ACE: An Aneurysm Coiling Efficiency Study of the Penumbra Coil 400 System
Phase: NA
Conditions: Intracranial Aneurysms, Peripheral Aneurysms
Sponsor: Penumbra Inc.

 
 
 
 
 
 
 
ACE: An Aneurysm Coiling Efficiency Study of the 
Penumbra Coil 400 System 
 
 
 
Protocol  
CLP 4492.D 
 
Date of Protocol 
November 10, 2011 
 
 
Device Name 
Penumbra Coil 400™ System 
 
 
Sponsor 
Penumbra, Inc. 
1351 Harbor Bay Parkway 
Alameda, CA 94502 
USA 
 
 
 
Contact Person 
Malia McPherson 
Telephone: 
510-748-3294 
Fax: 
510-814-8305 
E-mail: 
malia.mcpherson@penumbrainc.com 
 
 

 
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TABLE OF CONTENTS 
Contents 
1. 
PROTOCOL SYNOPSIS ................................................................................................ 4 
2. 
INTRODUCTION ........................................................................................................... 5 
3. 
STUDY OVERVIEW ...................................................................................................... 7 
4. 
STUDY PROCEDURES ................................................................................................. 9 
5. 
INVESTIGATOR RESPONSIBILITIES ...................................................................... 9 
6. 
SPONSOR RESPONSIBILITIES .................................................................................12 
7. 
CONTACT INFORMATION ........................................................................................14 
8. 
ETHICAL REQUIREMENTS ......................................................................................14 
9. 
STATISTICAL PROCEDURES ...................................................................................15 
10. 
PUBLICATION OF INFORMATION .........................................................................16 
11. 
BIBLIOGRAPHY ...........................................................................................................17 
 
 

 
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1. 
PROTOCOL SYNOPSIS 
 
CLP 4492 Protocol Synopsis 
Study Title: 
ACE: An Aneurysm Coiling Efficiency Study of  
the Penumbra Coil 400 System   
Objective: 
The primary objective of this study is to gather post market data on the Penumbra Coil 
400 (PC 400) System in the treatment of intracranial aneurysms, peripheral aneurysms 
and other malformations.  
Study Design: 
This study is a prospective, multi-center study of patients with intracranial aneurysms, 
peripheral aneurysms or other malformations who are treated by the PC 400 System. 
Data for each patient are collected up to 6 months post-procedure for the study. Long 
term follow-up to one year may also be conducted in accordance to the standard of care 
at each participating hospital at the discretion of the investigators.  
Patient 
Population: 
Approximately 2,000 patients with intracranial aneurysms, peripheral aneurysms or 
other malformations treated by the PC 400 System at up to 100 centers will be 
enrolled.  Each center must have had prior experience with endovascular embolization 
by the PC 400 System before being able to enroll patients. This is defined as having 
treated at least 5 patients according to the cleared indication for use, either before or 
after IRB/EC approval (roll-in). Roll-in patients will not be part of the study.     
Sample Size 
Justification: 
Approximately 2,000 patients will be enrolled.   With this sample size the precision is 
greater than ± 2.5% for the procedural device-related serious adverse event rate based 
on a binomial 95% confidence interval. Hence, the sample size provides a sufficient 
level of precision for the primary endpoint. 
Inclusion 
Criteria: 
Patients enrolled in this study must be those treated according to the cleared indication 
for the PC 400 System which is for the endovascular embolization of: 
1. Intracranial aneurysms 
2. Other neurovascular abnormalities such as arteriovenous malformations and 
arteriovenous fistulae 
3. Arterial and venous embolizations in the peripheral vasculature 
Exclusion 
Criteria: 
Patients in whom endovascular embolization therapies other than Penumbra Coils are 
used will be excluded from this study. However, adjunctive use of balloon and stent are 
acceptable.   
Primary 
Endpoint: 
1. Packing density with the number of coils implanted 
2. Time of fluoroscopic exposure 
3. Procedural device-related serious adverse events at immediate post-procedure 
4. Occlusion of the aneurysm sac at 6 months post-procedure  
Secondary 
Endpoints: 
1. Acute occlusion of the aneurysm sac at immediate post-procedure 
2. Intracranial hemorrhage at discharge or 3 days post-procedure 
Study Period: 
It is anticipated patient enrollment will take 3 years.  Patients will be followed up to 6 
months after the procedure for the study, and it may be up to one year in accordance to 
the standard of care at each participating hospital at the discretion of the investigators.  

 
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2. 
INTRODUCTION 
 
Intracranial aneurysms are a significant health problem in the United States with 
an estimated 1% to 6% of the adult population harboring cerebral aneurysms.1,2  
The annual risk of rupture of an intact intracranial aneurysm is estimated to be 
approximately 1.9%.2 If an intracranial aneurysm ruptures, blood leaks into the 
highly sensitive subarachnoid space around the brain, resulting in a subarachnoid 
hemorrhage (SAH). SAH is known to be a major risk factor for a stroke due to the 
irritation of the outer layer of the nearby blood vessels surrounding the brain.  
This condition is associated with a high rate of mortality; close to half of ruptured 
aneurysms result in death within six months.2-4 Patients who survived the initial 
SAH are at significant risk of subsequent re-rupture.  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.4,5 
 
Even if an intracranial aneurysm does not rupture, it can lead to severe 
complications.  As the aneurysm grows, it can press on nerves, put pressure on 
brain tissue, or interfere with other arteries or veins. Blindness, paralysis, and 
other morbidities often result. Thrombus can also form within the aneurysmal sac, 
break off, travel downstream, and cause an ischemic stroke. It has been reported 
that 2.2% to 23% of patients with unruptured aneurysms may eventually 
experience a rupture.7,8 The International Study of Unruptured Intracranial 
Aneurysms evaluated the natural history of 1,937 unruptured aneurysms in 1,449 
patients with a mean follow-up of 8.3 years.8 It reported that 2.2% of these 
patients had a confirmed rupture during follow-up, but 66% of them were fatal.  
Juvela et al. reported on the long term natural history of unruptured intracranial 
aneurysms in a series of 142 patients.7 With a median follow-up of 19.7 years, 
23% of the patients experienced a SAH, which corresponds to an annualized rate 
of 1.3%. The cumulative rate of SAH tended to increase with time, with a rupture 
rate of 10.5% at 10 years, 23% at 20 years, and 30.3% at 30 years after diagnosis. 
Approximately half of the SAH patients did not survive. Thus, regardless of the 
rate of occurrence, fatality associated with this event is high in this cohort.7, 8 
 
Prior to 1995, the traditional treatment for intracranial aneurysms was surgical 
clipping, in which the skull is surgically opened so metal clips can be applied to 
the aneurysm’s neck to occlude it from the parent artery to prevent a rupture.1 
This treatment, while effective, is high risk, highly invasive, requires an extended 
hospital convalescence, and is technically difficult to perform in certain regions of 
the brain (such as the posterior circulation).  Thus, this treatment modality is not a 
viable option for a significant number of patients, particularly during the acute 
phase of SAH, when the presence of cerebral edema and evolving thrombi 
formation render aneurysm access difficult, if not impossible. 
  
In the early 1990’s, an endovascular treatment technique for intracranial 
aneurysms was first introduced by Guido Guglielmi, who used electrolytically 
detachable platinum coils to pack and embolize the aneurysmal sac.9, 10 The 

 
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rationale was to exclude the aneurysm from the circulation and thus reduce the 
risk of a rupture and SAH.  The Guglielmi detachable coil (GDC) was not 
universally accepted at first but gained significant credibility after obtaining 
approval from the FDA for the intracranial aneurysm indication.  Moreover, a few 
well-conducted, prospective, randomized studies of both ruptured and unruptured 
aneurysms have demonstrated that angiographic and clinical outcomes from this 
treatment modality were equivalent, if not better, than those obtained from 
surgical clipping.6,8,11,12 Results were found to be similar for both treatments 
regardless of the inter-study differences in definitions for these outcome 
measures.6,8,11,12 The most important landmark study was the International 
Subarachnoid Aneurysm Trial (ISAT) in which a total of 2,143 patients with 
ruptured intracranial aneurysms were randomized to either neurosurgical clipping 
or endovascular GDC coiling. The results showed that at one year follow-up, 
30.6% of the patients treated by neurological clipping were either functionally 
dependent or dead as vs. 23.7% of those treated by GDC coiling, which resulted 
in a risk reduction rate of 22.6%. And thus, embolic coiling has now become the 
standard of care worldwide for endovascular occlusion for both incidental and 
ruptured intracranial aneurysms.   
 
In light of the natural history of the disease, the primary focus for management of 
an intracranial aneurysm must be to prevent its rupture and sequelae.   
 
The Penumbra Coil 400 (PC 400) System is a new generation of detachable coils 
developed by Penumbra Inc. It has recently received the CE Mark in Europe and 
is 510k cleared in the U.S. This coil system is specifically designed to promote 
aneurysm healing that is equivalent to standard platinum coils.  This System 
consists of: an implantable Coil attached to a Detachment Pusher as well as a 
Detachment Handle. The Detachment Pusher is comprised of a shaft with a 
radiopaque positioning marker, a Distal Detachment Tip, and a pull wire. The 
Detachment Handle is used to detach the Coil Implant from the Detachment 
Pusher. The PC 400 is designed for endovascular embolization in the neural and 
peripheral vasculature. Intended users for this device are physicians who have 
received appropriate training in interventional radiology.  
  
The Penumbra Embolization Coil is indicated for the endovascular embolization 
of aneurysms. The Embolization Coil functions to selectively embolize aneurysms 
by packing a sufficient quantity of soft platinum coils to achieve occlusion. The 
Coil Implant is constructed of 92% Platinum and 8% Tungsten round wire with a 
diameter approximately 0.0015in ± 0.0001in. The maximum primary diameter is 
0.022in and the coil implant will have a semi-spherical atraumatic distal tip.  
 
The Coil Implant is available in a standard Frame configuration, a soft Fill 
configuration, a Soft Fill/Finish configuration, and an Extra Soft Fill/Finish 
configuration.   
 

 
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The Frame Coil Implant is a three dimensional complex shape that follows the 
contours of the aneurysm surface and frames the inner surface of an aneurysmal 
sac when sized appropriately. The distal-most loop of a Frame Coil Implant is 
sized to prevent the coil from herniating into the parent vessel. The Implant is 
available in sizes to treat aneurysms in the 3-32mm diameter range and its 
stiffness must allow for atraumatic interaction with the aneurysm wall. 
 
The Fill Coil Implant has a three dimensional complex shape that conforms to the 
size and shape of empty space within an aneurysm. The Fill Coil Implant is 
available in sizes to treat aneurysms in the 3-24mm diameter range. The Fill Coil 
Implant’s stiffness must allow for atraumatic interaction with the aneurysm wall. 
The distal-most loop of a Fill Coil Implant is sized to prevent the coil from 
herniating into the parent vessel.  
 
The Soft Fill/Finish Coil Implant is a straight coil that will allow it to conform to 
empty space within an aneurysm with no preferential shape. The Soft Fill/Finish 
Coil Implant has a J-shaped tip to allow for atraumatic interaction with an 
aneurysm and its stiffness must allow for atraumatic interaction with the 
aneurysm wall. The Soft Fill/Finish Coil Implant fills small empty pockets within 
an aneurysm.   
 
The Extra Soft Fill/Finish Coil Implant is either a helical shape or complex shape 
coil that will allow it to conform to empty space within an aneurysm. The Extra 
Soft Fill/Finish Coil Implant’s stiffness allows for atraumatic interaction with the 
aneurysm wall.  
 
3. 
STUDY OVERVIEW 
 
The primary objective of this study is to gather post market data on the Penumbra 
Coil 400 (PC 400) System in the treatment of intracranial aneurysms, peripheral 
aneurysms and other malformations. 
 
3.1 
Study Design 
 
This study is a prospective, multi-center study of patients with intracranial 
aneurysms, peripheral aneurysms or other malformations who are treated by the 
PC 400 System. Data for each patient are collected up to 6 months post-procedure 
for the study.  It may also be collected up to one year in accordance to the 
standard of care at each hospital at the discretion of the investigators.  
 
3.2 
Study Objectives/Endpoints 
 
The primary objective of this study is to gather post market data on the PC 400 
System in the treatment of intracranial aneurysms, peripheral aneurysms, and 
other malformations. 
 

 
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Approximately 2,000 patients with intracranial aneurysms, peripheral aneurysms, 
or other malformations treated by the PC 400 System at up to 100 centers will be 
enrolled.  Each center must have had prior experience with endovascular 
embolization by the PC 400 System before being able to enroll patients. This is 
defined as having treated at least 5 patients according to the cleared indication for 
use, either before or after IRB/EC approval (roll-in). Roll-in patients will not be 
part of the study.    
  
3.2.1 The Primary Endpoints are: 
 Procedural device-related serious adverse events at immediate 
post-procedure 
 Occlusion of the aneurysm sac at 6 months post-procedure 
based on the classification by Roy, Milot and Raymond.13 
 
 
3.2.2 The Secondary Endpoints are:  
 
 Acute occlusion of the aneurysm sac at immediate post-
procedure 
 Intracranial hemorrhage at discharge or 3 days post-procedure 
 
3.3 
Study Population 
 
Patients enrolled in this study must be those treated according to the cleared 
indication for the PC 400 System in the Instructions for Use. Each center must 
have had prior experience with endovascular embolization by the PC 400 System 
before being able to enroll patients. This is defined as having treated at least 5 
patients according to the cleared indication for use, either before or after IRB/EC 
approval (roll-in). Roll-in patients will not be part of the study.    
 
3.3.1. Inclusion Criteria 
 Arterial and venous embolizations in the peripheral vasculature   
 
3.3.2. Exclusion Criteria 
 
Patients in whom endovascular embolization therapies other than 
PC 400 System are used will be excluded from this study. 
However, adjunctive use of balloon and stent are acceptable.   
 
 Packing density with the number of coils implanted 
 Time of fluoroscopic exposure 
 Intracranial aneurysms 
 Other neurovascular abnormalities such as arteriovenous 
malformations and arteriovenous fistulae 

 
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4. 
STUDY PROCEDURES 
 
All study procedures are to be conducted in accordance with the PC 400 System 
Instructions for Use. 
  
SCHEDULE OF ASSESSMENTS 
* Includes blood pressure and heart rate. 
 + Whichever is sooner.  
++ At the discretion of the investigators in accordance to the standard of care at the participating hospitals. 
** + 30 Days 
 
5. 
INVESTIGATOR RESPONSIBILITIES 
 
5.1 
Institutional Review Board Approval / 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.  
The IRB/EC shall approve all study documents, including the final protocol, 
amendments to the protocol, and the informed consent.   
 
5.2 
Informed Consent 
 
The investigator is responsible for ensuring that the study is conducted according 
to this protocol and that a signed informed consent is obtained according to 
national and state requirements prior to inclusion of patients in the study. 
 
5.3 
Adherence to Protocol/Amendments 
 
The investigator shall approve and adhere to this protocol and any amendments 
that arise during the course of the study.  Any deviations to the protocol shall be 
discussed with Penumbra prior to implementation, where possible, and shall be 
documented on the appropriate case report form.   
Assessment 
Admission 
Evaluation 
Immediate 
Post-
Procedure 
3 days Post-
Procedure or 
Discharge+ 
6 months 
Post-
Procedure** 
1 year Post-
Procedure** 
History 
√ 
 
 
 
 
Imaging 
√ 
√ 
 
 
 
Physical Exam* 
√ 
 
√ 
 
 
Modified Rankin Scale 
√ 
 
 
√ 
√++ 
Packing Density 
 
√ 
 
 
 
Aneurysm Occlusion13 
 
√ 
 
√ 
√++ 
Procedure Time 
 
√ 
 
 
 
Adverse Events 
 
√ 
√ 
√ 
√++ 
Retreatment 
 
 
 
√ 
√++ 

 
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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 the confidentiality statement. 
 
5.4 
Case Report Form Completion 
 
The investigator and study staff shall complete the case report forms (CRFs) 
associated with this study.  Patient numbers shall be used to identify individual 
patients in this study.  The CRFs should be a complete and accurate record of 
patient data collected during the study consistent with Good Clinical Practices 
(GCP) requirements.  It is the investigator's responsibility to ensure the quality of 
the data collected and recorded. 
 
5.5 
Reports 
 
The investigator will be responsible for the following reports: 
 
Protocol Deviation 
 
If the medical condition of patients requires deviation from the protocol, the 
investigator must contact the Clinical Research Associate and/or Sponsor as soon 
as possible to obtain advice on whether or not the patient is to participate in the 
study. Any protocol deviation must be clearly documented. 
 
Adverse Event Reporting 
 
An Adverse Event is any undesirable clinical event occurring to a patient, during 
a clinical trial, whether or not it is considered related to the investigational 
product. This includes a change in a patient's condition or laboratory results which 
has or could have a deleterious effect on the patient's health or well-being. 
 
Any Adverse Device Effect is any Adverse Event related to the investigational 
device. All Adverse Events or Adverse Device Effects should be recorded by the 
investigator in the Case Report Forms. They have to be carefully monitored 
during the entire study. 
 
A Serious Adverse Event is an event that:  
a) Led to death 
b) Led to a serious deterioration in the health of the patient that: 
 Resulted in life-threatening illness or injury 
 Resulted in permanent impairment of a body structure or a body 
function 
 Required in-patient hospitalization or prolongation of existing 
hospitalization 

 
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 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 
 
Minimum requirements of data to be recorded are:  type of event, duration of 
adverse event or adverse device effects (start through end), severity, seriousness, 
action taken, outcome and, if appropriate, causality. 
 
The Investigator will report any serious adverse event or adverse device effect to 
the Sponsor or its designee as soon as possible, but no later than 24 hours after the 
event is known.  All serious adverse events or serious device effects must be 
documented on the Serious Adverse Events form along with an explanation of any 
medical treatment administered.  The form must be completed, signed, and sent 
by fax or overnight courier to the Sponsor or its designee within five working 
days.  This report must be followed by full written documentation. 
 
An event need not be reported as a Serious Adverse Event if it represents only a 
relapse or an expected change or progression of the condition that was the cause 
of treatment without any other symptoms and signs than those present before 
treatment. This type of event need only be reported as an Adverse Event. 
 
When appropriate, the IRB/EC shall be informed by the investigator about serious 
adverse events and adverse device effects associated with the use of the product, 
and Penumbra is responsible for informing the Health Authorities and other 
investigators of such events as appropriate. 
 
5.6 
Withdrawal of Approval 
 
The investigator shall report to Penumbra immediately if, for any reason, the 
approval to conduct the investigation is withdrawn by the IRB/EC. The report will 
include a complete description of the reason(s) for which approval was 
withdrawn. The investigator shall submit all reports in a timely manner. 
 
5.7 
Records Retention 
 
The investigator shall maintain the records associated with this study for a period 
of at least two years after the date on which the investigation is completed.  These 
records include the following: 
 
 Correspondence with the Sponsor or designee, the Medical Monitor, and other 
investigators. 
 Patient Records, including Informed Consent Forms, copies of all completed 
CRFs, and supporting documents. 
 Current study protocol with dates and details of reasons for any deviations 
from the protocol that could affect the scientific quality of the study or the 
rights, safety, or welfare of the patients. 

 
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 Instructions for Use 
 Reports of any serious adverse event or adverse device effects. 
 A copy of all approvals related to the clinical investigation. 
 The approved, blank, informed consent form and blank CRFs. 
 Certification that the investigational plan has been approved by the IRB/EC. 
 Signed Agreements and current signed and dated curriculum vitae of the 
Study Investigator and all participating investigators. 
 
 
6. 
SPONSOR RESPONSIBILITIES 
 
6.1 
Training 
 
During study initiation, the Sponsor will train the investigator and study staff on 
the protocol for the study.    
 
6.2 
Investigator List 
 
The Sponsor shall keep a list of the names, addresses, and professional positions 
of the investigators for the study.   
 
6.3 
Serious Adverse Event Reporting 
 
The Sponsor shall evaluate serious adverse event reports received from the study 
sites and those found during data monitoring and shall report them to the 
regulatory bodies and other investigational sites as appropriate. 
 
6.4 
Data Monitoring 
 
Data monitoring will be performed remotely and on site when necessary.  
Standardized electronic CRFs will be used for queries and query resolution.  A 
Penumbra employee or designate will conduct the following site visits: 
 
 
Site Initiation Visit 
 
This is conducted on site or remotely to train the study staff on study 
requirements, and other relevant training. 
 
 
Data Monitoring Site Visit 
 
Conducted as needed to ensure the study site is operating in compliance 
with this protocol, and completing the CRFs. Clinical monitoring will 
include review and resolution of missing or inconsistent data and source 
document checks to ensure the accuracy of the reported data. CRFs for all 
enrolled patients will be made available to the Sponsor for review and 
collection as agreed with the investigator.  The Sponsor will evaluate and 
summarize the results of each site visit in written reports, identifying 

 
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repeated data problems with any investigator and specifying 
recommendations for resolution of noted deficiencies. 
 
 
Study Close-Out Site Visit 
 
This visit is conducted at the termination of the study to resolve any 
outstanding data queries. 
 
6.5 
Data Management 
All study data will be entered into an electronic data capture (EDC) system 
provided by a vendor. Study personnel will have individual login and password to 
access the clinical study information based upon each individual’s roles and 
responsibilities. For data security, the system operates within the Secure Socket 
Layer (SSL) 128-bit encryption protocol. This application is designed to fully 
support compliance with the following regulations and guidance documents: 
 
 Guidance for Industry 21 CFR Part 11; Electronic Records; Electronic 
Signatures; Scope and Application [FDA];  
 21 CFR Part 820, also known as FDA Quality System Regulation (QSR); 
 Guidance for Industry; E6 Good Clinical Practice: Consolidated Guidance; 
 Guidance for Industry; Computerized Systems used in Clinical Investigations; 
 General Principles of Software Validation; Final Guidance for Industry and 
FDA Staff; 
 Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
 
Data entry will be performed at the investigational sites. Standardized electronic 
Case Report Forms (eCRFs) will be provided for use at all investigational sites. 
Investigators are responsible for completion and timely submission of the data to 
Penumbra, Inc. 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. Incoming data are to be reviewed for quality & 
consistency before being locked for data export. Questions or problems with 
submitted data will be addressed with the principal investigator via an electronic 
querying system, or through direct contact.  
 
All hard copy forms and data files will be secured to ensure confidentiality. 
Investigators are required to maintain source documents required by the protocol, 
including laboratory results, patient report forms, supporting medical records, and 
Informed Consent Forms. The source documents will be used during the regular 
monitoring visits to verify information submitted on the CRFs.  
 
 
 

 
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7. 
CONTACT INFORMATION 
 
The address of Penumbra Incorporated is: 
Penumbra Incorporated  
1351 Harbor Bay Parkway 
Alameda, CA 94502 
Tel. (510) 748-3200  
Fax (510) 814-8305 
 
Key contacts at the company include: 
Malia McPherson, B.A. Clinical Research Associate 510-748-3294 
Siu Po Sit, Ph.D.  
VP, Clinical Affairs     
510-748-3221 
Arani Bose, M.D.  
Medical Monitor 
 
510-748-3200   
Adam Elsesser 
 
CEO  
 
 
510-748-3222 
 
8. 
ETHICAL REQUIREMENTS 
 
8.1 
Declaration of Helsinki 
 
The study will be performed in accordance with EN 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 IRB/EC and to keep the IRB/EC informed of any unexpected serious 
adverse events, 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. 
 
8.2 
Patient Information and Consent 
 
It is the responsibility of the investigator to give each patient full and adequate 
verbal and written information regarding the objective and procedure of the study 
and the possible risks involved and to obtain signed informed consent from all 
patients prior to inclusion in the study unless the patient's health condition does 
not allow informed consent, in which case the state and national procedures will 
be applied. The original, signed consent is filed with the patient study records, and 
a copy is provided to the patient or legally authorized representative. 
 
8.3 
Patient Data Protection 
 
The patients will be identified in the CRFs with patient number and initials.  Only 
the investigator and the Sponsor or designee will have access to individual patient 
data. Furthermore, the patients should be informed about the possibility of 
inspection of relevant parts of the hospital records, including angiograms and 

 
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other imaging scans, by the Sponsor or other Health Authorities, including the US 
FDA. 
 
9. 
STATISTICAL PROCEDURES 
 
9.1 
Sample Size Justification and Statistical Analysis 
 
The primary objective of this post-market single center experience is to determine 
the safety and effectiveness of the Penumbra Coil System in a cohort of patients 
treated for intracranial aneurysm.   
 
Approximately 2,000 patients will be enrolled.  With this sample size the 
precision is greater than ± 2.5% for the procedural device-related serious adverse 
event rate based on a binomial 95% confidence interval. Hence, the sample size 
provides a sufficient level of precision for the primary endpoint. 
 
This study is a single-treatment design.  Hence, descriptive statistics will provide 
a basis for the majority of the analyses with a 95% two-sided confidence interval 
presented.  For binary outcomes, the 95% two-sided confidence intervals will be 
calculated using exact binomial intervals. For numeric measures, a confidence 
bound for the mean or mean change from admission will be constructed. 
 
Standard descriptive statistics for categorical endpoints will be the number and 
percent of patients with each level of the endpoint.  For numeric endpoints, the 
standard descriptive statistics include the number of missing observations (n), the 
mean, the median, the standard deviation, the minimum value, and the maximum 
value. 
 
Results collected at multiple visits will be summarized at each visit for which they 
are collected. Summaries for all measures will include all observed data for each 
visit. 
  
9.2 
Safety 
 
All serious adverse events will be summarized by showing the number and 
percent of patients which report the event. Events will also be reported by 
relationship to the procedure or device. The denominator for the analyses is all 
enrolled patients. 
 
The proportion of deaths for any reason through one year follow up will be 
calculated and a 95% confidence interval will be presented.  The cause of death 
and time-to-death will be summarized. The proportion of patients with 
symptomatic intracranial hemorrhage will be summarized and reported. 
 

 
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Survival estimates will be generated to evaluate the time-to-death and time-to-
event using Kaplan-Meier methodology for all events through one year. Peto’s 
adjusted standard error estimates will be calculated.  
 
10. 
PUBLICATION OF INFORMATION 
 
The results of this study may be offered for publication and/or presentation. The 
investigators and the Sponsor shall collaborate in the writing of the study to 
ensure accuracy. 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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11. 
BIBLIOGRAPHY 
 
1. 
Brisman JL, Song JK, Newell DW. Cerebral Aneurysms.  N. Engl J 
Medicine 2006;355:928-939. 
 
2. 
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