Framing Eighteen Coils in Cerebral Aneurysms Trial: FEAT
Phase: NA
Conditions: Cerebral Aneurysm
Sponsor: Vanderbilt University Medical Center

 
 
 
 
Framing Eighteen Coils in Cerebral Aneurysms Trial 
(FEAT) 
 
 
 
 
NCT Number: NCT01655784 
 
 
 
 
 
Document Dates 
Protocol Version Date: 4/20/2015 
SAP Version Date: 3/27/2024 

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Framing Eighteen coils in cerebral Aneurysms Trial (FEAT) 
 
 April 20, 2015 
 
 
A randomized controlled trial of Eighteen (0.014-0.0155 inch) platinum coils versus 
standard (<0.014) platinum coils in the endovascular treatment of medium-sized (6 – 14 
mm) intracranial aneurysms 
 
 
Trial Sponsor: Vanderbilt University Medical Center 
Financial Sponsor: Stryker (Natick, MA) 
Lead Principal Investigator: J Mocco, M.D., M.S. – Mount Sinai 
 
 
 
  
 
 
 
 

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Contents 
1. Background ............................................................................................................................................... 4 
2. Purpose and Hypothesis ........................................................................................................................... 5 
2.1 Purpose ............................................................................................................................................... 5 
2.2 Hypothesis ........................................................................................................................................... 5 
3. Objectives .................................................................................................................................................. 5 
3.1 Primary Outcome ................................................................................................................................ 5 
3.2 Secondary Outcomes .......................................................................................................................... 5 
4. Trial Design ................................................................................................................................................ 6 
4.1 Inclusion Criteria ................................................................................................................................. 6 
4.2 Exclusion Criteria ................................................................................................................................. 7 
5. Treatment Protocol ................................................................................................................................... 9 
5.1 Methods .............................................................................................................................................. 9 
5.2 Intention to Treat .............................................................................................................................. 11 
5.3 Patient Numbering ............................................................................................................................ 11 
5.4 Patient Recruitment .......................................................................................................................... 11 
5.5 Randomization .................................................................................................................................. 12 
6. Visit schedule and Assessments .............................................................................................................. 13 
6.1 Visit Schedule .................................................................................................................................... 13 
6.2 Assessments ...................................................................................................................................... 13 
7. Safety Monitoring ................................................................................................................................... 14 
7.1 Adverse Events (AEs) Definitions and Reporting Procedures ........................................................... 14 
7.2 Serious Adverse Events (SAEs) Definition and Reporting Procedures .............................................. 16 
7.3 Protocol Deviation ............................................................................................................................ 17 
7.4 Data Safety Monitoring Board (DSMB) ............................................................................................. 18 

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8. Data Management and Entry .................................................................................................................. 18 
8.1 Data Collection .................................................................................................................................. 18 
8.2 Schedule of Data Entry ...................................................................................................................... 19 
8.3 Data Monitoring ................................................................................................................................ 19 
9. Statistical Methods ................................................................................................................................. 20 
9.1 Sample Size Estimate and Power of the Study ................................................................................. 20 
10. Committees and Centers ...................................................................................................................... 20 
10.1 Trial Steering Committee (TSC) ....................................................................................................... 20 
10.2 Trial Coordinating Center ................................................................................................................ 20 
10.3 Center and Investigator Requirements ........................................................................................... 20 
11. Publication Policy .................................................................................................................................. 21 
12. Financial and Insurance Matters ........................................................................................................... 21 
13. References ............................................................................................................................................ 21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. Background 
 
In recent years, the treatment of intracranial aneurysms has shifted from a primarily 
surgical paradigm to one of endovascular management. The International Subarachnoid 
Aneurysm Trial (ISAT), published in 2002, demonstrated improved mortality and dependency 
rates at 1-year in those undergoing endovascular coil embolization to those undergoing clipping1.  
However, follow-up data from the ISAT revealed a higher incidence of late re-bleeding and 
recurrence among aneurysms treated via embolization compared to clipping2. The difficulties 
with recurrence have been relatively consistent in the literature, with an estimated angiographic 
recurrence rate of approximately 10-20% (although as high as 33% in one study); fortunately, 
however, the re-bleed rate has consistently been very low3-8. In light of these factors, many 
institutions have shifted towards endovascular management, and close follow-up to detect 
recurrence, with surgical clipping as a secondary option for specific patients or those who fail 
endovascular means. 
 
Larger aneurysms have demonstrated higher hemorrhage rates when observed in 
longitudinal studies9, 10. Similarly, larger aneurysms are more difficult to treat successfully via 
coil embolization; initial and long-term occlusion is inversely related to aneurysm size11-13. 
Smaller aneurysms are generally easier to obtain satisfactory packing density and occlusion 
while giant aneurysms are much more challenging and plagued by high recanalization rates.  For 
this reason, studies of small aneurysms usually demonstrate uniformly excellent results while 
studies of large or giant aneurysms usually demonstrate poor long-term results. Therefore, mid-
sized aneurysms (6-14 mm) likely represents the optimal study group for evaluating true 
differences between coiling treatments. 
 
A major focus of clinical research has been improving aneurysm occlusion and 
recurrence rates through modification of techniques, devices and embolic materials. Until 
recently, bare platinum detachable coils, which are biologically inert, had been the mainstay for 
neuro-interventionists. The first bioactive coil approved by the U.S. Food and Drug 
Administration, the Matrix coil (Stryker), has only modest evidence supporting its use14-17.  More 
recent bioactive and non-bioactive coils, including hydrogel and Cerecyte coils, have more 
robust evidence supporting their use18-28. Both types of coil have recently completed evaluation 
in large, prospective randomized trials28, 29. Promisingly, the unpublished data suggests excellent 
aneurysm occlusion rates; however, the primary endpoints of both studies were not statistically 
different compared to bare platinum coils30-32. Although it is apparent that occlusion rates have 
improved since the initial ISAT data, new coil designs have yet to demonstrate superiority over 
bare platinum coils in a randomized controlled trial.  
Considerable emphasis has been placed on the volumetric filling of aneurysms, or 
‘packing density’, which has been related to long-term outcome33-35. Packing density of 20-30% 
has been suggested as being the desired packing to ensure stable occlusion33, 34, however 
achievement of densities exceeding 25% can be difficult in aneurysms larger than 5mm. The use 
of framing coils, or large-diameter coils initially placed into the aneurysm to serve as a 
foundation for the placement of smaller-diameter “filling” coils, has demonstrated efficacy in 

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case series36. Framing platinum coils of larger diameter are resistant to deformation regardless of 
flow rate in a flow-model, unlike smaller-diameter framing coils which became unstable as flow 
rate increases37. These studies suggest that larger diameter platinum coils may be more stable 
during and after endovascular aneurysm coil embolization, and that smaller-diameter framing 
coils may have a higher propensity towards recanalization. It should be noted that, contrary to 
the name, current “Eighteen” platinum coils produced by Stryker (Natick, MA) are actually 
0.014-0.0155 inches in size. These coils are larger than standard coils, which are usually sized 
0.010 or 0.012”.  
 
2. Purpose and Hypothesis 
 
2.1 Purpose: To compare angiographic outcomes in patients receiving 0.014-0.0155” platinum 
framing and filling coils followed by further aneurysm filling and finishing with less than 0.014” 
bare platinum coils (as deemed appropriate by the treating physician), versus those treated solely 
with coils less than 0.014”. 
 
2.2 Hypothesis: Angiographic occlusion on follow-up imaging will be more frequent in patients 
receiving 0.014-0.0155” platinum coils during embolization compared to those receiving 
smaller-diameter coils. 
 
3. Objectives 
3.1 Primary Outcome 
Occlusion rate: Angiographic occlusion, improvement or no change in the post-coiling 
appearance of the aneurysm as judged by an independent core lab on follow-up 
angiography at 12-18 months after endovascular embolization. 
 
3.2 Secondary Outcomes 
 
1. Treatment related morbidity and mortality, as measured by the NIH Stroke Scale 
 
 
2. Packing density as measured by volumetric filling of the aneurysm 
 
 
3. Clinical outcome at 3-6 and 12-18 months post-coiling, as measured by the modified  
Rankin Scale 
 
 
 
4. Re-hemorrhage and re-treatment rates 

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4. Trial Design 
FEAT will be a prospective, randomized trial comparing the utilization of 0.014-0.0155” coils 
versus smaller diameter coils in mid-sized aneurysm treatment. The 0.014-0.0155” bare platinum 
coils (Stryker, Natick, MA) are FDA-approved and in common use at institutions in this country 
and across the world. Patients will be enrolled who meet the inclusion criteria and consent to 
participate. Patients will be randomly assigned by a central web-based system in a 1:1 manner to 
either the framing coil treatment or the non-framing coil treatment. Data on each patient will be 
collected at the time of enrollment and treatment, and at first and second follow-up visits. 
 
4.1 Inclusion Criteria 
1. Patient presenting with ruptured or unruptured cerebral aneurysm appropriate for 
endovascular treatment as determined by the neurovascular treating team 
(neurointerventionist and/or neurosurgeon). 
 
2. The neurointerventionist feels that the aneurysm can be safely treated with either 
using, or not using, a 0.014-0.0155” platinum coil. 
 
3. Patient is 18-80 years of age (inclusive). 
 
4. Patient is Hunt and Hess grade 0 to 3. 
 
5. Patient has given fully informed consent to endovascular coiling procedure. If the 
patient cannot provide self-consent, appropriate written consent has been sought from 
their authorized surrogate or appropriate power of attorney. 
 
6. Aneurysm is 6-14 mm in maximum diameter. 
 
7. Patient is willing and able to return for clinical evaluation and follow-up imaging 
evaluation (angiography or MRA) at 3-6 months and 12-18 months after endovascular 
treatment.  
 
8. The patient has not been previously randomized into this trial or another 
conflicting/confounding trial. 
 
9. The aneurysm has not been previously treated by coiling or clipping. 
 

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4.2 Exclusion Criteria 
1. Patient has more than one aneurysm requiring treatment in the current treatment 
session, and only one of those to-be treated aneurysms fits the FEAT inclusion criteria 
(i.e., - if either (1) a patient has multiple aneurysms, but only one will be treated at 
enrollment; or (2) if two or more aneurysms are treated during the current treatment 
session and BOTH are able to be enrolled, then they remain eligible for the trial. Non-
treated additional aneurysms may be treated at a later date with any coil type that the 
operator chooses). 
 
 
2. Target aneurysm has had previous coil treatment or has been surgically clipped. 
 
 
3. Hunt and Hess score is 4 or 5 after subarachnoid hemorrhage. 
 
 
4. Inability to obtain informed consent. 
 
5. Medical or surgical co-morbidity such that the patient’s life expectancy is less than 2 
years. 
 
 
Death or procedural/disease-related morbidity may result in some subjects not having 
follow-up angiography. For the primary outcome of angiographic recurrence, the analysis will be 
conducted 2 ways: (1) among only those patients with angiographic assessment at 12-18 months, 
and (2) among patients with angiographic assessment, plus those with death or 
procedural/disease-related morbidity that precluded angiography, with such patients counted as 
incident events. Similarly, for the secondary outcome of treatment-related morbidity and 
mortality, patients without angiographic evaluation due to death or procedural/disease-related 
morbidity will be counted as incident events in the analysis. 
 
 
Use of coil-assist devices (stent, balloon, etc.) will be allowed. Intention to use such a 
device will be recorded pre-procedure, along with dome to neck ratio and rupture status. 
 
 
Additional critical components of the study design include the large number of patients 
required to demonstrate a statistically significant difference, and the subsequent significant 
length of time required to allow enrollment.  Therefore, we propose a three phase study design to 
address the following concerns: 
 
1) A 6-year time window renders any conclusions irrelevant due to progress in 
technology.  Typically the conclusions of long-term studies in the endovascular space are 
called into question because they do not include technology that is considered modern by 
the time the study is completed.  Stryker has multiple coil iterations planned over the next 
5 years.  To not involve these new technologies would make the study non-viable to 

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Stryker and irrelevant to current practice by the time it was completed. However, any 
incorporation of iterative technology needs be done in a regimented manner to ensure it 
does not affect the fundamental study question. 
2) There is an onus on the medical and device industry community to provide quality 
timely short/mid-term data on new technologic advances. 
3) All parties would like to complete the study with a concrete scientific conclusion that 
has legitimate and credible conclusions that move forward our understanding of this 
complex disease process and its methods of treatment. Unfortunately, a series of multiple 
underpowered studies obviates this process. 
These concerns create an overarching need to perform a scientifically valid study that 
develops our knowledge base in a statistically valid way, while simultaneously generating much 
needed early data on new product benefit and to provide useful medium-term knowledge to 
guide physician practice and industry product development. 
To address these concerns the investigative design will be one contiguous study completed in 
three phases. The theme across all phases will remain true to the fundamental study design 
question, “Does use of larger diameter framing coils improve treatment durability?”  However, 
the phases will be introduced to allow controlled involvement of developing technologies and, as 
a result, an avoidance of the above noted concerns. Stryker products will be used in both arms of 
the trial (18 plus non-18 versus non-18 only) to minimize potential differences from other coil 
design variables.  To ensure progressive relevance and to generate critical short-term technology 
evaluations the study will be divided into three phases:  
• Phase 1: GDC 18 as deemed appropriate plus current Stryker 10 coils (including Target) 
versus current Stryker 10 coils (including Target);  
• Phase II: Target XL as deemed appropriate plus all Target versus all Target;  
• Phase III: Future generation of Target coils as deemed appropriate plus all Target versus 
all Target.  
This study design will allow a number of important improvements over typical long term 
endovascular studies: 
1) A valid statistical analysis of the benefit of large diameter coil size in aneurysm treatment, 
with other variables removed as only Stryker coils will be used in both cohorts and there will be 
a consistent number of newly developing Stryker technologies on both sides of the 
treatment/control arm equation. Upon completion of the trial a legitimate scientific question can 
be answered with statistical validity. 

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2) Short/mid-term technology evaluations will be generated on iterative advances in coil 
technology. At the completion of each phase, the non-18 arm descriptive statistics will be 
analyzed and reviewed so as to provide short-term critical feedback about the developing 
technology. This will only be performed for the non-18 arm in order to avoid any potential 
statistical penalties in the analysis of the primary hypothesis. 
3) Data will have relevance to current practice upon completion as it will reflect inclusion of 
evolving technology. 
4) Long-term comparisons of progress over time will be able to be made across phases. 
5. Treatment Protocol 
5.1 Methods 
 
5.1.1 Clinical methods 
1. Patients randomized to the framing treatment arm will have an initial 0.014-
0.0155” framing coil placed. Following this coil, additional 0.014-0.0155” 
framing coils may be placed, in a “Russian doll technique”, and as recommended, 
until the treating physicians deem, in their best clinical judgment, that a transition 
to smaller, 0.010” or 0.012” bare platinum coils, is appropriate. Following 
placement of the primary framing coil (per the randomization assignment), further 
coil placement is at the treating physician’s clinical discretion, until satisfactory 
aneurysm occlusion is obtained. However, treating physicians are encouraged to 
use as many 0.014-0.0155” framing coils as they determine are safe and clinically 
appropriate.  Patients randomized to the control arm will have bare platinum coils 
less than 0.014” placed into the aneurysm only, under the operator’s discretion, 
until satisfactory aneurysm occlusion is obtained.  
 
2. Coiling of aneurysms will be performed according to the standard of care at 
each institution. Choice of catheters, guide wires and other devices will not be 
dictated. However, non-bare-platinum coils, such as bioactive or hydrogel coils, 
may NOT be used in this protocol. 
 
3. For ruptured aneurysms, the use of heparin and anti-platelet agents and the 
timing of their use will be according to treating physician preference. 
 
4. For unruptured aneurysms, use of and choice of anti-platelet agents will be 
according to treating physician preference and local standard of care. 
 

Page 10 of 23 
 
5. If, during the course of the procedure, the operator determines that it would be 
safer to use other coils or devices, such as bioactive or hydrogel coils, patient 
safety should take precedence over the randomly assigned treatment protocol. 
Reasons for protocol deviations, which are anticipated to be infrequent, will be 
recorded in the eCRF.  
 
5.1.2 Research methods 
1. Investigators should only randomize patients if they believe they can actually 
treat the patient equally safely and effectively regardless of the presence or 
absence of a 0.014-0.0155” platinum coil(s). 
 
2. As far as possible, the intention is to exclusively use 0.014-0.0155” bare 
platinum coils for the initial coil in the Eighteen coil treatment arm and for as 
many subsequent coils as safe and appropriate, as determined by the treating 
physician. However, if for any reason a treating physician needs to forego 
placement of a 0.014-0.0155” coil or use a different coil for this purpose, the 
patient will remain in the study according to the intention to treat principle. 
Conversely, in patients assigned to the non-Eighteen coil treatment arm, no 0.014-
0.0155” platinum coil is to be placed. However, if for any reason the treating 
physician determines he/she needs to place a 0.014-0.0155” bare platinum coil, 
the patient will remain in the study according to the intention to treat principle. 
  
3. JPG’s of de-identified images will be uploaded for independent evaluation and 
stored in the study’s electronic database.  These images will be reviewed by an 
independent, blinded core lab.   
 
4. An electronic case report form (eCRF) will be completed at the end of the 
procedure. The procedural details collected for the eCRF will include findings of 
angiographic anatomy, size, location, neck size and dome-to-neck ratio . 
 
5. At time of discharge, any adverse events will be recorded on the eCRF. 
 
6. Data on any further aneurysm treatment or re-treatment of the study treated 
aneurysm will be collected during the study period. 
 
5.1.3 Follow-up 
1. The following assessments will be performed at each standard care follow-up 
visit (3-6 months and 12-18 months post-coiling): (1) clinical outcome; (2) 
follow-up angiography/MRA; (3) modified Rankin Score; (4) NIH Stroke Scale. 
 

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2. The assessment window allowed for each follow-up visit is as follows: (1) 3-6 
month follow-up allowable window is 3-7 months post-coiling; (2) 12-18 month 
follow-up allowable window is 10-20 months post-coiling. 
 
5.2 Intention to Treat 
From the moment of randomization, the patient will be included in the trial irrespective 
of whether they receive the assigned treatment regimen. Similarly, all enrolled patients 
will receive clinical follow-up and will be included in the final analysis. 
 
5.3 Patient Numbering 
Upon randomization, each patient will be uniquely identified in the study by a five-digit 
identification number consisting of two parts, the two-digit center number (to be assigned 
by Vanderbilt University Medical Center) and the three-digit subject number. The 
investigator will assign patient numbers sequentially within each center (001, 002, 
003…). Once assigned to a patient, a subject number will not be re-used and will remain 
with the patient throughout the study. Subjects meeting all inclusion/exclusion criteria 
will be randomized to one of the two treatment groups. If the patient has signed the 
informed consent form and then fails to be randomized for any reason, the reason for not 
being randomized will be entered on the Screening and Enrollment Log. 
 
If subjects have more than one aneurysm that qualifies for the trial, each aneurysm will 
be assigned a subject number since each aneurysm will be randomized separately. 
 
5.4 Patient Recruitment 
Eligibility will be assessed once the neurovascular team makes a decision on 
endovascular treatment of an aneurysm. A Screening and Enrollment Log of all screened 
patients, consented patients, randomized patients, and completed patients will be kept and 
maintained in the study’s electronic data capture system. If a patient meets inclusion and 
exclusion criteria, a suitable member of the research team will discuss the trial and 
provide the patient or their acceptable surrogate with written information. This person 
will allow the patient or acceptable surrogate adequate time to consider inclusion in the 
trial, and will answer all questions regarding the trial. If a patient/acceptable surrogate 
agrees to participate in the trial and signs the informed consent document, the patient will 
be randomized. One copy of the signed informed consent document will be given to the 
patient, one retained by the local investigators and a copy uploaded into the secure web-
based database maintained by the coordinating center. 
 

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5.5 Randomization 
1. A research team member authorized to randomize will then perform randomization via 
a web-based randomization process.  The randomizer will communicate the result of the 
randomization to the neurointerventionalist who will coil the aneurysm. Alternatively, the 
neurointerventionalist can perform the randomization prior to performing the procedure. 
 
2. An algorithm that stratifies the randomization will be used to ensure balance between 
the two treatment groups on those parameters known to significantly affect the ability to 
coil and pack densely. The stratification of these variables is as follows:  
• Aneurysm status of recently ruptured (within 15 days) versus not recently 
ruptured; 
• Current trial phase 
• Dome to neck ratio: 
o Not wide neck – dome to neck ratio ≥ 2, or neck width < 4mm 
o Wide neck – dome to neck ratio < 2, or neck width ≥ 4mm 
 
3. Both treatment arms are anticipated to have approximately equal proportions of acutely 
ruptured aneurysms. Aneurysm location will be recorded but will not be a basis of 
stratification due to lack of location as contributing to the recurrence or packing density 
achieved.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6. Visit schedule and Assessments 
6.1 Visit Schedule 
Screening 
and 
Enrollment 
Embolization 
Procedure 
Discharge 
3-6 
Month 
Follow-
Up 
12-18 
Month 
Follow-
Up 
Unscheduled 
Visit(s) 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Randomization 
X 
Chart Review 
X 
Hunt Hess 
X 
Fisher (if applicable) 
X 
WFNS (if applicable) 
X 
Modified Rankin 
X 
X 
X 
X 
X 
NIHSS 
X 
X 
X 
X 
Research Data 
Collection 
X 
X 
X 
X 
X 
X 
Clinical Evaluation 
X 
X 
X 
X 
X 
Imaging 
X 
X 
X 
X (if indicated) 
Embolization 
X 
Re-Treat (if applicable) 
X 
X 
X 
Evaluate for AEs/SAEs 
X 
X 
X 
X 
X 
X 
 
6.2 Assessments 
 
6.2.1 Angiographic assessment 
1. Procedural angiograms (as part of standard of care) will be collected at 
enrollment and follow-up. Follow-up angiograms should be performed at 3-6 
months and again at 12-18 months post-coiling.  De-identified JPEG files of the 
imaging will then be uploaded into the electronic data-capture system and sent to 
the core lab for evaluation and subsequent analysis. Images should show 
measurements or a dime should be placed for scale. 
 
2. An independent core lab, not affiliated with Vanderbilt University Medical 
Center, will review and analyze all uploaded images. The core lab, using standard 
criteria and being blinded to treatment arm will confirm (1) aneurysm size/volume 
and dome to neck ratio, and (2) degree of occlusion at the end of treatment and on 
follow-up imaging. Digital subtraction angiography (DSA) or MRA are required 
for the 3-6 month and 12-18 months follow-up angiogram. 
 

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3. Volumetric filling will be determined by the core lab based on measurements of 
the aneurysms relative to dimes, and of the coils used provided by participating 
centers on the procedure case report form. 
 
6.2.2 Clinical outcome assessment 
Clinical status at 3-6 months and 12-18 months follow-up will be recorded as a 
secondary outcome. This will include a NIH Stroke Scale and modified Rankin 
Scale as administered by a member of the research team at the time of the follow-
up angiograms. Members of the treatment team may not administer these 
questionnaires. This data should be collected by a qualified, independent 
physician. If a qualified, independent practitioner is not available, a clinical 
research coordinator or nurse may administer the questionnaire, as long as they 
are not a member of the treatment team. The modified Rankin Scale and NIH 
Stroke Scale will be entered into the web-based data entry form. 
 
6.2.3 Safety assessment 
The Event eCRF allows for reporting of any adverse events, reporting of 
unanticipated problems, and reporting of protocol deviations. Local Principal 
Investigators are responsible for ensuring this form is accurately completed and 
entered in the web-based data entry system. 
 
6.2.4 Questionnaires and assessments 
Research/Clinical assessments: These scales are typically done as a way for the 
physician or independent evaluator, to measure the aneurysm’s effect on the 
patient. They include Hunt and Hess grade, Fisher scale/WFNS (if applicable), 
modified Rankin score, and NIH Stroke Scale. 
 
 
7. Safety Monitoring 
7.1 Adverse Events (AEs) Definitions and Reporting Procedures 
 
7.1.1 Definition 
An adverse event will be considered any undesirable sign, symptom or medical 
condition considered related to the intervention. Medical condition/diseases 
present before starting the intervention will be considered adverse events only if 
they worsen after starting the study and that worsening is considered related to the 
study intervention. An adverse event is also any undesirable and unintended effect 
of research occurring in human subjects as a result of the collection of identifiable 
private information under the research. AEs will be recorded up to the day of the 

Page 15 of 23 
 
final follow-up visit, and if still present, they will be recorded as “ongoing” at the 
end of the study. The occurrence of AEs should be sought by non-directive 
questioning of the patient at each visit during the study. AEs also may be detected 
when they are volunteered by the patient during or between visits. 
 
7.1.2 Known risks involved in cerebral angiography with coil embolization are: 
1. Bleeding 
2. Infection 
3. Allergic reaction to contrast or medication 
4. Hydrocephalus/inflammation 
5. Blood vessel injury or thrombosis 
6. Kidney damage or failure 
7. Stroke 
8. Vessel dissection/rupture 
9. Aneurysm perforation 
10. Clot formation 
11. Device malfunction 
12. Disruption of clot from aneurysm 
13. Distal emboli resulting in stroke 
14. Death 
15. Paralysis 
16. Cardiac arrest 
17. Brain damage 
 
7.1.3 Reporting 
All adverse events must be recorded on the Event eCRF with the following information: 
1. Whether it was anticipated 
2. Its relationship to the procedure, clinical course of the disease, device, or non-
procedure 
3. Outcome/Patient status 
4. Treatment provided 
5. Whether an action was taken and a description of said action 
 
All serious adverse events must also be recorded on the Event eCRF with the 
 
following additional information: 
6. Type of Serious Adverse Event 
7. Whether it was reported within 72 hours of becoming aware of the event 
8. Whether it happened during the procedure 
9. Background Information 
10. Whether it will be reported to the local IRB 
11. Territory where initial procedure occurred 

Page 16 of 23 
 
12. Whether it was serious (not life threatening), serious (life threatening) or lead 
to death 
 
7.2 Serious Adverse Events (SAEs) Definition and Reporting Procedures 
 
7.2.1 Definition 
1. An SAE will be considered any undesirable sign, symptom, or medical 
condition which is fatal, life-threatening, requires or prolongs inpatient 
hospitalization, results in persistent or significant disability/incapacity, constitutes 
a congenital anomaly or birth defect, is medically significant and which the 
investigator regards as serious based on appropriate medical judgment. An AE 
that may not result in death, be life-threatening, or require hospitalization may be 
considered an SAE when, based upon appropriate medical judgment, may 
jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definitions of SAEs. 
 
2. The Principal Investigator will report unexpected and serious AEs to the 
DSMB within 15 working days of notification and all others expeditiously. The 
DSMB will meet on a semi-annual basis or on ad hoc basis if the PI identifies 
unusual increases in AEs or unexpected events. The following events require 
expedited reporting: (1) unexpected serious adverse events (must be both serious 
and unexpected); (2) peri-procedural death within 30 days of procedure (site PIs 
may be required to provide additional information on such cases); (3) an increase 
in the rate of expected SAEs occurring in a center. 
 
3. Events NOT considered to be SAE are hospitalizations for: (1) the routine 
treatment or monitoring of the studied indication not associated with any 
deterioration in condition; (2) treatment, which was elective or pre-planned, for a 
pre-existing condition that is unrelated to the indication under study and did not 
worsen; (3) admission to a hospital or other institution for general care, not 
associated with any deterioration in condition; (4) treatment on an emergency, 
outpatient basis for an event not fulfilling any of the definitions of serious given 
above and not resulting in hospital admission. 
 
7.2.2 Reporting 
1. To ensure patient safety, every SAE, regardless of suspected causality, 
occurring after the patient has provided informed consent and until the final 
follow-up visit must be reported to Vanderbilt University Medical Center 
immediately and within 72 hours of learning of its occurrence. 
 

Page 17 of 23 
 
2. An SAE occurring at a different time point or otherwise considered completely 
unrelated to a previously reported event should be reported separately as a new 
event. 
 
3. Information about SAEs will be collected and recorded on the Event Form in 
the study’s electronic database. The investigator must assess the relationship to 
study intervention and complete the form.  This must be completed within 72 
hours of discovery for review by the Vanderbilt University Medical Center Study 
Team.  
 
4. Each re-occurrence, complication, or progression of the original event should 
be reported as a follow-up to that event regardless of when it occurs. The follow-
up information should describe whether the event has resolved or continues and if 
and how it was treated. 
 
7.3 Protocol Deviation 
 
1. A protocol deviation is defined as any change, violation, or departure from the study 
design or procedures of research project that is NOT approved by the Vanderbilt 
University Medical Center or the Trial Steering Committee prior to its initiation or 
implementation, or deviation from standard operating procedures, Good Clinical 
Practices, or federal, state, or local regulations. Protocol violations may or may not be 
under the control of the study team or Vanderbilt University Medical Center staff. These 
protocol violations may be major or minor and will be recorded in the electronic data 
capture system.   
 
2. Major protocol deviations: All major deviations must be reported to the Vanderbilt 
University Medical Center study team and the local IRB (according to local regulations)  
upon discovering them, and no later than seven calendar days from the time the study 
team receives knowledge of the event. A major violation meets one or more of the 
following criteria: (1) represents a serious or continuing failure on the part of the study 
team to comply with the protocol, standard operating procedures, Good Clinical 
Practices, federal, state or local regulations; (2) impacts subject safety or substantially 
alters risks to subjects and may or may not result in actual harm (emotional, clinical, 
social, financial, etc.); (3) significantly damages the completeness, accuracy and/or 
reliability of the data collected for the study; (4) is under control of the investigator/study 
team. 
 

Page 18 of 23 
 
3. Examples of major deviations may include, but are not limited to: (1) evidence of 
willful or knowing misconduct on the part of the investigators or team; (2) failure to 
obtain informed consent; (3) enrollment of a subject who did not meet all 
inclusion/exclusion criteria which would affect subject safety or would negatively impact 
data integrity; (4) performing study procedures not approved by The Vanderbilt 
University Medical Center study team or IRB; (5) failure to report serious unanticipated 
problems or AEs to the IRB and Vanderbilt; (6) failure to perform study procedures 
outlined in the protocol where subject safety or data integrity may be negatively 
impacted; (6) study visit or procedure conducted outside of required time frame that may 
negatively affect subject safety. 
 
7.4 Data Safety Monitoring Board (DSMB) 
The DSMB will be independent and comprised of neurosurgeons, neuro-
interventionalists, or others who are from institutions that are not participating in the trial. 
The DSMB will meet semi-annually to review any serious unexpected AEs. The DSMB 
will be supplied with an interim analysis of trial data on mortality/complication rates after 
the first 70 and 140 patients are randomized. The committee may request data or analyses 
from the trial or any other relevant information from other sources. In the light of these 
analyses, the DSMB will advise the Steering Committee if, in its view, the randomized 
comparisons have provided proof “beyond reasonable doubt” that (1) the use or non-use 
of Eighteen platinum coils achieves a significantly reduced recurrence rate with no 
greater risk of AEs, or (2) the use or non-use of Eighteen platinum coils is associated 
with a substantially poorer clinical outcome. The DSMB will advise the Steering 
Committee regarding trial continuation or discontinuation, or protocol modification as 
needed to address patient safety concerns. A third interim analysis will be performed after 
380 patients have been randomized (unless the DSMB decides the interim analysis should 
occur earlier or later). Site PIs and study coordinators will have the name and address of 
the DSMB chairman, and will be able to communicate confidentially with the chairman 
to express concerns about patient safety or trial design. 
8. Data Management and Entry 
8.1 Data Collection 
1. Each site will be required to have a local coordinator who will be responsible for 
entering the study information into the web-based database and uploading the identifiable 
source documents/medical records associated with the study information. A web-based 
database housing the electronic case report forms (eCRFs) has been designed for the 
study, which will improve efficiency, lower cost of the study, and speed up publication of 
the results. Use of drop-down selection lists, radio buttons, checkboxes, and validation 

Page 19 of 23 
 
checks will be incorporated to aid the speed, accuracy and consistency of data entry. The 
database will be backed up regularly.  
 
2. Data collected will include: (1) enrollment and screening logs; (2) demographic data; 
(3) admission data (Hunt and Hess grade, Fisher grade,  etc.) including the informed 
consent; (4) procedural data; (5) angiograms or MRA; (6) clinical course data; (7) 3-6 
month angiogram or MRA; (8) 3-6 month clinical status; (9) 12-18 month angiogram or 
MRA; (10) 12-18 month clinical status; and (11) as needed additional follow-up data. 
 
3. All data other than angiograms will be entered and/or uploaded into the web-based 
data entry forms. In addition, identifiable source documentation verifying all collected 
study data points will be securely uploaded into the web-based database. 
 
8.2 Schedule of Data Entry 
 
1. Within 48 hrs of randomization: Demographic and admission data 
 
2. Within 72 hrs of discharge: Procedural data, imaging data, clinical course data, and 
discharge data 
 
3. Within 72 hrs of follow-up imaging (angiogram or MRA): 3-6 month angiogram or 
MRA and 3-6 month clinical status 
 
4. Within 72 hrs of follow-up angiogram or MRA: 12-18 month follow-up angiogram, 
12-18 month clinical status 
 
5. Notification for serious, unexpected complications (procedural or otherwise) or deaths 
will be available for review by the DSMB within 15 days of the receipt 
 
8.3 Data Monitoring 
Routine data monitoring will occur to ensure data validity. For the first two subjects at each site, 
source documentation and target data points will be reviewed for accuracy and at least 20% of 
the source documentation and target data points will be monitored thereafter. Study data 
monitoring will be conducted remotely through the uploading of identifiable data via a secure 
web-based electronic data capture system. Monitoring may also occur in person, or by telephone, 
on an as needed basis. All monitoring activities will be tracked and stored in the web-based data 
capture system overseen by Vanderbilt University Medical Center. 

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9. Statistical Methods 
9.1 Sample Size Estimate and Power of the Study 
Based upon a presumed absolute improvement in recanalization rate (defined as an 
increase in Raymond Scale from immediate to 12-18 month follow-up, as determined by 
the core laboratory analysis) of 9% (73% recanalization rate for non-Eighteen versus 82% 
for Eighteen) with an Alpha 0.05 and Power = 80, 325 patients would be required for 
each arm (at least 650 total patients).  
 
10. Committees and Centers 
10.1 Trial Steering Committee (TSC) 
The TSC will meet as needed but no less than semi-annually. Its main function will be to 
monitor and supervise the progress of the randomized trial. It will consider 
recommendations of the DSMB and relevant ethics committees. At regular intervals it 
will review relevant information arising from other sources and make decisions regarding 
trial presentation/publication of interim and final results. 
 
10.2 Trial Coordinating Center 
The Trial Coordinating Center will be responsible for the daily running of the trial and 
will be located at the Vanderbilt University Medical Center. Duties include: facilitating 
site start-up, protocol and eDC training, facilitating timely completion of project 
milestones, oversight of regulatory affairs and compliance, data management, ensuring 
data integrity, site monitoring management, and safety oversight.  
 
10.3 Center and Investigator Requirements 
1. Neurosurgical care centers with case volume of aneurysm treatment greater than 60 
cases per year. 
 
2. Experienced endovascular treatment centers and operators. 
 
3. High quality digital subtraction angiography equipment, preferably with 3D and 
biplane capability. 
 
4. Willing to adhere to protocol and only use the required coils in enrolled patients and 
not polymer-enhanced, bioactive or other coils in same patient. 
 

Page 21 of 23 
 
5. Local ethics approval and multi-center ethics approval in process by coordinating 
center. 
 
11. Publication Policy 
The TSC will be responsible for organizing a writing committee once trial recruitment is 
completed. That committee will formulate timelines for presentation/publication of results on 
behalf of the TSC and advise on appropriate journals for submission. 
 
12. Financial and Insurance Matters 
As Eighteen platinum coils are FDA-approved and used at many institutions and no randomized 
data exists regarding the use of framing coils in aneurysm embolization, both the use or non-use 
of these coils in aneurysm embolization are considered Standard of Care and shall be covered by 
the patient (whether insurance or self-pay). 
 
13. References 
 
1. 
Molyneux A, Kerr R, Stratton I, et al. International Subarachnoid Aneurysm Trial (ISAT) of 
neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial 
aneurysms: a randomised trial. Lancet. Oct 26 2002;360(9342):1267-1274. 
2. 
Molyneux AJ, Kerr RS, Yu LM, et al. International subarachnoid aneurysm trial (ISAT) of 
neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial 
aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, 
subgroups, and aneurysm occlusion. Lancet. Sep 3-9 2005;366(9488):809-817. 
3. 
Byrne JV, Sohn MJ, Molyneux AJ, Chir B. Five-year experience in using coil embolization for 
ruptured intracranial aneurysms: outcomes and incidence of late rebleeding. J Neurosurg. Apr 
1999;90(4):656-663. 
4. 
Hayakawa M, Murayama Y, Duckwiler GR, Gobin YP, Guglielmi G, Vinuela F. Natural history 
of the neck remnant of a cerebral aneurysm treated with the Guglielmi detachable coil system. J 
Neurosurg. Oct 2000;93(4):561-568. 
5. 
Cognard C, Weill A, Spelle L, et al. Long-term angiographic follow-up of 169 intracranial berry 
aneurysms occluded with detachable coils. Radiology. Aug 1999;212(2):348-356. 
6. 
Ng P, Khangure MS, Phatouros CC, Bynevelt M, ApSimon H, McAuliffe W. Endovascular 
treatment of intracranial aneurysms with Guglielmi detachable coils: analysis of midterm 
angiographic and clinical outcomes. Stroke. Jan 2002;33(1):210-217. 
7. 
Thornton J, Debrun GM, Aletich VA, Bashir Q, Charbel FT, Ausman J. Follow-up angiography 
of intracranial aneurysms treated with endovascular placement of Guglielmi detachable coils. 
Neurosurgery. Feb 2002;50(2):239-249; discussion 249-250. 
8. 
Raymond J, Guilbert F, Weill A, et al. Long-term angiographic recurrences after selective 
endovascular treatment of aneurysms with detachable coils. Stroke. Jun 2003;34(6):1398-1403. 
9. 
Unruptured intracranial aneurysms--risk of rupture and risks of surgical intervention. 
International Study of Unruptured Intracranial Aneurysms Investigators. N Engl J Med. Dec 10 
1998;339(24):1725-1733. 

Page 22 of 23 
 
10. 
Wiebers DO, Whisnant JP, Huston J, 3rd, et al. Unruptured intracranial aneurysms: natural 
history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. Jul 12 
2003;362(9378):103-110. 
11. 
Gonzalez N, Sedrak M, Martin N, Vinuela F. Impact of anatomic features in the endovascular 
embolization of 181 anterior communicating artery aneurysms. Stroke. Oct 2008;39(10):2776-
2782. 
12. 
Vinuela F, Duckwiler G, Mawad M. Guglielmi detachable coil embolization of acute intracranial 
aneurysm: perioperative anatomical and clinical outcome in 403 patients. J Neurosurg. Mar 
1997;86(3):475-482. 
13. 
Standard SC, Guterman LR, Chavis TD, Fronckowiak MD, Gibbons KJ, Hopkins LN. 
Endovascular management of giant intracranial aneurysms. Clin Neurosurg. 1995;42:267-293. 
14. 
Pierot L, Leclerc X, Bonafe A, Bracard S. Endovascular treatment of intracranial aneurysms with 
matrix detachable coils: midterm anatomic follow-up from a prospective multicenter registry. 
AJNR Am J Neuroradiol. Jan 2008;29(1):57-61. 
15. 
Murayama Y, Vinuela F, Ishii A, et al. Initial clinical experience with matrix detachable coils for 
the treatment of intracranial aneurysms. J Neurosurg. Aug 2006;105(2):192-199. 
16. 
Ishii A, Murayama Y, Nien YL, et al. Immediate and midterm outcomes of patients with cerebral 
aneurysms treated with Matrix1 and Matrix2 coils: a comparative analysis based on a single-
center experience in 250 consecutive cases. Neurosurgery. Dec 2008;63(6):1071-1077; 
discussion 1077-1079. 
17. 
Roth C, Struffert T, Grunwald IQ, et al. Long-term results with Matrix coils vs. GDC: an 
angiographic and histopathological comparison. Neuroradiology. Aug 2008;50(8):693-699. 
18. 
Gunnarsson T, Tong FC, Klurfan P, Cawley CM, Dion JE. Angiographic and clinical outcomes in 
200 consecutive patients with cerebral aneurysm treated with hydrogel-coated coils. AJNR Am J 
Neuroradiol. Oct 2009;30(9):1657-1664. 
19. 
Geyik S, Ertugrul O, Yavuz K, Geyik P, Saatci I, Cekirge HS. Comparison of bioactive coils and 
bare platinum coils for treatment of intracranial aneurysms: a matched-pair analysis. J Neurosurg. 
Apr;112(4):709-713. 
20. 
Bendszus M, Bartsch AJ, Solymosi L. Endovascular occlusion of aneurysms using a new 
bioactive coil: a matched pair analysis with bare platinum coils. Stroke. Oct 2007;38(10):2855-
2857. 
21. 
Kang HS, Han MH, Kwon BJ, et al. Short-term outcome of intracranial aneurysms treated with 
polyglycolic acid/lactide copolymer-coated coils compared to historical controls treated with bare 
platinum coils: a single-center experience. AJNR Am J Neuroradiol. Sep 2005;26(8):1921-1928. 
22. 
Castro E, Villoria F, Castano C, et al. Spanish Registry for Embolization of Small Intracranial 
Aneurysms with Cerecyte Coils (SPAREC) Study. Early Experience and Mid-Term Follow-up 
Results. Interv Neuroradiol. Dec 29 2008;14(4):375-384. 
23. 
Veznedaroglu E, Koebbe CJ, Siddiqui A, Rosenwasser RH. Initial experience with bioactive 
cerecyte detachable coils: impact on reducing recurrence rates. Neurosurgery. Apr 
2008;62(4):799-805; discussion 805-796. 
24. 
Geyik S, Yavuz K, Ergun O, Koc O, Cekirge S, Saatci I. Endovascular treatment of intracranial 
aneurysms with bioactive Cerecyte coils: effects on treatment stability. Neuroradiology. Sep 
2008;50(9):787-793. 
25. 
O'Hare AM, Fanning NF, Ti JP, Dunne R, Brennan PR, Thornton JM. HydroCoils, Occlusion 
Rates, and Outcomes: A Large Single-Center Study. AJNR Am J Neuroradiol. Aug 12. 
26. 
Gaba RC, Ansari SA, Roy SS, Marden FA, Viana MA, Malisch TW. Embolization of intracranial 
aneurysms with hydrogel-coated coils versus inert platinum coils: effects on packing density, coil 
length and quantity, procedure performance, cost, length of hospital stay, and durability of 
therapy. Stroke. Jun 2006;37(6):1443-1450. 
27. 
Fanning NF, Berentei Z, Brennan PR, Thornton J. HydroCoil as an adjuvant to bare platinum coil 
treatment of 100 cerebral aneurysms. Neuroradiology. Feb 2007;49(2):139-148. 

Page 23 of 23 
 
28. 
White PM, Lewis SC, Nahser H, Sellar RJ, Goddard T, Gholkar A. HydroCoil Endovascular 
Aneurysm Occlusion and Packing Study (HELPS trial): procedural safety and operator-assessed 
efficacy results. AJNR Am J Neuroradiol. Feb 2008;29(2):217-223. 
29. 
Cerecyte Coil Trial.  http://cerecytecoiltrial.com/, 2010. 
30. 
Molyneux A, Coley S, Sneade M, Mehta Z. Cerecyte Coil Trial: The clinical outcome of 
endovascular coiling in patients with ruptured and unruptured intracranial aneurysms treated with 
cerecyte coils compared with bare platinum coils. Results of a prospective randomised trial. 
Abstract presented at: Society of NeuroInterventional Surgery Annual Meeting; July 26-29, 2010; 
Carlsbad, CA. . Vol. 
31. 
Molyneux A, Fox A, Sneade M, Mehta Z. Cerecyte Coil Trial: The angiographic outcome of 
endovascular coiling in patients with ruptured and unruptured intracranial aneurysms treated with 
cerecyte coils compared with bare platinum coils. Results of a prospective randomized trial. 
Abstract presented at: Society of NeuroInterventional Surgery Annual Meeting; July 26-29, 2010; 
Carlsbad, CA. 
32. 
White PM. HydroCoil Endovascular Aneurysm OccLusion & Packing Study (HELPS); Tales of 
HELPS. Presented at: Society of NeuroInterventional Surgery Annual Meeting; July 26-29, 2010; 
Carlsbad, CA. 
33. 
Kawanabe Y, Sadato A, Taki W, Hashimoto N. Endovascular occlusion of intracranial aneurysms 
with Guglielmi detachable coils: correlation between coil packing density and coil compaction. 
Acta Neurochir (Wien). 2001;143(5):451-455. 
34. 
Tamatani S, Ito Y, Abe H, Koike T, Takeuchi S, Tanaka R. Evaluation of the stability of 
aneurysms after embolization using detachable coils: correlation between stability of aneurysms 
and embolized volume of aneurysms. AJNR Am J Neuroradiol. May 2002;23(5):762-767. 
35. 
Reul J, Spetzger U, Weis J, Sure U, Gilsbach JM, Thron A. Endovascular occlusion of 
experimental aneurysms with detachable coils: influence of packing density and perioperative 
anticoagulation. Neurosurgery. Nov 1997;41(5):1160-1165; discussion 1165-1168. 
36. 
Ortiz R, Song J, Niimi Y, Berenstein A. Rate of Recanalization and Safety of Endovascular 
Embolization of Intracranial Saccular Aneurysms Framed with GDC 360 Coils. Interv 
Neuroradiol. Dec 29 2008;14(4):397-401. 
37. 
Schloesser PE, Pakbaz RS, Levy DI, Imbesi SG, Wong WH, Kerber CW. Analysis of complex 
framing coil stability in a wide-necked aneurysm model. AJNR Am J Neuroradiol. Feb 
2007;28(2):387-389. 
 
 

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Statistical Analysis Plan 
 
Framing Eighteen coils in cerebral Aneurysms Trial (FEAT) 
 
 
A randomized controlled trial of Eighteen (0.014-0.0155 inch) platinum coils versus 
standard (<0.014) platinum coils in the endovascular treatment of medium-sized (6 – 14 
mm) intracranial aneurysms 
 
 
 
 
 
 
 
Trial Sponsor: Vanderbilt University Medical Center 
Financial Sponsor: Stryker (Natick, MA) 
Lead Principal Investigator: J Mocco, M.D., M.S. – Mount Sinai 
 
 
Version: 1.0 
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MODIFCATION HISTORY 
 
Version Number Date of Document Version Significant Changes from Previous Authorized Version 
1.0 
3/27/2024 
Not applicable – first version 
 
 
 

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TABLE OF CONTENTS 
 
ABBREVIATIONS AND DEFINITIONS .................................................................................................. 5 
PURPOSE OF STATISTICAL ANALYTICAL PLAN (SAP) ................................................................... 6 
1. INTRODUCTION .................................................................................................................................... 7 
2. STUDY OBJECTIVES ............................................................................................................................. 7 
2.1 
PRIMARY OBJECTIVE .................................................................................................................... 7 
3. STUDY OVERVIEW ............................................................................................................................... 7 
3.1 
STUDY DESIGN .............................................................................................................................. 7 
3.1.1 Study Duration and Time Points ............................................................................................. 7 
3.1.2 Randomization and Masking ................................................................................................... 7 
4. ANALYSIS POPULATIONS ................................................................................................................... 8 
5. STUDY ENDPOINTS .............................................................................................................................. 8 
5.1 
PRIMARY ENDPOINT ..................................................................................................................... 8 
5.2 
SECONDARY CLINICAL ENDPOINTS .............................................................................................. 8 
5.2.1 Morbidity/Mortality .................................................................................................................. 8 
5.2.2 Clinical Outcome ...................................................................................................................... 9 
5.2.3 Re-hemorrhage/Re-treatment .................................................................................................. 9 
5.2.4 Packing Density ........................................................................................................................ 9 
5.3 
SECONDARY SAFETY ENDPOINTS ................................................................................................. 9 
5.3.1 Serious Adverse Events ............................................................................................................ 9 
6. STATISTICAL METHODOLOGY ......................................................................................................... 9 
6.1 
GENERAL PRINCIPLES .................................................................................................................. 9 
6.2 
MISSING DATA ............................................................................................................................ 10 
6.2.1 
Missing Baseline Data ....................................................................................................... 10 
6.2.2 
Missing Primary Outcome Data ........................................................................................ 10 
6.2.3 
Missing Secondary Outcomes Data ................................................................................... 10 
6.3 
CROSSOVER AND MISSED TREATMENT ...................................................................................... 10 
6.4 
PATIENT CHARACTERISTICS ....................................................................................................... 11 
6.4.1 
Patient Disposition ............................................................................................................. 11 
6.4.2 
Protocol Deviations ............................................................................................................ 11 
6.4.3 
Patient Characteristics ....................................................................................................... 11 
6.4.3.1 
Demographic characteristics .......................................................................................... 11 
6.4.3.2 
Baseline characteristics .................................................................................................. 11 
6.4.3.3 
Operative characteristics ................................................................................................ 11 
6.5 
PRIMARY EFFICACY ANALYSIS ................................................................................................... 11 
6.5.1    Analysis of the Primary Efficacy Endpoint ........................................................................... 12 
6.5.2 Determination of Sample Size ............................................................................................... 12 
6.5.3 Missing Primary Endpoint Data ............................................................................................ 12 
6.5.4 Multicenter Studies ................................................................................................................ 13 
6.5.5 Assessment of Balance of the Randomization ...................................................................... 13 
6.5.6 Examination of Subgroups .................................................................................................... 13 
6.6 
ANALYSES OF SECONDARY CLINICAL ENDPOINTS ..................................................................... 14 
6.6.1 
Neurologic Morbidity ......................................................................................................... 14 
6.6.2 
Survival ............................................................................................................................... 14 
6.6.3 
Modified Rankin Scale ....................................................................................................... 14 
6.6.4 
Re-hemorrhage/Re-treatment ............................................................................................ 15 
6.6.5 
Packing Density .................................................................................................................. 15 
6.7 
ANALYSES OF SECONDARY SAFETY ENDPOINTS ........................................................................ 15 

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6.7.1 
Adverse Events Reporting .................................................................................................. 15 
6.7.2 
Serious Adverse Events ...................................................................................................... 15 
6.8 
MULTIPLICITY ADJUSTMENT ...................................................................................................... 15 
REFERENCES .......................................................................................................................................... 17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ABBREVIATIONS AND DEFINITIONS 
 
ACT 
 
Activated Clotting Time 
AE 
 
Adverse event 
CI 
 
Confidence Interval 
DSMB  
Data and Safety Monitoring Board 
FEAT   
Framing Eighteen coils in cerebral Aneurysms Trial  
ISAT  
International Subarachnoid Aneurysm Trial 
ITT 
 
Intent-to-treat 
ICH 
 
Intracerebral hemorrhage 
IVH 
 
Intraventricular hemorrhage 
mRS 
 
Modified Rankin Scale 
NIHSS  
National Institutes of Health Stroke Scale 
SAE 
 
Serious adverse event 
SAP 
 
Statistical Analytical Plan 
WFNS  
World Federation of Neurosurgical Societies  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PURPOSE OF STATISTICAL ANALYTICAL PLAN (SAP) 
The purpose of this SAP is to outline the planned analyses to be completed for the FEAT trial.  
The analyses identified in this SAP will be included in abstracts and manuscripts reporting the 
results of the trial.  Exploratory analyses not necessarily identified in this SAP may also be 
performed. Any post hoc, or unplanned, analyses not explicitly identified in this SAP will be 
clearly identified as such in any published papers from this study. This SAP may be updated in 
response to additional developments, either within or outside the trial. All revisions will be made 
prior to the data lock and the primary analysis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. INTRODUCTION 
 
Since the results of the International Subarachnoid Aneurysm Trial (ISAT) were published in 2002, the 
treatment of intracranial aneurysms has increasingly shifted from surgical to endovascular management.  
ISAT demonstrated improved mortality and dependency rates at 1-year in patients that underwent 
endovascular coil embolization compared to patients that underwent clipping (Molyneux 2002).  
However, longer-term follow-up revealed a higher incidence of late re-bleeding and recurrence among 
aneurysms treated via embolization compared to clipping (Molyneux 2005). The incidence of recurrence 
has been consistent in the literature, with an estimated angiographic recurrence rate of approximately 10-
20% (although as high as 33% in one study); however, the re-bleed rate has consistently been low (Byrne 
1999, Hayakawa 2000, Cognard 1999, Ng 2002, Thornton 2002, Raymond 2003). As such, many 
institutions have shifted towards endovascular management with follow-up to detect recurrence. 
 
A major focus over the past decade has been improving aneurysm occlusion and recurrence rates through 
modification of techniques, devices, and embolic materials. Studies suggest that larger diameter platinum 
coils may be more stable during and after endovascular aneurysm coil embolization, and that smaller 
diameter framing coils may have a higher propensity towards recanalization. As such this study aims to 
evaluate the safety and effectiveness of larger diameter versus smaller diameter coils in patients 
undergoing endovascular treatment for a mid-sized aneurysm. 
 
 
2. STUDY OBJECTIVES 
 
2.1 Primary Objective 
The primary objective of this trial is to evaluate the effectiveness and safety of larger diameter (0.014-
0.0155 inch) coils compared to smaller diameter (<0.014 inch) coils for the endovascular treatment of 
mid-size aneurysms. 
 
 
3. STUDY OVERVIEW 
 
3.1 Study Design 
This is a prospective, multi-center, randomized, clinical trial in patients with mid-size aneurysm. 
Patients will be randomized (1:1) to receive either larger diameter coils or smaller diameter coils.    
 
3.1.1 
Study Duration and Time Points   
All patients will be followed for 12 to 18 months post-procedure.  Endpoints will be 
measured at discharge from the index procedure, 3 to 6 months post-procedure, and 12 to 18 
months post-procedure.  The 3 to 6 month visit and 12 to 18 month visit align with standard 
of care visits. 
 
3.1.2 
Randomization and Masking 
Patients will be randomly assigned in a 1:1 allocation to receive either larger or smaller 
coils. Patient randomization will be stratified by clinical site, aneurysm status (recently 
ruptured versus not), and dome to neck ratio (wide neck versus not). Randomization will be 
performed centrally through a web-based data collection system that automates the delivery 
of the randomization assignments.   
 

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Investigators will not be blinded to treatment assignment due to the nature of the treatment 
intervention.  Investigators will, however, be blinded to all data from other clinical sites.  
Clinical outcome assessments will be completed by certified research staff that are not part 
of the treatment team. All angiograms will be analyzed by a blinded angiogram core 
laboratory personnel who will be blinded to clinical outcomes. Trial oversight will be 
provided by an independent Data and Safety Monitoring Board (DSMB).   
4. ANALYSIS POPULATIONS
Three populations will be used for all summaries and analyses.
Screened Population 
The screened population will consist of all screened patients. A screened patient is defined as a 
subject referred to, or identified at, a clinical site for consideration of entry into the study. 
Intent-to-Treat (ITT) Population 
The ITT population will consist of all randomized subjects grouped by their assignment at 
randomization regardless of whether or not they actually received the treatment to which they 
were assigned. This sample will be used for summaries and analyses of the primary endpoint and 
the secondary clinical endpoints. The ITT population will be used for all effectiveness analyses 
and descriptions of patient and baseline characteristics.  
Safety Population 
The safety population will consist of all randomized subjects who initiate endovascular coiling, 
grouped by their assignment at randomization regardless of whether or not they actually received the 
coil size to which they were assigned. The safety population will therefore be identical to the ITT 
population if all randomized patients receive attempted vascular coiling. The safety population will 
be used to present safety summaries and for the analysis of safety data. 
5. STUDY ENDPOINTS
5.1 Primary Endpoint
The primary endpoint is angiographic occlusion at 12 to 18 months post-randomization as measured 
by a Raymond score of 1 or 2 (adequate occlusion).  Patients’ angiograms for the 3 to 6 month visit, 
the 12 to 18 month visit, and any clinically driven angiogram taken prior to 18 months post-
randomization or study exit will be considered for angiographic occlusion.  If any of these 
angiograms show inadequate angiographic occlusion (Raymond score >2), the patient will be 
considered to have inadequate occlusion at the 12 to 18 month visit and be considered a treatment 
failure. 
5.2 Secondary Clinical Endpoints 
The following secondary clinical endpoints will be assessed: 
5.2.1 
Morbidity/Mortality 
o
Neurologic morbidity measured at 24-hours post-procedure. Morbidity is defined by
neurologic worsening measured by a greater than or equal to 4-point change in the
NIH Stroke Scale (NIHSS) from pre-surgical baseline.

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o 
Mortality through end of study follow-up (12 to 18 month visit) 
 
5.2.2 
Clinical Outcome 
o 
Modified Rankin Scale score at the 3 to 6 month and 12 to 18 month visits.  The 
Modified Rankin Scale ranges from 0 (no symptoms) to 6 (dead) (Broderick 2017) 
 
Scale Score Clinical Outcome 
0 
No symptoms 
1 
No significant disability. Able to carry out all usual activities, 
despite some symptoms 
2 
Slight disability. Able to look after own affairs without 
assistance, but unable to carry out all previous activities 
3 
Moderate disability. Requires some help, but able to walk 
unassisted 
4 
Moderately severe disability. Unable to attend to own bodily 
needs without assistance, and unable to walk unassisted 
5 
Severe disability. Requires constant nursing care and 
attention, bedridden, incontinent. 
6 
Dead 
 
5.2.3 
Re-hemorrhage/Re-treatment 
o 
Incidence of re-hemorrhage through the end of study follow-up at the 12 to 18 month 
visit. 
o 
Incidence of re-treatment of the aneurysm through the end of study follow-up at the 
12 to 18 month visit. 
 
5.2.4 
Packing Density 
o 
Volumetric filling of the aneurysm, reported as a percentage and calculated using 
AngioCalc (www.angiocalc.com). 
 
5.3 Secondary Safety Endpoints 
The following secondary safety endpoints will be assessed: 
 
5.3.1 
Serious Adverse Events 
o 
Incidence of SAEs through end of study follow-up  
 
 
6. STATISTICAL METHODOLOGY 
 
6.1 General Principles 
Study day will be calculated from the reference start date and will be used to show the study days of 
assessments and events.  Reference start date is defined as the date of randomization unless otherwise 
specified.   
 
Continuous variables will be summarized using the following descriptive statistics: number of non-
missing values, means, standard deviations, medians, interquartile range, maximum, and minimum.  
Categorical variables will be summarized using number of non-missing values, counts, and percentages.  

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Rates of events will be calculated as the ratio of the total number of events recorded divided by the total 
patient-time. Total patient-time will be calculated by summing the time (in study time units, e.g., days or 
months) that patients were at risk for a specific event from the reference time point until either study exit 
or the end of the time period of interest. Rates and their 95% confidence intervals will be reported.   
Time-to-event variables will be summarized using the Kaplan-Meier method or, in the presence of 
competing risk, by cumulative incidence curves accounting for competing events as appropriate.    
 
In the situation where an event date is partial or missing, study day, and any corresponding durations are 
to appear partial or missing in listings.  If a partial event date is recorded (i.e. the month and year are 
known but not the day) and is necessary to calculate patient-time at risk or patient-time to the event, the 
missing event day will be imputed to the 15th day of the known month and year.    
 
For any variable measured at multiple points in time, change from baseline will be calculated as the 
difference between the value of the variable at a specific point in time (e.g. 1 year) minus the baseline 
value.  Relative change from baseline will be calculated as the value of a parameter at a specific point in 
time minus the baseline value of the parameter divided by the baseline value of the parameter.  Percent 
change will be calculated as the relative change multiplied by 100. 
 
All hypothesis testing will be conducted at the 0.05 two-sided significance level unless otherwise 
specified.   P-values will be rounded to three decimal places. P-values less than 0.001 will be reported as 
<0.001 in tables. P-values greater than 0.999 will be reported as >0.999. 
 
Should any of the statistical methods proposed prove unsuitable during data analysis, more appropriate 
methods will be used. These include data transformation (for example to a logarithmic scale) to satisfy 
model assumptions such as normally distributed residuals with constant variance, the application of non-
parametric techniques, or the use of a different link function or modeling technique. The SAP will be 
updated with the methods used and the justification for the change prior to data set and database lock. 
 
Additional ad-hoc analyses may be conducted as deemed appropriate. 
 
All analyses will be conducted using SAS V9.4 or higher and R V4.1.1 or higher. 
 
6.2 Missing Data 
 
6.2.1 
Missing Baseline Data 
Missing baseline values will not be imputed in summaries of baseline characteristics. 
Summaries will be based on all available data. 
 
6.2.2 
Missing Primary Outcome Data 
The plan for handling missing primary outcome data is outlined in section 6.5.3 below. 
 
6.2.3 
Missing Secondary Outcomes Data 
The plans for handling missing secondary outcome data are outlined by outcome in section 6.6 
below. 
 
6.3 Crossover and Missed Treatment 
Crossovers (patients who after randomization switch from the allocated treatment to the non-allocated 

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treatment) will be analyzed in the group they were randomized according to the ITT principle in all 
efficacy analyses. Safety analyses will be conducted according to section 4 above. 
 
6.4 Patient Characteristics 
 
6.4.1 
Patient Disposition 
Disposition will be summarized in the screened and ITT populations.   
 
Disposition summaries of the screened population will include: 
• 
The number of patients screened  
• 
The number and percentage of eligible patients randomized 
 
Disposition in the ITT population will be summarized by randomization group and will include: 
• 
The number of patients randomized  
• 
The number and percentage of patients who received their assigned treatment 
• 
The number and percentage of patients withdrawn or lost to follow-up by the 3 to 6 
month visit and the primary reason for withdrawals 
• 
The number and percentage of patients withdrawn or lost to follow-up by the final 
study visit at 12 to 18 months and the primary reason for withdrawals 
 
6.4.2 
Protocol Deviations 
Protocol deviations and violations are defined as deviations from the procedures outlined in the 
protocol. All statistical analyses and summaries will be conducted on an intent-to-treat basis 
with the exception of safety analyses, which will be conducted on the safety population. 
 
6.4.3 
Patient Characteristics 
 
6.4.3.1 Demographic characteristics  
Demographics including age, gender, race, and ethnicity will be summarized by randomization 
assignment using the appropriate descriptive statistics. 
 
6.4.3.2 Baseline characteristics  
Baseline characteristics will be summarized by randomization assignment using the appropriate 
descriptive statistics.  The specific baseline variables collected include randomization 
stratification factors, anthropometrics (weight, height), medical history (prior aneurysms treated, 
smoking status, pre-existing conditions), presenting symptoms, Modified Rankin Scale score, 
and rupture characteristics (if ruptured, time since rupture at randomization, Fisher Scale, Hunt 
and Hess scale, WFNS grade, IVH presence, ICH presence, and presence of infarct prior to 
embolization).   
 
6.4.3.3 Operative characteristics  
Operative data including aneurysm characteristics (height, width, depth, neck size, shape, type, 
and location), heparin dosing, activated clotting time (ACT), medications, presence of 
vasospasm, and coil/device log data will be summarized by randomization assignment using the 
appropriate descriptive statistics. 
 
6.5 Primary Efficacy Analysis 
 

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6.5.1 
Analysis of the Primary Efficacy Endpoint  
A log binomial regression model will be used to estimate and test differences in 
angiographic occlusion between randomization groups.  Similar to the logistic regression 
model, the log-binomial model is a generalized linear model. The models differ only in the 
link function used for the "success" probability p; logit (log odds) for logistic regression and 
log (log p) for log-binomial. The different links parameterize the model differently, with 
parameters of the log-binomial model yielding log relative risks rather than the log odds 
ratios of the logistic model. 
 
The basic form of the log binomial models is:  
 
log 𝑃𝑃[𝑌𝑌𝑖𝑖= 1|𝑋𝑋1𝑖𝑖, 𝑋𝑋2𝑖𝑖, 𝑋𝑋3𝑖𝑖] = 𝛽𝛽0 + 𝛽𝛽1𝑋𝑋1𝑖𝑖+ 𝛽𝛽2𝑋𝑋2𝑖𝑖+ 𝛽𝛽3𝑋𝑋3𝑖𝑖  , 
 
where Yi  is a binary indicator  of angiographic occlusion for the ith patient,  X1i  is a binary 
indicator of randomization assignment for the ith  patient, and X2i  and X3i are indicators of 
recently ruptured aneurysm status (X2i ) and wide neck (X3i) respectively, factors by which 
randomization will be stratified.  While randomization will also be stratified by randomizing 
center, the analysis will not adjust for center due to their relatively large number compared 
to the proposed sample size. The exponentiated estimate of β1 (𝑒𝑒𝛽𝛽෡1) in this model is the risk 
ratio for angiographic occlusion for patients randomized to larger coils compared to patients 
randomized to smaller coils.  The risk ratio and its associated 95% confidence interval will 
be used to quantify the relative risk of the endpoint.  Differences between randomization 
groups in the risk of angiographic occlusion will be determined by testing the null 
hypothesis H0:β1= 0 versus a two-sided alternative (H1:β1≠ 0) using a 0.05 level intention-
to-treat normal approximation test (i.e., the Wald test). 
 
6.5.2 
Determination of Sample Size 
Sample size calculations were based on the primary endpoint under the following 
assumptions and operating characteristics:  a) 73% angiographic occlusion at the 12-18 
month visit in patients receiving smaller coils (control arm); b) a 9% absolute improvement 
(to 82%) in the incidence of angiographic occlusion in patients receiving larger coils; c) 
Approximately 80% power on a two-sided proportion test; and d) a significance level of 
0.05. A sample size of 650 (325 in each arm) will allow us to detect the specified effect size 
with adequate power. Sample size was calculated using the power.prop.test function in R (R 
Core Team 2021). 
 
6.5.3 
Missing Primary Endpoint Data 
Patients without previous evidence of inadequate angiographic occlusion, either on the 3 to 
6 month visit angiogram or on a clinically driven angiogram taken prior to study exit, that 
miss the 12 to 18 month angiogram, or whose 12 to 18 month angiogram is not readable by 
the core lab, will be missing the primary endpoint.  Patients missing the primary endpoint 
who die prior to or during the 12 to 18 month visit window (up to 18 months post-
randomization) and die with known cause of death related to their aneurysm or unknown 
cause of death will be considered treatment failures with inadequate occlusion. Patients 
missing the primary endpoint with a known cause of death unrelated to their aneurysm will 
be considered missing.  
 
Patients with missing primary endpoint data will have their 12 to 18 month angiographic 

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occlusion status imputed via multiple imputation assuming that the data are missing at 
random.  The imputation model will be stratified by randomization assignment and include 
age, sex, randomization strata for aneurysm status, randomization strata for wide neck 
status, aneurysm size, and angiographic occlusion status at the 3 to 6 month visit.  Since this 
model includes a mixture of variables types (i.e. continuous and binary), a fully conditional 
specification method will be used (Berglund 2014).    
 
The main feature of the imputation approach is the creation of a set of clinically reasonable 
imputations for angiographic occlusion for each patient with missing data.  This will be 
accomplished using a set of repeated imputations created by predictive models based on the 
majority of participants with complete data.  The imputation models will reflect uncertainty 
in the modeling process and inherent variability in patient outcomes, as reflected in the 
complete data.  Thirty datasets will be imputed. 
 
After the imputations are completed, all of the data (complete and imputed) will be 
combined and the analysis performed for each imputed-and-completed dataset.  Rubin’s 
method of multiple (i.e., repeated) imputation will be used to estimate treatment effect 
(Rubin 1986). 
 
6.5.4 
Multicenter Studies 
The trial will be conducted in up to 25 clinical centers. Data will be pooled across all 
clinical centers. A sensitivity analysis of the primary endpoint will be conducted using a 
mixed effect log-binomial regression model with center as a random effect.   
 
6.5.5 
Assessment of Balance of the Randomization 
The success of the randomization procedure in balancing important covariates between 
randomization groups will be assessed. Continuous measures will be compared using t-tests, 
while chi-square tests will be used to compare categorical variables.  Should the treatment 
groups differ significantly with respect to any covariate at the 0.01 level, we will adjust for 
those covariates in a secondary analysis of the primary endpoint using multivariable log-
binomial regression.   
 
6.5.6 
Examination of Subgroups 
Subgroup analyses of the primary endpoint will be performed for key clinical subgroups, 
classified at baseline.  Pre-defined subgroups include:  
• 
Aneurysm status (recently ruptured (within 15 days) vs. not recently ruptured) 
• 
Dome to neck ratio (not wide neck vs. wide neck) 
• 
Aneurysm location (anterior vs posterior circulation) 
• 
Age (<65, vs. ≥65) 
• 
Sex (male vs. female) 
• 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Island, and White) 
• 
Ethnicity (Hispanic vs. non-Hispanic) 
• 
Presence of co-morbidities 
o Diabetes (yes vs. no) 
o Obesity (BMI ≥ 30 vs. BMI <30) 
o Smoking status (current, previous (>6 months), never) 
• 
Aneurysm shape (regular vs. irregular/multilobulated)  

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With the exception of severity of aneurysm status and wide neck status, for which formal 
interaction terms will be tested, these analyses will be descriptive and conducted to explore 
the effect of the treatment within the subgroups. Risk ratios with their respective 95% 
confidence intervals will be reported within each strata. Strata that contain less than 20% of 
the sample size and/or in which the number of patients assigned to a specific group is less 
than 20 will not be considered. 
 
6.6 Analyses of Secondary Clinical Endpoints 
All secondary clinical endpoints will be analyzed using the ITT population. 
 
6.6.1 
Neurologic Morbidity 
The number and percentage of patients who experience neurologic morbidity at 24-hours 
post-operation will be reported by randomization group. The proportion of patients with 
neurologic morbidity will be compared between groups using a log binomial model and 
differences between the groups will be summarized using relative risk and the 
corresponding 95% confidence interval. 
 
Patients that die within 24-hours will be counted as having neurologic morbidity. Survivors 
missing the 24-hour NIHSS assessment will have their neurologic morbidity outcome 
imputed via multiple imputation assuming that the data are missing at random. The 
imputation model will be stratified by randomization assignment and include age, sex, 
randomization strata for wide neck status, randomization strata for aneurysm status, 
aneurysm size, and baseline NIHSS. Since this model includes a mixture of variables types 
(i.e. continuous and binary), a fully conditional specification method will be used (Berglund 
2014).  Thirty datasets will be imputed and Rubin’s methods will be use to combine them 
and estimate treatment effect (Rubin 1986). 
 
6.6.2 
Survival 
Survival over the full duration of follow-up will be described using Kaplan-Meier curves 
and compared between the randomization groups using a log-rank test.  The hazard ratio and 
corresponding 95% confidence interval for death in the larger coil group compared to the 
smaller coil group will be estimated using a Cox proportional hazards model. Patients who 
withdraw consent or are lost-to-follow up will be censored at the time of study exit. Time to 
event will be computed as the date of death (or the date of censoring) – randomization date.  
In cases where the patient dies or is censored the day they are randomized, the time will be 
coded as 0.5 days.   
 
Causes of death and relatedness to the procedure will also be described by randomization 
group.  The number and proportion of patients that have a procedure related mortality within 
30 days post-procedure will be presented by group and group differences will be 
summarized as a relative risk with the corresponding 95% confidence interval. 
 
6.6.3 
Modified Rankin Scale  
The number and percentage of patients in each mRS score category will be reported at the 3 
to 6 month and the 12 to 18 month visits by group. For each visit, a Cochran-Mantel-
Haenszel “shift” analysis (also known as van Elteren’s test, Savitz 2007) will be used to 
evaluate differences in the mRS distribution between groups.  The distribution of mRS 

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scores is expected to differ by aneurysm status.  Analyses will be repeated separately by 
randomization strata for aneurysm status (recently ruptured vs. not recently ruptured). 
 
Patients with missing mRS data at the 3 to 6 and/or 12 to 18 month visit will have their data 
imputed via multiple imputation assuming that the data are missing at random.  The 
imputation model will be stratified by randomization assignment and aneurysm status and 
include age, sex, randomization strata for wide neck status, aneurysm size, and baseline 
mRS.  Since this model includes a mixture of variables types (i.e. continuous, binary and 
ordinal), a fully conditional specification method will be used (Berglund 2014).  Thirty 
datasets will be imputed and Rubin’s methods will be use to combine them and estimate 
treatment effect (Rubin 1986). 
 
6.6.4 
Re-hemorrhage/Re-treatment 
The difference in the rates of re-hemorrhage and re-treatment will be compared between 
randomization groups over the full duration of follow-up.  Patients who withdraw consent or 
are lost-to-follow up will be censored at the time of study exit. Time to event will be 
computed as the date of the event (or the date of censoring) – randomization date.  In cases 
where the patient has the event or is censored the day they are randomized, the time will be 
coded as 0.5 days.  Re-hemorrhage or re-treatment may not occur because death from any 
cause precedes the event; thus, it is possible that censoring patients at all-cause mortality 
will lead to biased estimates when analyzing time to first event. Therefore, competing risks 
analysis using the methods of Fine and Gray (Fine & Gray 1999) will be used to estimate 
group differences for each endpoint. 
 
6.6.5 
Packing Density 
The mean packing density will be compared between groups using a T-test and summarized 
as the mean difference and corresponding 95% confidence interval.  Missing packing 
density data will not be imputed and analyses will be based on all available data. 
 
6.7 Analyses of Secondary Safety Endpoints 
All secondary safety endpoints will be analyzed using the safety population. 
 
6.7.1 
Adverse Events Reporting 
All adverse events, serious and non-serious, will be summarized in tabular form for 
reporting to the DSMB. Adverse events will be tabulated by seriousness, severity and 
relatedness to the investigational agent or the aneurysm. 
 
6.7.2 
Serious Adverse Events 
Serious adverse event rates will be calculated as the ratio of the total number of events over 
study follow-up days divided by total patient-time at risk for the specific event.  Patient time 
at risk will be defined as the duration in which the patient is enrolled in the study since their 
date of randomization, inclusive of the day they were randomized [Time in study = (Study 
end date – Randomization date)+1].  Poisson models with robust variance estimation will be 
used to compare serious adverse events between randomization groups. 
 
 
6.8 Multiplicity Adjustment 
Secondary endpoints will provide insights regarding the value of this therapy. The most clinically 
important secondary endpoints are neurologic morbidity and the mRS scores at the 3 to 6 month visit.  

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To control type I error across these endpoints we will use a step-wise gate keeping procedure for four 
hierarchical families of hypotheses, tabled below. 
 
Family 
Hypothesis 
Description 
F1 
H1 
There is no difference in the risk of angiographic occlusion between 
randomization groups 
F2 
H2 
There is no difference in the risk of neurologic morbidity between 
randomization groups 
F3 
H3 
There is no difference in the distribution of mRS at the 3 to 6 month 
visit 
F4 
H4 
There is no difference in the distribution of mRS at the 3 to 6 month 
visit within patients with an aneurysm status of recently ruptured  
H5 
There is no difference in the distribution of mRS at the 3 to 6 month 
visit within patients with an aneurysm status of not recently ruptured  
 
The type I error control procedure will be as follows: 
1. Test the hypothesis in F1 
a. If the p-value is greater than or equal to 0.05 stop and conclude no treatment effect 
b. If the p-value is less than 0.05 proceed to step 2 
2. Test the hypothesis in F2 
a. If the p-value is greater than or equal to 0.05 stop and conclude a treatment effect in F1 
only 
b. If the p-value is less than 0.05 proceed to step 3 
3. Test the hypothesis in F3 
a. If the p-value is greater than or equal to 0.05 stop and conclude a treatment effect in F1 
and F2 only 
b. If the p-value is less than 0.05 proceed to step 4 
4. Test the hypotheses in F4 using a 0.05-level Holm-step down procedure.  With this procedure, the 
p-values of both tests are ranked from smallest to largest.   
a. If the smallest p-value is greater than 0.025, stop and conclude a treatment effect in F1, 
F2, and F3 only 
b. If the smallest p-value is less than 0.025 and the largest p-value is greater than 0.05, stop 
and conclude a treatment effect in F1, F2, F3 and H4 or H5 (whichever had the smallest 
p-value) only 
c. If the smallest p-value is less than 0.025 and the largest p-value is less than 0.05, declare 
a treatment effect across F1, F2, F3 and F4 
 
While other secondary endpoint data will be featured in the publication of the trial, there will be no 
formal correction of the Type I error rate for multiple testing of statistical hypotheses for any of the 
other secondary endpoints.   
 
 
 
 
 
 
 
 

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