Use of the Zenith® Dissection Endovascular System in the Treatment of Patients With Acute, Complicated Type B Aortic Dissection
Phase: NA
Conditions: Aortic Dissection
Sponsor: Cook Research Incorporated

Cook Research Incorporated 
Zenith® Dissection Clinical Trial 
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COMPANY CONFIDENTIAL 
CIP 11-007-08 
 
 
 
 
 
CLINICAL INVESTIGATION PLAN  
 
 
 
 
Use of the Zenith® Dissection Endovascular System in the Treatment of Patients  
with Acute, Complicated Type B Aortic Dissection 
 
 
 
 
Global Clinical Number 11-007 
 
 
 
 
Sponsor: 
Cook Research Incorporated 
 
 
1 Geddes Way 
West Lafayette, IN 47906 
USA 
 
 
 
Summary of Revisions 
Version # 
Description 
 
 
 
 
 
 
Date 
11-007-01 
Original version 
 
 
 
 
 
4 Nov 2011 
11-007-02 
Updated data analysis plan 
 
 
 
 
30 Mar 2012 
11-007-03 
Updates regarding adjunctive device use 
 
 
23 Jan 2013 
11-007-04 
Updates to exclusion criteria and updates to follow-up 
9 July 2013 
                        schedule  
 
11-007-05 
Updated enrollment total and data analysis                         8 Jan 2014 
 
 
plan 
11-007-08 
Updated sponsor name, address, and contact information     19 Mar 2018 
 

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CONFIDENTIALITY STATEMENT 
 
 
 
 
 
 
 
 
 
This document shall be treated as a confidential document for 
the sole information and use of the clinical investigation team 
and the Ethics Committee/IRB. 
 
 

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TABLE OF CONTENTS 
 
1.0  
Clinical Investigation Plan Overview ...................................................................7 
2.0 
Summary of Preliminary Investigations ..............................................................8 
2.1 
Preclinical Testing ........................................................................................8 
2.2 
Previous Clinical Experience ........................................................................8 
2.3 
Justification for the Investigation .................................................................8 
3.0 
Objectives of the Clinical Investigation ...............................................................8 
3.1 
Primary Objectives .......................................................................................8 
3.2 
Secondary Objectives ...................................................................................9 
3.3 
Specific Hypothesis to be Accepted or Rejected by Statistical Data ...........9 
4.0 
Product Description and Intended Use ..............................................................10 
4.1 
 General Product Description .....................................................................10 
4.2 
Intended Use ...............................................................................................13 
4.3 
Product Identification and Tracking ...........................................................13 
4.4 
Instructions for Use ....................................................................................13 
4.5 
Summary of Necessary Training and Experience ......................................13 
4.6 
Description of the Necessary Medical or Surgical Procedures ..................14 
4.7 
Adjunctive Devices .....................................................................................14 
5.0 
Design of the Clinical Investigation ....................................................................14 
5.1 
Type of Investigation ..................................................................................14 
5.2 
Endpoints ....................................................................................................14 
5.3 
Variables to be Measured to Demonstrate Achievement of Endpoints ......15 
5.4 
Measures to be Taken to Avoid or Minimize Bias .....................................15 
5.5 
Study Criteria ..............................................................................................15 
5.6 
Point of Enrollment ....................................................................................18 
5.7 
Enrollment Objective ..................................................................................18 
6.0 
Methods .................................................................................................................19 
6.1 
Subject Consent ..........................................................................................19 
6.2 
Pre-procedure ..............................................................................................19 
6.3 
Procedure ....................................................................................................19 
6.4 
Peri-operative Care .....................................................................................20 
6.5 
Post-operative Treatment of Entry-flow .....................................................20 
6.6 
Follow-up Treatment of Entry-flow and Flow Through Secondary Tears .21 
6.7 
Treatment of Obstruction ............................................................................21 
6.8 
Secondary Interventions .............................................................................21 
6.9 
Follow-up....................................................................................................22 
6.10 
Criteria and Procedures for Study Termination ..........................................22 
7.0 
Statistical Considerations ....................................................................................22 
7.1 
Sample Size Calculations ...........................................................................22 
7.2 
Performance Goals .....................................................................................23 
7.3 
Site-level Poolability ..................................................................................24 

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7.4 
Missing Data ...............................................................................................24 
7.5 
Future Use of Study Data ...........................................................................25 
8.0 
Risk Analysis and Risk Assessment ...................................................................25 
8.1 
Risks and Foreseeable Adverse Device Effects .........................................25 
8.2 
Methods to Minimize Risks ........................................................................25 
9.0 
Safety Monitoring and Event Reporting............................................................26 
9.1 
Data Safety Monitoring Board ...................................................................26 
9.2 
Clinical Events Committee .........................................................................26 
9.3 
Adverse Event Reporting ............................................................................26 
10.0 
Administrative ......................................................................................................27 
10.1 
Data Collection ...........................................................................................27 
10.2 
Data Reporting ............................................................................................28 
10.3 
Emergency Situations and Vulnerable Subjects .........................................29 
10.4 
Criteria and Procedures for Withdrawal .....................................................29 
10.5 
Deviations from Clinical Investigation Plan ..............................................29 
10.6 
Early Termination or Suspension of the Investigation ...............................29 
10.7 
Limitations of the Investigation ..................................................................29 
10.8 
Publication Policy .......................................................................................30 
10.9 
Approvals and Agreements ........................................................................30 
10.10 General Information ...................................................................................30 
11.0 
Bibliography .........................................................................................................32 
 
 
 
Appendices  
Contact Information ........................................................................................... Appendix A 
Written Procedures for Monitoring Investigation .............................................. Appendix B 
Definitions.......................................................................................................... Appendix C 
References .......................................................................................................... Appendix D

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1.0 Clinical Investigation Plan Overview 
This clinical investigation is designed as a prospective, non-randomized study enrolling 
73 patients (67 patients for hypothesis testing) to receive the Zenith® Dissection 
Endovascular System at up to 30 global clinical sites with a maximum enrollment of up 
to 14 patients per individual site.  The primary safety and effectiveness endpoints, as 
described in Section 3.1, will be compared to the performance goals derived from the 
combined physician-sponsored studies reported by the Society for Vascular Surgery 
Outcomes Committee.1 
Any patient with an acute, complicated, type B aortic dissection with either aortic rupture 
or branch vessel obstruction/compromise that results in malperfusion (see Appendix C, 
Definitions) is eligible for enrollment in the study.  The study flow diagram is presented 
in Figure 1. 
 
 
Patient with  an acute, complicated, type B aortic dissection with either aortic rupture or branch vessel 
obstruction/compromise  
 
 
 
 
 
 
 
 
Physician reviews available medical history and imaging and considers patient candidate for enrollment 
 
 
 
 
 
 
 
 
 
Informed consent is obtained 
 
 
 
 
 
 
 
 
Pre-procedural CT, blood tests, clinical exam 
 
 
 
 
 
 
 
 
Patient meets inclusion/exclusion criteria 
 
 
 
 
 
 
Endovascular repair with procedural angiography 
 
 
 
 
30-day: CT, blood tests, clinical exam 
 
 
 
 
6-month: CT, blood tests, clinical exam 
 
 
 
 
12-month and yearly thereafter to 5 years: CT, blood tests, clinical exam 
 
Figure 1.  Study flow diagram 
 

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2.0 
Summary of Preliminary Investigations 
2.1 
Preclinical Testing 
Non-clinical tests were conducted in accordance with Good Laboratory Practice 
requirements, or performed in compliance with verified methods and Standard Operating 
Procedures to maintain the integrity of the results.  In vitro testing has established 
reasonable safety of the device for the expected duration of the study and in the trial 
population to be studied.  Please refer to the Clinical Investigator Brochure for a 
summary of non-clinical testing. 
 
2.2 
Previous Clinical Experience 
Refer to the Clinical Investigator Brochure for a complete description of the previous 
clinical experience with similar devices. 
 
2.3 
Justification for the Investigation 
This study design and the performance goal are justified given there are no other 
treatment alternatives that are being commonly practiced at present for patients with 
acute, complicated Type B aortic dissection.  Open surgical repair is rarely performed in 
these patients due to the very high rate of mortality associated with the procedure.  
Likewise, medical therapy is not practical as the definitive treatment for these patients, 
who often require a more aggressive therapy in the form of endovascular/surgical 
intervention to relieve symptoms and prevent any further adverse clinical sequelae. 
 
3.0 
Objectives of the Clinical Investigation 
 
3.1 
Primary Objectives 
The objective of the study is to evaluate the safety and effectiveness of the Zenith® 
Dissection Endovascular System in the treatment of patients with complicated, type B 
aortic dissection. The primary safety endpoint will be rate of freedom from major adverse 
events (see Appendix C, Definitions) at 30 days.  The primary effectiveness endpoint will 
be the survival rate at 30 days.   

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Zenith® Dissection Clinical Trial 
3.2 
Secondary Objectives 
Information redacted 
3.3 
Specific Hypothesis to be Accepted or Rejected by Statistical Data 
3.3.1 Primary Safety Hypothesis 
The primary safety endpoint is the rate of freedom from 30-day major adverse events (see 
Appendix C, Definitions).  The published rate of freedom from 30-day MAE from the 
combined physician-sponsored studies is 61.2%.1 With a clinically relevant non-
inferiority margin of 10%, a performance goal of 51.2% has been established for the 
primary safety endpoint.  The performance goal will be said to have been met provided 
that the null hypothesis is rejected in favor of the alternative with a one-tailed exact 
binomial test at the 0.025 level.  Given that πnoMAE(30) is the probability that a randomly 
selected patient did not experience any MAE at 30 days, the null and alternative 
hypotheses are as follows. 
Null Hypothesis: The rate of freedom from 30-day MAE, πnoMAE(30), does not meet the 
performance goal (51.2%). 
H0: πnoMAE(30)  ≤ 51.2% 
Alternate Hypothesis: The rate of freedom from 30-day MAE, πnoMAE(30), meets the 
performance goal (51.2%). 
Ha: πnoMAE(30) > 51.2% 
3.3.2 Primary Effectiveness Hypothesis 
The primary effectiveness endpoint is the survival rate at 30 days.  The published 
survival rate at 30 days from the combined physician-sponsored studies is 89.4%.1 With a 
clinically relevant non-inferiority margin of 10%, a performance goal of 79.4% has been 
established for the primary effectiveness endpoint.  The performance goal will be said to 
have been met provided that the null hypothesis is rejected in favor of the alternative with 
a one-tailed exact binomial test at the 0.025 level.  Given that πs(30) is the probability that 

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a randomly selected patient is alive at 30 days, the null and alternative hypotheses are as 
follows. 
 
Null Hypothesis: The survival rate at 30 days, πs(30), does not meet the performance goal 
(79.4%). 
 
H0: πs(30) ≤ 79.4% 
 
Alternate Hypothesis: The survival rate at 30 days, πs(30), meets the performance goal 
(79.4%). 
 
Ha: πs(30) > 79.4% 
 
For each endpoint, the hypothesis will be assessed by a one-sided exact binomial test, at a 
type I error rate of 0.025 and a power of 0.8.  The safety and effectiveness of the device 
will be established if both null hypotheses are rejected in favor of the alternatives at the 
above mentioned error rates. 
 
4.0 
Product Description and Intended Use 
 
The Zenith® Dissection Endovascular System is a disease-specific family of components 
intended for the treatment of patients with Type B aortic dissection.   
 
4.1 
General Product Description 
As depicted in Figure 2, the system is comprised of a covered proximal component 
(Zenith® TX2® Dissection Endovascular Graft) and an uncovered distal component 
(Zenith® Dissection Endovascular Stent). 

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Figure 2.  Zenith® Dissection Endovascular System 
   
Zenith® TX2® Dissection Endovascular Graft  
The Zenith® TX2® Dissection Endovascular Graft is predicated on the Zenith® TX2® 
TAA Endovascular Graft, which is commercially-available in the United States for the 
treatment of patients with descending thoracic aortic aneurysms and ulcers, and in many 
countries outside the U.S. for the treatment of patients with aneurysms, dissections, or 
contained ruptures.  The design of the Zenith® TX2® Dissection Endovascular Graft is 
identical to the Zenith® TX2® TAA Endovascular Graft, except for the removal of 
fixation barbs in order to provide a disease-specific covered component (Figure 3).   
 
Figure 3. Zenith® TX2® Dissection Endovascular Graft 
 
Zenith® TX2® Dissection 
Endovascular Graft 
Zenith® Dissection 
Endovascular Stent 

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As shown in Table 1, the Zenith® TX2® Dissection Endovascular Graft is available in 
multiple sizes ranging from 22 to 42 mm in diameter and 79 to 218 mm in length and is 
also available in both straight and tapered configurations.  Tapered components with 
diameter changes of 4 mm or 8 mm are available. 
 
Table 1. Zenith® TX2® Dissection Endovascular Graft sizes 
Graft 
Diameter  
 
(mm) 
Length of Straight 
Component  
(mm) 
Length of Tapered 
Component – 4 mm 
Taper  
(mm) 
Length of Tapered 
Component – 8 mm 
Taper  
(mm) 
22 
79 / 117 
n/a 
n/a 
24 
79 / 117 
n/a 
n/a 
26 
79 / 136 
n/a 
n/a 
28 
82 / 142 / 202 
n/a 
n/a 
30 
82 / 142 / 202 
n/a 
n/a 
32 
82 / 142 / 202 
162 / 202 
158 / 196 
34 
79 / 154 / 204 
159 / 199 
156 / 194 
36 
79 / 154 / 204 
159 / 199 
159 / 199 
38 
79 / 154 / 204 
154 / 204 
159 / 199 
40 
83 / 164 / 218 
160 / 210 
165 / 205 
42 
83 / 164 / 218 
160 / 210 
160 / 210 
 
Zenith® Dissection Endovascular Stent 
The Zenith® Dissection Endovascular Stent consists of multiple z-stent segments, made 
of nitinol, sewn together end-to-end with polyester sutures (Figure 4).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Figure 4. Zenith® Dissection Endovascular Stent 
 

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As shown in Table 2, the Zenith® Dissection Endovascular Stent is available in multiple 
sizes. 
 
Table 2. Zenith® Dissection Endovascular Stent sizes 
Stent Diameter 
(mm) 
Stent Length 
(mm) 
36 
80 / 120 / 180 
46 
80 / 120 / 185 
 
 
4.2 
Intended Use 
The Zenith® Dissection Endovascular System is intended for the endovascular treatment 
of patients with symptomatic aortic dissection of the descending thoracic aorta having 
morphology suitable for endovascular repair.  Refer to the Instructions for Use (IFU) for 
further details. 
 
4.3 
Product Identification and Tracking 
Products under investigation will have a unique lot number and will be tracked 
throughout the course of the study through use of a Product Log, upon which lot 
numbers, quantity and disposition of product will be recorded.  Product Logs will be 
maintained in the site’s Investigator File.  Additionally, the quantity(s), size(s) and lot 
number of products used in subjects will be recorded on the case report forms. 
 
4.4 
Instructions for Use  
Please reference the manufacturer’s Instructions for Use for complete instructions 
including installation, storage and handling requirements, preparation for use and 
precautions to be taken after use. 
 
4.5 
Summary of Necessary Training and Experience 
Please reference the manufacturer’s Instructions for Use for a summary of the necessary 
training and experience required for use of this product. 
 
 
 

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4.6 
Description of the Necessary Medical or Surgical Procedures 
Please reference the manufacturer’s Instructions for Use for a description of the 
procedures involved in the use of this product. 
 
4.7 
Adjunctive Devices 
At physician discretion, adjunctive devices may be used on an individual basis during 
either the initial implant procedure or secondary intervention and may include the 
following (as discussed in Section 6, Methods): aneurysm stent-graft components (for 
coverage of reentry tears), coils/occluders (for embolization of sources for false lumen 
flow), uncovered balloon-expandable or self-expanding stents (for branch vessel 
obstruction), and covered balloon-expandable or self-expanding stents (for coverage of 
reentry tears involving branch vessels).  If adjunctive devices are used, it is recommended 
that the Instructions for Use (IFU) of that device be reviewed, and the risks of using that 
device be considered.  The specific type/make/model of any adjunctive device implanted 
during either the initial implant procedure or secondary intervention should be recorded 
on the case report forms.  Additionally, the performance of any adjunctive device placed 
should be monitored during follow-up.     
 
5.0 
Design of the Clinical Investigation 
 
5.1 
Type of Investigation 
The current investigation is a prospective, non-randomized, non-blinded study. 
 
5.2 
Endpoints 
The primary safety endpoint will be rate of freedom from major adverse events (see 
Appendix C, Definitions) at 30 days.  The primary effectiveness endpoint will be the 
survival rate at 30 days.  Mortality is the greatest procedural risk associated with 
alternative treatments and is also the principal outcome any treatment is intended to 
prevent (up to 50% of patients are at risk for mortality within 48 hours if untreated2). 
 
 
 

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5.3 
Variables to be Measured to Demonstrate Achievement of Endpoints 
To evaluate deployment characteristics, procedural outcome and follow-up, the following 
data points will be collected: 
1) 
Assessment of system performance including: deployment issues, ease of 
insertion, visualization, and ease of removal; 
2) 
Clinical utility measures such as days to discharge from hospital; 
3) 
Ancillary equipment needed; 
4) 
Adjunctive maneuvers including: balloon dilation of iliac arteries, additional 
stents required, and additional surgical procedures; 
5) 
Complications including major adverse events during procedure and at follow-up; 
6) 
Device integrity findings at completion of procedure and follow-up: device 
patency, stent fracture, and graft  kinks; 
7) 
Type and sources of entry-flow at procedure and follow-up; 
8) 
Dimensions of the true and false lumen over the course of follow-up; and 
9) 
Secondary interventions performed. 
 
5.4 
Measures to be Taken to Avoid or Minimize Bias 
This study is not randomized or blinded.  It is intended to prospectively collect 
information regarding the safety and effectiveness of the Zenith® Dissection 
Endovascular System.  The study will utilize uniform definitions for study endpoints, 
event adjudication by an independent clinical events committee, and imaging data 
analysis by a centralized core laboratory.  Study results will be analyzed in accordance 
with a prospectively defined analysis plan. 
 
5.5 
Study Criteria 
Assessment of entry criteria will be based upon data available pre-operatively.  Data 
obtained peri-operatively and post-operatively (including the results from core lab 
analysis of pre-procedure imaging) may contradict pre-operative assessment.  However, 
such contradiction is not considered a violation of the Clinical Investigation Plan and 
should not be construed as evidence of inadequate or inaccurate pre-operative assessment 
with respect to the enrollment criteria or evidence of inappropriate enrollment.  
Enrollment is to be based upon best available pre-operative data.  Some criteria relate to 
subjective assessment while other criteria are considered absolute and able to be 

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determined definitively.  Variability in assessment between centers, investigators, and 
observers is expected with several criteria.  
  
5.5.1 Inclusion Criteria 
A patient is deemed suitable for inclusion in the study if the patient has an acute, 
complicated, Type B aortic dissection with at least one of the following characteristics 
(see Appendix C, Definitions): 
1) Aortic rupture; or 
2) Branch vessel obstruction/compromise resulting in malperfusion  
 
5.5.2 Exclusion Criteria 
Patients must be excluded from the study if any of the following conditions are true: 
 
General Exclusion Criteria 
1) Age < 18 years;  
2) Other medical condition (e.g., cancer, congestive heart failure) that may cause the 
patient to be non-compliant with the Clinical Investigation Plan, confound the results, 
or is associated with limited life expectancy (i.e., less than 2 years); 
3) Pregnant, breast-feeding, or planning on becoming pregnant within 60 months; 
4) Unwilling or unable to comply with the follow-up schedule; 
5) Inability or refusal to give informed consent; or 
6) Simultaneously participating in another investigative device or drug study.  (The 
patient must have completed the primary endpoint of any previous study at least 
30 days prior to enrollment in this study.) 
 
 
Medical Exclusion Criteria 
 
7) Suspicion of bowel necrosis (as determined by the implanting physician based on 
imaging observations, peritoneal signs, surgical exploration, elevated serum lactate 
levels, and/or acidosis) 
8) ASA risk class V (i.e., moribund patient not expected to live 24 hours with or without 
operation) 
9) Embolic stroke within the last 14 days prior to potential enrollment in the study or 

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hemorrhagic stroke within 30 days prior to potential enrollment in the study; 
10) Diagnosed or suspected congenital degenerative connective tissue disease (e.g., no 
Marfan’s or Ehler-Danlos syndrome);  
11) Systemic infection (e.g., sepsis); 
12) Bleeding diathesis, uncorrectable coagulopathy, or refuses blood transfusion; 
13) Allergy to stainless steel, polyester, solder (tin, silver), polypropylene, nitinol, or 
gold; 
14) Untreatable reaction to contrast, which, in the opinion of the investigator, cannot be 
adequately pre-medicated; 
15) Surgical or endovascular AAA repair within 30 days before or after dissection repair; 
16) Previous placement of a thoracic endovascular graft; 
17) Prior open repair involving descending thoracic aorta including suprarenal aorta 
and/or arch; or 
18) Interventional and/or open surgical procedures (unrelated to dissection) within 
30 days before or after dissection repair. 
 
Anatomical Exclusion Criteria 
 
19) Dissection of aorta proximal to left subclavian artery (either primary entry tear or 
most proximal extent of dissection);  
20) Proximal landing zone length measuring < 20 mm between the left common carotid 
artery and most proximal extent of dissection (covering left subclavian artery is 
acceptable, except in patients with a dominant vertebral artery off of the arch in the 
region of the subclavian or a dominant vertebral off of the subclavian); 
21) Proximal landing zone diameter for proximal stent-graft component < 20 mm or 
> 38 mm, measured outer-wall to outer-wall on a sectional image or multiplanar 
reconstruction; 
22) Aortic arch radius of curvature < 35 mm (if device deployed in the arch);  
23) Distal landing zone diameter for proximal stent-graft component < 20 mm (estimate 
based on transaortic diameter) or > 38 mm (estimate based on true lumen diameter), 
measured outer-wall to outer-wall on a sectional image or multiplanar reconstruction; 
24) Diameter < 20 mm (estimate based on transaortic diameter) or > 38 mm (estimate 
based on true lumen diameter) for any segment of vessel into which deployment of 
bare stent device is intended, measured outer-wall to outer-wall on a sectional image 
or multiplanar reconstruction; 
25) Prohibitive angulation in segments of vessel into which deployment of bare stent 

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device is intended (e.g., radius of curvature < 35 mm, or localized angle 
> 45 degrees); 
26) Both iliac arteries having prohibitive tortuosity, calcification, occlusive disease or 
arterial diameter, measured inner-wall to inner-wall on a sectional image, that are not 
conducive to placement of the introducer sheath (use of access conduit permitted); 
27) Prohibitive calcification, occlusive disease, or angulation in intended proximal 
landing zone; 
28) Circumferential thrombus in region of intended proximal landing zone; 
29) Inability to preserve the native left common carotid artery and celiac artery origins; or 
30) Aneurysm or angulation in the distal thoracic aorta that would preclude advancement 
of the introduction system. 
 
5.6 
Point of Enrollment 
Point of enrollment will be based on the intent-to-treat population, and is defined to 
include any patient for whom the treatment procedure is initiated.  More specifically, 
once a procedure has begun (i.e., cutdown or percutaneous access initiated), the patient 
would be included in the intent-to-treat population.  The patient’s informed consent will 
be obtained and assessment of the patient’s conformance to the inclusion/exclusion 
criteria will occur prior to the procedure.   
Study results will also be analyzed with respect to the consented patient population (i.e., 
all patients who gave consent to participate in the study, regardless of treatment). 
 
5.7 
Enrollment Objective 
67 patients will be enrolled in accordance with Version 4 of the CIP at up to 30 global 
clinical sites with a maximum enrollment of up to 14 patients per individual site.   In 
order to account for patients who would not be eligible for enrollment based on the 
clarifications reflected in Version 4 of the CIP,  the total enrollment for the study has 
increased to provide for six additional patients (73 patients total).  
 
 
 
 
 

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6.0 
Methods 
 
6.1 
Subject Consent 
Patients who meet the inclusion/exclusion criteria will be invited to participate in this 
investigation.  All patients eligible for entry into the investigation will have the Clinical 
Investigation Plan explained to them, as well as potential risks and benefits of their 
participation in the investigation.  Each patient who agrees to participate will be required 
to sign an informed consent document prior to the procedure. 
 
6.2 
Pre-procedure 
Stent-grafts and dissection stents are sized based on the findings from pre-operative 
computerized tomography (CT) in conjunction, if necessary, with other imaging 
modalities such as angiograms and intravascular ultrasound (IVUS).  Refer to the 
Instructions for Use for details regarding the suggested sizing guidelines.     
 
6.3 
Procedure 
Standard techniques for placement of arterial access sheaths, guiding catheters, 
angiographic catheters, and wire guides should be employed during use of the Zenith® 
Dissection Endovascular System.  Care must be exercised in placing of sheaths and 
wireguides, and in advancing the delivery system of the devices.  Molding balloon 
angioplasty in the dissected region of the aorta must be avoided.     
Precautions should be taken to minimize the risk of stroke.  All air should be flushed 
from sheaths and lumens before insertion using elevated tip technique.  Wire placement 
and manipulation in the ascending thoracic aorta and aortic arch should be minimized. 
Fluoroscopic guidance and angiography should be used throughout the procedure to 
verify positioning of the device with respect to the patient’s anatomy. 
Refer to institutional protocols relating to anesthesia, anticoagulation, access technique, 
spinal drainage and monitoring of vital signs.  Coverage of the left subclavian artery is 
acceptable; however, revascularization of the left subclavian artery should be 
considered.3   
Refer to the Instructions for Use for complete details regarding use of the Zenith® 
Dissection Endovascular System.  In general, placement of a bare stent following 

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coverage of the primary tear with a stent-graft is recommended to support the distal, 
delaminated segments of the aorta.  However, bare stent placement following stent-graft 
coverage of the primary entry tear may not be necessary in patients for whom all of the 
following are applicable: 
- No continued signs or symptoms of obstructed/compromised branch vessel (if 
patient was included in the study for obstructed/compromised branch vessel) after 
placement of the proximal component 
- Systolic pressure gradient ≤ 20 mm Hg between the aortic root and a distal 
obstructed aortic segment/vessel (if patient was included in the study for 
obstructed/compromised branch vessel) 
- No false lumen flow through secondary re-entry tears 
Bare stent deployment within regions of tortuosity or acute angulation should be avoided.  
It might be necessary to use multiple Zenith® Dissection Endovascular Stents of shorter 
length, so as to avoid deployment of the bare stents within tortuous or acutely angled 
segments. 
 
6.4  
Peri-operative Care  
Refer to institutional protocols for peri-operative management of patients undergoing 
treatment for aortic dissection.   
 
6.5  
Post-operative Treatment of Entry-flow 
All instances of entry-flow should be evaluated promptly with an angiogram, and if 
necessary a selective angiogram, to determine the origin of the flow.  The completion 
angiogram should be examined carefully for entry-flow.    
Type I entry-flow should be promptly considered for treatment using additional balloon 
seating or if necessary, placement of additional stent-graft prostheses (use of Zenith main 
body extensions is recommended).  Placement of embolization coils may be needed to 
occlude sources of Type II entry-flow and collateral flow if the leak is believed to be 
significant and/or in the presence of an enlarging false lumen.  Use of occluder devices 
(e.g., Amplatzer) to embolize the left subclavian artery has also been reported.  Type III 
entry-flow represents graft or junctional defects and should be promptly considered for 
treatment with additional ballooning or prostheses.  Type IV entry-flow is generally 

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associated with grafts with a high porosity and is unlikely with the graft component of 
this system.  Secondary/reentry tears may also require coverage with placement of 
additional stent-graft prostheses in the aorta or covered balloon-expandable and/or self-
expanding stents in branch vessels if flow through the tear is significant and/or in the 
presence of an enlarging false lumen. 
 
6.6  
Follow-up Treatment of Entry-flow and Flow Through Secondary Tears 
Perfusion of the false lumen should be carefully monitored over the course of the follow-
up exams.  Treatment for significant entry-flow and flow through secondary tears should 
be considered especially in the presence of enlarging false lumen (as described in Section 
6.5).   
 
6.7 
Treatment of Obstruction 
Obstruction of the aortic true lumen resulting in end-organ ischemia/malperfusion may 
require placement of additional stent-graft prostheses or Dissection stents.  Obstruction 
within a branch vessel true lumen resulting in end-organ ischemia/malperfusion may 
require placement of uncovered balloon-expandable and/or self-expanding stents. 
 
6.8 
Secondary Interventions  
Some patients may need secondary intervention(s) for treatment of entry-flow, flow 
through secondary tears, obstruction/compromise of branch vessels, device migration, 
etc.  The use of Zenith stent-graft components is recommended when additional stent-
graft placement in the aorta is necessary to extend the length of primary graft coverage or 
to selectively cover secondary/reentry tears.  The placement of uncovered balloon-
expandable and/or self-expanding stents may be necessary to assist with true lumen 
patency in obstructed/malperfused branch vessels.  Similarly, the placement of balloon-
expandable and/or self-expanding covered stents may be necessary to assist with sealing 
secondary tears involving branch vessels.  The timing and method of such interventions 
are based on the judgment of the treating physician.  If ancillary devices (such as 
balloons, stents, etc.) are used during these interventions, it is recommended that the 
Instructions for Use (IFU) of that device be reviewed, and the risks of using that device 
be considered.   
 

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6.9 
Follow-up  
The study follow-up schedule is provided in Table 3.  The suggested guidelines for 
scheduling the clinical and/or imaging evaluation is as follows:  at the time of graft 
insertion, within 7 days post-procedure, at 30 days (± 10 days), 6 months (180 ± 30 days), 
12 months (365 ± 45 days), 2 years (730 ± 60 days), 3 years (1095 ± 60 days), 4 years 
(1460 ± 90 days), and 5 years (1825 ± 90 days). 
Table 3.  Study follow-up schedule 
 
Pre-
operative 
Intra-
operative 
Post-procedure 
30-day 
6-month 
12-month  
24-month to  
5-year5 
 Clinical Exam 
X 
 
X 
X 
X 
X 
X 
 Blood Tests1 
X 
 
X 
X 
X 
X 
X6 
 Contrast  
 CT Scan 
 X  
 
 X3,4 
 X3 
 X3 
 X3  
 Angiography 
X2 
X 
 
 
 
 
 
1. Including tests to evaluate kidney and liver function. 
2. Required only to resolve any uncertainties in anatomical measurements necessary for graft sizing. 
3. TEE or non-contrast CT imaging may be used for those patients experiencing documented renal failure (eGFR 
< 30) or who are otherwise unable to undergo contrast enhanced CT scan.   
4. CT must be performed prior to hospital discharge.  In case of impaired renal function at the time of discharge,  
CT may be performed at 30 days. 
5. Yearly through 5 years. 
6. Required only for patients with malperfusion that has not stabilized. 
  
6.10 
Criteria and Procedures for Study Termination  
A patient’s follow-up in the study will end after: 
1) 
Failure to deploy the device + 30 days; 
2) 
Conversion to open surgical repair + 30 days; 
3) 
Patient withdrawal; 
4) 
Patient death; 
5) 
Closure of the investigation; or 
6) 
Completion of all scheduled clinical and imaging visits through 5 years. 
 
7.0  
Statistical Considerations 
 
7.1  
Sample Size Calculations 
The study is designed to enroll 67 patients to evaluate the safety and effectiveness 
hypotheses (Section 3.3).   
For the primary safety endpoint, based on the data from the combined physician-
sponsored studies1, the rate of freedom from 30-day major adverse events (see Appendix 

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C, Definitions) was estimated to be 61.2%.  With a clinically relevant non-inferiority 
margin of 10%, a performance goal of freedom from 30-day MAE was established to be 
51.2%.  Sixty patients will be necessary to assess the primary safety hypothesis, under an 
expected rate of freedom from 30-day MAE at 69.2% (estimated from an on-going 
clinical trial with the Zenith® Dissection Endovascular System in patients with 
complicated, type B aortic dissection), with a one-sided exact binomial test, at a type I 
error rate of 0.025 and a power of 0.8.  
 
For the primary effectiveness endpoint, based on the data from the combined physician-
sponsored studies, the survival rate at 30 days was estimated to be 89.4%.  With a 
clinically relevant non-inferiority margin of 10%, a performance goal for 30-day survival 
was established to be 79.4%.  Forty patients will be necessary to assess the primary 
effectiveness hypothesis, under an expected 30-day survival rate of 94.9% (estimated 
from an on-going clinical trial with the Zenith® Dissection Endovascular System in 
patients with complicated, type B aortic dissection), with a one-sided exact binomial test, 
at a type I error rate of 0.025 and a power of 0.8.   
Cook intends to enroll 73 patients, to allow for additional patients who may withdraw or 
be lost to follow-up, and to account for six previously enrolled patients that would not be 
eligible for enrollment based on the clarifications provided in Version 4 of the CIP (i.e., 
patients who were ASA class V or who were without confirmed absence of bowel 
necrosis at the time of enrollment).  While the data from all 73 patients enrolled in the 
study will be reported, the primary safety and effectiveness hypotheses will be assessed 
based on the 67 patients enrolled according to the inclusion/exclusion criteria specified in 
Version 4 of the CIP.   
 
7.2 
Performance Goals 
The performance goals used in the hypotheses of section 3.3 and the sample size 
calculations in section 9.1 were derived from the combined physician-sponsored studies. 
Using those data, the performance goal for the 30-day freedom from major adverse 
events was 61.2%, while the performance goal for the 30-day survival rate was 89.4%. 
With a clinically relevant margin of 10%, the performance goals are established as 51.2% 
and 79.4%, respectively. 
 

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7.3  
Site-level Poolability 
Poolability of data from multiple sites will be verified by examining the primary and 
secondary safety and effectiveness measures among sites as well as important patient 
baseline characteristics.  Site-level poolability will be considered appropriate provided 
that these measures are similar among sites. 
It is expected that many sites will have too few patients to provide reasonable site-level 
estimates of primary, secondary, and baseline measures.  Each investigative site will be 
allowed to enroll no more than 14 patients (20% of the total enrollment) to ensure the 
overall result is not biased by the results from a single site. Pooling of this information 
will be explored based on hospital size (large versus small), site enrollment (large versus 
small), type of hospital (community versus teaching), and other group-wise strategies. 
It is recognized that patient baseline characteristics may differ among sites, with some 
sites routinely treating patients with more severe disease progression.  It is anticipated 
that the primary and secondary endpoint measures may be related to covariates that  
reflect this disease progression, which are in turn related to outcome.  Thus, any observed 
site-specific differences among the primary or secondary endpoints will be checked for 
confounding with other measured covariates.  This can be accomplished using regression 
models (linear and logistic where appropriate) that include site and other measured 
covariates as independent variables. 
Should one or more sites significantly differ from the rest, then all subsequent analyses 
will include the discriminating covariate or a covariate to distinguish between the unusual 
site(s) and those sites that are considered poolable. 
 
7.4 
Missing Data 
Missing data will be addressed using three primary strategies: 1) estimating missing data 
with the best available data, 2) case deletion, and 3) multiple imputation. 
The first strategy may be used for missing imaging data.  Previous clinical trial 
experience suggests that some portion of the imaging data may not meet the criteria for 
accurate measurements by the core laboratory.  However, it is recognized that the treating 
physician uses this information to provide the best possible care for the patient.  
Therefore, it is reasonable to substitute any missing core laboratory measurements with 
the corresponding measurements made by the treating physician (or their staff).  In 
addition, the absence or presence of clinical sequelae may provide the required missing 

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core laboratory assessment of device performance.  Furthermore, imaging at subsequent 
time points may be available, making it possible to infer patient status at the time point of 
interest.  This strategy is a best approximation of the missing data value. 
The second strategy is case deletion.  If the amount of missing data does not result in a 
reduction of analyzable patients to a number that is below that required for sufficient 
statistical power of the primary endpoints, then case deletion will be the method of choice 
for that analysis. 
The third method is multiple imputation.  This method will be used to predict missing 
endpoint or covariate data.  It may be that the primary study endpoints may depend upon 
certain covariates. Therefore, it may be possible to model study endpoints, given a series 
of related covariates.  This model-based imputation exercise may provide estimates of the 
missing data that can be utilized in estimating event rates and confidence bounds.   
Strategies originating from Schafer4 will be used, supplemented with notes provided by 
Schafer.5  The computations will be performed using PROC MI and PROC 
MIANALYZE in SAS version 9.1 or later, or WinBUGS 1.4 or later.  
Additional analyses of missing data may be performed as appropriate, including a tipping 
point analysis and a worst-case analysis. 
 
7.5 
Future Use of Study Data 
Information redacted due to confidential content  
 
8.0 
Risk Analysis and Risk Assessment 
 
8.1 
Risks and Foreseeable Adverse Device Effects 
Information redacted. Please refer to the Instructions for Use 
 
8.2 
Methods to Minimize Risks 
The device design, non-clinical testing, clinical study design, and the Instructions for Use 
are intended to minimize the risks associated with the endovascular procedures. 
 
 

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9.0 
Safety Monitoring and Event Reporting 
 
9.1 
Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) consisting of independent physicians, who are 
not investigators in the investigation, nor have a perceived conflict of interest with the 
conduct and administration of the investigation, will be convened on a regular basis to 
evaluate investigation progress and review adverse events. 
 
9.2 
Clinical Events Committee 
An independent Clinical Events Committee (CEC) consisting of physicians, who are not 
investigators in the investigation, nor have a perceived conflict of interest with the 
conduct and administration of the investigation, will be established to adjudicate clinical 
events reported during the investigation.  This adjudication will be performed according 
to standard operating procedures to assess whether the events were due to a pre-existing 
or unrelated condition, procedure-related, technique-related, and/or device-related. 
Regularly scheduled review/monitoring of all patient data will be conducted at the Data 
Coordinating Center, in part, for identification of adverse events and assurance that they 
are correctly reported to the DSMB and CEC. 
 
9.3 
Adverse Event Reporting 
Events known to be related to pre-existing conditions or existing at admission are not 
considered adverse events (e.g., prior medically-treated cardiac arrhythmia with no 
change in status during the endovascular procedure).  Additionally, common standard of 
care practices are not considered adverse events (e.g., centers located at high 
geographical altitudes that discharge all patients on home oxygen therapy regardless of 
procedure).   
All adverse events (i.e., device-related and non-device-related) are to be reported using 
the appropriate case report form (Adverse Event/Complication form).  In cases of adverse 
device effects (adverse event with relation to the study device) or serious adverse events, 
completed forms should be submitted to the Data Coordinating Center immediately upon 
knowledge of the event.   
 
Cook Research Incorporated 
 
1 Geddes Way 

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West Lafayette, IN  47906 
Telephone:  
765-463-7537 
 
Fax: 
 
765-497-0641 
 
The Data Coordinating Center will notify the sponsor accordingly.  In accordance with 
applicable requirements, the investigator will notify the local Ethics Committee/IRB, 
while the sponsor will notify the regulatory authority.  Furthermore, if the sponsor 
determines that the device presents a potential risk to the study patients, all investigators 
in the study will be notified.  Refer to section 8.1 for a list of potential adverse events 
related to this study. 
 
10.0 
Administrative 
 
10.1 
Data Collection 
Patient data will be collected and entered by the investigative site into an electronic case 
report form (eCRF) system.  This is a secure, web-based system, allowing those with 
permission to access data from any location at any time.  Data will be entered by 
qualified site personnel.  Site personnel are required to have unique login names and 
passwords in order to enter patient data, and, in accordance with 21 CFR Part 11, the 
eCRF system creates a secure, computer-generated, time stamped audit trail to record the 
date and time of operator entries and actions that create, modify, or delete electronic 
records. 
 
10.1.1 Data Archiving 
Patient data and documents pertaining to the study are to be kept for the longest time 
required by the regulatory bodies overseeing the study.  Archiving will be done in such a 
way that the data are not lost during this period.  Both investigators and sponsor are 
obliged to keep the documents. 
 
10.1.2 Data Protection 
Each patient will be assigned a unique enrollment number, and will be identified to the 
sponsor only by this unique enrollment number and patient initials.  While monitors 
necessarily will have access to protected health information, all monitors will have 

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appropriate training and follow procedures for proper handling of patient-identified 
information.  Furthermore, whenever feasible, de-identified health information will be 
used by researchers involved in the study.  “Researchers” include the patient’s physician 
and the staff of collaborators, investigators in other locations studying this device, the 
sponsor, and the companies or individuals with research responsibilities delegated by the 
sponsor.   
These data may be used to gain additional experience with this device and to advance 
medical knowledge through presentations and articles regarding the study.  These data 
may also be reviewed by government agencies that oversee research and may approve 
medical devices for commercial use. 
These data may also be combined with health information about other patients.  The 
sponsor or their designee will keep the data in an ongoing database of information about 
the Zenith® Dissection Endovascular System, so that information can be studied and 
analyzed.  When the follow-up period is complete, no new information about individual 
patients will be added, but review of the data may continue.  Presentations, reports, and 
articles about this investigation will contain only de-identified information. 
 
10.1.3 Data Protection Agency 
If applicable, the Danish Data Protection Agency will be notified about this investigation 
to conform with The European Act on Processing of Personal Data (Act No 429 of May 
31, 2000) which entered into force on July 1, 2000, and which implements the Directive 
95/46/EC on the protection of individuals with regard to the processing of personal data 
and on the free movement of such data. 
 
10.2 
Data Reporting 
Progress reports and a final report at the conclusion of the clinical investigation will be 
submitted by the investigators and sponsor to the Ethics Committees and regulatory 
bodies as required by local regulations. 
 
 
 
 

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10.3 
Emergency Situations and Vulnerable Subjects 
Patients will not be treated with the Zenith® Dissection Endovascular System in 
emergency situations where prior consent of the patient or the patient’s legally-authorized 
representative in accordance with   21 CFR Part 50 is not possible. 
 
10.4 
Criteria and Procedures for Withdrawal 
The investigator must make a reasonable effort to ascertain and record the reason for 
withdrawal or discontinuation for each patient while fully respecting the subject’s rights.  
The reasons for withdrawal and discontinuation of any patient from the investigation 
shall be recorded.  If such discontinuation is because of problems with safety or lack of 
effectiveness, that patient shall still be followed-up in the investigation, if possible. 
 
10.5 
Deviations from Clinical Investigation Plan 
Deviations or non-compliances will be recorded together with an explanation.  Deviations 
shall be reported to the sponsor, regulatory authorities, and Ethics Committee/IRB as 
required.   
 
10.6 
Early Termination or Suspension of the Investigation 
The sponsor reserves the right to terminate/suspend the study at any point should they 
believe that important harmful events might result from its continuation.  Subjects may 
withdraw from the study at any time without penalty or loss of benefits.  The investigator 
may also decide to withdraw a subject from the study at any time on the basis of medical 
judgement.  In any case, the reasons for withdrawal will be documented, when available. 
 
10.7 
Limitations of the Investigation 
This study is inherently limited by the number of patients who will be excluded due to 
general, medical, and anatomical exclusion criteria.  Additional challenges to the study 
include the anticipated comorbidities, which may confound data analysis.   
 
 

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10.8 
Publication Policy 
Publication policy, rights and obligations for this investigation have been negotiated, 
detailed and defined in the Investigation Contractual Documents and Agreements with 
the Investigation Site and Investigators. 
 
10.9 
Approvals and Agreements 
The sponsor, coordinating investigator (if applicable), and the principal clinical 
investigators for each site shall agree to this document and any modifications.  A 
justification for any modifications will be documented.  Approval and agreement will be 
indicated by signing and dating the appropriate document. 
 
10.10 General Information 
10.10.1 Sponsor  
The Sponsor for this investigation is Cook Research Incorporated.  See Appendix A for 
contact information. 
 
10.10.2 Manufacturer 
The Manufacturer for this investigation is William Cook Europe, ApS.  See Appendix A 
for contact information. 
 
10.10.3 Data Coordinating Center  
The Data Coordinating Center for this investigation will be Cook Research Incorporated .  
See Appendix A for contact information. 
 
10.10.4 Investigation Compliance 
The investigation shall be performed according to the Declaration of Helsinki.  
The investigator is responsible for obtaining approval of this clinical investigation by the 
relevant Ethics Committee/IRB.  The sponsor must be provided with a copy of this 
approval before delivery of any study device.  Furthermore, the investigator will ensure 
that local regulations concerning data protection are followed. 

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Cook Research Incorporated is certified with the U.S. Department of Commerce's Safe 
Harbor Privacy program for the transfer of clinical study data pertaining to residents of 
the European Union.  The Safe Harbor Privacy Program, which is jointly sponsored by 
the Department of Commerce and the EU Commission, allows organizations to self-
certify to privacy standards that are higher than those currently required in the United 
States. 
The U.S. companies that participate in the Safe Harbor Privacy Program voluntarily agree 
to uphold seven Safe Harbor Privacy Principles: Notice, Choice/Consent, Onward 
Transfer, Access and Correction, Data Integrity, Security, and Enforcement. 
Adherence to these Safe Harbor Privacy Principles may be limited to the extent required 
by any legal, governmental, national security or public interest obligation. 
 
10.10.5 Investigators 
A complete list of the coordinating clinical investigator, principal clinical investigators, 
and clinical investigators will be updated and maintained by the Data Coordinating 
Center.  Updates will be sent to sites periodically.   
 
10.10.6 Monitoring Arrangements 
The monitor for this investigation will be Cook Research Incorporated.  See Appendix A 
for contact information. 
The investigation will be monitored in accordance with written standard operating 
procedures consistent with applicable regulations.  Written procedures for monitoring the 
investigation are maintained by the monitors and can be found in Appendix B. 
 
10.10.7 Insurance 
The devices are covered by sponsor’s product liability insurance with Chubb Group of 
Insurance Companies, and a clinical study insurance policy will be taken out according to 
local requirements.  A copy of the insurance certificate(s) will be included in the 
investigator file.  By signing the Clinical Investigation Plan, all the investigators and co-
investigators involved declare to be covered by liability insurance in case of an adverse 
event due to medical error occur during the Zenith® Dissection investigation. 

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10.10.8 Exposition of the Clinical Investigation Plan 
In case of translation of the Clinical Investigation Plan into the language of the 
participating countries, the English version is to be considered as the original; i.e., when 
expounding the contents of the Clinical Investigation Plan in these languages, the English 
version is definitive in case of doubt. 
 
11.0 
Bibliography 
Please reference the Clinical Investigator Brochure for a complete literature review and 
evaluation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A 
Contact Information 
 
 
 
 
 

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Contact Information 
 
Sponsor  
Cook Research Incorporated 
1 Geddes Way 
West Lafayette, IN 47906 
USA 
 
Contact 
Jennifer Kerr / President 
Telephone:   765-463-7537 
Fax:    
765-497-0641 
E-mail:  
Jennifer.Kerr@CookMedical.com 
 
 
Manufacturer 
William Cook Europe, ApS 
Sandet 6 
4632 Bjaeverskov, Denmark 
 
 
Data Coordinating Center/Monitor 
Cook Research Incorporated 
1 Geddes Way 
West Lafayette, IN  47906 
USA 
 
Contact: 
Jennifer Kerr / President 
Telephone:   765-463-7537 
Fax:    
765-497-0641 
E-mail:  
Jennifer.Kerr@CookMedical.com 
 
 
 

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APPENDIX B 
Written Procedures for Monitoring Investigations 
 
 
 
 
 

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Written Procedures for Monitoring Clinical Investigations 
 
 
A. 
Selection of the monitor. 
Designated by the sponsor to oversee the investigation, the monitor may be an 
employee of Cook, an employee of a monitoring organization (CRO) or an 
independent contractor or consultant.  The monitor shall be qualified by training 
and experience to monitor the investigation in accordance with all applicable 
regulations and standards for conducting clinical investigations. 
 
B. 
General duties of the monitor. 
The monitor must ensure that the investigation is conducted in accordance with: 
1. 
The signed investigator agreement. 
2. 
The Clinical Investigation Plan (CIP). 
3. 
Any conditions imposed by the IRB/EC or regulatory authority. 
4. 
The requirements of the applicable regulations and standards. 
 
C. 
Reports by the monitor to the sponsor. 
1. 
Any noncompliance with the items listed above.  In the event that the 
investigator is not complying with the requirements outlined above, it is 
the sponsor's responsibility to secure compliance. 
2. 
Any adverse events or effects that are potentially reportable to a regulatory 
authority. 
 
D. 
Initiating the investigation. 
Prior to initiating any clinical use of the device, the monitor will participate in a 
pre-investigation or initiation visit with each investigative site.  
At a minimum, the following items shall be addressed during the site initiation 
visit: 
• 
Provide training to investigator on his/her responsibilities per the investigator 
agreement, applicable laws, regulations and standards; and 
• 
Provide training to investigator that the IRB/EC approval letter and informed 
consent/patient information is on file before initiation of the clinical 
investigation. 
Additionally, training may be provided to the investigator on: 
• 
The regulatory status of the device/product(s) and the requirements for the 
accountability of same;  

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• 
The nature of the clinical investigation plan (CIP); 
• 
The requirements for an adequate and well-controlled clinical investigation; 
• 
His or her obligation to obtain informed consent in accordance with 
applicable regulations; 
• 
His or her obligation to ensure continuing review of the clinical investigation 
by the IRB/EC in accordance with conditions of approval and applicable 
regulations and to keep the sponsor informed of such IRB/EC approval and 
subsequent IRB/EC actions concerning the investigation; 
• 
The importance of access to an adequate number of suitable subjects to 
conduct the investigation; 
• 
The importance of adequate facilities for conducting the clinical 
investigation; and 
• 
The importance of sufficient time from other obligations to carry out the 
responsibilities to which the investigator is committed by applicable 
regulations. 
E. 
During the course of the investigation, at the direction of the Project Manager, the 
monitor should visit the site frequently enough to ensure that: 
• 
The facilities and research staff used by the investigator continue to be 
acceptable for purposes of the clinical investigation; 
• 
The applicable version of the CIP and agreements are being followed; 
• 
Changes to the CIP, informed consent/patient information have been 
approved by the IRB/EC and/or reported to the sponsor and the IRB/EC; 
• 
Accurate, complete, and current records are being maintained; 
• 
Accurate, complete, and timely reports are being made to the sponsor and 
IRB/EC; and 
• 
The investigator is carrying out the agreed-upon activities and has not 
delegated them to other previously unspecified staff. 
As appropriate, the following tasks could be performed during periodic visits:  
• 
Device/product accountability review; 
• 
Adverse event review to ensure that events are appropriately reported within 
the time periods required by the sponsor, CIP, IRB/EC, and applicable 
regulatory requirements; and 
• 
Source data verification per the monitoring plan to determine that : 
o 
Informed consent/patient information has been documented in 
accordance with applicable regulations and expectations of local 
IRB/EC; 

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o 
The information recorded in the case report forms (paper or electronic) 
is complete, accurate, and legible; 
o 
There are no omissions in the case report forms (CRFs) of specific data 
elements, such as the administration to any patient of concomitant test 
articles or the development of an intercurrent illness; 
o 
Missing visits or examinations are noted; and 
o 
Subjects failing to complete the clinical investigation and the reason for 
each failure are noted. 
F. 
Records of the monitor. 
The monitor shall prepare and maintain records of each initiation visit and each 
periodic visit, general site contact, or discussion.  These will include: 
1. 
Date, name and address of the investigator, and names of other staff 
members present at each meeting. 
2. 
A summary of the findings of the visit. 
3. 
A statement of any action taken by the monitor or investigator to correct 
any deficiencies noted. 
4. 
The monitor shall immediately notify the sponsor of any conditions of 
non-compliance with the Clinical Investigations Plan, conditions of 
IRB/EC or regulatory authority approval, or the applicable regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX C 
Definitions 
 
 
 
 

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Calcification:  Landing zone and iliac calcification will be graded based upon the 
following: 
 
 
None:  
Lack of calcification;  
 
 
Mild:         
Less than 40% circumferential calcification; 
 
 
Moderate:   
40-70% circumferential calcification; or 
 
 
 
Severe:    
Greater than 70% circumferential. 
Clinical Utility Measures:  Number of blood transfusions; Ventilator days;  Days to 
resumption of oral fluids; Days to resumption of normal diet; Days to resumption of normal 
bowel function; Duration of ICU stay; Days to discharge. 
Disabling Chronic Obstructive Pulmonary Disease:   Forced expiratory volume (FEV1) 
< 1.0 liter or receiving home oxygen therapy. 
Dissection Grade: 
 
 
 
Acute:    
 
Within 14 days of onset; 
 
 
 
Subacute:   
 
Between 15 days and 30 days of onset; or 
 
 
 
Chronic:   
 
Between 31 days and 90 days of onset. 
Embolization:  Clinical evidence of ischemic tissue remote from the operative field, 
caused by air, thrombus dislodged from the aneurysmal sac, aortic neck, and/or false 
lumen, including those tissues supplied by vessels in the head, renal arteries, aortic 
visceral branches,  pelvic vessels, and vessels of the upper and lower limbs.  This is, of 
course, distinct from pre-operative, operative or post-operative intentional embolization 
procedures (e.g., to treat Type II entry-flow).   
Entry-flow: Contrast-enhanced blood entering the false lumen for one or more of the 
following reasons: 
Type I entry-flow:  Entry-flow caused by peri-prosthetic flow at the proximal 
and/or distal seal zones; 
Type II entry-flow:  Entry-flow caused by retrograde flow from patent collateral 
vessels into the false lumen through the primary tear;   
Collateral entry-flow:  Entry-flow caused by retrograde flow from collateral 
vessels directly into the false lumen; 
 
 

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Type III entry-flow:  Entry-flow caused by a defect in the graft fabric, inadequate 
seal (between covered graft components only), or disconnection of covered graft 
ancillary components; 
Type IV entry-flow:  Entry- flow caused by graft fabric porosity, often resulting in 
a generalized blush of contrast within the false lumen; or 
Unknown entry-flow:  Entry-flow through undefined origin. 
Left Ventricular Ejection Fraction:  The measurement of the left ventricular function in 
the resting state. The normal LVEF ranges between 55% and 80% (mean = 67%). 
Major Adverse Events:   Myocardial infarction, chronic renal insufficiency/chronic renal 
failure requiring dialysis, bowel ischemia, stroke, paraplegia or paraparesis, and 
prolonged (> 72 hours) ventilatory support.   
Malperfusion:  Malperfusion in the setting of an aortic dissection is defined as one or 
more of the following1: 
1. Visceral hypoperfusion by an acute abdomen, abdominal pain out of proportion to 
physical examination findings in setting of radiographic hypoperfusion of 
mesenteric bed, lactic acidosis attributed to visceral malperfusion, or need for 
bowel resection. 
2. Renal hypoperfusion including oliguria or aneuria in setting of rising rnalfunction 
tests (creatinine or blood urea nitrogen) or radiographic evidence of impaired 
renal artery blood flow. 
3. Lower extremity hypoperfusion indicated by abnormal pulse examinations in 
conjunction with leg pain, pallor, paresthesias or paralysis. 
4. Spinal cord hypoperfusion as noted by altered motor function of one or both of 
legs attributed to a possible spinal cord source. 
MI (Non-Q-Wave):  Clinical evidence of a myocardial infarction with elevated peak CK 
values greater than three times the upper limit of normal with elevated CK-MB (above 
the institutions upper limit of normal) in the absence of new pathological Q-waves or 
clinical evidence of a myocardial infarction with troponin greater than three times the 
upper limit of normal, as determined by the investigator. 
MI (Q-Wave):   Post-procedure chest pain or other acute symptoms consistent with 
myocardial ischemia and the presence of new pathological Q-waves in two or more 
contiguous ECG leads.  
 
 

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Migration (radiographic):  Antegrade or retrograde movement of the proximal or distal 
components of the endoprosthesis > 10 mm relative to anatomical landmarks identified 
on the first post-operative CT scan as evaluated by core laboratory. 
Migration (clinical):  Antegrade or retrograde movement of the proximal or distal 
components of the endoprosthesis resulting in the need for a secondary intervention. 
New York Heart Association Classification:  
1. Patient with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, palpitation, or 
dyspnea. 
2. Patients with cardiac disease resulting in slight limitation of physical activity.  
They are comfortable at rest; ordinary physical activity results in fatigue, palpitation 
or dyspnea. 
3. Patients with cardiac disease resulting in marked limitation of physical activity.  
They are comfortable at rest; less than ordinary physical activity causes fatigue, 
palpitation or dyspnea. 
4.   Patients with cardiac disease resulting in inability to carry out any physical 
activity without discomfort.  Symptoms of cardiac insufficiency may be present 
even at rest.  If any physical activity is undertaken, discomfort is increased. 
Occlusive Disease of iliacs:  Occlusive disease will be graded based upon the following: 
 
 
 
None: 
       Lack of occlusive disease; 
 
 
 
Mild:        
Some disease, focal with less than 30% narrowing; 
            Moderate:   
Between 30-50% narrowing not requiring interventional 
techniques to meet inclusion criteria; or 
 
 
 
Severe:     
Greater than 50% or any patient requiring angioplasty prior 
to endograft delivery. 
 
 

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Pain/Symptoms rating: 
 
 
 
None:  
 
No pain/symptoms; 
 
 
 
Mild:  
 
Nagging, annoying, interfering little with activities of daily 
living (ADLs); 
 
 
 
Moderate:  
Interferes significantly with ADLs; or 
 
 
 
Severe: 
 
Disabling; unable to perform ADLs. 
Resistant Hypertension:  arterial pressure > 140/90 mm Hg despite use of three 
antihypertensive medications.  (Kaplan NM.  Resistant hypertension.  Journal of 
Hypertension 2005; 23: 1441-1444.)  
Renal Failure:  Acute or progressive renal insufficiency leading to the need for dialysis 
or hemofiltration.   
Reversible ischemic neurologic deficit (RIND):  Clinically significant central nervous 
system deficit lasting > 24 hours and < 72 hours. 
Renal Insufficiency:  A rise in serum creatinine of more than 30% above the pre-
procedure level, resulting in a serum creatinine level > 2.0 mg/dl that does not 
spontaneously resolve (does not include those patients with a pre-procedure serum 
creatinine > 2.0 mg/dl). 
Rupture:  Rupture in the setting of aortic dissection is defined by the presence of 
hemorrhage outside the aortic boundaries, which is noted on CT scans.1 
Stent/attachment system fracture/break:  Fracture or breakage of any portion of the stent 
or attachment system including metallic fracture or breakage of any suture material used 
to construct the stent or secure the stent or attachment system to the graft material. 
Stroke:  Permanent, clinically significant central nervous system deficit. 
Tortuosity of iliac arteries:  Tortuosity will be graded based upon the following: 
 
 
None:          Lack of tortuosity; 
 
 
Mild:  
Fairly straight arteries; 
 
 
Moderate: 
Angulation manageable with stiff wires, < 70 degrees; or 
 
 
Severe: 
Angulation difficult, may require surgical exposure for  
 
 
 
 
 
  
straightening, not straightened entirely with wires. 
 
 

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Transient Ischemic Attack (TIA):  Central nervous system deficit lasting ≤ 24 hours. 
Type B Aortic Dissection: Thoracic aortic dissection with the most proximal extent of 
dissection distal to the left subclavian artery. 
 
 

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APPENDIX D 
References 
 
 

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1. White RA, Miller DC, Criado FJ et al. Report on the results of thoracic endovascular 
repair for acute, complicated, type B aortic dissection at 30 days and 1 year from a 
multidisciplinary subcommittee of the Society for Vascular Surgery Outcomes 
Committee.  J Vasc Surg 2011; Apr; 53(4):1082-90. 
 
2. Fann JI, Miller DC.  Aortic dissection.  Ann Vasc Surg 1995; 9:311-323. 
 
3. Matsumura et al., The Society for Vascular Surgery practice guidelines: management 
of the left subclavian artery with thoracic endovascular aortic repair. J Vasc Surg 2009; 
Nov; 50(5):1155-8.  
 
4. Schafer, JL. Analysis of Incomplete Multivariate Data. London: Chapman & Hall; 
1997. 
 
5. Schafer, JL. Missing Data: A Review. A seminar sponsored by the Cleveland Chapter 
of the American Statistical Association; October 14, 2002; Cleveland, OH.