Multicenter Observational Cohort Study to Evaluate Cerebral AneurysmFlow Results in Occlusion
Conditions: Intracranial Aneurysm
Sponsor: Philips Clinical & Medical Affairs Global

Philips
Post-Market Clinical Study Plan
XCY61O-1 30253
IGT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 1 of 23
Security Classification:
Confidential
Author:
Joris AH de Groot
lnCs: Clinical Study Specialist
Company:
Sponsor’s Legal Entity:
Business:
Department:
Philips
Philips Medical Systems Nederland B.V.
Veenpluis 4
5684 PC Best
The Netherlands
Document ID:
Date:
Revision:
Status:
XCY61 0-130253
2018 Apr 06
2.0
Approved
APPROVAL
—
Date (yyyy Mon dd)
/
2
0
gaç” 6
‘“
Post-Market Clinical Study Plan
Multicenter observational cohort study to evaluate
Cerebral AneurysmFlow Results in Occlusion (CARO)
IGT Systems
Clinical Science
Name
Bart Carelsen
Joris AH de Groot
Inge Jenniskens
loana Ulea
Function
lnCs: Clinical Study
Specialist Manager
lnCs: Study Leader
lnCs: Clinical Study
Specialist
Q&R: RA officer
Form ID: XCT-0302018 revO6f 2016 Feb01
PtiliIps’ proprietary Information, unauthorized use is prohibited

Philips
Post-Market Clinical Study Plan
XCY61O-1 30253
IGT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 2 of 23
REVISION HISTORY
Date
Rev.
Author
Changes/Comments
2018 Jan09
1.0
Joris AR de Groot
Initial version
2018 Mar 13
2.0
Joris AR de Groot
Removed 3 month follow-up to better
resemble current clinical practice
Updated approval status in participating
countries
Added extra motivation for the
multicenter nature of the study
Minor correction to Flowchart
Updated Section 10 Compliance
Statement to secure compliance for all
participating centers.
Form ID: XCT.0302018 revOGI 2016 Feb01
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Philips
Post-Market Clinical Study Plan
XCY61 0-1 30253
IGT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 3 of 23
TABLE OF CONTENTS
APPROVAL
1
REVISION HISTORY
2
TABLE OF CONTENTS
3
SUMMARY
5
1.
DEVICE DESCRIPTION
8
1.1. Summary description of the study device
8
1.2.
Intended Purpose
9
1.2.1.
Medical Purpose
9
1.2.2.
Patient Population
9
1.2.3.
Clinical Environment
9
1.3. Necessary training and experience needed to use the research device
9
1.4. Materials that will be in contact with tissues or body fluids
9
1.5. DeviceTraceability
10
2.
JUSTIFICATION FOR THE DESIGN OF THE STUDY
10
2.1.
Clinical study Justification
11
3.
OBJECTIVES AND HYPOTHESES
11
3.1. Primaryobjective
11
3.2. Secondary objectives
11
3.3.
Exploratory objectives
11
4.
STUDYDESIGN
11
4.1. General
11
4.2. Study device exposure
12
4.3. Subjects
12
4.3.1.
In- and exclusion criteria
12
4.3.2.
Enrollment and duration
12
4.3.3.
Numberofsubjects
12
4.3.4.
Subject withdrawal or discontinuation
12
4.4. Procedures
13
4.5. Monitoring Plan
15
5.
STATISTICAL CONSIDERATIONS
16
5.1. Sample Size Justification
16
5.2. General Consideration
16
5.3. Subject disposition
16
5.4. Primary objective
16
5.5. Secondary objectives
17
5.5.1.
Secondary objective: Predictive value at 6 months follow-up
17
5.5.2.
Secondary objective: Optimal MAFA ratio threshold
17
5.5.3.
Secondary objective: Adverse events
17
5.6.
Exploratory objectives
18
5.6.1.
Exploratory objective: Potential value additional AneurysmFlow parameters
18
5.6.2.
Exploratory objective: Potential Value of Adding Clinical Variables
18
6.
DATA MANAGEMENT
18
6.1.
Retention period
19
7.
AMENDMENTS TO THE CLINICAL STUDY PLAN
19
8.
DEVIATIONS FROM THE CLINICAL STUDY PLAN
19
9.
DEVICE ACCOUNTABILITY
19
10.
STATEMENTS OF COMPLIANCE
19
11.
INFORMED CONSENT PROCESS
20
11.1 .Subject unable to read or write
20
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Philips
Post-Market Clinical Study Plan
XCY6IO-1 30253
IGT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 4 of 23
12.
SAFETY REPORTING
20
13.
EARLY TERMINATION OR SUSPENSION OF THE CLINICAL STUDY
20
14.
PUBLICATION POLICY
21
15.
ABBREVIATIONS USED
21
16.
REFERENCES
21
APPENDIX I LIST OF INVESTIGATORS AND SITES
22
APPENDIX II: LIST OF MONITOR(S)/CLINICAL SCIENTIST
23
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Philips
Post-Market Clinical Study Plan
XCY61O-1 30253
ICT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 5 of 23
SUMMARY
Identification of study device
AneurysmFlow Ri .0 is an approved (CE labeled, cleared in US, Canada and Argentina), software tool
intended to provide relevant information on the blood flow in a cerebral aneurysm and its parent artery
based on angiography. It provides color coded and vector field representation of a digital subtraction
angiography (DSA). It can quantify blood flow rates in the artery based on DSA and 3-D Rotational
Angiogram (3DRA) data. It can visualize blood flow patterns in an aneurysm based on DSA data.
Specifically, it calculates the Mean Aneurysm Flow Amplitude (MAFA) ratio to measure the volumetric flow
rate quotient before and after Flow Diverter Stent (FDS) implantation in the region of interest.
It is manufactured by Philips Medical Systems By., a Philips Healthcare company.
Study design
This is a prospectively planned, single arm, observational, multicenter cohort study to assess the
prognostic value of the MAFA ratio for predicting full aneurysm occlusion 12 months after flow diverter
placement.
Objectives
Primary objective;
•
To assess the prognostic value of the MAFA ratio for predicting full aneurysm occlusion 12
months after flow diverter placement.
Secondary objectives:
•
To assess the prognostic value of the MAFA ratio for predicting full aneurysm occlusion 6 months
after flow diverter placement.
•
To determine optimal MAFA ratio threshold.
•
To register (serious) adverse events (i.e. re-operations, ruptures and deaths).
Exploratory objectives:
•
To evaluate the potential value of additional AneurysmFlow parameters for predicting full
aneurysm occlusion 6 and 12 months after flow diverter placement.
•
To evaluate the potential value of additional clinical variables to predict full aneurysm occlusion 6
and 12 months after flow diverter placement using multivariate logistic regression.
Primary and secondary endpoints
The primary endpoint is the prognostic value (i.e. c-statistic including confidence intervals) of the MAFA
ratio with respect to full aneurysm occlusion (i.e. using the Raymond-Roy Occlusion Classification
I on
standard-of-care head imaging) 12 months after Flow Diverter Stent placement. Secondary endpoints are
the prognostic value (i.e. c-statistic including confidence intervals) of the MAFA ratio with respect to full
aneurysm occlusion on standard-of-care head imaging 6 months after flow diverter placement, the optimal
threshold for the MAFA ratio and the number of adverse events.
Main inclusion criteria
•
Subject with unruptured, 5rnm saccular aneurysm(s) located in the anterior intracranial
circulation and suitable for an endovascular treatment with a Flow Diverter Stent
•
Subject is 18 years of age or older, or of legal age to give informed consent per state or national
law
•
Subject is available for clinical follow-ups
Main exclusion criteria
•
Non-saccular brain aneurysm(s) (i.e., dissecting, fusiform, atherosclerotic, mycotic, bifurcational)
Prior aneurysm treatment with either endovascular (stenting, coiling) or surgical (clipping)
techniques
•
Endovascular treatment assisted with coils or intracranial stents
•
Significant or severe allergy to intra-arterial contrast medium uncontrolled by pre-procedure
medications
•
Severe kidney disease (e-GFR < 60)
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Philips
Post-Market Clinical Study Plan
XCY61 0-1 30253
IGT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 6 of 23
.
Subjects not willing (or able) to attend post FDS insertion standard-of-care follow up clinic visits
requiring DSA, head MRI or CTA imaging
.
Subject participates in a potentially confounding drug or device trial during the course of the study.
.
Subject meets an exclusion criteria according to national law (e.g. age, pregnant woman, breast
feeding woman)
No. of subjects
In total 120 subjects will be enrolled in the study. The enrollment period is expected to last for 1 year.
Study procedures
Physician investigators participating in this study are expected to follow their normal clinical practice in
enrolling, treating and following patients with intracranial aneurysms that are amenable to treatment with
flow diverter stents, No additional procedures are required of patients in order to participate in this
observational study.
Pre-Screening
Patients presenting with intracranial saccular aneurysm(s) will be evaluated by the neuro interventional
team, in accordance with institutional practice, to establish an appropriate treatment plan based on the
patient’s medical condition and available diagnostic screening procedures prior to recruitment in the study.
More than one aneurysm in a single patient may be treated, but only the target aneurysm(s) treated with
FDS devices initially will be considered as part of this study. If treatment of the aneurysm with the EDS is
deemed appropriate, the institution’s guidelines regarding their ethics committee and informed consent
process will be followed.
Screening
After obtaining the consent form(s) approved by the local research ethics board (REB), the principal
investigator will screen the potential investigation subjects for the CARD study. The principal investigator
or his delegates on the study team will enter data in a pre-designed e-CRF. This will include patient
demographics, relevant past medical and surgical history, and specific target aneurysm data along with
pre-procedural/screening imaging details.
Only patients who meet all inclusion and none of the exclusion criteria will qualify for this study. The
measurement and size of each aneurysm will be verified by the principal investigator. If the size of the
aneurysm is acceptable, then it will be included in the study. It is recommended that this measurement
should be done within 180 days before the procedure.
Index Procedure and Discharge
The investigator will proceed with standard of care procedures on the day of Index Procedure (i.e. FDS
insertion) for the target aneurysm(s). Then, endovascular treatment procedure details should be provided
under the “INDEX PROCEDURE & DISCHARGE” field for each eligible patient.
Blood flow velocity will be calculated using the dedicated software AneurysmElow (Philips Healthcare,
Best, The Netherlands), which will be installed on standard of care imaging equipment. For this purpose,
digital subtraction angiograms will be acquired during the procedure; just before and right after placement
of the FDS.
Calculation of blood flow velocity will be performed automatically on the AneurysmFlow software. The
operator will have access to the results of the calculation in addition to all of the regular information that is
at his/her disposal during routine clinical practice. There are no additional devices or medications required
for the study. The AneurysmFlow software uses standard-of-care 2D DSA and 3D-RA image sequences
to determine this flow information. All raw image sequences will be stored for future reference.
Figure 1 shows the workflow for using the AneurysmFlow software in this study.
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In step 1 a 3D rotational angiogram (SD-RA) will be performed in the neuro-interventional suite with the x
ray C-arm to acquire a 3D image volume of the aneurysm anatomy to be treated. From this 3D-RA, an
optimal viewing angle for the C-arm will be determined to obtain good flow information. This angle should
show the parent artery, aneurysm neck and aneurysm itself clearly without any overlap. The 3D-RA will
also help to determine a good C-arm viewing angle to help position and deploy the FDS across the
aneurysm.
In Step 2 a 2D DSA x-ray run with contrast agent injection (i.e. advised injection rate 1.5 to 2 cc/s) will be
acquired at the optimal C-arm viewing angle determined by the 3D-RA scan to obtain dynamic blood
motion information before FDS deployment at the location of the aneurysm. If the initial contrast agent
injection was insufficient, the injection will be altered and repeated with another DSA run to obtain high
quality image information. The FDS will then be placed at the location of the aneurysm.
In Step 3, after FDS deployment, a second DSA run with contrast agent will be acquired (i.e. injection rate
=1.5 to 2 ccfs) at the optimal C-arm viewing angle determined from the 3D-RA to qualitatively evaluate
blood motion in the region of the aneurysm after deployment of the FDS. The C-arm angle and injection
rate of this second DSA run (post FDS deployment) must be the same as the first DSA run (pre FDS
deployment). The 2 DSA runs and the 3D-RA image volume will automatically be sent to the
AneurysmFlow workstation right after they are acquired. If the FDS is ballooned after placement, the
physician is asked to repeat Step 3 after ballooning.
In Step 4 a routine VasoCT scan, which is another 3D rotational x-ray C-arm scan, will then be performed
with the x-ray C-arm in the neuro-interventional suite to evaluate the 3D apposition of the deployed FDS
with respect the vessel wall.
The region of interest around the aneurysm and the corresponding arterial segment from which it has
developed will be automatically segmented by the AneurysmFlow software, but manual controls are
available in the software if modifications to the anatomical segment of interest are desired by the
interventionalist. These modifications can be performed by an appropriately trained study member. The
software will then automatically calculate the flow parameters of the aneurysm both before and after FDS
deployment, along with the MAFA ratio.
For this study, the operator will have the choice of selecting which target aneurysms are amenable to FDS
treatment. Patients that have single or multiple target aneurysms that are suitable for FDS treatment as a
first treatment step would be acceptable for this study. Each target aneurysm in the patient will have a
separate CRF sub-form to fill out. Additionally, each target aneurysm sub-form can be further divided into
several FDS sub4orms to account for multiple flow diverters, if needed. To summarize, if the patient has
more than one target aneurysm and/or needs more than one flow diverter per aneurysm, then a sub4orm
on the CRF will need to be filled out for each aneurysm and for each FDS used.
As shown in Figure 1, if a target aneurysm is treated with a FDS (or more than one) initially, and is then
treated using another approach (such as coiling) then this target aneurysm can remain included as part of
the study. However, if a target aneurysm is treated using a non-FDS approach initially (such as with
Philips
Post-Market Clinical Study Plan
XCY61 0-1 30253
IGT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 7 of 23
Step 3: DSA
Step 4: vaso-a
High sioc DSA
verily the location
of the stent
An eu rys m F ow
Pro Flow bisector
placement
L_i
flow/MAFA L_J
analysis
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Follow-up visit
Start visit window
Target date
End visit window
(days post-procedure)
(days post-procedure)
(days post-procedure)
6-months
134
183
225
12 months
316
365
414
Adverse Events
All (serious) adverse events (i.e. re-operations, ruptures and deaths) whether or not related to the
investigational device will be collected and reported conform local rules and regulations.
Follow up
The subjects will be followed-up at 6 and 12 months according to regular clinical standard of care.
Duration of the study
The total duration of the study is expected to take approximately 2.5 years. Patient enrollment will take
place between March 2018 and September 2019. Each subject will be in the study for 1 year (follow-up).
1.
DEVICE DESCRIPTION
1.1.
Summary description of the study device
AneurysmFlow Ri .0 is an approved (CE labeled, cleared in US, Canada and Argentina), software tool
intended to provide relevant information on the blood flow in a cerebral aneurysm and its parent artery based
on angiography. It provides color coded and vector field representation of a digital subtraction angiography
(DSA). It can quantify blood flow rates in the artery based on DSA and 3-D Rotational Angiogram (3DRA)
data. It can visualize blood flow patterns in an aneurysm based on DSA data.
Specifically, it calculates the Mean Aneurysm Flow Amplitude (MAFA) ratio to measure the volumetric flow
rate quotient before and after Flow Diverter Stent (FDS) implantation in the region of interest.
It is manufactured by Philips Medical Systems By., a Philips Healthcare company.
When treating intracranial aneurysms, neuro-interventionalists are interested in the flow patterns inside and
around those aneurysms because these flow patterns are likely to impact the natural evolution of aneurysms,
such as growth and risk of rupture. In order to evaluate the flow, physicians use high speed angiograms. By
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Philips
Post-Market Clinical Study Plan
XCY61O-1 30253
IGT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 8 of 23
coiling), followed by placement of an FDS or other approach, then the aneurysm will be excluded from the
study.
The MAFA ratio will be calculated after the placement of each FDS. For each FDS, this ratio will be
determined with the flow information before any stents were placed and also with the flow information after
each FDS was placed. The final MAFA ratio will be calculated using the flow information before any FDS
devices were placed and using the flow information after the last FDS was placed. Clinical and imaging
outcomes of a procedure will be assessed using a combination of the flow metrics calculated by the
AneurysmFlow software available to the operator during interventional treatment in addition to information
that is routinely acquired during FDS placement. This information acquired across the patient population in
the study will also contribute to determine mare precise MAFA ratio thresholds to improve prediction of
complete aneurysm occlusion after FDS placement. This study will not make any recommendation on
patient management or on treatment strategy. Also, this software will not disrupt standard-of-care
workflow for the interventionalist.
Follow-Ups (6 and 12 months)
All registry patients treated with FDS are expected to follow their routine post treatment clinical visits,
which will include a standard-of-care head imaging (e.g. CTA, MRA and/or DSA) test to classify aneurysm
occlusion (i.e. Raymond-Roy Occlusion Classification
I (Roy et at, 1997)) at 6 months (±49 days) and 12
months (±49 days). During the 6 and 12 month follow up visits, patient medical charts will be accessed to
collect adverse events (if applicable) and document any post-treatment neurological deterioration
(neurological assessment, mRs scale). De-identified data (i.e. clinical notes, imaging reports etc.) will be
entered in the relevant e-CRF sections.

Philips
Post-Market Clinical Study Plan
XCY61O-1 30253
IGT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 9 of 23
observing and analyzing the displacement and dispersion of the injected contrast they develop an
understanding and can measure the rate of the blood flow.
The Aneurysm Flow Visualization option serves to extract and enhance the flow patterns from those high
speed angiograms, assisting the physician in the observation and analysis of these patterns.
Aneurysm Flow Visualization does not change the basic functionality of the Interventional Workspot and/or
the interventional X-ray system. Users need to adhere to the normal handling and safety precautions as
mentioned in the IFU.
The study device includes a software release number to permit full identification.
The manufacturer of the study device is:
Philips Medical Systems Nederland B.V.
Veenpluis 4-6
5684 PC Best
The Netherlands
1.2.
Intended Purpose
AneurysmFlow is a software tool intended to provide relevant information on the blood flow in a
cerebral aneurysm and its parent artery based on angiography.
AneurysmFlow is a software medical device and is intended to be used in combihation with a Philips
interventional X-ray system and 3D rotational angiogram (SD-RA) data.
AneurysmFlow is a software product (Interventional Tool) that provides color coded and vector field
representation of a digital subtraction angiography (DSA). It can quantity blood flow rates in the artery based
on DSA and 3D-nA data. It can visualize blood flow patterns in an aneurysm based on DSA data. It can also
provide a side by side visual and quantitative comparison between two acquisitions.
1.2.1.
Medical Purpose
AneurysmFlow assists during endovascular procedures for treating of saccular cerebral aneurysms, by:
- Visualization of blood flow patterns in the aneurysm and parent vessel, based on DSA.
- Quantification of the blood flow in the aneurysm parent vessel, based on DSA and 3D-RA.
- Comparison of blood flow, both visual and quantified between two acquisitions.
1.2.2.
Patient Population
AneurysmFlow is suitable for use with patients who were elected for a cerebral endovascular aneurysm
treatment procedure using fluoroscopy.
The study device manual contains safety precautions and handling of the study device.
1.2.3.
Clinical Environment
Aneurysm Flow is intended to be used in the control room and in the exam room of an interventional
suite or hybrid operating room. The system is connected to a Philips Interventional X-ray system.
1.3.
Necessary training and experience needed to use the research device
The Intended Operator profile is a clinical specialist who is fully skilled and responsible for sound clinical
judgment and for applying the best clinical procedure, for example (but not limited to): interventional
neuroradiologists, skilled radiology technicians (or nurses) assisting the physician,
vascular/endovascular/neuro surgeons.
1.4.
Materials that will be in contact with tissues or body fluids
No materials of the study device will be in contact with tissue or body fluids.
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Philips
Post-Market Clinical Study Plan
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IGT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 10 of 23
1.5.
Device Traceability
The study device includes a name, including software version and accessories to permit full identification.
Device traceability will be maintained by Philips. Records shall be kept to document when the device is
received, installed or uninstalled at the hospital.
2.
JUSTIFICATION FOR THE DESIGN OF THE STUDY
Intracranial aneurysms IA(s) are a prevalent medical condition for which their rupture can produce a major
impact in a patient’s life and also in society because of collective costs associated with disability recovery,
treatment and rehabilitation (Bruno et at, 1998). The physiopathology of IA(s) is still undefined and there is
no corresponding animal model to better study and understand the disease (Bruno et at, 1998). Treatment
of IA(s) progressed over the years with advances in the surgical field and the development of minimally
invasive techniques (Krings et at, 2011). This progress generated a major impact on clinical practice such as
the development of coil embolization with or without balloon remodeling, intracranial stent assisted coiling
and more recently, implantation of flow diverting stent (FDS) devices (Pereira at at, 2013). An FDS is an
endoluminal prosthesis that changes the intra-aneurismal flow and progressively replaces it with thrombosis
until the whole aneurysm is excluded from blood circulation, along with parent vessel remodeling (Lylyk et
at, 2009). This technology brought a significant advance to the neuroradiology field and some important
questions started to be raised concerning its mode of use, efficacy, procedural risks, post procedural
bleeding risk and time taken to complete aneurysm thrombosis after treatment (Lylyk at at, 2009). The
evaluation of this new technology remains uncertain, but over the past years, many discussions and meeting
sessions have been dedicated to intracranial hemodynamics and aneurysmal flow.
A new method to determine intracranial flow from x-ray digital subtracted angiography (DSA) images during
endovascular treatment procedures has been developed. This method forms the basis of the new Philips
AneurysmFlow visualization software used for the proposed research in this protocol. The method is based
on optical flow analysis to estimate velocity vectors from both temporal and spatial variations of contrast
agent density, measured from 2D time-series DSA images (Bonnefous at at, 2012).
2.2 Data from Pre-Clinical Studies
The technique behind the AneurysmFlow software is based on the acquisition of 2D DSA sequences, in
combination with a 3D rotational angiography (3D-RA) acquisition. These image acquisitions are already part
of routine, standard-of-care imaging for brain aneurysm patients. Using the AneurysmFlow software, the
proposed technique measures the flow values from an angiographic DSA sequence. It exploits the
transportation of contrast agent injected into the arterial blood stream. Due to the pulsatile character of the
blood flow, contrast media patterns are created that propagate in the vascular network. Using image
processing techniques, velocity profiles are obtained from the motion of these patterns. Finally, the velocity
profiles are converted into flow values. To validate the approach described above, it has been tested using
vascular phantoms. In an in vitro setup, X-ray based flow estimations were compared to flow values recorded
by flow meters. Furthermore, various contrast medium injection protocols were explored to determine the
appropriate injection parameters. The results of the in vitro tests suggested that the proposed technique can
be used in routine clinical conditions with standard image acquisition protocols (Bonnefous at at, 2012).
2.3 Clinical Experience
The clinical feasibility of the technique mentioned above using AneurysmFlow was previously evaluated
using several clinical cases acquired during interventional procedures. This work compared Doppler
ultrasound flow measurements with X-ray based flow measurements. The outcomes of these tests
suggested that the use of the AneurysmFlow software is feasible during interventional procedures
(Bonnefous at at, 2012). Further validation of the technique was performed on a set of 22 clinical cases
(Pereira at at, 2014). During that study, blood flow velocity in the internal carotid artery measured using
AneurysmFlow was validated with Doppler sonography. Mean flow rates measured with the AneurysmFlow
method significantly matched Doppler sonography measurements (slope regression coefficient, b083 ±
0.19, P0.05). These initial results proved that blood flow velocity measurements can be measured reliably
and accurately using the Aneurysm Flow software.
The AneurysmFlow software has also been used for patients presenting with saccular unruptured lAs, to
assess both flow modification after FDS implantation and correlation with aneurysm thrombosis. A metric has
been defined, the Mean Aneurysm Flow Amplitude (MAFA) ratio, to measure the volumetric flow rate
quotient before and after FDS implantation in the region of interest. Though preliminary, this MAFA ratio
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• Philips
Post-Market Clinical Study Plan
XCY61 0-1 30253
IGT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 11 of 23
index predicted thrombosis accurately with commercialized flow diverter stents. This was the first time blood
flow could be appraised in in-vivo intracranial vessels during endovascular procedures (Pereira at a!., 201 3).
Recently, a larger study conducted by the coordinating investigator confirmed these results (not yet
published).
2.1.
Clinical study Justification
Previously published data has indicated that blood flow changes measured by the Aneurysm Flow software
predicted thrombosis accurately with commercialized Flow Diverting Stents (FDS).(Pereira et at, 2014) The
purpose of the clinical study in this protocol is to investigate the ability of the intra-operative, intra-aneurysmal
flow evaluation to assist with the treatment of intracranial aneurysms
5mm using FDS.
The clinical hypothesis of this protocol to be tested is that by knowing the potential aneurysm occlusion rates
by calculation of the MAFA ratio during a procedure, one might be able to adapt the therapeutic strategy
intra-operatively to maximize the flow diverting effect for inducing complete aneurysm occlusions. Different
strategies can be used to accelerate the aneurysm occlusion such as the addition of another stent layer or
stent-assisted coiling with a jailed micro-catheter. Current treatment strategies are based on personal
physician preferences or on subjective evaluation of aneurysm stagnation.
In this protocol, we propose to test a more quantitative assessment of the intra-aneurysmal flow, which may
be able to support intra-operative clinical decisions which improve the occlusion rate of IA(s) after FDS
treatment. Additionally, data collected in this proposed study will further expand the body of clinical
knowledge concerning the relationship between blood flow metrics (including but not limited to the MAFA
ratio) as determined by the AneurysmFlow software and clinical outcome in patients undergoing treatment
for intracranial aneurysms with FDS.
3.
OBJECTIVES AND HYPOTHESES
3.1.
Primary objective
The primary objective of this clinical study is:
•
To assess the prognostic value of the MAFA ratio for predicting full aneurysm occlusion 12 months
after flow diverter placement.
3.2.
Secondary objectives
The secondary objective are:
•
To assess the prognostic value of the MAFA ratio for predicting full aneurysm occlusion 6 months
after flow diverter placement.
•
To determine optimal MAFA ratio threshold.
•
To register (serious) adverse events (i.e. re-operations, ruptures and deaths).
3.3.
Exploratory objectives
The exploratory objectives are:
•
To evaluate the potential value of additional AneurysmFlow parameters for predicting full aneurysm
occlusion 6 and 12 months after flow diverter placement.
•
To evaluate the potential value of additional clinical variables to predict full aneurysm occlusion 6
and 12 months after flow diverter placement using multivariate logistic regression.
4.
STUDY DESIGN
4.1.
General
This is a prospectively planned, single arm, observational, multicenter cohort study to assess the prognostic
value of the MAFA ratio for predicting full aneurysm occlusion 12 months after flow diverter placement.
A prospective observational multi-center study has been chosen to observe standard of care with the study
device. The multi-center nature of the study will not only enable more efficient patient enrollment and thus a
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Post-Market Clinical Study Plan
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CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 12 of 23
shorter study duration, but it will also provide information on heterogeneity between centers and enable
(cross) validation of study results.
4.2.
Study device exposure
This is an observational study, in which data is collected during the regular clinical procedure: a treatment of
an aneurysm with (a) flow diverter(s). During this procedure, high-speed angiograms will be made before and
after placement of the flow diverter device. Clinical decision making is not affected by this study.
There are no additional devices or medications required for the study.
4.3.
Subjects
4.3.1.
In- and exclusion criteria
Subjects participating in the study will be carefully selected based on the next inclusion and exclusion
criteria.
4.3.1.1.
Inclusion criteria
•
Subject with unruptured, Smm saccular aneurysm(s) located in the anterior intracranial circulation
and suitable for an endovascular treatment with a Flow Diverter Stent
•
Subject is 18 years of age or older, or of legal age to give informed consent per state or national law
•
Subject is available for clinical follow-ups
4.3.1.2.
Exclusion criteria
•
Non-saccular brain aneurysm(s) (i.e., dissecting, fusiform, atherosclerotic, mycotic, bifurcational)
Prior aneurysm treatment with either endovascular (stenting, coiling) or surgical (clipping) techniques
•
Endovascular treatment assisted with coils or intracranial stents
•
Significant or severe allergy to intra-arterial contrast medium uncontrolled by pre-procedure
medications
•
Severe kidney disease (e-GFR c 60)
•
Subjects not willing (or able) to attend post FDS insertion standard-of-care follow up clinic visits
requiring DSA, head MRI or CTA imaging
•
Subject participates in a potentially confounding drug or device trial during the course of the study.
•
Subject meets an exclusion criteria according to national law (e.g. age, pregnant woman, breast
feeding woman)
4.3.2.
Enrollment and duration
Subjects are considered to be enrolled in the study after they have signed the informed consent form.
The subjects will be followed-up at 6 and 12 months according to regular clinical standard of care.
The total duration of the study is expected to take approximately 2.5 years. Patient enrollment will take place
between March 2018 and September 2019. Each subject will be in the study for 1 year (follow-up).
4.3.3.
Number of subjects
In total 120 subjects will be enrolled in the study. The enrollment period is expected to last for 1 year.
See section 5 Statistical considerations for more details on the number of subjects.
4.3.4.
Subject withdrawal or discontinuation
Subjects can withdraw informed consent at any time during the clinical investigation. There are no specific
criteria for subject withdrawal or discontinuation.
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CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 13 of 23
4.4.
Procedures
Physician investigators participating in this study are expected to follow their normal clinical practice in
enrolling, treating and following patients with intracranial aneurysms that are amenable to treatment with flow
diverter stents. No additional procedures are required of patients in order to participate in this observational
study.
Pie-Screening
Patients presenting with intracranial saccular aneurysm(s) will be evaluated by the neuro interventional team,
in accordance with institutional practice, to establish an appropriate treatment plan based on the patient’s
medical condition and available diagnostic screening procedures prior to recruitment in the study. More than
one aneurysm in a single patient may be treated, but only the target aneurysm(s) treated with FDS devices
initially will be considered as part of this study. If treatment of the aneurysm with the FDS is deemed
appropriate, the institution’s guidelines regarding their ethics committee and informed consent process will
be followed.
Screening
After obtaining the consent form(s) approved by the local research ethics board (REB), the principal
investigator will screen the potential investigation subjects for the CARO study. The principal investigator or
his delegates on the study team will enter data in a pre-designed e-CRF. This will include patient
demographics, relevant past medical and surgical history, and specific target aneurysm data along with pre
procedurallscreening imaging details.
Only patients who meet all inclusion and none of the exclusion criteria will qualify for this study. The
measurement and size of each aneurysm will be verified by the principal investigator. If the size of the
aneurysm is acceptable, then it will be included in the study. It is recommended that this measurement
should be done within 180 days before the procedure.
Index Procedure and Discharge
The investigator will proceed with standard of care procedures on the day of Index Procedure (i.e. FDS
insertion) for the target aneurysm(s). Then, endovascular treatment procedure details should be provided
under the “INDEX PROCEDURE & DISCHARGE” field for each eligible patient.
Blood flow velocity will be calculated using the dedicated software AneurysmFlow (Philips Healthcare, Best,
The Netherlands), which will be installed on standard of care imaging equipment. For this purpose, digital
subtraction angiograms will be acquired during the procedure; just before and right after placement of the
FDS.
Calculation of blood flow velocity will be performed automatically on the AneurysmFlow software. The
operator will have access to the results of the calculation in addition to all of the regular information that is at
his/her disposal during routine clinical practice. There are no additional devices or medications required for
the study. The AneurysmFlow software uses standard-of-care 2D DSA and 3D-RA image sequences to
determine this flow information. All raw image sequences will be stored for future reference.
Figure 1 shows the workflow for using the AneurysmFlow software in this study.
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CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 14 of 23
Standard
.
f&Jowup
3, 6 and 12 months
[
Aneurysm
I
thrornbo_J
In step 1 a 3D rotational angiogram (3D-RA) will be performed in the neuro-interventional suite with the x-ray
C-arm to acquire a 3D image volume of the aneurysm anatomy to be treated. From this 3D-RA, an optimal
viewing angle for the C-arm will be determined to obtain good flow information. This angle should show the
parent artery, aneurysm neck and aneurysm itself clearly without any overlap. The 3D-RA will also help to
determine a good C-arm viewing angle to help position and deploy the FDS across the aneurysm.
In Step 2 a 2D DSA x-ray run with contrast agent injection (i.e. advised injection rate 1,5 to 2 cc/s) will be
acquired at the optimal C-arm viewing angle determined by the 3D-RA scan to obtain dynamic blood motion
information before FDS deployment at the location of the aneurysm. If the initial contrast agent injection was
insufficient, the injection will be altered and repeated with another DSA run to obtain high quality image
information. The FDS will then be placed at the location of the aneurysm.
In Step 3, after FDS deployment, a second DSA run with contrast agent will be acquired (i.e. injection rate
=1.5 to 2 cc/s) at the optimal C-arm viewing angle determined from the 3D-RA to qualitatively evaluate blood
motion in the region of the aneurysm after deployment of the ADS. The C-arm angle and injection rate of this
second DSA run (post FDS deployment) must be the same as the first DSA run (pre FEDS deployment). The
2 DSA runs and the 3D-RA image volume will automatically be sent to the AneurysmFlow workstation right
after they are acquired. If the FDS is ballooned after placement, the physician is asked to repeat Step 3 after
ballooning.
In Step 4 a routine VasoCT scan, which is another 3D rotational x-ray C-arm scan, will then be performed
with the x-ray C-arm in the neuro-interventional suite to evaluate the 3D apposition of the deployed FDS with
respect the vessel wall.
The region of interest around the aneurysm and the corresponding arterial segment from which it has
developed will be automatically segmented by the AneurysmFlow software, but manual controls are available
in the software if modifications to the anatomical segment of interest are desired by the interventionalist.
These modifications can be performed by an appropriately trained study member. The software will then
automatically calculate the flow parameters of the aneurysm both before and after FDS deployment, along
with the MAFA ratio.
For this study, the operator will have the choice of selecting which target aneurysms are amenable to FDS
treatment. Patients that have single or multiple target aneurysms that are suitable for FDS treatment as a
first treatment step would be acceptable for this study. Each target aneurysm in the patient will have a
separate CRF sub-form to fill out. Additionally, each target aneurysm sub-form can be further divided into
several FDS sub-forms to account for multiple flow diverters, if needed. To summarize, if the patient has
more than one target aneurysm and/or needs more than one flow diverter per aneurysm, then a sub-form on
the CRF will need to be filled out for each aneurysm and for each FDS used.
As shown in Figure 1, if a target aneurysm is treated with a FDS (or more than one) initially, and is then
treated using another approach (such as coiling) then this target aneurysm can remain included as part of
the study. However, if a target aneurysm is treated using a non-FDS approach initially (such as with coiling),
followed by placement of an FDS or other approach, then the aneurysm will be excluded from the study.
Flow/MAFA L
1
analysis
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CARD
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The MAFA ratio will be calculated after the placement of each FDS. For each FDS, this ratio will be
determined with the flow information before any stents were placed and also with the flow information after
each FDS was placed. The final MAFA ratio will be calculated using the flow information before any FDS
devices were placed and using the flow information after the last FDS was placed. Clinical and imaging
outcomes of a procedure will be assessed using a combination of the flow metrics calculated by the
AneurysmFlow software available to the operator during interventional treatment in addition to information
that is routinely acquired during FDS placement. This information acquired across the patient population in
the study will also contribute to determine more precise MAFA ratio thresholds to improve prediction of
complete aneurysm occlusion after FDS placement. This study will not make any recommendation on patient
management or on treatment strategy. Also, this software will not disrupt standard-of-care workilow for the
interventionalist.
Follow-Ups (6 and 12 months)
All registry patients treated with FDS are expected to follow their routine post treatment clinical visits, which
will include a standard-of-care head imaging (e.g. CTA, MRA and/or DSA) test to classify aneurysm
occlusion (i.e. Raymond-Roy Occlusion Classification
I (Roy et a!., 1997)) at 6 months (±49 days) and 12
months (±49 days). During the 6 and 12 month follow up visits, patient medical charts will be accessed to
collect adverse events (if applicable) and document any post-treatment neurological deterioration
(neurological assessment, mRs scale). De-identified data (i.e. clinical notes, imaging reports etc.) will be
entered in the relevant e-CRF sections.
Follow-up visit
Start visit window
Target date
End visit window
l (days post-procedure)
(days post-procedure)
(days post-procedure)
6-months
134
183
225
12 months
316
365
414
Adverse Events
All (serious) adverse events (i.e. re-operations, ruptures and deaths) whether or not related to the
investigational device will be collected and reported conform local rules and regulations.
4.5.
Monitoring Plan
Monitoring will be performed by a trained person appointed by Philips to ensure compliance with the
investigation plan, applicable national regulations and international standards, patient safety and data
validity. The Sponsor may designate one or more individuals to monitor the progress of a clinical study. The
Sponsor may also delegate the monitoring responsibilities to a third party. However, the Sponsor remains
ultimately responsible for the conduct of the study. The Institution is responsible for the appropriate de
identification of subject data. The investigational site should provide access to the source data of the
subjects.
All regulatory documents (e.g. MEC/IRB approval, contracts, etc.) will be reviewed for each actively
participating center.
The first visit will occur as soon as possible after the first subject is enrolled at each study site. The
monitoring schedule is based on the following considerations: enrollment rate, study compliance at the
center, magnitude of data corrections required, study stage (e.g. start-up or follow-up), complexity of the
investigation, IRB/MEC request, audit/inspection.
Critical data and processes will be monitored for this study prior to clinical report completion based on a risk
based monitoring approach. Dependent on the risk a high or lower sample will be monitored.
The monitor will review critical clinical data that effect study endpoints. Data collection for reasons other than
to support the protocol-defined endpoints will not be monitored.
A close-out visit for sites that have enrolled subjects will be conducted once the site has completed collecting
data for the study.
Names of the monitor(s) can be found in Appendix II of this protocol. An update of this list can be provided to
the site under separate cover.
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Status: Approved
A multicenter observational cohort study
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5.
STATISTICAL CONSIDERATIONS
Baseline patient characteristics and follow-up results will be summarized descriptively using frequencies and
percentages or summary statistics like means and medians (including confidence intervals and interquartile
ranges). Multiple imputation methods will be used to correct for missing data (Rubin, 1987).
5.1.
Sample Size Justification
The total sample size for this study was calculated using the following formulas for Receiver Operating
Characteristics Studies (Obuchowski, 2000):
I:.. /II.(I792
(1 ±
I 1
n) +
nfl —
where V(s) is the variance function of 8 given by:
V(øi = (I).III)!)hi
.11)
( %l +S’
I.1 jSJ/n)
i.e., the variance of S is equal to V(S)/nD; A = 0—1(0) x 1.414; 0—1 is the inverse of the cumulative normal
distribution function; x is the ratio of the number of control patients (nC) to the number of diseased patients
(nD) in the study sample (i.e., K = nC/nD); 0 is the conjectured area under the ROC curve (under the
alternative hypothesis); za is the upper ath percentile of the standard nomial distribution, where a is the type
I error rate (usually a = 0.05); and 43 is the upper th percentile of the standard normal distribution, where f3
is the type II error rate (often 3 = 0.10 or 0.20).
Assuming k0.25 (i.e., 4 times as many occluded aneurysms than non-occluded aneurysms after 1 year), a
fair AUC of 0.70, a type I error of 0.05 and a type II error rate of 0. 10 (power 0.90), a total of 100 subjects
should be included in the study. This total number of 100 subjects also accommodates the pre-planned
explorative multivariate analysis allowing inclusion of 8 candidate predictors including AneurysmFlow (Peduz
et al. 1996). Allowing for an expected drop-out rate of 15% we aim to include a total of 120 patients into the
study.
Any deviation from the planned analysis described below will be documented with justification in the final
clinical end report.
5.2.
General Consideration
The primary analysis of the prognostic value of the MAFA ratio for predicting full aneurysm occlusion 12 months
afterfiow diverter placement will be performed including all subjects who underwent treatment. Baseline patient
characteristics and follow-up results will be summarized descriptively using frequencies and percentages or
summary statistics like means and medians (including confidence intervals and interquartile ranges). Multiple
imputation methods will be used to correct for missing data (Rubin, 1987). All statistical analysis will be
performed using R statistical software (www.https:l/www.r-project.org)
5.3.
Subject disposition
Subject disposition, including the total number of subjects evaluated will be presented. In addition, a listing
will be provided with the reasons for why the subject was not evaluated.
5.4.
Primary objective
Objective
To assess the prognostic value of the MAFA ratio for predicting full aneurysm occlusion 12 months after flow
diverter placement.
Endpoint
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The primary endpoint is the prognostic value (i.e. c-statistic including confidence intervals) of the MAFA ratio
with respect to full aneurysm occlusion (i.e. Raymond-Roy Occlusion Classification
I (Roy et al., 1997)on
standard-of-care head imaging) 12 months after flow diverter placement.
Experimental design
We will use logistic regression analysis to evaluate the univariate predictive association between the index
test (i.e. the MAFA ratio) and complete aneurysm occlusion (i.e. complete occlusion yes/no) at 12 months
(Moons et al., 2012). All subjects with complete follow-up will be included in this analysis.
Presentation format
The primary endpoint will be presented using an ROC curve including the c-statistic and confidence intervals.
5.5.
Secondary objectives
5.5.1.
Secondary objective: Predictive value at 6 months follow-up
Objective
To assess the prognostic value of the MAFA ratio for predicting full aneurysm occlusion 6 months after flow
diverter placement.
Endpoint
The secondary endpoint is the prognostic value (i.e. c-statistic including confidence intervals) of the MAFA
ratio with respect to full aneurysm occlusion (i.e. Raymond-Roy Occlusion Classification
I (Roy et aL, 1997)
on standard-of-care head imaging) 6 months after flow diverter placement.
Experimental design
We will use logistic regression analysis to evaluate the univariate predictive association between the index
test (i.e. the MAFA ratio) and complete aneurysm occlusion on standard-of-care head imaging at 6 months
(Moons et aL, 2012). All subjects with complete follow-up will be included in this analysis.
Presentation format
This secondary endpoint will be presented using a ROC curves including the c-statistic and confidence
intervals.
5.5.2.
Secondary objective: Optimal MAFA ratio threshold
Objective
To determine optimal MAFA ratio threshold.
Endpoint
The endpoint for this secondary analysis is the optimal threshold to make treatment decisions.
Experimental design
To determine the optimal threshold for the MAFA ratio, ROC analysis will be performed. The optimal
threshold for clinical decision making will be determined using net-benefit analysis (Mallett et aL, 2012). Net
benefit incorporates estimates of prevalence and misclassification costs, and it is clinically interpretable since
it reflects changes in correct and incorrect diagnoses when a new diagnostic test is introduced.
Presentation format
This secondary analysis will be presented within (the legend of) the various ROC curves composed for the
primary and secondary objectives.
5.5.3.
Secondary objective: Adverse events
Objective
To register (serious) adverse events (i.e. re-operations, ruptures and deaths).
Endpoint
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The endpoint fort his secondary analysis is the (total) number of adverse events.
Experimental design
The number of adverse events will be described using frequencies and percentages
Presentation format
The (total) number of adverse events will be presented in tabular format.
5.6.
Exploratory objectives
5.6.1.
Exploratory objective: Potential value additional AneurysmFlow parameters
Objective
To evaluate the potential value of additional AneurysmFlow parameters for predicting full aneurysm
occlusion 6 and 12 months after flow diverter placement.
Endpoint
The endpoint of this exploratory objective is the identification of one or more additional AneurysmFlow
parameters for predicting full aneurysm occlusion 6 and 12 months after flow diverter placement.
Experimental design
To explore which additional AneurysmFlow parameters (e.g. maximum inflow, number of jets) independently
contribute to the prediction of, i.e., are associated with, full aneurysm occlusion 6 and 12 months after flow
diverter placement predictor finding methods will be used. These methods will be applied to the raw imaging
data, collected during the study.
Presentation format
The identified additional AneurysmElow parameters for predicting full aneurysm occlusion 6 and 12 months
after flow diverter placement will be presented in a tabular form, including the strength of the association.
5.6.2.
Exploratory objective: Potential Value of Adding Clinical Variables
Objective
•
To evaluate the potential value of additional clinical variables to predict full aneurysm occlusion 6
and 12 months after flow diverter placement using multivariate logistic regression.
Endpoint
The endpoint of this exploratory objective is the final selected multivariate logistic regression model after
shrinkage including its performance measures (i.e. calibration and discrimination).
Experimental design
To explore which clinical variables have (independent) added value for predicting full aneurysm occlusion 6
and 12 months after flow diverter placement we use multivariate logistic regression methods. Candidate
predictors (e.g., aneurysm location, size, medication) will be selected based on literature and expert opinion.
Then, variable selection (i.e. backward selection using Akaike Information Criteria) will be used to determine
the final set of predictors. Finally, internal validation and shrinkage of the model (i.e. using bootstrap methods)
will be performed to correct for optimism. Information gained from this exploratory analysis can be used as
valuable input for a future clinical prediction model for aneurysm occlusion.
Presentation format
The final prediction model and its performance measures (i.e. calibration and discrimination) will be
presented using graphs (i.e. calibration curve and ROC curve) and tables (i.e. model including intercept and
regression coefficients, c-statistic and calibration slope).
6.
DATA MANAGEMENT
An e-CRF will be used to collect de-identified medical history, subjects demographics, procedure related
information, protocol deviations, adverse events and device deficiencies.
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A multicenter observational cohort study
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The e-CRF will be used for data review, data cleaning and issuing and resolving queries. This e-CRF is a
web-based e-CRF which is password protected and is 21 CFR part 11 compliant. At the end of the study the
data will be stored as a frozen dataset and will be retained.
Raw image data is collected directly from the detector, and therefore is free from any subject information. All
other exported data will be de-identified. This data will be collected and stored in a secure location.
6.1.
Retention period
The investigator shall maintain the records related to this study during the investigation and 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 premarket approval application
in the US or a notice of completion of a product development protocol. Or longer if national regulation
requires this.
Philips will maintain the records for the same period as the investigator or for a period of device End of Life
(EoL) plus 15 years, whichever is later.
The sponsor and principal investigator shall take measures to prevent accidental or premature destruction of
these documents.
7.
AMENDMENTS TO THE CLINICAL STUDY PLAN
Amendment to the Clinical investigational plan and the informed consent shall be notified to, or approved by
the Medical Ethics Committee (MEC) and regulatory authority. The version number and date of amendments
shall be documented. Significant changes (such as device modifications, study procedures) shall be
discussed with the principal investigator prior approval. All changes will be documented with a justification
and described in the latest version of the Clinical Investigation Plan.
8.
DEVIATIONS FROM THE CLINICAL STUDY PLAN
The investigator is not allowed to deviate from the clinical study plan or to enroll subjects that do not comply
with all inclusion and exclusion criteria. Under emergency circumstances, deviations from the clinical study
plan to protect the rights, safety and well-being of human subjects may proceed without prior approval of the
sponsor and the MEC. Such deviations shall be documented and reported to the sponsor and the MEC as
soon as possible.
All deviations from the clinical study plan will be documented with date, subject, reason, actions taken and if
the deviation affects subjects rights, safety and well-being or the scientific integrity of the clinical study, The
deviation shall be notified to the Sponsor as soon as possible via the e-CRF. Deviations will be reviewed by
the sponsor and in case of serious or repetitive deviations a corrective action plan may represent a need to
initiate a corrective action plan with the principal investigator. In some cases, necessitate suspension of
enrollment at the site or ultimately the principal investigator will be disqualified.
9.
DEVICE ACCOUNTABILITY
The device used in this study (i.e. AneurysmFlow) is market released, CE marked and cleared in US,
Canada and Argentina. AneurysmFlow is not regulated in India as a software medical device. Therefore no
device accountability (e.g. documented return and disposal) will be performed.
10.
STATEMENTS OF COMPLIANCE
This clinical study shall be conducted in accordance with the clinical study plan, and with the ethical
principles that have their origin in the Declaration of Helsinki and all applicable regional and/or national
regulations.
Furthermore, in Europe this clinical Investigation shall be conducted in accordance with
the International Standards ISO 14155 Clinical investigation of medical devices for human subjects — Good
clinical practice and the Medical Device Directive (MDD). Studies conducted in Canada shall follow as well
the ISO 14155 Clinical investigation of medical devices for human subjects — Good clinical practice.
Form ID: XCT-0302018 revo6!2016 Feb01
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I
•
I
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Post-Market Clinical Study Plan
XCY61O-1 30253
IGT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 20 of 23
Furthermore all investigators will complete financial disclosures, as outlined in the 21 CFR part 54 and will
also comply with part 11. Investigators located in the US shall follow applicable requirements to clinical
investigations and GCP: 21 CFR part 50, 56 and 812.
Clinical trials conducted in India shall follow the Ethical Guidelines issued by Indian Council of Medical
Research.
This study shall not be started prior to obtaining a favorable opinion from a Medical Ethics Committee
(MEC)/Institutional Review Board (IRB) and regulatory authority, if required. Any additional requirements
imposed by the MEC/IRB and regulatory authority shall be followed.
Insurance shall be provided for the subjects participating in this clinical trial according to local law.
11.
INFORMED CONSENT PROCESS
Informed consent will be obtained from every subject in writing by the Investigator or his authorized designee
before the clinical study is started.
The subject will be informed both orally and in writing about all aspects that are relevant to the subject’s
decision to participate in the clinical study, including the clinical study procedures. Ample lime should be
provided for the subject to read and understand the informed consent form and to consider participation. The
informed consent will include personally dated signatures of the subject and the principal investigator or an
authorized designee responsible for conducting the informed consent process. A copy of the signed and
dated informed consent form and any other written information will be provided to the subject.
Subjects who are unwilling to provide informed consent will not be included in the clinical study.
If new information becomes available that might significantly affect the subject’s future health and medical
care, it shall be provided to the subjects in written form, If relevant, subject shall be asked to reconfirm their
continuing informed consent in writing.
11.1.
Subject unable to read or write
Informed consent shall be obtained through a supervised oral process if a subject is unable to read or write.
An independent witness shall be present throughout the process. The written informed consent form and any
other information shall be read aloud and explained to the prospective subject or his/her legally authorized
representative and, whenever possible, either shall sign and personally date the informed consent form. The
witness also signs and personally dates the informed consent form attesting that the information was
accurately explained and that informed consent was freely given.
12.
SAFETY REPORTING
The following event should be reported to Philips for Medical Device Reporting (MDR) according to 21 CFR
part 803: Deaths and serious injuries that a device has or may have caused or contributed to. Caused or
contributed means that a death or serious injury was or may have been attributed to a medical device, or that
a medical device was or may have been a factor in a death or serious injury, including events occurring as a
result of: (1) Failure; (2) Malfunction; (3) Improper or inadequate design; (4) Manufacture; (5) Labeling; or (6)
User error. Medical Device Reporting shall be reported to the regular Philips Healthcare customer feedback
system, i.e. contact the local Helpdesk (optional to add phonenumber e.g. +31402764777) to report these
events. Also report these to the Clinical Scientist (see Appendix II List of monitor(s)/clinical scientist).
13.
EARLY TERMINATION OR SUSPENSION OF THE CLINICAL STUDY
There are no provisions or interim analyses planned that can result in an early termination of the trial.
Serious or repetitive occurrence of deviations from study protocol or non-compliance with regulations may
also be reason for early termination or suspension of a study site.
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A multicenter observational cohort study
Page 21 of 23
14.
PUBLICATION POLICY
It is the intention of the investigator and sponsor to submit the clinical study data for publication. Prior to
submission, claims on intellectual property will be assessed. This study will also be registered on
clinicaltrial.gov before first enrollment.
15.
ABBREVIATIONS USED
•n of ab$4..
3D-RA
3D Rotational Angiogram
CE
Conformite Européenne (European Conformity)
CAR
Code of Federal Regulation
CRF
Case Report Form
DSA
Digital Subtraction Angiography
e-CRF
Electronic Case Report Form
FDS
Flow Diverter Stent
IA
Intracranial Aneurysm
IFU
Instructions for Use
IRB
Institutional Review Board
ISO
International Organization for Standardization
MAFA
Mean Aneurysm Flow Amplitude
MEC
Medical Ethic Committee
MDD
Medical Device Directive
MDR
Medical Device Reporting
16.
REFERENCES
Bonnefous, 0., Pereira, V. M., Quared, R., Brina, 0., Aerts, H., Hermans, R., van Nijnatten, F., Stawiaski, J.
and Ruijters, D. (2012) ‘Quantification of arterial flow using digital subtraction angiography’, Medical Physics,
39(10), p.6264. doi: 10.1118/1.4754299.
Bruno, G., Todor, R., Lewis, I. and Chyatte, D. (1998) ‘Vascular extracellular matrix remodeling in cerebral
aneurysms’, 89, pp. 431—440.
Krings, T., Mandell, D M., Kiehl, T., Geibprasert, S., Tymianski, M., Alvarez, H., Karel, G. and Hans, F.
(2011) ‘Intracranial aneurysms: from vessel wall pathology to therapeutic approach’, Nature Publishing
Group. Nature Publishing Group, 7(10), pp. 547—559. doi: 10.1038/nrneurol.2011.136.
Lylyk, P., Miranda, C., Ceratto, R., Ferrario, A., Scrivano, E., Luna, H. R., Berez, A. L., Tran, Q., Nelson, P.
K. and Fiorella, D. (2009) ‘Curative Endovascular Reconstruction Of Cerebral Aneurysms With The Pipeline
Ernbolization Device: The Buenos Aires Experience’, 64(4), pp. 632—643. doi:
10.1227/01 .NEU.00003391 09.98070.65.
Malleti, S., Halligan, S., Thompson, M., Collins, S. S. and Allman, D. 5. (2012) ‘Interpreting diagnostic
accuracy studies for patient care’, 3999(July), pp. 1—7. doi: 10.1 136/bmj.e3999.
Moons, K. S. M., De Groot, .1. A. H., Linnet, K., Reitsma, J. B. R. and Bossuyt, P. M. M. (2012) ‘Quantifying
the added value of a diagnostic test or marker’, Clinical Chemistry. doi: 10.1373/clinchem.2012.182550.
Obuchowski, N. A. (2000) ‘Sample Size Tables For Receiver Operating Characteristic Studies’, (September),
pp. 603—608.
Peduz, P., Concato, J., Kemper, E., Holford, T. R. and Feinstein, A. R. (1996) ‘Study of the Number of
Events per Variable in Logistic Regression Analysis’, 49(12), pp. 1373—1 379.
Pereira, V. M., Bonnefous, 0., Ouared, R., Brina, 0., Stawiaski, J., Aerts, H., Ruijters, D., Narata, A. P.,
Bijlenga, P., Schaller, K. and Lovblad, K. 0. (2013) ‘A DSA-based method using contrast-motion estimation
for the assessment of the intra-aneurysmal flow changes induced by fiow-diverter stents’, American Journal
Farm ID: XCT-0302018 revOGf2DlG Feb01
Philips’ proprietary Information, unauthorized use is prohibited.

Philips
Past-Market Clinical Study Plan
XCY61O-1 30253
IGT Systems
2018 Apr06
CARO
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 22 of 23
of Neuroradiology, 34(4), pp. 808—81 5. doi: 10.31 74/ajnr.A3322.
Pereira, V. M., Quared, R., Brina, 0., Bonnefous, 0., Satwiaski, J., Aerts, H., Ruijters, D., van Nijnatten, F.,
Perren, F., Bijienga, P., Schaller, K. and Lovblad, K.-0. (2014) ‘Quantification of internal carotid artery flow
with digital subtraction angiography: validation of an optical flow approach with Doppler ultrasound.’, AJNR.
American journal of neuroradiology, 35(1), pp. 156—63. doi: 10.3174/ajnr.A3662.
Roy, D., Raymond, J., Bouthillier, A., Bojanowski, M. W., Moumdjian, R. and L’Esperance, G. (1997)
‘Endovascular treatment of ophthalmic segment aneurysms with Guglielmi detachable coils’, American
Journal of Neuroradiology, 18(7), pp. 1207—1 21 5.
Rubin, D. B. (1987) Multiple Imputation for Nonresponse in Surveys.
APPENDIX I LIST OF INVESTIGATORS AND SITES
Update of this list can be provided to the study site under separate cover.
Table 1: Clinical Coordinating Investigator
Name
Dr. Ricardo Hanel
Baptist Medical Center Jacksonville
800 Prudential Drive
Jacksonville, Fl 32207
USA
Table 2: List ofprinciple Investigators
me
Toronto Western Hospital
Department of Medical Imaging
399 Bathurst St.
Toronto ON M5T 258
Canada
‘n site(s)
Dr. Vitor Mendes Pereira
Dr. Civan Islak
Istanbul Universitesi Cerrahpaa Tip FakUltesi
34098 Cerrahpaa-Fatih Istanbul
Turkey
Dr. Ajay Wakhloo
UMass Memorial Medical Center
- University Campus
55 Lake Avenue North
Worcester, MA 01655
USA
Dr. Santhosh Joseph
Sri Ramachandra Medical Centre
No.1 Ramachandra Nagar, Porur
Chennai, Tamil Nadu,
India 600 116
Dr. Pedro Lylyk
ENERI
Av. del Libertador 6647
(C1428ARJ) CABA, Argentina
Form ID: XCT-0302018 reva6/ 2016 Feb01
Philips proprietary information. Unauthorized use is prohibited.

Philips
Post-Market Clinical Study Plan
XCY610-1 30253
IGT Systems
2018 Apr06
CARD
Revision: 2.0
Status: Approved
A multicenter observational cohort study
Page 23 of 23
APPENDIX II: LIST OF MONITOR(S)/CLINICAL SCIENTIST
Update of this list can be provided to the Investigational sites under separate cover.
Table 3: List of monitor/clinical scientist
Joris de Groot
Best, The Netherlands
Clinical Trial Manager
Telephone: +316 11645 166
ioris.ah.degroot(amhiIips.com
Martijn van de Giessen
Singapore, WA, USA
Clinical Scientist
Telephone: 65 963 08211
martU n van .de.giessen(äph il ips .com
Martine van Alfen
Boston, MA, USA
Clinical Scientist
Telephone: +1 617 7350 209
martine.van.alfen@philips.com
Form ID’ XCI-0302018 reva6) 2016 Feb01
Philips’ propdetary Irifonnation. Unauthorized use is probbted.