediate hazards to human subjects.   
 
The investigator must report to the IRB at least yearly on the progress of the 
investigation.  A letter from the IRB should document continuing IRB review.  

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 97 of 121 
Notification to the IRB by the investigator within 3 months after completion, 
termination, or discontinuation of the study at the specific site must be 
documented. 
 
Other investigator responsibilities to the IRB and sponsor include the 
following: 
 
• During the conduct of the study, submit progress reports to the IRB as 
required. 
• Report unexpected adverse device effects (UADE) that occur during the 
study to the IRB and Sponsor.  A copy of the correspondence should be 
provided to the study monitor. 
• As required, obtain approval from the IRB for protocol amendments and 
for revisions to the informed consent or subject recruitment 
advertisements. A copy of the correspondence should be provided to the 
study monitor. 
• Notify the IRB and Sponsor of any protocol deviation to protect the life or 
physical well-being of a subject in an emergency within 24 hours but in no 
instance later than 5 days after the emergency occurred. 
• Provide IRB with any other information it requests before or during the 
conduct of the study. 
• Maintain 
a 
file 
of 
study-related 
information 
that 
includes 
all 
correspondence with the IRB. 
• Notify IRB within 3 months after study completion, termination or 
discontinuation. 
• Notify the Sponsor, within 24 hours, of withdrawal of approval by the 
reviewing IRB.  
 
 
12.2 Informed Consent 
 
Subject's informed consent must be obtained (and other locally required 
documents) and documented according to the principles of informed consent 
in the current version of the Declaration of Helsinki for Protection of Human 
Subjects. 
 
Prior to obtaining informed consent, information should be given in a 
language and at a level of complexity understandable to the subject in both 
oral and written form by the Investigator or designee. Subjects should not be 
coerced, persuaded, or unduly influenced to participate or continue to 
participate in the study. Subject must be given ample time and opportunity 
to inquire about details of the study and all questions about the study should 
be answered to the satisfaction of the subject or the representative. 
 
The subject must receive a copy of the signed and dated informed consent. 
 
The consent form that is to be used must be approved by both the reviewing 
IRB and by the Sponsor. 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 98 of 121 
In emergency cases, where it may not be possible to obtain the subject’s 
written informed consent in order to save the life and well-being of the 
subject, the investigator must complete the following actions: 
 
 
• If an investigator uses a device without obtaining informed consent, 
the investigator shall report such use to the Sponsor and the 
reviewing IRB within 24 hours after the use occurs.  
• For failure to obtain written informed consent prior to the subject’s 
participation in the study, the investigator must document why 
informed consent was not obtained, obtain written concurrence by 
another licensed physician, and provide a brief description of the 
circumstances justifying the failure to obtain informed consent.   
 
 
 
12.3 Confidentiality  
 
All information and data sent to the Sponsor concerning subjects or their 
participation in this study will be considered confidential. All data used in the 
analysis and reporting of this evaluation will be used in a manner without 
identifiable reference to the subject.  The Principal Investigator consents to 
visits by the staff of the Sponsor  and its authorized representatives as well 
as regulatory authorities, which governs the conduct of clinical investigations 
in the EU/US.  
 
 
12.4 Insurance  
 
The Sponsor will take out liability insurance coverage concerning the device 
for every subject included in the study. This product liability insurance 
coverage is available to the investigator and to the subject. 
 
 
13 RECORD KEEPING 
 
13.1 Study Initiation  
 
Before the study at a site can begin, the Sponsor must have all of the 
following required regulatory documents:  
 
• IRB approval of the  study protocol and informed consent 
• Principal Investigator’s C.V.  
• Sub-investigator(s) C.V(s) , if applicable 
• Principal Investigator’s Financial Disclosure 
• Sub-investigator(s) Financial Disclosure, if applicable 
• Executed Clinical Research Agreement  
• Statement of Investigator Agreement of Principal Investigator  
• Statement of Investigator Agreement of Sub-Investigator, if applicable  
• Name and address of Laboratory 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 99 of 121 
• Laboratory certification (current) 
• Laboratory normal values/reference ranges (current) 
 
In addition to the documents required prior to the study, other documentation 
may be required during the course of the study. 
 
 
13.2 Retention of Records 
 
The investigator must retain the following essential study documents until 
the Sponsor authorizes disposal.  Records that relate to each subject’s 
identity (subject identification code) to his or her identity on the CRF’s must 
be retained for a period of 2 years after the latter of the following two dates:  
the date on which the study is terminated or completed, or the date that the 
records are no longer required for purposes of supporting a pre-market 
approval application.   The following documentation must be available: 
 
• Signed protocol and any amendments, and blank approved informed 
consent form 
• Investigator Brochure and any revisions if applicable 
• Signed Clinical Research Agreement between the Sponsor and 
investigator 
• IRB approval and correspondence 
• Study authorization from the Regulatory Authority for the initiation of the 
clinical study 
• Relevant communications (e.g. letter, meeting notes, notes of telephone 
calls) 
• Laboratory normals and certificates for any laboratory procedure or test 
included in the protocol 
• Documentation of shipment of investigational devices and investigational 
device accountability at site 
• Signed informed consent  
• Signed, dated and completed CRF (copy), documentation of CRF 
corrections, and signature sheet of all persons authorized to make entries 
and/or corrections on CRFs 
• Notification by investigator to the Sponsor and IRB of serious adverse 
events, if any  
• Subject identification codes 
 
The subject’s medical record and other source documents must be kept for 
the maximum time permitted by the hospital, institution or private practice.  
The investigator should take measures to prevent accidental or premature 
destruction of records. 
 
These documents serve to demonstrate investigator compliance with the 
standards of Good Clinical Practices, and with applicable regulatory 
requirements. 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 100 of 121 
If the responsible investigator retires, relocates, or for other reasons 
withdraws from the responsibility of keeping the study records, custody must 
be transferred to a person who will accept the responsibility.  The Sponsor 
must be notified in writing of the names and address of the new custodian. 
 
 
14 REPORTS 
 
14.1 Investigators Final Report  
 
Upon completion or termination of the study a final report will be prepared.  
This report will contain a critical evaluation of all data collected during the 
course of the investigation at each institution.  The report must be signed by 
all participating investigators in the study and will be provided to the IRB as 
required by country specific law.  Any modifications to this final report must 
be reviewed and approved by the Sponsor. 
 
 
15 END OF STUDY 
 
15.1 Planned End 
 
The study will close when all subjects have completed the 24 month follow-
up or have discontinued prematurely. 
 
15.2 Premature End  
 
The study may be discontinued or put on “hold” because of: 
 
• New findings invalidate the earlier positive benefit-risk assessment. 
• The time schedule (recruitment phase) cannot be met (e.g. more than 
doubling of recruitment time). 
• The Sponsor decides to discontinue the study at any time. 
 
15.3 Termination of Center by Sponsor 
 
The Sponsor reserves the right to terminate an investigational site; this may 
include for any of the following reasons (but not be limited to): 
 
• The center cannot comply with the requirements of the protocol 
• Repeated failure to complete eCRFs in a timely manner 
• Failure to report Serious Adverse Events within within 10 business 
days  of knowledge 
• Loss of or unaccounted for investigational device inventory 
• Repeated protocol deviations/violations 
• Investigator leaves the institution and no adequate replacement 
 
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 101 of 121 
15.4 Resumption of Terminated Studies   
 
The Sponsor may not resume a terminated study without IRB and 
FDA/regulatory approval. 
 
 
16 PUBLICATION  
 
 
All submissions for publication will be sent to the Sponsor as outlined in the 
Clinical Research Agreement.   
 
 
 
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 102 of 121 
17 REFERENCES  
 
Alg VS, Sofat R, Houlden H, Werring DJ. Genetic risk factors for intracranial 
aneurysms: a meta-analysis in more than 116 000 individuals. Neurology 2013; 80: 
2154–65. 
 
Atkinson JL, Sundt TM Jr, Houser OW, Whisnant JP. Angiographic frequency of 
anterior circulation intracranial aneurysms. J Neurosurg 1989; 70: 551–55. 
 
Batjer HH, Adamson TE, Bowman GW. Sickle cell disease and aneurysmal 
subarachnoid hemorrhage. Surg Neurol 1991; 36: 145–49. 
 
Bonita R. Cigarette smoking, hypertension and the risk of subarachnoid 
hemorrhage: a population-based case-control study. Stroke 1986; 17: 831–35. 
 
Broderick, T. Brott, T. Tomsick, R. Miller, and G. Huster, “Intracerebral hemorrhage 
more than twice as common as subarachnoid hemorrhage,” Journal of 
Neurosurgery, vol. 78, no. 2, pp. 188–191, 1993. 
 
Broderick JP, Viscoli CM, Brott T, et al, and the Hemorrhagic Stroke Project 
Investigators. Major risk factors for aneurysmal subarachnoid hemorrhage in the 
young are modifiable. Stroke 2003; 34: 1375–81. 
 
Bromberg JE, Rinkel GJ, Algra A, et al. Familial subarachnoid hemorrhage: 
distinctive features and patterns of inheritance. Ann Neurol 1995; 38: 929–34. 
 
Bromberg JE, Rinkel GJ, Algra A, Limburg M, van Gijn J. Outcome in familial 
subarachnoid hemorrhage. Stroke 1995; 26: 961–63. 
 
Brown RD Jr, Wiebers DO, Forbes GS. Unruptured intracranial aneurysms and 
arteriovenous malformations: frequency of intracranial hemorrhage and relationship 
of lesions. J Neurosurg 1990; 73: 859–63. 
 
Burns, Huston 3rd, Layton, Piepgras, Brown Jr., “Intracranial aneurysm 
enlargement on serial magnetic resonance angiography: frequency and risk 
factors,” Stroke, vol. 40, no. 2, pp. 406–411, 2009a. 
 
Burns and Brown Jr., “Treatment of unruptured intracranial aneurysms: surgery, 
coiling, or nothing?” Current neurology and neuroscience reports, vol. 9, no. 1, pp. 
6–12, 2009b. 
 
Chapman AB, Rubinstein D, Hughes R, et al. Intracranial aneurysms in autosomal 
dominant polycystic kidney disease. N Engl J Med 1992; 327: 916–20. 
 
Chason JL, Hindman WM. Berry aneurysms of the circle of Willis; results of a 
planned autopsy study. Neurology 1958; 8: 41–44. 
 
Connolly HM, Huston J 3rd, Brown RD Jr, Warnes CA, Ammash NM, Tajik AJ. 
Intracranial aneurysms in patients with coarctation of the aorta: a prospective 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 103 of 121 
magnetic resonance angiographic study of 100 patients. Mayo Clin Proc 2003; 78: 
1491–99. 
Edwards A, Taylor GW. Ehlers-Danlos syndrome with vertebral artery aneurysm. 
Proc R Soc Med 1969; 62: 734–35. 
 
Fargen et al.; Long-term Results of Enterprise Stent-Assisted Coiling of Cerebral 
Aneurysms; Neurosurgery 71:239–244, 2012 
 
Fiorella, F. C. Albuquerque, P. Han et al., “Preliminary experience using the 
neuroform stent for the treatment of cerebral aneurysms,” Neurosurgery, vol. 54, 
no. 1, pp. 6–16, 2004. 
 
Fogelholm, J. Hernesniemi, and M. Vapalahti, “Impact of early surgery on outcome 
after aneurysmal subarachnoid hemorrhage. A population-based study,” Stroke, 
vol. 24, no. 11, pp. 1649–1654, 1993. 
 
Foroud T, Koller DL, Lai D, et al, and the FIA Study Investigators. Genome-wide 
association study of intracranial aneurysms confirms role of Anril and SOX17 in 
disease risk. Stroke 2012; 43: 2846–52. 
 
Gibbs GF, Huston J 3rd, Qian Q, et al. Follow-up of intracranial aneurysms in 
autosomal-dominant polycystic kidney disease. Kidney Int 2004; 65: 1621–27. 
 
Gounis, M. J. de Leo 3rd, and A. K. Wakhloo, “Advances in interventional 
neuroradiology,” Stroke, vol. 41, no. 2, pp. e81–e87, 2010. 
 
Guglielmi, F. Vinuela, J. Dion, and G. Duckwiler, “Electrothrombosis of saccular 
aneurysms via endovascular approach. Part 2: preliminary clinical experience,” 
Journal of Neurosurgery, vol. 75, no. 1, pp. 8–14, 1991a. 
 
Guglielmi, F. Vinuela, I. Sepetka, and V. Macellari, “Electrothrombosis of saccular 
aneurysms via endovascular approach. Part 1: electrochemical basis, technique, 
and experimental results,” Journal of Neurosurgery, vol. 75, no. 1, pp. 1–7, 1991b. 
 
Inagawa T, Hirano A. Autopsy study of unruptured incidental intracranial 
aneurysms. Surg Neurol 1990; 34: 361–65. 
 
International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured 
intracranial aneurysms—risk of rupture and risks of surgical intervention. N Engl J 
Med 1998; 339: 1725–33. 
 
Johnston SC, Colford JM Jr, Gress DR. Oral contraceptives and the risk of 
subarachnoid hemorrhage: a meta-analysis. Neurology 1998; 51: 411–18. 
 
Juvela S, Hillbom M, Numminen H, Koskinen P. Cigarette smoking and alcohol 
consumption as risk factors for aneurysmal subarachnoid hemorrhage. Stroke 
1993; 24: 639–46. 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 104 of 121 
Kassell NF, Torner JC, Haley EC Jr, Jane JA, Adams HP, Kongable GL. The 
International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: overall 
management results. J Neurosurg 1990; 73: 18–36. 
 
Kissela BM, Sauerbeck L, Woo D, et al. Subarachnoid hemorrhage: a preventable 
disease with a heritable component. Stroke 2002; 33: 1321–26. 
Kivisaari, M. Porras, J. O¨ hman, J. Siironen, K. Ishii, and J. Hernesniemi, “Routine 
cerebral angiography after surgery for saccular aneurysms: is it worth it?” 
Neurosurgery, vol. 55, no. 5, pp. 1015–1024, 2004. 
 
Klatsky AL, Armstrong MA, Friedman GD. Alcohol use and subsequent 
cerebrovascular disease hospitalizations. Stroke 1989; 20: 741–46. 
 
Knekt P, Reunanen A, Aho K, et al. Risk factors for subarachnoid hemorrhage in a 
longitudinal population study. J Clin Epidemiol 1991; 44: 933–39. 
 
Lanterna, G. Tredici, B. D. Dimitrov et al., “Treatment of unruptured cerebral 
aneurysms by embolization with Guglielmi detachable coils: case-fatality, morbidity, 
and effectiveness in preventing bleeding—a systematic review of the literature,” 
Neurosurgery, vol. 55, no. 4, pp. 767–775, 2004. 
 
Laskowitz and B. J. Kolls, “Neuroprotection in subarachnoid hemorrhage,” Stroke, 
vol. 41, supplement 10, pp. S79– S84, 2010. 
 
Lee, M. Baytion, R. Sciacca, J. P.Mohr, and J. Pile-Spellman, “Aggregate analysis 
of the literature for unruptured intracranial aneurysm treatment,” American Journal 
of Neuroradiology, vol. 26, no. 8, pp. 1902–1908, 2005. 
 
Li MH, Chen SW, Li YD, et al. Prevalence of unruptured cerebral aneurysms in 
Chinese adults aged 35 to 75 years: a cross-sectional study. Ann Intern Med 2013; 
159: 514–21. 
 
Longstreth WT Jr, Nelson LM, Koepsell TD, van Belle G. Cigarette smoking, alcohol 
use, and subarachnoid hemorrhage. Stroke 1992; 23: 1242–49. 
 
Longstreth WT, Nelson LM, Koepsell TD, van Belle G. Subarachnoid hemorrhage 
and hormonal factors in women. A population-based case-control study. Ann Intern 
Med 1994; 121: 168–73. 
 
Magnetic Resonance Angiography in Relatives of Patients with Subarachnoid 
Hemorrhage Study Group. Risks and benefits of screening for intracranial 
aneurysms in first-degree relatives of patients with sporadic subarachnoid 
hemorrhage. N Engl J Med 1999; 341: 1344–50. 
 
Maher CO, Piepgras DG, Brown RD Jr, Friedman JA, Pollock BE. Cerebrovascular 
manifestations in 321 cases of hereditary hemorrhagic telangiectasia. Stroke 2001; 
32: 877–82. 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 105 of 121 
Mariani L, Bianchetti MG, Schroth G, Seiler RW. Cerebral aneurysms in patients 
with autosomal dominant polycystic kidney disease—to screen, to clip, to coil? 
Nephrol Dial Transplant 1999; 14: 2319–22. 
 
Meyer FB, Sundt TM Jr, Fode NC, Morgan MK, Forbes GS, Mellinger JF. Cerebral 
aneurysms in childhood and adolescence. J Neurosurg 1989; 70: 420–25. 
 
Mocco, K. V. Snyder, F. C. Albuquerque et al., “Treatment of intracranial 
aneurysms with the Enterprise stent: a multicenter registry,” Journal of 
Neurosurgery, vol. 110, no. 1, pp. 35–39, 2009. 
Moret, C. Cognard, A. Weill, L. Castaings, and A. Rey, “Reconstruction technic in 
the treatment of wide-neck intracranial aneurysms. Long-term angiographic and 
clinical results. Apropos of 56 cases,” Journal of Neuroradiology, vol. 24, no. 1, pp. 
30–44, 1997. 
 
Moyle and A. B. Patel, “Intracranial aneurysms: endovascular treatment,” Mount 
Sinai Journal of Medicine, vol. 77, no. 3, pp. 279–285, 2010. 
 
Müller TB, Sandvei MS, Kvistad KA, et al. Unruptured intracranial aneurysms in the 
Norwegian Nord-Trøndelag Health Study (HUNT): risk of rupture calculated from 
data in a population-based cohort study. Neurosurgery 2013; 73: 256–61. 
 
Nagayama Y, Okamoto S, Konishi T, Suzuki H, Hamanaka H. Cerebral berry 
aneurysms and systemic lupus erythematosus. Neuroradiology 1991; 33: 466. 
 
Naggara, P. M. White, F. Guilbert, D. Roy, A. Weill, and J. Raymond, “Endovascular 
treatment of intracranial unruptured aneurysms: systematic review and meta-
analysis of the literature on safety and efficacy,” Radiology, vol. 256, no. 3, pp. 
887–897, 2010. 
 
Nussbaum, M. T. Madison, M. E. Myers, and J. Goddard, “Microsurgical treatment 
of unruptured intracranial aneurysms. A consecutive surgical experience consisting 
of 450 aneurysms treated in the endovascular era,” Surgical Neurology, vol. 67, no. 
5, pp. 457–464, 2007. 
 
Palubinskas AJ, Perloff D, Newton TH. Fibromuscular hyperplasia, an arterial 
dysplasia of increasing clinical importance. Am J Roentgenol Radium Ther Nucl 
Med 1966; 98: 907–13. 
 
Pierot, L. Spelle, X. Leclerc, C. Cognard, A. Bonafe, and J. Moret, “Endovascular 
treatment of unruptured intracranial aneurysms: comparison of safety of remodeling 
technique and standard treatment with coils,” Radiology, vol. 251, no. 3, pp. 846–
855, 2009. 
 
Raaymakers TW. Aneurysms in relatives of patients with subarachnoid 
hemorrhage: frequency and risk factors. MARS Study Group. Magnetic Resonance 
Angiography in Relatives of patients with Subarachnoid hemorrhage. Neurology 
1999; 53: 982–88. 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 106 of 121 
Rinne J, Hernesniemi J, Puranen M, Saari T. Multiple intracranial aneurysms in a 
defi ned population: prospective angiographic and clinical study. Neurosurgery 
1994; 35: 803–08. 
 
Schievink WI. Genetics of intracranial aneurysms. Neurosurgery 1997; 40: 651–62. 
 
Schievink WI. Genetics and aneurysm formation. Neurosurg Clin N Am 1998; 9: 
485–95. 
 
Schievink WI. Marfan syndrome and intracranial aneurysms. Stroke 1999; 30: 
2767–68. 
 
Schievink WI, Riedinger M, Maya MM. Frequency of incidental intracranial 
aneurysms in neurofi bromatosis type 1. Am J Med Genet A 2005; 134A: 45–48. 
 
Sedat, Y. Chau, L. Mondot, J. Vargas, J. Szapiro, and M. Lonjon, “Endovascular 
occlusion of intracranial wide-necked aneurysms with stenting (Neuroform) and 
coiling: mid-term and long-termresults,” Neuroradiology, vol. 51, no. 6, pp. 401– 
409, 2009. 
Shapiro, J. Babb, T. Becske, and P. K. Nelson, “Safety and efficacy of adjunctive 
balloon remodeling during endovascular treatment of intracranial aneurysms: a 
literature review,” American Journal of Neuroradiology, vol. 29, no. 9, pp. 1777–
1781, 2008. 
 
Shiue I, Arima H, Hankey GJ, Anderson CS, and the ACROSS Group. Modifiable 
lifestyle behaviours account for most cases of subarachnoid hemorrhage: a 
population-based case-control study in Australasia. J Neurol Sci 2012; 313: 92–94. 
 
Storrs BB, Humphreys RP, Hendrick EB, Hoff man HJ. Intracranial aneurysms in 
the pediatric age-group. Childs Brain 1982; 9: 358–61. 
 
Vernooij MW, Ikram MA, Tanghe HL, et al. Incidental fi ndings on brain MRI in the 
general population. N Engl J Med 2007; 357: 1821–28. 
 
Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial 
aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a 
systematic review and meta-analysis. Lancet Neurol 2011; 10: 626–36. 
 
Wiebers DO, Torner JC, Meissner I. Impact of unruptured intracranial aneurysms on 
public health in the United States. Stroke 1992; 23: 1416–19. 
 
Wiebers DO, Whisnant JP, Huston J 3rd, et al, and the International Study of 
Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial 
aneurysms: natural history, clinical outcome, and risks of surgical and endovascular 
treatment. Lancet 2003; 362: 103–10. 
 
Winn HR, Jane JA Sr, Taylor J, Kaiser D, Britz GW. Prevalence of asymptomatic 
incidental aneurysms: review of 4568 arteriograms. Stroke 1983; 14: 121. 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 107 of 121 
Yaşargil MG, Smith RD. Association of middle cerebral artery anomalies with 
saccular aneurysms and moyamoya disease. Surg Neurol 1976; 6: 39–43. 
 
Yong-Zhong G, van Alphen HA.  Pathogenesis and histopathology of saccular 
aneurysms: review of the literature.  Neurol Res.  1990; 12:249–55. 
 
Zacharia BE, Hickman ZL, Grobelny BT, et al. Epidemiology of aneurysmal 
subarachnoid hemorrhage. Neurosurg Clin N Am 2010; 21: 221–33. 
 
 
 
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 108 of 121 
19 APPENDICES 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 109 of 121 
APPENDIX 1: STUDY DEFINTIONS 
 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 110 of 121 
DEFINITIONS 
 
ABRUPT CLOSURE 
New reduced (TICI 0 or 1) flow at the target vessel during the index procedure as 
a result of a mechanical obstruction such as dissection or luminal thrombus.  
Abrupt closure requires proven association with a mechanical dissection of the 
treatment site or instrumented vessel, thrombus, or severe spasm.  
 
ACUTE COMPLETE ANEURYSM OCCLUSION 
The percentage of aneurysms in which a score of 1 (complete obliteration) is 
achieved on the Raymond Scale, without additional procedures for treatment of 
the aneurysm since the index procedure, as assessed immediately post-
procedure. 
 
ACUTE COMPLETE/PARTIAL ANEURYSM OCCLUSION 
The percentage of aneurysms in which a score of 1 or 2 (complete obliteration or 
residual neck) is achieved on the Raymond Scale, without additional procedures 
for treatment of the aneurysm since the index procedure, as assessed 
immediately post-procedure. 
 
ACUTE PERCENT ANEURYSM OCCLUSION  
The percentage of aneurysms, without additional procedures for treatment of the 
aneurysm since the index procedure, as assessed by the Core Laboratory 
immediately post procedure, categorized as follows: 100%, ≥95-99%, ≥90-94%, 
and <90% occlusion.   
 
ACUTE PROCEDURE SUCCESS 
The percentage of aneurysms in which complete coverage across the aneurysm 
neck is achieved and for whom coil mass position is maintained within the sac 
with parent artery patency without additional procedures for treatment of the 
aneurysm since the index procedure, as assessed immediately post-treatment.  
 
ACUTE THROMBOSIS  
Angiographic evidence of thrombosis within the stent within 24 hours of stent 
deployment. 
 
ADVERSE DEVICE EFFECT 
A device-related Adverse Event 
 
ADVERSE EVENT  
Any untoward medical occurrence in a study subject, and which does not 
necessarily have a causal relationship with the product or treatment.; any 
unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of the study devices, whether or not considered related to the 
devices. A preexisting condition should not be reported as an adverse event 
unless the condition worsens or episodes increase in frequency during the 
adverse event reporting period.  Recanalization is not considered an adverse 
event since this is not an untoward medical occurrence to the subject, but rather 
an anticipated occurrence in the evolution of aneurysms.  

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 111 of 121 
 
ADVERSE EVENT OF SPECIAL INTEREST 
Adverse events of Special Interest include:  
• rupture > 24 hours post-treatment,  
• major ipsilateral stroke > 1 month post-treatment,  
• ipsilateral parenchymal hemorrhage > 1 month post-treatment, and/or  
• device migration at the 6 month angiogram.   
 
ANEURYSM DOME 
Refers to the body of the aneurysm. 
 
ANEURYSM NECK 
Refers to the aperture or orifice of an aneurysm. 
 
ANEURYSM SIZE 
Aneurysm size (Meyers et al. 2010):  
 
small (≤ 5mm) 
 
medium (>5 to < 15mm) 
 
large (15 to < 25mm) 
 
BARTHEL INDEX 
Mahoney FI, Barthel D. “Functional evaluation: the Barthel Index.” 
Maryland State Med Journal 1965;14:56-61. Used with permission. 
Feeding 
0 = unable 
5 = needs help cutting, spreading butter, etc., or requires modified diet 
10 = independent 
Bathing 
0 = dependent 
5 = independent (or in shower) 
Grooming 
0 = needs to help with personal care 
5 = independent face/hair/teeth/shaving (implements provided) 
Dressing 
0 = dependent 
5 = needs help but can do about half unaided 
10 = independent (including buttons, zips, laces, etc.) 
Bowels 
0 = incontinent (or needs to be given enemas) 
5 = occasional accident 
10 = continent 
Bladder 
0 = incontinent, or catheterized and unable to manage alone 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 112 of 121 
5 = occasional accident 
10 = continent 
Toilet Use 
0 = dependent 
5 = needs some help, but can do something alone 
10 = independent (on and off, dressing, wiping) 
Transfers (bed to chair, and back) 
0 = unable, no sitting balance 
5 = major help (one or two people, physical), can sit 
10 = minor help (verbal or physical) 
15 = independent 
Mobility (on level surfaces) 
0 = immobile or < 50 yards 
5 = wheelchair independent, including corners, > 50 yards 
10 = walks with help of one person (verbal or physical) > 50 yards 
15 = independent (but may use any aid; for example, stick) > 50 yards 
Stairs 
0 = unable 
5 = needs help (verbal, physical, carrying aid) 
10 = independent  
TOTAL (0–100): 
 
The Barthel ADL Index: Guidelines 
1. The index should be used as a record of what a patient does, not as a 
record of what a patient could do.  
2. The main aim is to establish degree of independence from any help, 
physical or verbal, however minor and for whatever reason.  
3. The need for supervision renders the patient not independent.  
4. A patient's performance should be established using the best 
available evidence. Asking the patient, friends/relatives and nurses 
are the usual sources, but direct observation and common sense are 
also important. However direct testing is not needed.  
5. Usually the patient's performance over the preceding 24-48 hours is 
important, but occasionally longer periods will be relevant.  
6. Middle categories imply that the patient supplies over 50 per cent of 
the effort.  
7. Use of aids to be independent is allowed.  
BLEEDING 
A loss of > 50cc of blood 
 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 113 of 121 
BLEEDING COMPLICATION  
Defined as a procedure-related hemorrhagic event that requires a transfusion 
and/or surgical intervention, a new hospitalization, or a lengthen hospital stay. 
These complications may include a hematoma requiring treatment (i.e., a 
hematoma > 5 cm in diameter occurring at the access site), or retroperitoneal 
bleeding. 
 
CASE RERORT FORM (CRF)  
A printed, optical, or electronic document designed to record all of the protocol-
required information to be reported to the Sponsor on each trial subject. 
 
CEREBRAL ANEURYSM  
An abnormal focal dilatation of a cerebral artery with attenuation of the vessel 
wall. 
 
CEREBROVASCULAR ACCIDENT (CVA), symptomatic (of Neurological Deficit)  
Greater than 30 days duration  
Major: 
NIHSS ≥ 4, mRS ≥ 3 
Minor:  
NIHSS < 4, mRS ≤ 2 
 
CLINICAL COMPLICATION 
A complication that results in an adverse event (i.e., there is a clinical/safety 
impact on the subject). 
 
COILING PROCEDURE 
Placement of one or more endovascular coil(s) used for embolizing an 
intracranial aneurysm.  
 
COMPLETE ANEURYSM OCCLUSION  
The percentage of aneurysms in which a score of 1 (complete obliteration) is 
achieved on the Raymond Scale on a post-procedure angiogram, without 
additional procedures for treatment of the aneurysm since the index procedure. 
 
COMPLETE/PARTIAL ANEURYSM OCCLUSION  
The percentage of aneurysms in which a score of 1 or 2 (complete obliteration or 
residual neck) is achieved on the Raymond Scale on a post-procedure 
angiogram, without additional procedures for treatment of the aneurysm since the 
index procedure. 
 
DATE OF PRESENTATION 
Refers to the date on which subject experienced signs or symptoms leading to 
medical evaluation and diagnosis of the cerebral aneurysm.  Date of presentation 
may not be the same as the date of medical evaluation or diagnosis of the 
aneurysm but should be temporally related. 
 
DEATH  
 
Cardiac death.  Any death due to proximate cardiac cause (eg, MI, low-output 
failure, fatal arrhythmia), unwitnessed death and death of unknown cause, and all 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 114 of 121 
procedure-related deaths, including those related to concomitant treatment, will 
be classified as cardiac death.  
 
Vascular death.  Death caused by non-coronary vascular causes, such as 
cerebrovascular disease, pulmonary embolism, ruptured aortic aneurysm, 
dissecting aneurysm, or other vascular diseases. 
 
Non-cardiovascular death.  Any death not covered by the above definitions, 
such as death caused by infection, malignancy, sepsis, pulmonary causes, 
accident, suicide, or trauma.  
 
All deaths are considered cardiac unless an unequivocal non-cardiac cause can 
be established. Specifically, any unexpected death even in subjects with 
coexisting potentially fatal non-cardiac disease (eg, cancer, infection) should be 
classified as cardiac. 
 
DE NOVO STENOSIS 
An intracranial stenosis that has not been previously treated. 
 
DEVICE MALFUNCTION 
The failure of a device to meet its performance specifications or otherwise 
perform as intended.  Performance specifications include all claims made on the 
labeling for the device. The intended performance of a device refers to the 
intended use for which the device is labeled or marketed. 
 
DISSECTION 
A flow-limiting tear or flap in the arterial wall requiring intervention to correct. 
 
DYNA CT 
An x-ray imaging software option which allows the reconstruction of 2-dimensional 
images acquired with an angiographic C-arm into 3-dimensional image format 
 
DISTAL EMBOLIZATION  
Defined as a new abrupt cut off or filling defect distal to the treated lesion.  
 
ENROLLED, Subject 
A subject is enrolled into the study at the time the study informed consent is 
signed. 
 
EFFECTIVENESS 
Reasonable assurance that in a significant portion of the target population, the 
use of the device for its intended uses and conditions of use, when 
accompanied by adequate directions for use and warnings against unsafe use, 
will provide clinically significant results.  [Tillman D-B, Director, Office of Device 
Evaluation, CDRH given at the ECRI Conference on Comparative Effectiveness 
of Health Interventions, October 2007.  Fostering Comparative Effectiveness: An 
FDA Device Perspective] 
 
EMERGENT PROCEDURE 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 115 of 121 
Subjects requiring emergency intervention will not be responsive to any form of 
therapy except the procedure proposed.  An emergency procedure is one in which 
there should be no delay providing intervention. 
 
END OF PROCEDURE 
The time the guiding catheter is removed from the subject. 
 
ENTERED, Subject 
Subjects will actually be “entered” in the study (if the intent is to proceed with 
stent deployment) at the time of the start of the index procedure as defined in 
this protocol (see definitions).    
 
EVOLUTION OF ANEURYSM OCCLUSION 
 
Stable = if the aneurysm is unchanged in size, configuration, and volumetric 
occlusion. 
 
Improved = if progressive aneurysm occlusion or involution has occurred, using 
the 3 point category Raymond Scale. 
 
Recanalized = if there is an increase in aneurysm filling resulting in a change in 
Raymond classification, using the 3 point category Raymond Scale.   
 
Retreatment = defined as any additional treatment of the target aneurysm after 
the index procedure (retreatment includes staged procedures), and (regardless of 
whether retreatment is by surgery or endovascular treatment) due to 
recanalization, rupture or bleeding.  
 
FEVER 
Documented temperature > 38 degree C 
 
FOCAL NEUROLOGICAL DEFICIT 
Refers to signs including any peripheral, axial, and cranial nerve dysfunction. 
 
GROIN HEMATOMA 
An accumulation of blood at the puncture site requiring evacuation, transfusion, 
or extended hospital stay 
 
 
 
HEADACHE 
Subjective head pain often thunderclap in onset and classified as secondary in 
type attributed to subarachnoid hemorrhage 
 
HEMMORHAGE 
Acute loss of blood requiring transfusion 
 
HUNT AND HESS SAH GRADING SCALE  
Grade I  Asymptomatic or mild headache  
Grade 1a Fixed neurological deficit without meningeal or brain reaction 
Grade II Moderate to severe headache, cranial nerve palsy, nuchal  

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 116 of 121 
rigidity 
Grade III Lethargy, confusion, mild focal deficit 
Grade IV Stupor, hemiparesis, early decerebrate posturing 
Grade V Coma, decerebrate rigidity posturing, moribund appearance  
 
HYDROCEPHALUS 
A clinical entity in which a disturbance of cerebrospinal fluid circulation causes the 
accumulation of cerebrospinal fluid, resulting in progressive ventricular dilatation 
and increased intracranial pressure. 
 
INDEX DATE 
The treatment session during which the initial stenting of the aneurysm is 
attempted. 
 
INDEX PROCEDURE 
The treatment session during which stenting of the aneurysm is attempted will be 
referred to as the “index” procedure. 
 
IN-SEGMENT MEASUREMENT  
Defined as the measurements either within the stented segment or within 5 mm 
proximal and distal to the stent edges.  
 
IN-STENT MEASUREMENT  
Defined as the measurements within the boundaries of the stent.  
 
IN-STENT STENOSIS (PARENT VESSEL STENOSIS) 
In-stent stenosis defined as greater than 50% narrowing of the vessel within the 
stent or within 10mm of either end of the stent.  
 
MAJOR IPSILATERAL STROKE 
Defined as a new neurological event which is ipsilateral and in the vascular 
distribution territory of the stenting procedure and that results in an increase of ≥ 
4 on the National Institute of Health Stroke Scale (NIHSS) as compared to 
baseline and persists for greater than 24 hours 
 
MAJOR VASCULAR COMPLICATION  
All pseudoaneurysms, vascular access site bleeding associated with a decrease 
in hemoglobin ≥ 5.0 g/dL as well as vascular events which require surgical repair 
or transfusion prior to discharge after procedure. 
 
MODIFIED RANKIN SCALE 
An instrument for the assessment of neurological status. 
 
NEUROLOGICAL DETERIORATION  
An increase from baseline NIHSS score of ≥ 4 points 
 
PARENT VESSEL STENOSIS (IN-STENT STENOSIS) 
In-stent stenosis defined as greater than 50% narrowing of the vessel within the 
stent or within 10mm of either end of the stent.  

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 117 of 121 
 
PERCENT ANEURYSM OCCLUSION  
The percentage of aneurysms, without additional procedures for treatment of the 
aneurysm since the index procedure, as assessed by the Core Laboratory on a 
follow-up angiogram, categorized as follows: 100%, ≥95-99%, ≥90-94%, and 
<90% occlusion.  Subjects who are retreated prior to the post-procedure follow-
up visit will be included in the analysis and will be categorized as “Retreated.” 
POST-PROCEDURE 
After the end of the index procedure (removal of the guiding catheter from the 
subject) 
 
POST-TREATMENT 
During the index procedure, it is the time period after treatment with the 
ENTERPRISE study device is completed and prior to the end of the index 
procedure (removal of the guiding catheter from the subject) 
 
PRE-PROCEDURE 
Prior to the start of the index procedure (access of the femoral artery) 
 
PRE-TREATMENT 
After start of the index procedure (access of the femoral artery) and prior to 
treatment with the ENTERPRISE study device 
 
PROCEDURE SUCCESS 
The percentage of aneurysms in which complete coverage across the aneurysm 
neck is achieved and for whom coil mass position is maintained within the sac 
with parent artery patency without additional procedures for treatment of the 
aneurysm since the index procedure, as assessed post-procedure. 
 
PROCEDURAL SERIOUS ADVERSE EVENT  
A SAE that occurs between the start of the procedure and within 24 hours of the 
baseline stenting procedure 
 
PRODUCT COMPLAINT 
Any written, electronic or oral communication that alleges deficiencies related to 
the identity, quality, durability, reliability, safety, effectiveness or performance of 
a device. 
 
PROTOCOL DEVIATION 
Action which deviates (varies) from the specified elements of a trial protocol 
including but not limited to non-adherence to inclusion/exclusion criteria; missed 
Subject visit or out-of-range visit interval; and, omitted or non-compliant tests or 
procedures required by the protocol.  A protocol deviation may be intended or 
unintended; however, the result is the same as it compromises scientific 
integrity. 
 
Observed Protocol Deviation: 
Any protocol non-conformance identified by the Sponsor through monitoring 
visits, periodic reports, verbal communication or other trial-related mechanisms. 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 118 of 121 
 
RAYMOND SCALE (3 POINT CATEGORY SCALE) 
Classification of angiographic results:  
• Class 1, complete obliteration;  
• Class 2, residual neck; and  
• Class 3, residual aneurysm.   
 
Class 1 is defined as complete obliteration 
 
Class 2 is defined as the 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 is defined as any opacification of the sac. 
 
RECANALIZATION 
An increase in aneurysm filling resulting in a change in (i.e., worsening of) the 
Raymond classification 
 
REMNANT OPACIFICATION OR REMNANT RECANALIZATION 
Describes an untreated component of the aneurysm in which there is no 
prosthetic material  
 
RECANALIZATION RATE 
The percentage of aneurysms in which recanalization is documented at any time 
up to and including the follow-up visit.   
 
RETREATMENT 
Retreatment will be defined as any additional treatment of the target aneurysm 
after the index procedure (retreatment includes staged procedures) and 
(regardless of whether retreatment is by surgery or endovascular treatment) due 
to recanalization, rupture or bleeding. The treatment session during which 
stenting of the aneurysm is attempted will be referred to as the “index” procedure.  
 
RETREATMENT RATE 
The percentage of target aneurysms that are retreated at any time up to and 
including the follow-up visit. 
 
SEIZURE 
A seizure refers to abnormal epileptiform neuronal discharge that results in focal 
or generalized alterations of sensation, motor function, behavior, or 
consciousness. 
 
SERIOUS ADVERSE EVENT  
Any significant adverse experience, including those that may be either life-
threatening or involving permanent or long term injuries but excluding injuries that 
are non-life-threatening and/or that are temporary and reasonably reversible. A 
Serious Adverse Event includes any of the following events that may or may not 
be considered related to the device;  

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 119 of 121 
• Results in Death, 
• Is life-threatening, 
• Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization, 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
 
SOURCE DOCUMENTS 
Original documents, data, and records (e.g. hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries, or evaluation checklists, 
dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the hospital, at the laboratories, and at technical 
departments involved in the clinical studies. 
 
SPONSOR 
Cerenovus 
 
STAGED COILING PROCEDURE 
A staged procedure is a procedure where entire treatment with the device (e.g. 
coils/stents) is completed over separate sessions. 
 
START OF PROCEDURE 
The time the femoral artery is accessed. 
 
STENT MIGRATION 
A change in placement of the stent from the initial placement at the end of the 
index procedure that is documented during a post-placement angiogram.    
 
STENT MOVEMENT 
A change in placement of the stent that occurs during the index procedure, or a 
retreatment procedure.   
 
STROKE  
Any sudden development of neurological deficits attributable to cerebral ischemia, 
infarction, or hemorrhage. 
 
SUBACUTE CLOSURE 
New reduced (TICI 0 or 1) flow at the target vessel observed as unintentional or 
persistent occurrence as a result of a mechanical obstruction, such as dissection 
or luminal thrombosis, occurring after completion of the index procedure but 
within 30 days of stent deployment. 
 
SUBARACHNOID HEMORRHAGE (SAH) 
Bleeding in the subarachnoid, intracerebral, intraventricular, or subdural spaces. 
 
TARGET ANEURYSM 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 120 of 121 
The target aneurysm must be an aneurysm that is a unruptured wide-neck, 
intracranial, saccular anterior circulation aneurysms (≤ 10 mm) arising from a 
parent vessel with a diameter of ≥ 2.5 mm and ≤ 4 mm, and which is intended to 
be treated with the ENTERPRISE device. 
 
TECHNICAL COMPLICATION 
 
Study device-related technical complications 
Study device-related technical complications refer to those events that are directly 
related to the performance of the ENTERPRISE stent.   
 
Examples include, but are not limited to: failure to access the target site with the 
device, or failure of the device to deploy.  
 
All study device-related technical complications will be reported on the eCRF. 
 
Non-study device-related technical complications 
Non-device-related technical complications refer to those events that are 
technical in nature, but are not directly related to the performance of the 
ENTERPRISE stent.   
 
Examples include, but are not limited to: the required stent size for treatment is 
not available, or equipment failure occurs (other than the device) precluding 
continuation of the procedure.   
 
All non-study device-related technical complications will be reported on the eCRF. 
 
TICI Score  
(Roth et al. Stroke, 2010) 
Grade 0 
No perfusion: No antegrade flow beyond the point of occlusion. 
Grade 1 
Penetration with minimal perfusion:  The contrast material 
passes beyond the area of obstruction but fails to opacify the 
entire cerebral bed distal to the obstruction for the duration of 
the angiographic run. 
Grade 2: 
Partial perfusion:  The contrast material passes beyond the 
obstruction and opacifies the arterial bed distal to the 
obstruction.  However, the rate of entry of contrast into the 
vessel distal to the obstruction and/or its rate of clearance from 
the distal bed are perceptibly slower than its entry into and/or 
clearance from comparable areas not perfused by the 
previously occluded vessel, eg, the opposite cerebral artery or 
the arterial bed proximal to the obstruction. 
Grade 2a 
Only partial filling (~2/3) of the entire vascular territory is 
visualized 
Grade 2b 
Complete filling of all of the expected vascular territory is 
visualized, but the filling is slower than normal. 
Grade 3 
Complete perfusion: Antegrade flow into the bed distal to the 
obstruction occurs as promptly as into the obstruction, and 
clearance of contrast material from the involved bed is as rapid 

  
 
 
 
ENTERPRISE WNA IDE Protocol  
Protocol Number: NV-IDE-1001 
 23 Mar 2018 Version 4.0    Page 121 of 121 
as from an uninvolved other bed of the same vessel or the 
opposite cerebral artery. 
 
TRANSIENT ISCHEMIC ATTACK (TIA) (of Neurological Deficit) 
Resolution of new focal deficit within 24 hours.  No CT or MRI evidence of 
infarction. 
 
THROMBOSIS 
In-stent thrombosis   
 
UNANTICIPATED ADVERSE DEVICE EFFECT (UADE)  
An UADE is defined as 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 problem associated with a 
device that relates to the rights, safety, or welfare of study subjects  
 
VASCULAR COMPLICATIONS  
Vascular complication may include the following: 
• Hematoma at access site > 4 cm 
• Pseudoaneurysm 
• Arteriovenous fistula 
• Retroperitoneal bleed 
• Peripheral ischemia/nerve injury 
• Procedure related transfusion 
• Vascular surgical repair