A Prospective, Multicenter Study Assessing the Embolization of Intracranial Aneurysms Using WAVE™ Extra Soft Coils, a Part of the Penumbra SMART COIL® System
Conditions: Aneurysm, Brain
Sponsor: Penumbra Inc.

 
 
 
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SURF: A Prospective, Multicenter Study Assessing the 
Embolization of Intracranial Aneurysms using WAVE™ Extra 
Soft coils, a part of the Penumbra SMART COIL® System 
 
Protocol  
CLP 13669.C 
 
Date of Protocol 
01 May 2020 
 
Device Name 
Penumbra SMART COIL® System including WAVE™ Extra Soft Coils 
 
Sponsor 
Penumbra, Inc. 
One Penumbra Place 
Alameda, CA 94502 
USA 
 
 
 

 
 
 
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TABLE OF CONTENTS 
1. 
Introduction and Rationale .................................................................................................. 6 
2. 
Penumbra SMART COIL System with WAVE Extra Soft Coil .................................... 10 
2.1 Coil ................................................................................................................................................ 10 
2.2 Detachment Pusher ...................................................................................................................... 11 
2.3 Detachment Handle ..................................................................................................................... 11 
2.4 Indications .................................................................................................................................... 11 
3. 
Risk Analysis ....................................................................................................................... 11 
4. 
Study Overview ................................................................................................................... 12 
4.2 Study Objectives/Endpoints ........................................................................................................ 12 
4.2.1 
Primary Endpoints .............................................................................................................. 12 
4.2.2 
Secondary Endpoints .......................................................................................................... 13 
5. 
Study Population ................................................................................................................. 13 
5.1 
Inclusion Criteria ................................................................................................................ 13 
5.2 
Exclusion Criteria ............................................................................................................... 13 
6. 
Study Procedures ................................................................................................................ 14 
6.1 Overview of Study Flow .............................................................................................................. 14 
6.2 Study Visits ................................................................................................................................... 15 
6.3 Recruitment .................................................................................................................................. 15 
6.4 Screening and Enrollment ........................................................................................................... 16 
6.5 Informed Consent ........................................................................................................................ 16 
6.6 Screening and Baseline Evaluation ............................................................................................ 16 
6.7 Procedure ...................................................................................................................................... 17 
6.8 7 Day and/or Discharge ............................................................................................................... 17 
6.9 Final Follow-Up (1 Year ± 90 Days) ........................................................................................... 17 
7. 
Investigator Responsibilities .............................................................................................. 20 
7.1 Institutional Review Board / Ethics Committee Approval ....................................................... 20 
7.2 Informed Consent ........................................................................................................................ 20 
7.3 Adherence to Protocol/Amendments and Applicable Law ...................................................... 20 
7.4 Case Report Form Completion ................................................................................................... 20 
7.5 Image Upload ............................................................................................................................... 21 
7.6 Reporting ...................................................................................................................................... 21 
7.6.1 
Adverse Events .................................................................................................................... 21 
7.6.2 
Analysis of Adverse Events................................................................................................. 22 
7.6.3 
Device Deficiencies .............................................................................................................. 23 
7.6.4 
Protocol Deviation ............................................................................................................... 24 
7.7 Records Retention ........................................................................................................................ 24 
8. 
Sponsor Responsibilities ..................................................................................................... 24 
8.1 Training ........................................................................................................................................ 24 
8.2 Investigator List ........................................................................................................................... 25 
8.3 Adverse Event Reporting ............................................................................................................ 25 
8.4 Data Monitoring ........................................................................................................................... 25 
8.4.1 
Site Qualification Visit ........................................................................................................ 25 
8.4.2 
Site Initiation Visit .............................................................................................................. 25 
8.4.3 
Interim Monitoring Visit .................................................................................................... 25 
8.4.4 
Site Close Out Visit ............................................................................................................. 26 
8.5 Data Management ........................................................................................................................ 26 
9. 
Ethical Requirements ......................................................................................................... 26 
9.1 Declaration of Helsinki ................................................................................................................ 26 

 
 
 
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9.2 Informed Consent ........................................................................................................................ 27 
9.3 Subject Data Protection ............................................................................................................... 27 
10. Statistical Procedures ......................................................................................................... 27 
10.1 General Statistical Considerations ............................................................................................. 27 
10.2 Sample Size Estimation for the Primary Outcome ................................................................... 27 
10.3 Control of Systematic Error and Bias ........................................................................................ 28 
10.4 Missing Data and Imputation Methods ..................................................................................... 28 
10.5 Definition of Populations ............................................................................................................. 28 
10.5.1 Screened ............................................................................................................................... 28 
10.5.2 Screen Failure ...................................................................................................................... 28 
10.5.3 Enrolled ................................................................................................................................ 28 
10.5.4 Completed ............................................................................................................................ 28 
10.5.5 Early Termination ............................................................................................................... 29 
10.6 Definition of Analysis Populations ............................................................................................. 29 
10.6.1 Intent to Treat Sample ........................................................................................................ 29 
10.7 Interim Analysis ........................................................................................................................... 29 
10.8 Statistical Analysis of Primary Efficacy Endpoint .................................................................... 29 
10.9 Statistical Analysis of Primary Safety Endpoint ....................................................................... 29 
10.10 
Secondary Statistical Analysis ................................................................................................ 29 
10.11 
Analysis of Adverse Events ..................................................................................................... 30 
10.12 
Imaging Outcomes Analysis ................................................................................................... 30 
10.13 
Baseline Characteristics .......................................................................................................... 30 
10.14 
Pooling Across Centers ........................................................................................................... 30 
10.15 
Final Report ............................................................................................................................. 30 
11. Core Lab .............................................................................................................................. 30 
11.1 Imaging Core Lab ........................................................................................................................ 30 
12. Study Administration ......................................................................................................... 31 
12.1 Clinical Trial Termination/Withdrawal .................................................................................... 31 
12.2 Missing Visits ................................................................................................................................ 32 
12.3 Protocol Adherence and Amendments ....................................................................................... 32 
12.4 Trial Registration ......................................................................................................................... 32 
13. Publication of Information ................................................................................................. 32 
14. Contact Information ........................................................................................................... 33 
15. Bibliography ........................................................................................................................ 34 
16. Appendix .............................................................................................................................. 37 
16.1 Acronyms and Abbreviations ..................................................................................................... 37 
16.2 Modified Rankin Scale ................................................................................................................ 38 
16.3 Hunt and Hess Grading Scale ..................................................................................................... 39 
16.4 Definitions ..................................................................................................................................... 40 
16.4.1 Stroke ................................................................................................................................... 40 
16.4.2 Major Ipsilateral Stroke ..................................................................................................... 40 
16.4.3 Intracranial Hemorrhage ................................................................................................... 40 
16.4.4 Morbidity ............................................................................................................................. 40 
16.4.5 Perforation ........................................................................................................................... 40 
16.4.6 Dissection ............................................................................................................................. 40 
16.4.7 Vasospasm ............................................................................................................................ 40 
16.4.8 Recanalization ..................................................................................................................... 41 
16.4.9 Aneurysm Size ..................................................................................................................... 41 
16.4.10 Angiographic Outcome ....................................................................................................... 41 
 

 
 
 
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1. Introduction and Rationale 
Intracranial aneurysms are a significant health problem in the United States and Europe 
with an incidence rate as high as 6% [1-3]. If an intracranial aneurysm ruptures, blood leaks 
into the highly sensitive subarachnoid space around the brain, resulting in a subarachnoid 
hemorrhage (SAH). The annual risk of rupture of an intact intracranial aneurysm is 
estimated to be approximately 1.9% [4].  Of all SAH incidences, 85% are attributed to 
ruptured aneurysms [5] and approximately half of all ruptured aneurysms are fatal within 
the first six months [6]. Patients who survive the initial SAH are at significant risk of 
subsequent re-rupture as well.  Various reports indicate that if left untreated, there is a re-
bleeding rate of more than 50% within the first six months from initial presentation of a 
SAH [4]. In addition, permanent disability is reported to occur in 50% of patient’s that 
survive a SAH and only one-third of patient’s will have a positive outcome [7]. 
Neurosurgical clipping was the initial intervention for intracranial aneurysms (IA) prior to 
the introduction of alternative endovascular treatment options. The International 
Subarachnoid Aneurysm Trial (ISAT) was a randomized, prospective, multicenter trial that 
compared the safety and efficacy of endovascular coiling compared to neurosurgical 
clipping. The ISAT Trial enrolled 2143 subjects with ruptured IA and randomized them to 
endovascular detachable coil (n=1073) treatment or standard neurosurgical clipping 
(n=1070) [8]. The primary endpoint was the Modified Rankin Scale (mRS) of 3-6 
(dependency or death) at one year. The clinical follow-up included assessment for 
rebleeding and death at 2 months and at one year. An interim analysis was conducted per 
the trial’s steering committee and recruitment was stopped. The outcomes showed a 
statistically significant difference between the treatment arms in favor of the endovascular 
coiling arm (P=0.0019). Of the 801 subjects treated with endovascular coiling, 190 (23.7%) 
achieved an mRS of 3-6 at one year. Of the 793 subjects treated with neurosurgical 
clipping, 243 (30.6%) achieved an mRS of 3-6. The absolute risk reduction of dependency 
or death at one year was 6.9% (95% CI 2.5-11.3) and the relative risk reduction was 22.6% 
(95% CI 8.9-34.2) in favor of the endovascular coil arm. The risk of rebleeding from the 
ruptured aneurysm at one year was 2 per 1276 of the endovascular coil arm compared to 0 
per 1081. The authors concluded that survival free disability at one-year post-treatment 
was significantly better with endovascular coiling. 
The ISAT Trial demonstrated that coiling was a safe and efficacious alternative treatment 
option for IA. The trial has maintained long-term follow-up with 1644 subjects from 22 
United Kingdom sites and collected clinical outcomes from 10-18.5 years post initial study 
procedure [9]. The mRS was collected annually from self-reported questionnaires and data 
on rebleeding and recurrent aneurysms were also collected by questionnaires and medical 
records. The rate of death was obtained from data provided by the Office of National 
Statistic. At a 10-year follow-up, 1003 subjects (n=435 coiling and n=370 clipping) had 
returned questionnaires and survival was higher for subjects that were initially treated with 
coiling (82%) compared to the surgical clipping arm (78%). Furthermore, subjects from 
the endovascular coiling arm were more likely to be alive and independent at 10 years 
compared to subjects from the clipping arm (OR 1.34, 95% CI 1.07-1.67). The durability 

 
 
 
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of endovascular coiling in the study provided level 1 evidence to support coiling for 
subjects with IA that are suitable for endovascular therapy. 
Several factors influence which treatment the interventionalist selects, such as patient risk 
factors, rupture status, aneurysm neck diameter and width, as well as cerebral vessel 
location [10]. Current treatment options include bare metal coiling, stent assisted coiling, 
balloon assisted coiling, bioactive-hydrocoils, surgical clipping, flow diverters, and more 
recently, intrasaccular devices. Over the past decade, endovascular coiling has now been 
widely accepted for the treatment of both ruptured and unruptured aneurysms [9-17]. Coils 
that are considered to have ‘stiff’ properties are typically effective for the early stages of 
the aneurysm packing, while softer coils are more effective to complete the packing of 
residual empty spaces with ‘finishing’ coils. Finishing coils are beneficial to use at the end 
of the aneurysm packing process, because they are designed to fill-in the empty spaces to 
tighten the packing [18-21]. Earlier studies on coils demonstrated that there was a 
correlation between packing density and rates of recanalization [18, 20, 21]. Finishing coils 
were initially bare-metal, but the development of polymer or gel-coated coils have become 
available. The Hydrosoft and Hydroframe finishing coils (Microvention, Tustin, CA) were 
developed with a gel that expands when in contact with liquids[22].  
The HELPS Trial was a randomized controlled trial comparing Hydrocoils to bare platinum 
coils and initial results showed a significantly higher rate of adverse outcomes in the bare 
platinum coil arm [23-25]. A subgroup analysis of the HELPS Trial further demonstrated 
that hydrocoils were associated with statistically significant lower rates of major recurrence 
for subgroups with recently ruptured aneurysms and medium-sized aneurysms[26-28]. 
There have been varying results published for hydrogel coils in the HELPS, PRET, and 
MAPS trials, but the recent results from the GREAT randomized trial showed favorable 
outcomes for the hydrogel coil arm [22]. The GREAT Trial enrolled 513 patients 
(hydrogel=256 and bare platinum=257 patients) in France and Germany. The investigators 
suggested that the significantly higher packing density observed in the hydrogel arm 
translated to better long-term angiographic results and lower retreatment rates.  
The Hydrogel Endovascular Aneurysm Treatment Trial (HEAT) was a multicenter, 
randomized, controlled trial that evaluated the second-generation HydroCoil Embolic 
System (HES) compared to bare-platinum coils (BPC) for the treatment of intracranial 
aneurysms [29]. The primary endpoint was aneurysms recurrence over 24 months (defined 
by Raymond aneurysm scale). There were six hundred subjects enrolled at 46 sites with 
ruptured or unruptured intracranial aneurysms randomized to both arms (n=297 HES and 
n=303 BPC). The HES arm was superior to bare platinum coils at reducing the aneurysm 
recurrence rate. The recanalization rate was 4.4% for HES compared to 15.4% for BPC 
and no significant differences in adverse event rates. 
An analysis of other coils available (Target Ultra Helical, MicroPlex Hypersoft, Axium 
Helix, ED Coil Extrasoft, and DeltaPlush) were evaluated by Ota et al. for area, perimeter, 
and circularity in an experimental model[30].  The authors suggested that Target Ultra 
Helical and MicrPlex may be more suitable for early procedure; Axium Helix and ED Coil 
Extrasoft for mid-procedure; and Deltaplush was better suited for finishing[30]. Therefore, 
coils with varying properties at different procedure times and stages may be beneficial. 

 
 
 
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Penumbra, Inc. (Alameda, CA) has developed the Penumbra SMART COIL® System to 
address the limitations of conventional embolization coil systems. SMART COIL is unique 
from other microcoils, because they do not have uniform stiffness, they have a tight 
conformational structure, and they have a robust stretch-resistance platform [32]. The 
SMART COIL system offers softer coil technology including the WAVE™ Extra Soft coil 
designed for filling and finishing. Penumbra SMART COIL System has been evaluated in 
multiple publications [31-38]. 
A multicenter retrospective review was performed by Spiotta et al.[31, 35] to capture data 
on all patients treated with at least one SMART Coil as part of an endovascular intracranial 
aneurysm (IA) embolization between July 2015 to January 2016. Fifty-nine patients 
underwent treatment for IAs with SMART Coils (44% were ruptured aneurysms). The 
mean aneurysm size was 5.9 ± 2 mm by 4.5 ± 2 mm. More than half (54.2%) of the patients 
underwent coiling with SMART Coils alone; the remainder used either framing or finishing 
coils of another type. About one-third (33.9%) of patients underwent balloon-assisted 
coiling, and 47.5% underwent stent-assisted coiling. Raymond I or II occlusion was 
achieved in 71.2% of patients. There were no device malfunctions or rebleeds observed. 
Six patients experienced a minor complication without clinical sequelae. Occlusion 
outcomes included 33.9% Class I, 37.3% Class II, and 28.8%. No rebleeds have been 
observed. The authors concluded that the SMART coil progressive design offered 
appreciable clinical advantages during deployment and demonstrated satisfactory safety 
and efficacy outcomes in treatment of a wide variety aneurysms, both ruptured and 
unruptured [31]. 
 
Another retrospective study was performed by Ilyas et al. to analyze baseline and initial 
outcomes data on consecutive patients treated by IA embolization from June 2016 to 
January 2017. Thirty-two patients with 33 aneurysms were included in the study; 15.2% 
presented with subarachnoid hemorrhage. Mean aneurysm diameter was 6.0 ± 2.5 mm, 
with 85% in the anterior circulation. Dome irregularity and fusiform aneurysm morphology 
were noted in 33% and 9% of aneurysms, respectively. Coiling was performed exclusively 
with SMART coils in 30 (90.9%) cases. Single- and dual-microcatheter techniques were 
utilized in 16 (48.5%) and one (3.0%) case, respectively. Balloon- and stent-assistance 
were used in three (9.1%) and 11 (33.3%) cases, respectively. The mean packing density 
was 25.2%. Raymond I or II occlusion was achieved in 75.8% of patients. No serious 
procedural complications were observed, and one device malfunction occurred in a patient 
with a wide-necked aneurysm (3.0%). The authors concluded that initial results showed a 
favorable risk to benefit profile of the SMART coil for the embolization of IAs [36]. 
Padmanadhan (2017) reported on a retrospective analysis of 75 consecutive patients treated 
in a single center for cerebral aneurysms with the SMART coil system [33]. There were 20 
aneurysms treated exclusively with the SMART coil and 58 were treated with a 
combination of coils; 252 SMART coils were used (13 Standard, 27 Soft, and 212 
ExtraSoft coils). Adjunctive devices were used in 57 cases (41 balloons and 16 stents). The 
results showed that no coil migration, coil stretching, premature detachment, or failure of 
coil detachment occurred with the SMART coils and three coils were retrieved and not 
detached. One event of intra-procedural rupture (controlled with balloon inflation) and 3 

 
 
 
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cases of intra-procedural thrombosis treated with IV Absciximab occurred. There three 
patient deaths of presenting subarachnoid hemorrhage and one case of delayed procedure 
related mortality (remote hemorrhage in stent assisted coiling case). The author reported 
that there was no change in the baseline modified Rankin score (mRS) for the remaining 
patients. In addition, the 6-month follow-up was available in 39/75 patients and showed 
complete aneurysm occlusion with no remnants in 32 patients and small neck remnants in 
7 patients (under observation).The author concluded that the SMART (Penumbra, Inc.) coil 
system was safe, easy to use, and effective especially in the treatment of otherwise difficult 
to treat very small intracranial aneurysms [33]. 
A retrospective cohort study was recently completed by Sokolowski et al. is to assess the 
angiographic outcomes at interim follow-up after aneurysm embolization with SMART 
coils between June 2016 and August 2017 [38]. Baseline data and follow-up angiographic 
outcomes using the modified Raymond-Roy classification (MRRC) were reported from 33 
patients with 34 aneurysms. The initial mean coil packing density was 26%, and the initial 
MRRC was I, II, IIIa, and IIIb in 24%, 26%, 35%, and 15%, respectively. The overall 
complication rate was 12%. At last follow-up (mean duration 7.7 ± 3.2 months), the 
retreatment rate was 14.7%, the MRRC was I, II, IIIa, and IIIb in 62%, 26%, 3%, and 9%, 
respectively. The authors reported that the majority of residual aneurysms after the initial 
embolization procedure would progress to complete or near-complete occlusion at interim 
follow-up [38]. In conclusion, they reported that the SMART coil was efficacious for the 
treatment of appropriately selected aneurysms and had an acceptable risk profile.  
The SMART Registry is a prospective, multicenter registry sponsored by Penumbra, Inc. 
to assess the treatment of intracranial aneurysms and other neurovascular abnormalities. 
For eligibility, the intervention must have implanted at least 75% SMART COIL, 
Penumbra Coil 400TM, and or Penumbra Occlusion Device (POD®) (Penumbra, Inc.). 
Study endpoints included retreatment through one-year follow-up, procedural device-
related serious adverse events (SAE), occlusion status at immediate post-procedure, and at 
one-year follow-up. 
The interim analysis from the first 500 consecutive subjects enrolled included cerebral 
aneurysms (90.6%, 451/498), of which 31.0% were ruptured; arteriovenous malformations 
(1.4%); fistulae (4.6%); and other lesions (3.4%)[39]. At admission, 70.8% of subjects 
were female, and the mean age was 60.0 ± 13.3 years. Aneurysms were small (87.7%), 
large (12.1%), and giant (0.2%), with 64.2% (265/413) having a wide neck. 
The median time of fluoroscopic exposure was 36.5 minutes (IQR 24.0-56.0). Stent-
assisted coiling was performed in 29.8% of patients, whereas balloon-assisted coiling was 
performed in 19.4% of patients. For all aneurysms, the median packing density was 29.5% 
(IQR 21.4-38.3). For all subjects, adequate occlusion at immediate post-procedure was 
achieved for 97.6% (483/495). In aneurysm subjects, Raymond I or II was achieved in 
79.7% (354/444) of patients at immediate post-procedure, and 88.6% (124/140) at one-
year follow-up. The retreatment rate through one-year follow-up was 3.8% (6/157).  

 
 
 
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2.2 Detachment Pusher 
The detachment pusher is a stainless steel and polymer 185 cm wire-like assembly 
used to advance and detach the coil at the target location. The coil is loaded onto the 
distal end of the detachment pusher via mechanical attachment to the distal 
detachment tip. The coil is detached from the pusher by actuating the detachment 
handle. The coil/detachment pusher assembly is provided sterile and is a single use 
device. 
2.3 Detachment Handle 
The SMART COIL Detachment Handle is a plastic handle used to mechanically 
detach the Coil. The Detachment Handle is provided sterile and is intended for use in 
multiple coil detachments performed during a single procedure. 
2.4 Indications 
The Penumbra SMART COIL System is indicated for the embolization of: 
• Intracranial aneurysms 
• Other neurovascular abnormalities such as arteriovenous malformations 
and arteriovenous fistulae 
• Arterial and venous embolizations in the peripheral vasculature 
Embolization coils perform their intended function by volume filling of the aneurysm 
sac or target location. Achievement of aneurysmal occlusion is based on volume 
filling of the aneurysm, causing blood flow diversion from the aneurysmal sac to the 
parent artery, leading to secondary clot formation and organization within the target 
location. 
The Penumbra SMART COIL System originally received the CE Mark in December 
2014, FDA 510(k) clearance in March 2015, and Health Canada approval in October 
2015. 
3. Risk Analysis 
A thorough risk analysis was performed as part of design control requirements of the 
Quality System Regulation (21 CFR 820). The current potential complications listed on 
the Instructions For Use (IFU) label include the following:  
• acute occlusion 
• air embolism 
• allergic reaction and anaphylaxis from 
contrast media 
• aneurysm rupture 
• arteriovenous fistula 
• coagulopathy 
• infection 
• intima dissection 
• intracranial hemorrhage 
• ischemia 
• myocardial infarction 
• neurological deficits including stroke 
• parent artery occlusion 

 
 
 
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• coil herniation into parent vessel 
• death 
• device malfunction 
• distal embolization 
• emboli 
• embolic stroke and other cerebral 
ischemic events 
• false aneurysm formation 
• hematoma or hemorrhage at access site 
of entry 
• incomplete aneurysm occlusion 
• peripheral thromboembolic events 
• post-embolization syndrome 
• premature device detachment 
• recanalization 
• renal failure 
• respiratory failure 
• revascularization 
• thromboembolic episodes 
• vessel spasm, thrombosis, dissection, or 
perforation 
Potential complications associated with cerebral endovascular coiling procedures are 
similar to other angiographic and coiling procedures and may include: 
• Allergic reaction to contrast agents 
• Access site complications 
• Infections 
• Pseudoaneurysms 
• Arterial dissection 
• Parent vessel occlusion 
• Thromboembolism (or other embolism) 
• Aneurysm perforation (ruptured and unruptured) 
• Rebleed 
• Procedure-related morbidity 
• Procedure-related mortality 
• Coil migration 
4. Study Overview 
The objective of this study is to demonstrate the safety and efficacy of the Penumbra 
SMART COIL System including WAVE Extra Soft as a fill and finish coil in the treatment 
of intracranial aneurysms. Imaging will be analyzed by an independent core lab to assess 
aneurysm occlusion rates and perform a comparative analysis between imaging modalities.  
   4.1 Study Design 
Post-market, real world, prospective, multi-center study that will enroll 
approximately 800 subjects at up to 60 global sites.  
4.2 Study Objectives/Endpoints 
4.2.1 Primary Endpoints 
 
 

 
 
 
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Efficacy: 
• Adequate occlusion defined as Raymond-Roy Occlusion Class I and II at 
final follow-up  
Safety: 
• SAEs within 24 hours post-procedure 
• Device-related SAE up to 7 days or discharge 
4.2.2 Secondary Endpoints 
Efficacy: 
 
• Immediate post-procedure occlusion rates 
• Retreatment rate at final follow-up 
• Aneurysm Occlusion Raymond I post treatment 
• Aneurysm Occlusion Raymond I at final follow-up 
• Aneurysm recanalization or progressive thrombosis from post procedure to 
final follow-up 
Safety:  
• Major ipsilateral stroke  
• Device related SAE at final follow-up 
• All-cause morbidity and mortality 
5. Study Population 
5.1 Inclusion Criteria 
1. Patient age ≥ 18 years 
2. Patient having embolization of intracranial aneurysms  
3. WAVE Extra Soft Coil is the final finishing coil 
4. Penumbra SMART COIL System accounts for at least 75% of total number of 
coils implanted   
5. Informed consent obtained per IRB/EC requirements 
5.2 Exclusion Criteria 

 
 
 
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1. Life expectancy less than 1 year 
2. Patient previously enrolled in the SURF Study 
3. Known multiple intracranial aneurysms requiring treatment during index 
procedure 
4. Patient is unwilling or unable to comply with protocol follow up schedule 
and/or based on the Investigator’s judgment the patient is not a good study 
candidate 
5. Participation in an interventional drug or device study that may confound the 
results of this study 
6. Study Procedures 
6.1 Overview of Study Flow 
Patients ≥18 years of age having embolization of intracranial aneurysms should be 
assessed for eligibility. All sites will keep a screen failure log of all potential study 
candidates who are screened and not enrolled or screened, consented, and not 
enrolled. Reason(s) for exclusion will be recorded. Screening information will be 
reported in Electronic Data Capture System (EDC).  
Recruitment rates will be tracked over time for each site. The actual recruitment rates 
will be useful for planning further clinical trials and determining the widespread 
impact of the therapy. 
 
 

 
 
 
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Figure 1: Study Flow  
 
 
 
6.2 Study Visits 
Subjects enrolled in this study will follow the visit schedule below and will continue 
to receive routine practice/ standard of care treatment. Procedure is day 0 for 
determining follow-up visit dates.  
• Screening & Baseline 
• Procedure 
• 7 Day and/or Discharge 
• 1 Year Follow-Up ± 90 Days 
6.3 Recruitment 
The target population are subjects ≥18 years of age presenting with an intracranial 
aneurysm(s). No study specific screening tests or procedures are required for 
enrollment in the study. Standard of care evaluations will be used to confirm 
eligibility. 

 
 
 
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Potential study participants and/or their legal authorized representative (LAR) will 
be identified by the study team at each site to obtain consent and determine eligibility. 
The study allows for enrollment up to 800 subjects at up to 60 global sites.  
6.4 Screening and Enrollment 
The subject will be clinically evaluated in the same manner as any patient presenting 
with 
intracranial 
aneurysm(s). 
The 
medical 
history 
screen, 
available 
clinical/neurological exams obtained, and imaging information per institutional 
routine care will be evaluated to determine patient eligibility.  
Pre-procedure angiography will be performed per institutional standard of care and 
will allow to define aneurysm location, size and best treatment strategy. 
Patients will be considered enrolled once informed consent is obtained per IRB/EC, 
the index procedure is complete, and all eligibility is confirmed. Patients who fail to 
meet entry criteria pertaining to coil selection will be considered a screen fail.  
6.5 Informed Consent 
The Investigator or designee will obtain written informed consent from the subject or 
LAR using the current IRB/EC approved consent form per IRB/EC policy. For sites 
in North America, patients who have had an index procedure with SMART Coils and 
all eligibility is confirmed, may be consented up to 2 days post-procedure but prior 
to discharge. For sites outside of North America, the informed consent signature 
process will be described in Informed Consent Form and will be applied per local 
Ethics Committee approvals. 
All informed consent documents used under this protocol will be consistent with 
applicable elements of EN ISO 14155:2011, Clinical investigation of medical devices 
for human subjects – Good Clinical Practice and 21 CFR Part 50, Protection of 
Human Subjects, and will be approved by the site’s reviewing IRB/EC prior to study 
initiation.  
Any modification to the sample informed consent form made by the study site must 
be approved by the Sponsor and the IRB/EC before use. Each study site will provide 
the Sponsor with a copy of the IRB/EC approved consent forms. Informed consent 
completion will be monitored regularly by the Sponsor.  
 
6.6 Screening and Baseline Evaluation  
All assessments are to be conducted in accordance with routine care at each 
participating hospital; the following data will be collected but is not limited to: 
• Demographics 
• Vital signs  
• Review of medical history 

 
 
 
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• Baseline mRS 
• If a patient has a SAH at baseline, the Hunt and Hess score will be collected 
6.7 Procedure  
All procedures are to be conducted in accordance with routine care at each 
participating hospital and the Instructions for Use for each device used.  
At a minimum, the following information will be captured in the Case Report Form 
(CRF) for the target aneurysm, data will not be captured for ancillary aneurysms 
treated during the index procedure: 
• Sedation  
• Type of aneurysm 
• Size of aneurysm  
• Aneurysm location 
• Procedural information  
• Devices used 
• Aneurysm occlusion grade 
• Adverse event review 
• Angiography 
Procedural angiography will be performed per institutional standard of care.  Imaging 
will be uploaded and sent to an Imaging Core Laboratory to make a final 
determination on aneurysm occlusion rate. 
6.8 7 Day and/or Discharge   
The 7 day and/or discharge visit should be done within 1 day prior to discharge or at 
day 7, whichever occurs first. All assessments are to be conducted in accordance with 
routine care at each participating hospital, the following data will be collected but is 
not limited to: 
• Vital signs 
• mRS 
• Adverse event review 
In addition to the assessments above the following will be collected at discharge:  
• The location that the subject is discharged to and the date of discharge  
• If any adverse events occurred, it will be reported on the Adverse Event Form 
6.9 Final Follow-Up (1 Year ± 90 Days) 
All assessments are to be conducted in accordance with routine care at each 
participating hospital, the following data will be collected but is not limited to: 

 
 
 
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• Aneurysm occlusion grade 
• Vital signs 
• mRS 
• Retreatment information 
• Adverse event review 
• Angiography*  
 
*Angiography will be performed per institutional standard of care. DSA, CTA, or 
MRA are accepted for imaging modality. Images will be sent to an Imaging Core 
Laboratory to make a final determination on aneurysm occlusion rate. If both DSA 
and MRA are available, then both imaging modalities should be submitted for Core 
Laboratory review. 

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7. Investigator Responsibilities 
7.1 Institutional Review Board / Ethics Committee Approval 
 
Prior to enrolling patients into the study, the investigator will ensure that proper 
Institutional Review Board (IRB)/Ethics Committee (EC) approval is obtained in 
accordance with applicable local laws and regulations.  The IRB/EC shall approve all 
study documents as appropriate, including but not limited to the final protocol, 
amendments to the protocol, Instructions for Use (where applicable), Investigator 
Brochure (where required), and the informed consent. 
The investigator will report to the Sponsor or designee immediately if the approval to 
conduct the investigation is withdrawn by the IRB/EC or Competent Authority. The 
report will include a complete description of the reason(s) for which approval was 
withdrawn. 
7.2 Informed Consent 
 
The investigator is responsible for ensuring that a signed and dated informed consent is 
obtained in accordance with Section 6.5 of this protocol and according to country and 
local requirements. 
7.3 Adherence to Protocol/Amendments and Applicable Law 
 
The investigator is responsible for overseeing, ensuring that the study is conducted, and 
completing the study according to this protocol and in accordance with the relevant 
aspects of EN ISO 14155:2011, Declaration of Helsinki, along with any conditions 
imposed by the reviewing IRB or EC, and all other applicable regulations. The 
investigator shall approve and adhere to this protocol and any amendments that arise 
during the course of the study. 
It is the investigator’s responsibility to ensure that the staff assisting with the study have 
the appropriate qualifications, are fully instructed on the study procedures, and will 
respect study confidentiality.  
7.4 Case Report Form Completion 
The Investigator and study staff shall complete the case report forms (CRFs) associated 
with this study. Subject numbers shall be used to identify individual participants in this 
study. The CRFs should be a complete and accurate record of subject data collected 
during the study according to relevant aspects of I.S. EN ISO 14155, 21 CFR 11, 
Electronic Records; Electronic Signatures and GCP requirements. It is the Investigator's 
responsibility to ensure the quality of the data collected and recorded is appropriate and 
collected in accordance with GCP and all applicable regulations. Data entry will be 
performed by the study site(s). Investigators are responsible for completion and timely 
submission of data to Penumbra, Inc. Every reasonable effort should be made to complete 
data entry within 7 business days of data collection. 

 
 
 
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7.5 Image Upload  
Images from Immediate Post Procedure and Final Follow-Up visit may be uploaded to 
an image management system for Core Lab review.  Instructions for image collection 
and upload will be provided. Study staff shall ensure that no images contain any 
personally identifying information about the subject or study site (e.g. Physician name, 
Institution name, patient name, etc.). 
Sites will be provided with instructions for how images should be collected and 
submitted within 14 days of the acquisition of the required imaging. If the site is unable 
to provide the images within this time frame, the appropriate Sponsor contact should be 
notified.  
7.6 Reporting 
The investigator will be responsible for reporting the following: 
7.6.1 Adverse Events 
Adverse events (AE) must be recorded by the Investigator on the CRFs and will be 
monitored during the study. Only adverse events related to the procedure or device, 
and all SAEs will be collected starting at procedure through discharge for enrolled 
subjects. After discharge only neurological SAEs will be collected. Additional 
information for Symptomatic Intracranial Hemorrhage and Ischemic Stroke will be 
collected on Event of Interest CRFs. 
Minimum requirements of data to be recorded are: Adverse event term, event start 
date, seriousness, action taken, outcome and procedure / device-relatedness or 
causality.  
In order to ensure prompt reporting of AEs, all reportable AEs (as well as all related 
study data) are required to be entered into the EDC in a timely manner. Any 
suspected UADEs should be reported immediately by calling the Sponsor. All 
device related SAEs should be reported in the EDC within 72 hours of the site staff 
first being made aware of the occurrence of the SAE. If the EDC is unavailable, an 
email can be sent to Penumbra. 
The Investigator must report adverse events to the IRB/EC according to local 
requirements. The investigator is responsible for reporting time frames and 
complying with local or national requirements.  In addition, the investigator will 
report to the sponsor and IRB/EC any device deficiencies that could have led to a 
SAE, if required by national regulations or by local authorities. 
For the purpose of reporting within this protocol, pre-existing conditions or planned 
procedures for pre-existing conditions are not reportable as AEs unless there is 
worsening of the condition with an increase in severity or frequency during the 
course of the study. All deaths will be reported regardless of causality. When 
reporting a death, the primary condition or diagnosis that contributed to the fatal 

 
 
 
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outcome should be reported as a SAE with an outcome of death. Only a single cause 
of death should be reported in EDC. If the cause of death is unknown, report 
“unknown cause of death” as a SAE.  
7.6.2 Analysis of Adverse Events  
A Medical Monitor will review events related to primary and secondary safety 
endpoints as they are reported. Events of Interest related to Symptomatic 
Intracranial Hemorrhage and Ischemic Stroke will also be reviewed by the medical 
monitor. Redacted source documents may be collected for events where the medical 
monitor deem necessary. 
7.6.2.1 Definitions 
• Adverse Event (AE): any untoward medical occurrence, unintended 
disease or injury, or untoward clinical signs (including abnormal 
laboratory findings) in subjects, users or other persons, whether or not 
related to the study medical device. 
• Adverse Device Effect (ADE): An adverse event related to the use of 
the study medical device.  
• Definition of SAE  
An SAE is an event that: 
o Led to death  
o Led to a serious deterioration in the health of the patient that: 
− Resulted in life-threatening illness or injury  
− Resulted in chronic disease 
− Resulted in permanent impairment of a body structure or a 
body function  
− Required in-patient hospitalization or prolongation of 
existing hospitalization  
− Resulted in medical or surgical intervention to arrest 
permanent impairment to body structure or a body function  
− Led to fetal distress, fetal death or a congenital abnormality 
or birth defect 
 
• Unanticipated Adverse Device Event (UADE): An unanticipated 
adverse device effect is any serious adverse effect on health or safety or 
any life-threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the protocol, or instructions 
for use. Unanticipated adverse device effect also includes any other 
unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects. 

 
 
 
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7.6.2.2 Relationship to the Study Device 
An AE is considered to be device-related when it is reasonable to believe that 
the event may have been caused by or is related to the device. The following 
definitions will be used to assess the relationship of the adverse event to the use 
of study device. Grading for relatedness of ‘probable’ or ‘definite’ will be 
considered device related. 
• 
Definite:  The temporal sequence is relevant and the event abates upon 
device application completion/removal, or reappearance of the event on 
repeat device application 
• 
Probable:  The temporal sequence is relevant or the AE abates upon 
device application completion/removal or the AE cannot be reasonably 
explained by the subject’s condition or comorbidities.  The AE is related 
or most likely associated with the device 
• 
Possible: The temporal sequence between the device and the AE is such 
that the relationship is not unlikely or there is no contradicting evidence 
that can reasonably explain the subject’s condition.  There is a possibility 
of a relationship between the AE and the device 
• 
Unrelated:  The AE is not associated with the device.  There is no relation 
between the AE and the device 
Similar grading will be used for assessing the relationship to index procedure, 
target aneurysm, and comorbidities.  
7.6.3 Device Deficiencies  
All device deficiencies related to the identity, quality, durability, reliability, safety 
or performance of the study device shall be documented and reported through the 
standard commercial process. Investigators must report all possible device 
deficiencies associated with the device observed during the study. This includes 
unexpected outcomes or device deficiencies that might have led to a serious adverse 
event if a) suitable action had not been taken or b) intervention has not be made or 
c) if circumstances had been less fortunate.  
Device manufacturers are required to report qualifying medical device incidents to 
the relevant national competent authorities. An incident is defined as “any 
malfunction or deterioration in the characteristics and/or performance of a device, 
as well as any inadequacy in the labeling or the instructions for use which, directly 
or indirectly, might lead to or might have led to the death of a subject or to a serious 
deterioration in their state of health.” A deterioration in state of health is not 
considered unanticipated if the condition leading to the event was considered in a 
risk analysis.  

 
 
 
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7.6.4 Protocol Deviation 
Deviations defined in this protocol should be clearly documented, if identified 
during monitoring or through other means.  For this study, deviations should be 
reported for the following categories 
• 
Inclusion/exclusion criteria deviation(s) 
• 
Informed Consent deviation(s) 
7.7 Records Retention 
The Investigator shall maintain the records associated with this study for a period of 
at least two years after either the date on which the investigation is completed or the 
date that the records are no longer required for supporting a premarket 
approval/notification submission, whichever is later. A Trial Master File (TMF) will 
be used as the master repository for all site and Sponsor regulatory documents. These 
records include the following: 
• Correspondence with the Sponsor or designee, the Medical Monitor, and other 
investigators 
• Subject source records, including but not limited to: Informed Consent Forms, 
copies of all completed CRFs, and supporting documents (laboratory reports and 
reports of diagnostic tests, medical records, etc.) 
• All versions of study protocol  
• Documentation of protocol deviations 
• Reports of any serious adverse event or serious device effects 
• A copy of all approvals related to the clinical investigation 
• The approved, blank, informed consent form and blank CRFs 
• All approval/acknowledgment letters from the IRB/EC for all versions of the 
study protocol, ICF and other documents 
• Clinical Trial Agreement 
• Signed and dated curriculum vitae for all study personnel  
• Medical licenses for the Principal Investigator and all participating sub-
investigators 
• Financial disclosure for the Principal Investigator and all participating sub-
investigators  
• All required regulatory documents such as Delegation of Authority and training 
logs 
• Signed Protocol Signature Page(s)  
8. Sponsor Responsibilities 
8.1 Training 
The Sponsor is responsible for providing training on the protocol, CRF completion, 
and image upload, as applicable for all study staff per delegation of authority log.  

 
 
 
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8.2 Investigator List 
The Sponsor shall keep a list of the names and addresses of the clinical Investigators 
for the study. 
8.3 Adverse Event Reporting 
The Sponsor shall evaluate adverse event reports received from the study sites and 
found during data monitoring and shall report them to the appropriate regulatory 
bodies and other study sites as necessary. 
8.4 Data Monitoring 
 
Penumbra is responsible for ensuring that the study is conducted according to the 
appropriate regulations (US Food and Drug Administration 21 CFR §812, ISO 
14155:2011). A Penumbra employee or designate will conduct the following site 
visits: 
8.4.1 Site Qualification Visit 
Conducted to ensure the study site has the appropriate staff, facilities, and expertise 
to participate in the study. Site Qualification can be waived under certain 
circumstances. 
8.4.2 Site Initiation Visit 
Conducted to train the study staff on use of the device, study requirements, and 
other relevant training. 
8.4.3 Interim Monitoring Visit 
Conducted as needed to ensure the study site is operating in compliance with this 
protocol, continues to have the appropriate staff and facilities, and is correctly 
completing the CRFs.  
To ensure that investigators and their staff understand and accept their defined 
responsibilities, the Sponsor will maintain regular correspondence and perform 
periodic site visits during the course of the study to verify the continued 
acceptability of the facilities, compliance with the study plan, and maintenance of 
complete records. Clinical monitoring will include review and resolution of missing 
or inconsistent data and source document checks to ensure the accuracy of the 
reported data. Informed consent, CRFs and medical records for all enrolled and 
screen failed subjects will be made available to the Sponsor for review and 
collection.  
 
 

 
 
 
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8.4.4  Site Close Out Visit  
Conducted to ensure all study, device, and regulatory-related activities have been 
completed prior to site closure. 
8.5 Data Management 
Case Report Forms (CRFs) will be used at all study sites. All study data will be 
entered into commercially available web-based electronic data capture system 
(EDC). Data entry will be performed by the study site personnel. Investigators are 
responsible for completion and timely submission of the data to the Sponsor. Every 
reasonable effort should be made to complete data entry within 7 days of data 
collection. This EDC system requires no on-site software installation or specific 
hardware to operate. Investigators, clinical coordinators, data managers, and 
Penumbra clinical personnel access project information and study data centrally via 
a web browser.  
Automated data quality checks will display warnings for invalid data. Additionally, 
manual review of data listings may be used to identify data discrepancies or 
inconsistencies. The study site may be queried for clarification concerning CRF 
discrepancies or inconsistencies identified. If CRF corrections are necessary, they 
will be made by the Investigator or an authorized member of the Investigator's staff 
that is delegated to CRF/EDC. Questions or problems with submitted data will be 
addressed with the Principal Investigator via an electronic querying system, or 
through direct contact. The Investigator will review the CRFs for completeness and 
accuracy and provide his/her electronic signature and date to CRFs as evidence 
thereof. Any data items that have been changed will require reapplication of the 
electronic signature. 
Study personnel will have individual login and password to access the clinical study 
information based upon each individual’s roles and responsibilities. The application 
provides hierarchical user permission data entry, viewing, and reporting options. 
All data entry and data update information, including the date and person performing 
the action, will be available via the audit trail, which is part of the EDC system. 
All CRFs and data files will be secured to ensure confidentiality. Investigators are 
required to maintain source documents required by the protocol, including laboratory 
results, reports, supporting medical records, and Informed Consent Forms. The 
source documents will be used during the regular monitoring visits to verify 
information entered on the CRFs. 
9. Ethical Requirements 
9.1 Declaration of Helsinki 

 
 
 
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The study will be performed in accordance with the applicable aspects of ISO 
14155:2011, recommendations guiding physicians in biomedical research involving 
human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland 
(1964 and later revisions), ICH and US FDA GCP guidelines. 
It is the responsibility of the investigator to obtain approval of the study protocol 
from the Institutional Review Board/Ethics Committee (IRB/EC) and to keep the 
IRB/EC informed of any serious adverse event, serious adverse device effects, and 
amendments to the protocol. All correspondence with the IRB/EC should be filed by 
the investigator and copies sent to the Sponsor or its designee. 
9.2 Informed Consent 
The Investigator is responsible for ensuring that a signed and dated informed consent 
is obtained in accordance with Section 6.5 of this protocol, as delegated by the site-
specific Delegation of Authority, and according to country and local requirements. 
9.3  Subject Data Protection 
Each subject will be assigned a unique subject identification number at the time of 
enrollment. This subject identification number will be retained throughout the study. 
All case report forms (CRFs) will be tracked, evaluated, and stored using only the 
subject ID number. No personal identifying information will be included on the case 
report forms. 
The informed consent form will notify subjects that study monitors, auditors, and 
representatives of government agencies and ethics committees will have access to 
personal identifying information to ensure that data reported on the CRFs 
corresponds to the person who signed the consent form and the information contained 
in the source documentation. Each subject must be informed that the data collected 
will be stored by computer and the applicable national regulations for handling of 
computerized data will be followed. Furthermore, each subject should be informed 
about the possibility of inspection of relevant parts of the hospital records by the 
Sponsor, or other Health Authorities, including the FDA. 
10. Statistical Procedures 
10.1 General Statistical Considerations  
All statistical analyses will be descriptive in nature. Descriptive statistics will include 
the number of observations, mean, median, standard deviation, inter-quartile range, 
minimum and maximum for continuous variables and counts and percentages for 
discrete variables. All confidence intervals presented will be two-sided. Analyses will 
be conducted using SAS (SAS Institute, Cary, NC). The specific details of the 
planned analyses will be described completely in the statistical analysis plan. 
10.2 Sample Size Estimation for the Primary Outcome 

 
 
 
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Approximately 800 patients will be enrolled in this post market study with 
estimated 10% attrition at final follow-up. Assuming an observed rate of 89% 
(641/720) for the endpoint of Raymond-Roy I-II at follow-up, the sample size 
precision is greater than ± 3% for this endpoint (95% CI: 87%% to 91%). Assuming 
an observed rate of 2.8% (22/800) for the primary endpoint of device-related 
serious adverse events up to 7 days or discharge, the sample size precision is greater 
than ± 1.5% for this endpoint (95% CI: 1.6% to 3.9%). Assuming an observed rate 
of 8.9% (71/800) for the primary endpoint of serious adverse events at 24 hours 
post procedure, the sample size precision is greater than ± 2.5% for this endpoint 
(95% CI: 6.9% to 10.9%). These precision estimates are based on the normal 
approximation binomial 95% confidence intervals and SMART Registry interim 
results (data on file at sponsor). Hence, the sample size provides an adequate level 
of precision for these primary endpoints.  
10.3 Control of Systematic Error and Bias 
The study will be conducted under a common protocol for each investigational site 
with the intention of pooling the data for analysis. Every effort will be made to 
promote consistency in study execution at each investigational site. 
10.4 Missing Data and Imputation Methods 
Every effort is to be made to keep all missing data, particularly the Final Follow-Up, 
to a minimum. Some data may be missing, mainly due to lost-to-follow-up subjects. 
The primary analysis will be data as observed. Sensitivity analysis will be performed. 
10.5 Definition of Populations 
10.5.1 Screened 
Screened subjects are all subjects considered for participation in the study, whether 
or not they sign informed consent. 
10.5.2 Screen Failure 
Screen failure subjects are all subjects considered for participation in the study, who 
failed to meet inclusion criteria or met exclusion criteria. Patients can be screen 
failed based on general or procedure criteria. These patients may or may not have 
signed an informed consent form. 
10.5.3 Enrolled  
An eligible patient is considered enrolled once informed consent is obtained, index 
procedure is complete, and all inclusion criteria is confirmed.  
10.5.4 Completed 

 
 
 
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Completed subjects are all subjects who were enrolled and completed the study 
follow-up or were known to have died prior to the follow-up timepoint are 
considered completed. The completed subject metric will be provided for Final 
Follow-Up. 
10.5.5 Early Termination  
Early termination subjects are all subjects who were enrolled but did not complete 
follow-up and were not known to have died are considered early termination 
subjects. The early termination subject metric will be provided for Final Follow-
Up. 
10.6 Definition of Analysis Populations 
10.6.1 Intent to Treat Sample 
As the primary analysis, all performance and safety outcome measures will be 
analyzed under the intent-to-treat (ITT) principle. Under this principle, the ITT 
sample includes all subjects who are enrolled. This population is the primary 
analysis population.   
10.7 Interim Analysis 
No interim analyses are planned for the purpose of stopping the study early. Interim 
analysis may be performed for regulatory submission or publication of study results. 
No adjustments will be made to the confidence bounds for the final analysis.  
10.8 Statistical Analysis of Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the rate of aneurysm occlusion at Final Follow-
Up per Raymond-Roy classification. The proportion of subjects assessed as 
Raymond-Roy I or II will be provided along with the corresponding 95% 
confidence interval.  
10.9 Statistical Analysis of Primary Safety Endpoint 
The primary safety endpoints are the following: 
• SAEs up to 24 hours post-procedure 
• Device-related SAE up to 7 days or discharge  
The proportion of subjects experiencing each event will provided along with the 
corresponding 95% confidence interval.  
10.10 Secondary Statistical Analysis 
The secondary efficacy and safety endpoints will be assessed via proportions based 
on the endpoint criteria and 95% confidence intervals will be presented.  Survival 

 
 
 
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estimates will also be utilized to evaluate the time-to-event using Kaplan-Meier 
methodology for deaths through 365 days. With the date of procedure set at day 0, 
any event occurring on or before day 365 will be included.  
 
10.11 Analysis of Adverse Events 
All adverse events will be summarized by showing the number and percent of 
subjects which report the event.  Events will also be reported by relationship to the 
procedure or device. Adverse events judged as probably or definitely related to the 
SMART COIL System will be analyzed as device-related. 
10.12 Imaging Outcomes Analysis 
Aneurysm occlusion outcomes as assessed by the core lab will be evaluated for subjects 
that have both a DSA and MRA at follow-up. A sensitivity and specificity analysis will 
be conducted to evaluate the ability of MRA to detect residual flow in the coiled 
aneurysms. 
10.13 Baseline Characteristics 
Baseline data including, but not limited to demographics, clinical characteristics, 
and angiographic characteristics will be summarized using descriptive statistics.  
10.14 Pooling Across Centers 
Analyses will be presented using data pooled across centers. Key baseline and study 
endpoint variables will be presented by study site to assess any potential site effects. 
10.15  Final Report  
A final report will be completed, even if the study is prematurely terminated. At the 
conclusion of the trial, a multi-center abstract reporting the results will be prepared 
and may be presented at a major meeting(s). A multi-center publication may also 
be prepared for publication in a reputable scientific journal.  The publication of 
results from any single center experience within the trial is not allowed until the 
aggregate study results have been published, unless there is written consent from 
the Sponsor. Data may also be used for submissions to regulatory agencies as part 
of post-market clinical follow-up. 
11.  Core Lab  
11.1 Imaging Core Lab 
The Imaging Core Lab is composed of independent medical doctor(s) who are not 
participants in the study. The Core Lab is responsible for assisting in the development 
of specific criteria used for the categorization of clinical endpoints in the study.  A 

 
 
 
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web-based electronic database will be provided for Core Lab to review and adjudicate 
images. Additional details related to the Core Lab are specified in the Core Lab 
Charter.  
The independent imaging core lab will review images from the Immediate Post 
Procedure and Final Follow-Up to assess at minimum occlusion grading. An imaging 
core lab charter will provide procedure for core lab review. Penumbra is responsible 
for tracking images received and basic quality review.   
12.  Study Administration 
12.1   Clinical Trial Termination/Withdrawal 
Subjects may be terminated or withdrawn from the study for the following reasons: 
• Voluntary withdrawal of consent–– meaning that a subject voluntarily chooses 
not to participate further in the study.  All data collected up to the withdrawal of 
consent will be maintained in the study database. Withdrawn subjects will not 
have any additional follow-up and will not be replaced. 
• Lost to follow-up–– a subject will be considered lost-to-follow-up when contact 
is not achieved at the last required follow-up visit window.  At a minimum, the 
effort to obtain follow-up information will include three (3) attempts to make 
contact via telephone or e-mail. These efforts to obtain follow-up will be recorded 
in the subject’s study files. 
• Subjects may also be withdrawn at the Investigator’s discretion if within their 
best interest. A subject’s participation in the clinical study will be terminated if 
the Investigator believes that this is in the subject’s best medical interest or if the 
subject no longer complies with the clinical study requirements 
The sponsor may temporarily suspend or prematurely terminate the study at any time 
for the following reasons: 
• Suspicion of risk to subjects 
• If no positive IRB/EC decision is obtained or if the judgement of the IRB/EC is 
revoked 
• If the applicable regulatory body has made an irrevocable objection 
• If it transpires that continuation of study cannot serve any scientific purpose, and 
this is confirmed by the IRB/EC 
• Business reasons  
The Sponsor will document reasons for study suspension or premature termination 
and notify the PIs. The Sponsor will ensure that the IRB/ECs and regulatory 
authorities are notified in a timely manner.  
The Sponsor will continue to provide resources to fulfil the obligations from the 
study protocol and existing agreements for following up the subjects enrolled in the 
study. 

 
 
 
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The Principal Investigators will promptly inform the enrolled subjects at his/her 
site, if appropriate. 
If the Sponsor temporarily suspends the study and wishes to resume it, the Sponsor 
will inform the PIs, IRB/ECs, and (if appropriate) regulatory authorities.  The 
Sponsor will provide a rationale for resuming the study.  IRB/ECs must provide 
written approval before the study is resumed. 
 
12.2 Missing Visits 
Every effort should be made to bring subject in to scheduled follow-up visits. Any 
study subject who does not attend a scheduled follow-up visit should be contacted by 
site personnel to reschedule. If the missed visit was due to a reportable adverse event, 
an AE CRF must be completed. 
12.3 Protocol Adherence and Amendments 
Prior to beginning the study, the Principal Investigator must sign the protocol 
signature page documenting his/her agreement to conduct the study in accordance 
with this protocol. Deviations outlined in section 7.6.4 from the protocol must be 
documented and reported to Penumbra as soon as possible, and to the IRB/EC per 
local guidelines and government regulations. 
12.4 Trial Registration 
The study will be registered in a publicly accessible trial database (e.g., clinical 
trials.gov) prior to study initiation. 
13.  Publication of Information 
All information and data generated in association with this study will be held in strict 
confidence and remain the sole property of the Sponsor. The Investigator agrees to use this 
information for the sole purpose of completing this study and for no other purpose without 
written consent from the Sponsor. 
The results of this study may be offered for publication. The investigators and the Sponsor 
shall collaborate in the writing of the study to ensure accuracy.  All information not 
previously published concerning the test device and research, including patent applications, 
manufacturing processes, basic scientific data, etc., is considered confidential and should 
remain the sole property of Penumbra.  The investigator agrees to use this information only 
in connection with this study and will not use it for other purposes without written 
permission from the Sponsor. 
 
 

 
 
 
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14.  Contact Information 
The address of Penumbra Incorporated is: 
Penumbra, Inc. 
One Penumbra Place 
Alameda, CA 94502 
Tel. (510) 748-3200 
Fax (510) 814-8305 
Key contacts for the Study include: 
 
 
  
 
 
  
 
 
 

 
 
 
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15. Bibliography 
1. 
Etminan, N. and G.J. Rinkel, Unruptured intracranial aneurysms: Development, rupture 
and preventive management. Nature Reviews Neurology, 2016. 12(12): p. 699-713. 
2. 
Brisman, J.L., J.K. Song, and D.W. Newell, Cerebral aneurysms. New England Journal 
of Medicine, 2006. 355(9): p. 928-939. 
3. 
Ramgren, B., M. Drake, and G. Andsberg, Aneurysm rupture during thrombectomy 
whattodo. Neuroradiology, 2017. 59(1): p. S97-S98. 
4. 
Rinkel, G.J.E., et al., Prevalence and risk of rupture of intracranial aneurysms: A 
systematic review. Stroke, 1998. 29(1): p. 251-256. 
5. 
Williams, L.N. and R.D. Brown, Jr., Management of unruptured intracranial aneurysms. 
Neurology. Clinical practice, 2013. 3(2): p. 99-108. 
6. 
Nishioka, H., J.C. Torner, and C.J. Graf, Cooperative study of intracranial aneurysms 
and subarachnoid hemorrhage: A long-term prognostic study. III. Subarachnoid 
hemorrhage of undetermined etiology. Archives of Neurology, 1984. 41(11): p. 1147-
1151. 
7. 
Keedy, A., An overview of intracranial aneurysms. McGill Journal of Medicine, 2006. 
9(2): p. 141-146. 
8. 
Molyneux, A., International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical 
clipping versus endovascular coiling in 2143 patients with ruptured intracranial 
aneurysms: a randomised trial. The Lancet, 2002. 360(9342): p. 1267-1274. 
9. 
Molyneux, A.J., et al., The durability of endovascular coiling versus neurosurgical 
clipping of ruptured cerebral aneurysms: 18 year follow-up of the UK cohort of the 
International Subarachnoid Aneurysm Trial (ISAT). The Lancet, 2015. 385(9969): p. 
691-697. 
10. 
Gawlitza, M., et al., Aneurysm Characteristics, Study Population, and Endovascular 
Techniques for the Treatment of Intracranial Aneurysms in a Large, Prospective, 
Multicenter Cohort: Results of the Analysis of Recanalization after Endovascular 
Treatment of Intracranial Aneurysm Study. AJNR. American journal of neuroradiology, 
2019. 40(3): p. 517-523. 
11. 
Broeders, J.A., et al., Bioactive versus bare platinum coils for the endovascular treatment 
of intracranial aneurysms: Systematic review and meta-analysis of randomized clinical 
trials. Journal of NeuroInterventional Surgery, 2016. 8(9): p. 898-908. 
12. 
Jaja, B.N.R., et al., Development and validation of outcome prediction models for 
aneurysmal subarachnoid haemorrhage: The SAHIT multinational cohort study. BMJ 
(Online), 2018. 360. 
13. 
Molyneux, A.J., et al., Cerecyte coil trial: Angiographic outcomes of a prospective 
randomized trial comparing endovascular coiling of cerebral aneurysms with either 
cerecyte or bare platinum coils. Stroke, 2012. 43(10): p. 2544-2550. 
14. 
Oudshoorn, S.C., et al., Aneurysm treatment <24 versus 24-72 h after subarachnoid 
hemorrhage. Neurocritical Care, 2014. 21(1): p. 4-13. 
15. 
Rezek, I., et al., Differences in the angiographic evaluation of coiled cerebral aneurysms 
between a core laboratory reader and operators: Results of the cerecyte coil trial. 
American Journal of Neuroradiology, 2014. 35(1): p. 124-127. 

 
 
 
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16. 
Scott, R.B., et al., Improved cognitive outcomes with endovascular coiling of ruptured 
intracranial aneurysms: Neuropsychological outcomes from the international 
subarachnoid aneurysm trial (ISAT). Stroke, 2010. 41(8): p. 1743-1747. 
17. 
Pierot, L., M. Gawlitza, and S. Soize, Unruptured intracranial aneurysms: management 
strategy and current endovascular treatment options. Expert Review of 
Neurotherapeutics, 2017. 17(10): p. 977-986. 
18. 
Slob, M.J., M. Sluzewski, and W.J. van Rooij, The relation between packing and 
reopening in coiled intracranial aneurysms: A prospective study. Neuroradiology, 2005. 
47(12): p. 942-945. 
19. 
Slob, M.J., W.J. Van Rooij, and M. Sluzewski, Coil thickness and packing of cerebral 
aneurysms: A comparative study of two types of coils. American Journal of 
Neuroradiology, 2005. 26(4): p. 901-903. 
20. 
Slob, M.J., W.J. Van Rooij, and M. Sluzewski, Influence of coil thickness on packing, 
reopening and retreatment of intracranial aneurysms: A comparative study between two 
types of coils. Rivista di Neuroradiologia, 2005. 18(SUPPL. 2): p. 39-43. 
21. 
Slob, M.J., W.J. Van Rooij, and M. Sluzewski, Influence of coil thickness on packing, re-
opening and retreatment of intracranial aneurysms: A comparative study between two 
types of coils. Neurological Research, 2005. 27(SUPPL. 1): p. S116-S119. 
22. 
Taschner, C.A., et al., Second-Generation Hydrogel Coils for the Endovascular 
Treatment of Intracranial Aneurysms: A Randomized Controlled Trial. Stroke, 2018. 
49(3): p. 667-674. 
23. 
White, P. and J. Du Plessis, Hydrocoil reduces recurrences but at what cost? 
Interventional Neuroradiology, 2011. 17: p. 146. 
24. 
White, P. and R. Sellar, HELPS Trial: angiographic primary trial results. 
Neuroradiology Journal, 2010. 23: p. 177. 
25. 
White, P.M., et al., HydroCoil Endovascular Aneurysm Occlusion and Packing Study 
(HELPS trial): Procedural safety and operator-assessed efficacy results. American 
Journal of Neuroradiology, 2008. 29(2): p. 217-223. 
26. 
Brinjikji, W., et al., Hydrocoils reduce recurrence rates in recently ruptured medium 
sized intracranial aneurysms: A subgroup analysis of the helps trial. Stroke, 2015. 46. 
27. 
Brinjikji, W., et al., HydroCoils reduce recurrence rates in recently ruptured medium-
sized intracranial aneurysms: A subgroup analysis of the HELPS trial. American Journal 
of Neuroradiology, 2015. 36(6): p. 1136-1141. 
28. 
Brinjikji, W., et al., HydroCoils are associated with lower angiographic recurrence rates 
than are bare platinum coils in treatment of "difficult-to-treat" aneurysms: A post hoc 
subgroup analysis of the HELPS trial. American Journal of Neuroradiology, 2015. 36(9): 
p. 1689-1694. 
29. 
Abi-Aad, K.R., et al., New generation Hydrogel Endovascular Aneurysm Treatment Trial 
(HEAT): a study protocol for a multicenter randomized controlled trial. Neuroradiology, 
2018. 60(10): p. 1075-1084. 
30. 
Ota, K., et al., Evaluation of the characteristics of various types of finishing coils for the 
embolization of intracranial aneurysms in an experimental model with radiolucent coils. 
Interventional Neuroradiology, 2017. 23(2): p. 143-150. 
31. 
Spiotta, et al., Progressively soft coils for treatment of intracerebral aneurysms-an initial 
experience with the smart coil at two centers. Journal of NeuroInterventional Surgery, 
2017. 9: p. A66-A67. 

 
 
 
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32. 
Stapleton, C.J., C.M. Torok, and A.B. Patel, Early experience with the Penumbra SMART 
coil in the endovascular treatment of intracranial aneurysms: Safety and efficacy. 
Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical 
procedures and related neurosciences, 2016. 22(6): p. 654-658. 
33. 
Padmanabhan, R., "smart" coils in the treatment of intracranial aneurysms-a 
retrospective audit of Results, device related complications and adverse events. Journal 
of NeuroInterventional Surgery, 2017. 9: p. A57. 
34. 
Padmanabhan, R., Endovascular treatment of very small intracranial aneurysms (< 3mm) 
with the extra soft smart (penumbra) coils-early experience. Journal of 
NeuroInterventional Surgery, 2017. 9: p. A60. 
35. 
Spiotta, A.M., et al., Initial Technical Experience with the SMART Coil for the 
Embolization of Intracranial Aneurysms. World Neurosurg, 2017. 97: p. 80-85. 
36. 
Ilyas, A., et al., SMART coils for intracranial aneurysm embolization: Initial outcomes. 
Clinical Neurology and Neurosurgery, 2018. 164: p. 87-91. 
37. 
Spiotta, A., et al., Interim analysis of the smart registry on the utility of the penumbra 
smart coil system in treatment of intracranial aneurysms and malformations. Stroke, 
2018. 49. 
38. 
Sokolowski, J.D., et al., SMART coils for intracranial aneurysm embolization: Follow-up 
outcomes. Journal of Clinical Neuroscience, 2019. 59: p. 93-97. 
39. 
Frei, D. et al., Utility of the Penumbra SMART COIL System in the Treatment of 
Intracranial Aneurysms and Malformations: Interim Analysis of the SMART Registry. 
Electronic Poster Abstract E-013, SNIS Annual Meeting, July 23-28, 2018, San 
Francisco, CA. Journal of Neurointerventional Surgery, 2018. 10:Suppl. 2. 
 

 
 
 
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16.2 Modified Rankin Scale 
0 
No Symptoms at all 
1 
No significant disability, despite symptoms; able to perform all 
usual duties and activities 
2 
Slight disability; unable to perform all previous activities but able 
to look after own affairs without assistance 
3 
Moderate disability; requires some help, but able to walk without 
assistance 
4 
Moderately severe disability; unable to walk without assistance and 
unable to attend to own bodily needs without assistance  
5 
Severe disability; bedridden; incontinent, and requires constant 
nursing care and attention 
6 
Death 
 
 
 

 
 
 
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16.3 Hunt and Hess Grading Scale 
Grade 
Clinical Features 
I 
No symptoms or minimal headache and slight nuchal 
rigidity 
II 
Moderate to severe headache, nuchal rigidity, and no 
neurologic deficit other than cranial nerve palsy 
III 
Drowsiness, confusion, or mild focal neurologic deficit 
IV 
Stupor, moderate to severe hemiparesis, possible 
decerebrate rigidity, and vegetative disturbances 
V 
Deep coma, decerebrate rigidity, and moribund 
appearance 
 
 
 

 
 
 
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16.4 Definitions  
16.4.1 Stroke 
An acute episode of focal or global neurological dysfunction due to brain or 
retinal infarction, or from any intracranial hemorrhage inclusive of subarachnoid, 
intraventricular or intraparenchymal hemorrhages with signs and symptoms that 
persist for 24 hours or more. The 24-hour criterion is excluded if the patient 
undergoes cerebrovascular surgery or dies during the first 24 hours. 
16.4.2 Major Ipsilateral Stroke 
Major ipsilateral stroke is an acute episode of focal or global neurological 
dysfunction due to brain or retinal infarction, or from any intracranial hemorrhage 
(ICH) inclusive of subarachnoid, intraventricular or intraparenchymal 
hemorrhages in the same hemisphere of the target aneurysm and which is 
associated with an increase of 4 or more points on the NIHSS at 24 hours after 
stroke onset. 
16.4.3 Intracranial Hemorrhage  
Bleeding in the cranium of the brain inclusive of subarachnoid, intraventricular or 
intraparenchymal hemorrhages, symptomatic or asymptomatic. A symptomatic 
intracranial hemorrhage is associated with a 4 or more points increase on the NIHSS 
from baseline. 
16.4.4 Morbidity  
Defined as mRS 3 to 5 or worsening of mRS from baseline by 2 points 
16.4.5  Perforation 
The piercing or rupturing of a blood vessel; perforations can be detected or 
observed angiographically. 
16.4.6 Dissection 
Angiographic evidence of a tear in the arterial wall as defined by the occurrence of 
intramural hematoma. 
16.4.7 Vasospasm 
Spasm of a blood vessel, resulting in prolonged decrease in lumen diameter. 
Symptomatic vasospasm is defined as the development of new focal neurological 
signs, deterioration in level of consciousness, or both, when the cause was felt to 
be ischemia attributable to vasospasm after other possible causes of worsening 
(for example, hydrocephalus, seizures, metabolic derangement, infection, or 
oversedation) had been excluded. 

 
 
 
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Figure 3: Classification of Angiographic Results 
 
 
Class 1 
Class 2 
Class 3 
Complete Obliteration 
Residual Neck 
Residual Aneurysm 
 
Adopted from Roy, Milot and Raymond. Stroke 2001;32:1998-2004 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1 
 
STATISTICAL ANALYSIS PLAN 
SURF: A Prospective, Multicenter Study Assessing the Embolization of 
Intracranial Aneurysms using WAVE™ Extra Soft coils, a part of the 
Penumbra SMART COIL® System 
Protocol CLP 13669 
 
 
Version 3.0 
 
 
 
 
 
 
 
 
 
 
 
 
 

2 
 
Contents 
1 
Overview ........................................................................................................................................ 3 
2 
Sample Size .................................................................................................................................. 3 
3 
Interim Analysis ............................................................................................................................. 4 
4 
Analysis Populations ..................................................................................................................... 4 
4.1 
Definitions .............................................................................................................................. 4 
5 
Statistical Methods ........................................................................................................................ 4 
6 
Baseline Characteristics ............................................................................................................... 5 
7 
Patient Disposition ........................................................................................................................ 5 
8 
Effectiveness Analysis .................................................................................................................. 5 
8.1 
Primary Effectiveness Analysis ............................................................................................ 5 
8.2 
Secondary Effectiveness Analysis ....................................................................................... 6 
8.3 
Imaging Outcomes Analysis ................................................................................................. 7 
8.4 
Economic Analysis ................................................................................................................ 7 
8.5 
Handling of Multiplicity .......................................................................................................... 8 
9 
Subgroup Analysis ........................................................................................................................ 8 
10 
Safety Analysis .......................................................................................................................... 9 
10.1 
Primary Safety Analysis ........................................................................................................ 9 
10.2 
Secondary Safety Analysis ................................................................................................... 9 
10.3 
Analysis of Adverse Events ................................................................................................ 10 
10.4 
Analysis of Deaths ............................................................................................................... 10 
11 
Pooling Across Centers .......................................................................................................... 10 
12 
Missing Data and Imputation Methods .................................................................................. 11 
13 
Changes to Planned Analyses ............................................................................................... 11 
14 
References............................................................................................................................... 12 
15 
Revision History ...................................................................................................................... 12 
 
 
 
 

3 
 
1 Overview 
SURF is a postmarket, real-world, prospective, multicenter single-arm study. Its objective is to 
demonstrate the safety and efficacy of the Penumbra SMART COIL® System, including the 
WAVE™ Extra Soft Coils (WAVE) as a fill and finish coil, in the treatment of intracranial 
aneurysms. An independent core lab will read images to assess aneurysm occlusion rates, 
facilitating an analysis on the sensitivity and specificity of MRA imaging to detect residual 
aneurysm blood flow at final follow-up as compared to DSA (Section 8.3 of this document). 
Approximately 800 patients will enroll at up to 60 global sites. Each site will be limited to a 
maximum enrollment of 120 patients (15% of total enrollment). An estimated 10% of enrolled 
patients will experience attrition by final follow-up. 
This Statistical Analysis Plan (SAP) elaborates on statistical methods outlined in the study 
protocol and presents analysis conventions. The SAP will be signed off prior to database lock. 
2 Sample Size 
Approximately 800 patients will enroll in this post-market study, resulting in 720 patients who 
achieve final follow-up after 10% anticipated attrition. This sample size provides adequate 
precision to estimate the primary effectiveness and safety endpoints. 
Primary Endpoint 
Assumption for 
Observed Rate[1] 95% CI[2] 
Precision 
Adequate occlusion defined as 
Raymond-Roy Occlusion Class I 
and II at final follow-up 
89% (320/360) 
86% to 92% 
Greater than ±3.5% 
89% (401/450) 
86% to 92% 
Greater than ±3% 
89% (481/540) 
86% to 92% 
Greater than ±3% 
89% (561/630) 
87% to 91% 
Greater than ±3% 
89% (641/720) 
87% to 91% 
Greater than ±3% 
Device-related SAE up to 7 days 
or discharge 
2.8% (11/400) 
1.1% to 4.4% 
Greater than ±2% 
2.8% (14/500) 
1.4% to 4.2% 
Greater than ±1.5% 
2.8% (17/600) 
1.5% to 4.2% 
Greater than ±1.5% 
2.9% (20/700) 
1.6% to 4.1% 
Greater than ±1.5% 
2.8% (22/800) 
1.6% to 3.9% 
Greater than ±1.5% 
SAEs within 24 hours post-
procedure 
9.0% (36/400) 
6.2% to 11.8% Greater than ±3% 
9.0% (45/500) 
6.5% to 11.5% Greater than ±2.5% 
8.8% (53/600) 
6.6% to 11.1% Greater than ±2.5% 
8.9% (62/700) 
6.8% to 11.0% Greater than ±2.5% 
8.9% (71/800) 
6.9% to 10.9% Greater than ±2.5% 
[1] Set at SMART CLP 10023 Registry interim observed results (data on file at sponsor) 
[2] Two-sided 95% Wald normal approximation binomial proportion confidence interval 
 

4 
 
3 Interim Analysis 
As there will be no interim analyses for the purpose of terminating the study early for success or 
futility, alpha adjustments will not be made to the confidence intervals in the final analysis. 
However, interim analysis may be performed for the purpose of publication or regulatory 
submission of SURF results. 
4 Analysis Populations 
4.1 Definitions 
The following analysis population definitions apply to this study: 
• 
Screened: All patients considered for participation in the study, whether or not they sign 
informed consent. 
• 
Screen Failure: All screened patients who failed to meet inclusion criteria or met 
exclusion criteria. Patients can be screen failed for general or procedure criteria. 
• 
Enrolled: All eligible patients who obtained informed consent, completed the index 
procedure, and have inclusion-exclusion criteria confirmed. 
• 
Intent-to-Treat (ITT): All enrolled patients. The primary analysis, including all 
effectiveness, safety, and subgroup reporting, will be run on this population. 
• 
Completed: All enrolled patients who completed the study follow-up or were known to 
have died prior to the follow-up. 
5 Statistical Methods 
Continuous variables will be summarized using the following descriptive statistics: N, Mean 
(SD), Median [IQR], Range (Min, Max). Categorical variables will be summarized using 
frequency counts and percentages of patients within each category. Confidence intervals will be 
reported for the following analyses only: effectiveness, safety, sensitivity, and change from 
baseline. Two-sided 95% confidence intervals will be reported using asymptotic intervals for 
continuous variables and Wald normal approximation binomial proportion intervals for 
categorical variables. 

5 
 
6 Baseline Characteristics 
Baseline characteristics, including demographics, clinical characteristics, and angiographic 
characteristics, will be summarized using descriptive statistics for continuous variables and 
using frequency counts and percentages for categorical variables. 
7 Patient Disposition 
To summarize patient disposition outcomes, the number of patients in the following analysis 
populations will be recorded: 
 
● Screen Failure 
● Enrolled 
● Intent-to-Treat (ITT) 
● Completed 
The number of patients who do not complete the study will be reported as well, broken down by 
their reasons for discontinuation. 
8 Effectiveness Analysis 
8.1 Primary Effectiveness Analysis 
For the primary effectiveness endpoint, frequency counts, percentages, and two-sided 95% 
Wald confidence intervals will be reported using the ITT population: 
• 
Adequate occlusion defined as Raymond-Roy Occlusion Class I and II at final 
follow-up: The percentage of patients assessed as Raymond-Roy Class I or II out of 
patients who had a Raymond-Roy evaluation done (Class I, II, or III) at the time of final 
follow-up. Retreatments at final follow-up will be modelled as Raymond-Roy Class III. 
The core lab data supersede the investigator-reported data in primary and secondary 
effectiveness analyses. 

6 
 
8.2 Secondary Effectiveness Analysis 
For the secondary effectiveness endpoints, frequency counts, percentages, and two-sided 95% 
Wald confidence intervals will be reported using the ITT population: 
• 
Immediate post-procedure occlusion rate: The percentage distribution of patients 
assessed as each of Raymond-Roy Class I, Class II, and Class III out of patients who 
had a Raymond-Roy evaluation done (Class I, II, or III) at immediate post-procedure. 
• 
Retreatment rate at final follow-up: The percentage of patients who had the target 
aneurysm retreated since the index procedure out of patients who have data on this 
question (Retreatment, No Retreatment) at the time of final follow-up. Staged 
procedures are not retreatments for the purposes of running all SURF study analyses.  
• 
Aneurysm Occlusion Raymond I post treatment: The percentage of patients 
assessed as Raymond-Roy Class I out of patients who had a Raymond-Roy evaluation 
done (Class I, II, or III) at immediate post-procedure. 
• 
Aneurysm Occlusion Raymond I at final follow-up: The percentage of patients 
assessed as Raymond-Roy Class I out of patients who had a Raymond-Roy evaluation 
done (Class I, II, or III) at the time of final follow-up. Retreatments at final follow-up will 
be modelled as Raymond-Roy Class III. 
• 
Aneurysm recanalization or progressive thrombosis from post procedure to final 
follow-up: The percentage of patients who experienced a deterioration in Raymond-Roy 
Occlusion Grading (aneurysm recanalization; Class I becoming II or III, or Class II 
becoming III) or improvement in Raymond-Roy occlusion (progressive thrombosis; Class 
II becoming I, or Class III becoming I or II) out of patients who had a Raymond-Roy 
evaluation done at both time points. Retreatments at final follow-up will be modelled as 
aneurysm recanalization. 
The effectiveness endpoints will be reported using only the Raymond-Roy Occlusion Grading 
Scale. However, frequency counts, percentages, and two-sided 95% Wald confidence intervals 
will also be provided for the Meyers Consensus Grading Scale Grades 0, 1, 2, 3, 4, and 5 at 
immediate post-procedure and final follow-up, using the ITT population and core lab data. 
Aneurysm packing densities will be reported as the coil volume of all Penumbra and non-
Penumbra coils implanted divided by the aneurysm volume as measured by the core lab, based 
on two-dimensional geometric modeling as the primary analysis and the ABC method as a 
supplemental analysis. 

7 
 
8.3 Imaging Outcomes Analysis 
DSA is the reference standard imaging modality for aneurysm assessment after coiling, but 
MRA imaging is safer for patients and less expensive. Therefore, an imaging outcomes analysis 
will assess how successfully MRA scans detect residual aneurysm blood flow at final follow-up 
as compared to DSA scans, based on sensitivity, specificity, and related summary measures. 
For each of Raymond-Roy Class II to III (any residual flow), Class II (residual neck), and Class 
III (residual aneurysm) at the time of final follow-up, the following statistics will be reported using 
the ITT population and core lab data: 
• 
Sensitivity: The proportion of true positives (patients belonging to each of the three 
Raymond-Roy groups above on DSA) that are correctly identified as such on MRA as 
well. The percentages of patients assessed as each of Raymond-Roy (1) Class II to III, 
(2) Class II, and (3) Class III on MRA and DSA out of patients with the same Raymond-
Roy group assessed on DSA at the time of final follow-up will be computed. 
• 
Specificity: The proportion of true negatives (patients not belonging to each of the three 
Raymond-Roy groups above on DSA) that are correctly identified as such on MRA as 
well. The percentages of patients assessed as each of Raymond-Roy (1) Class I, (2) 
Class I or Class III, and (3) Class I to II on MRA and DSA out of patients with the same 
Raymond-Roy group assessed on DSA at the time of final follow-up will be computed. 
• 
Positive likelihood ratio (LR): Sensitivity divided by (1 - Specificity). 
• 
Negative likelihood ratio (LR): (1 - Sensitivity) divided by Specificity. 
• 
Cohen’s κ: Summary measure of agreement between DSA and MRA in detecting each 
of Raymond-Roy Class II and III, Class II, and Class III. 
As a secondary comparison, this analysis will be repeated using each of Meyers Consensus 
Grading Scale Grades 1 to 5 (any residual flow), Grade 1 (90% or greater aneurysm occlusion), 
Grade 2 (70-89% aneurysm occlusion), Grade 3 (50-69% aneurysm occlusion), Grade 4 (25-
49% aneurysm occlusion), and Grade 5 (Less than 25% aneurysm occlusion). 
8.4 Economic Analysis 
Frequency counts and percentages will be reported for the following healthcare utilization data: 
• 
Devices used: Access guide catheters, microcatheters, and Penumbra coils 
• 
Follow-up and additional follow-up clinic and office visits 

8 
 
• 
Follow-up and additional follow-up DSA, MRA, and CTA scans 
The healthcare utilization information will be used to estimate healthcare costs. 
8.5 Handling of Multiplicity 
There will be no adjustment for multiplicity in SURF study reporting. 
9 Subgroup Analysis 
The following subgroup analyses will be performed for all primary and secondary effectiveness 
and safety endpoints using the ITT population: 
• 
Adjunctive technology used during treatment: Balloon, Stent, Other, None 
• 
Age at time of informed consent (years): < 65, ≥ 65 
• 
Sex: Female, Male 
• 
Ethnicity: Hispanic or Latino, Not Hispanic or Latino 
• 
Race: American Indian or Alaska Native, Asian, Black or African American, White, Other 
• 
Site country: North America (US/Canada), Europe 
• 
Target aneurysm location: Extradural ICA, ICA, ACA, MCA, Posterior Circulation, 
Other 
• 
Target aneurysm size: Small (≤ 5 mm at its largest diameter), Medium (6 to 14 mm at 
its largest diameter), Large (15 to 24 mm at its largest diameter), Giant (≥ 25 mm at its 
largest diameter) 
• 
Target aneurysm status: Ruptured, Unruptured 
• 
Target aneurysm anatomical location: Bifurcation, Sidewall, Other 
• 
Neck width: Small-Neck (< 4 mm Neck Width), Wide-Neck (≥ 4 mm Neck Width or 
Dome-to-Neck Ratio (defined as the maximum of dome width, depth, and height divided 
by neck width) < 2) 
• 
Target aneurysm previously treated: Previous Treatment at Admission, No Previous 
Treatment at Admission 
Descriptive statistics and two-sided 95% Wald confidence intervals will be presented for each 
subgroup. 

9 
 
10 Safety Analysis 
10.1  Primary Safety Analysis 
For the primary safety endpoints, frequency counts, percentages, and two-sided 95% Wald 
confidence intervals will be reported using the ITT population: 
• 
SAEs up to 24 hours post-procedure: The percentage of patients who experience 
serious adverse event(s) with start date on the date of procedure (day 0) or the next 
calendar day. 
• 
Device-related SAE up to 7 days or discharge: The percentage of patients who 
experience serious adverse event(s) with probable or definite relationship to the SMART 
Coil System from the date of procedure (day 0) through the date of discharge or seven 
calendar days from the date of procedure, whichever occurs earlier. 
10.2  Secondary Safety Analysis 
For the secondary safety endpoints, frequency counts, percentages, and two-sided 95% Wald 
confidence intervals will be reported using the ITT population: 
• 
Major ipsilateral stroke: The percentage of patients who experience major ipsilateral 
stroke adverse event(s), as defined in the SURF study protocol. 
• 
Device related SAE at final follow-up: The percentage of patients who experience 
serious adverse event(s) with probable or definite relationships to the SMART Coil 
System from the date of procedure (day 0) through the final follow-up visit at 1 Year ± 90 
Days from the date of procedure. 
• 
All-cause morbidity and mortality: The percentage of patients who experience either 
of the following events: 
o All-cause morbidity: mRS 3 to 5 at the final follow-up evaluation or worsening 
of mRS by 2+ points the date of procedure (day 0) through the final follow-up visit 
at 1 Year ± 90 Days from the date of procedure. If the final follow-up mRS is 
missing, mRS as assessed at the 7-day and/or discharge visit will be substituted. 
o All-cause mortality: Death for any reason from the date of procedure (day 0) 
through calendar day 365 
Adverse events occurring after the final follow-up visit at 1 Year ± 90 Days and deaths occurring 
after day 365 will be separately tabulated and not included in endpoint and adverse event rates. 

10 
 
10.3 Analysis of Adverse Events 
In the SURF study, only device-related or procedure-related adverse events and serious 
adverse events (SAEs) will be collected from procedure through discharge. After discharge, only 
neurological SAEs will be collected. Additional information for Symptomatic Intracranial 
Hemorrhage and Ischemic Stroke will be collected on Event of Interest case report forms. 
Frequency counts and percentages will be provided for all reportable adverse events and 
broken down as well based on relationships to the device and procedure. Reportable adverse 
event data will be listed for each patient, including the type of event/verbatim term, start date, 
seriousness, action taken, outcome, and causality (if appropriate). The onset of adverse events 
will also be shown relative (in number of days) to the date of procedure. 
The specific categories analyzed will be those that are reported by at least three (3) percent of 
the patients. As there is no CEC for this study, all adverse events will be reported based on the 
assessment from the clinical study sites. 
10.4  Analysis of Deaths 
Survival estimates will be used to evaluate the time-to-event using the Kaplan-Meier product-
limit method for deaths through 365 days. With the date of procedure set at day 0, any event 
occurring on or before day 365 will be included. If clinical assessment is missing for a patient 
who has not died, the patient will be censored at the last follow-up date. Patients who are alive 
at day 365 will be censored at day 365. The time to death will be plotted with 95% confidence 
intervals.  
Additionally, the frequency and percentage of deaths for any reason (all-cause mortality) will be 
presented with the two-sided 95% Wald confidence interval. 
11 Pooling Across Centers 
Analyses will be presented using data pooled across centers. The primary and secondary 
effectiveness and safety endpoints will be presented by study site to assess any potential site 
effects. 
Pooling analyses will be conducted across study sites on the primary effectiveness and primary 
safety endpoints. Fisher’s exact test (univariate analysis) and stepwise binary logistic regression 

11 
 
on study site, adjusted for key baseline and other appropriate variables (multivariate analysis), 
will be used. The multivariate results will take precedence in testing for site heterogeneity. 
To assess the validity of pooling North America (US/Canada) and Europe sites, logistic 
regression models will be used for the primary effectiveness and primary safety endpoints. 
Stepwise multivariate binary logistic regression models with geographic location (North America 
(US/Canada versus Europe), study site, and a subset of key baseline and procedural predictors 
will be used for each primary endpoint to test for heterogeneity across geographic locations.  
Wald odds ratios of the treatment effects for geographic location and study site will be 
presented with two-sided p-values to test whether the odds ratios equal 1. Centers enrolling 
three or fewer patients will be eliminated from all pooling analyses. 
12 Missing Data and Imputation Methods 
The primary analysis will be data as observed, in which results are reported using the data that 
are available without imputing missing values. 
As sensitivity analyses, the primary effectiveness and primary safety endpoints will be 
recomputed using the ITT population after imputing missing data: 
• 
Imputation using baseline scores (run for primary effectiveness only) 
• 
Imputation using the worst clinical scenario, assuming the subject was assessed as 
Raymond-Roy Class III at the time of final follow-up (effectiveness) or experienced a 
primary safety event (safety) 
• 
Imputation using the best clinical scenario, assuming the subject was assessed as 
Raymond-Roy Class I and II at the time of final follow-up (effectiveness) or did not 
experience a primary safety event (safety) 
13 Changes to Planned Analyses 
All changes to this Statistical Analysis Plan (SAP) will be documented in a revised SAP or the 
clinical study report. 
 

12 
 
14 References 
Agresti A (2013). Categorical data analysis. John Wiley & Sons. 
CLP SURF – SURF: A Prospective, Multicenter Study Assessing the Embolization of 
Neurovascular aneurysms using WAVE™ Extra Soft coils, a part of the Penumbra SMART 
COIL® System. 13669 protocol. 
Hosmer DW, Lemeshow S, and May S (2008). Applied survival analysis: regression modeling of 
time-to-event data (Vol. 618). Wiley-Interscience. 
Meyers PM, et al (2010). Reporting standards for endovascular repair of saccular intracranial 
cerebral aneurysms. American Journal of Neuroradiology, 31(1), E12-E24. 
Roy D, Milot G, and Raymond J (2001). Endovascular treatment of unruptured aneurysms. 
Stroke, 32(9), 1998-2004. 
CLP SMART – A prospective, multicenter registry assessing the embolization of neurovascular 
lesions using the Penumbra SMART COIL® System. 10023 protocol. 
van Amerongen MJ, et al (2014). MRA versus DSA for follow-up of coiled intracranial 
aneurysms: a meta-analysis. American Journal of Neuroradiology, 35(9),1655-1661. 
Woodward K and Forsberg DA (2013). AngioSuite: an accurate method to calculate aneurysm 
volumes and packing densities. Journal of Neurointerventional Surgery, 5(Suppl 3), iii28-iii32. 
15 Revision History 
Version 
Prepared By 
Description of Changes 
1.0 
Sam Watcha 
Initial Release 
2.0 
Sam Watcha 
Updated number of sites, 
subgroup analysis, and 
pooling analysis to reflect 
global site enrollment under 
protocol revision C 
Updated sample size and 
endpoint definitions 
3.0 
Sam Watcha 
Added sample size scenarios 
to Section 2. Sample Size