New Generation Hydrogel Endovascular Aneurysm Treatment Trial
Phase: NA
Conditions: Cerebral Aneurysm
Sponsor: Northwestern University

This protocol contains confidential information for use by the Investigators and their designated representatives participating in this 
clinical investigation. It should be held confidential and maintained in a secure location. By accepting this document, you agree to 
maintain the information as confidential and to use it only for the purpose of conducting the study. 
 
 
 
 
 
 
 
“HEAT” 
New Generation Hydrogel Endovascular Aneurysm 
treatment Trial 
 
 
September 4, 2014 
Protocol #1908:  Version 07 
 
A randomized controlled trial of new generation Hydrogel 
coils versus bare platinum coils in the endovascular 
treatment of intracranial aneurysms 
 
 
 
 
 
 
 
 
 
Sponsor: Northwestern University 
Bernard R. Bendok, M.D. 
676 N. St. Clair Street, Suite 2210 
Chicago, IL 60611 
Phone:  (312) 695-0464 
bbendok@nmff.org  
 
 
Funder: MicroVention, Inc. 
1311 Valencia Ave. 
Tustin, CA  92780 

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1 
Protocol Synopsis 
 
FULL STUDY 
TITLE 
New Generation Hydrogel Endovascular Aneurysm Treatment Trial 
 
 
STUDY 
OBJECTIVES 
Comparing initial complete occlusion, recanalization, retreatment and 
adverse event rates of the HydroCoil® Embolic System to those of bare 
platinum coils. 
 
STUDY DESIGN 
International, randomized, prospective, controlled, multicenter trial 
 
 
DEVICES 
Second generation hydrogel coils from the HydroCoil® Embolic System 
TM (including the HydroSoft®, HydroFill® and HydroFrame® and future 
FDA and HPB approved Hydrogel coils) (“Hydrogel Group”) and Platinum 
coils (“Platinum Group”) 
 
 
TREATMENT 
POPULATION 
Subjects with intracranial aneurysms between the ages of 18 and 75 
years inclusive 
 
 
ESTIMATED 
TRIAL SIZE 
600 randomized subjects 
 
 
NUMBER OF 
SITES 
Approximately 50 sites inside and outside of the U.S. 
 
 
PRIMARY 
ENDPOINT  
Aneurysm recurrence at any point during follow-up defined as any 
progression on the Raymond aneurysm occlusion scale. 
 
 
SECONDARY 
ENDPOINTS 
 
Packing density as measured by volumetric filling of the aneurysm 
 
Clinical outcome at 18 to 24 months (mRS)  
 
Peri-procedural and post-procedural adverse events related to the 
procedure and/or the device. 
 
Mortality rate 
 
Initial complete occlusion 
 
Aneurysm retreatment 
 
Hemorrhage from target aneurysm during follow-up 
 
Aneurysm occlusion stability 
 
Major vs. minor recurrence 
 
 
VISIT SCHEDULE 
Baseline, Procedure, 1 day post-procedure, 3 days to 28 days, 3 months 
to 12 months, 18 months to 24 months 
 
 
PRINCIPAL 
INVESTIGATOR 
OF THE STUDY 
Bernard R. Bendok, M.D. 
676 N. St. Clair Street, Suite 2210 
Chicago, IL 60611 
Phone:  (312) 695-0464 
bbendok@nmff.org  
 
 

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CORE 
LABORATORY 
(“CORE LAB”) 
Andrew DeNardo, MD; John Scott, MD; & Daniel Sahlein, MD 
Indiana University 
Goodman Campbell Brain and Spine 
355 W. 16th Street. Suite 5100 
Indianapolis, IN 46202-2207 
Phone: (317) 396-1300 
"Andrew DeNardo, MD": adenardo@goodmancampbell.com 
"John Scott, MD": johnscottmd@gmail.com 
 
“Daniel Sahlein, MD”: dsahlein@goodmancampbell.com 
 
DATA SAFETY 
MONITORING 
BOARD CHAIR 
(“DSMB”) 
Adnan H. Siddiqui, MD, PhD 
3 Gates Circle 
Buffalo, NY 14209 
Phone: (716) 887-5200 
asiddiqui@ubns.com 
 
 
 
 
 
 

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Introduction and Background on endovascular treatment of Intracranial Aneurysms 
 
Over the last two decades, the endovascular treatment of intracranial aneurysms has seen significant 
advances. The first landmark came with the advent of the Guglielmi Detachable Coils (GDC) in the early 
nineties.1 Almost a decade later, the publication of the ISAT trial validated the use of endovascular coils and, in 
general, the endovascular approach to treating select intracranial aneurysms.2  
One major limitation of the endovascular approach, however, is the durability of treatment. Aneurysm 
recurrences have been shown to be more frequent with coiling than with an open microsurgical approach.2,3 
Major recurrences occur in 15%4,5 to 19%6 of cases by 3-6 months and rises to 33% at a mean of 18 months of 
follow-up.5,7,8 Major recurrences following endovascular treatment are associated with retreatment rates as 
high as 58.8%.5 Although rare, the risk of re-bleeding is also increased with endovascular treatment when 
compared to open surgical clipping.2,3 Byrne et al. assessed the risk of aneurysmal rebleeding and found that 
the risk is significantly increased from 0.4% in stable aneurysms to 7.9% in recurrent aneurysms.4 A number of 
approaches have been pursued over the past five years to enhance results.  Because recanalization has been 
associated with poor packing density in aneurysms, one approach has been to enhance packing density which 
has resulted in the development of a hydrogel coated coil. The hydrogel expands over time and enhances 
packing density.   
3 
HydroCoil® Embolic System  
3.1 
Hydrogel characteristics and the Hydrocoil Embolic System 
The Hydrocoil Embolic System, developed and manufactured by MicroVention, Inc. (referred to in this 
Protocol as “MicroVention” or “Funder”), consists of porous hydrogel that either surrounds the platinum coil (as 
in the first generation of the HydroCoil Embolic System), or is surrounded by the platinum coil (as in the second 
generation of the HydroCoil Embolic System). Hydrogel consists of cross-linked hydrophilic copolymers. This 
material has been widely used in other medical applications (e.g. contact lenses and wound dressings). 
Hydrogel swells once exposed to the biological pH.  
3.2 
First Generation of the HydroCoil Embolic System: HydroCoil® 
The first generation of the HydroCoil Embolic System is constructed using a core platinum coil surrounded 
by a sleeve of expandable hydrogel and an outer wire with gaps which allow expansion to occur. As such, the 
Hydrogel device is relatively stiff because of its dehydrated state, especially when compared to soft, platinum 
coils. The Hydrogel undergoes substantial swelling over time, markedly increasing its outer diameter and 
surface area over approximately 20 minutes. The increase in volume of the coil varies among the different 
HydroCoils. The HydroCoil 10 swells up to 0.022”, 5 times the volume of a platinum 10 coil; the HydroCoil 14 
and HydroCoil 18 swell to 3 and 6 times the volume of Platinum 18 coils, respectively. The HydroCoil 14 and 
18 coils swell up to 0.027” and 0.034”, respectively. Although substantial swelling is advantageous for 
aneurysm filling volume, there are limits associated with deployment time and size of the coils. Difficulty in 
deployment may lead to the need for multiple repositionings and potential untoward early swelling of the device 
which limits delivery through certain microcatheter systems. The HydroCoil is generally used as filling coils.  
3.3 
Second Generation of the HydroCoil Embolic System: HydroSoft®, HydroFrame®, 
HydroFill® and Future Hydrogel Products 
In an attempt to offer a hydrogel coil as a soft finishing coil to allow ease in placing gel coils at the neck 
of the aneurysm, MicroVention developed the HydroSoft® line of embolic coils. These coils which are 
constructed with a filament of expandable hydrogel within the platinum coil are essentially as soft as platinum 
coils based on benchtop experiments and thus have handling properties similar to traditional platinum coils. 
Furthermore, since the hydrogel does not expand excessively, repositioning time is markedly prolonged to 30 
minutes per the Instructions for Use (IFU). When fully hydrated, the HydroSoft swells up to approximately 

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0.013” to fill the gaps between the spirals of the platinum coil.7,9 The HydroSoft coils are primarily used as 
finishing or filling coils.  
The next coil introduced by MicroVention, Inc., was HydroFrame®, a framing coil with hydrogel on the 
inside of the coil that is available in both 10 and 18 systems.  MicroVention then developed HydroFill® which is 
used primarily as a filling coil, has a longer working time than HydroCoil (10 minutes in a .0165 microcatheter 
or 30 minutes in a .021 microcatheter), and swells to .018”. The HydroFrame®, HydroSoft® and HydroFill® do 
not require steaming or prepping of the coil. 
3.4 
Studying the New Generation of the HydroCoil Embolic System 
Studies to date on hydrogel coils have necessitated mixing hydrogel coils with platinum coils. With the 
introduction of the HydroFrame embolic coils, it is now possible to initiate a prospective randomized, 
multicenter trial to evaluate the effectiveness of packing an aneurysm exclusively with all Hydrogel coils 
compared to that exclusively with bare platinum coils.  The question that remains unanswered is whether the 
new hydrogel technology improves results over traditional platinum coils. 
For the purpose of this Protocol, subsequent references to the “HydroCoil Embolic System” refer 
specifically to the second generation of the HydroCoil Embolic System being utilized in this study and includes 
the HydroFrame®, HydroSoft®, HydroFill® and future FDA and HPB approved hydrogel products.   
  
3.5 
Previous Clinical Experience and studies of the HydroCoil and the Hydrocoil Embolic 
System 
 
In early data from the prospective non-randomized HydroCoil for Endovascular Aneurysm occLusion 
(HEAL) study,10 the overall recurrence rate at 3 to 6 months was 28.1% (38/135 aneurysms). Further analysis 
of the data showed that when HydroCoil comprised 75% or more of total coil length the recurrence rate at 3 to 
6 months dropped to 0% (0 out of 18 aneurysms). In contrast, when HydroCoil comprised less than 75% of 
total coil length, the recurrence rate was 23% (16 out of 71 aneurysms). Furthermore, when the last deposited 
coil was a HydroCoil, the recurrence rate was found to be 11% compared to 29% when the last deposited coil 
was a platinum coil. The difference was statistically significant. This difference in results, however, reflects one 
of the major limitations of the HEAL trial which was that no aneurysm was treated exclusively with HydroCoil.  
In a prospective study, Gaba et al.11 compared 50 aneurysms treated primarily with Hydrocoil (mean 
71.8% based on coil length) to 57 volume- and shape-matched aneurysms embolized with bare platinum coils. 
The overall recurrence rate of the Hydrocoil treated aneurysms was 17% and compared favorably to those 
treated with bare platinum coils (24%) during a mean follow-up period of 12.3 months. These results also 
compare favorably to those reported by Murayama et al12 from their 11 year experience with bare platinum 
coils where the overall recanalization rate was 20.9%. Geyik et al.13 studied the recurrence rate in 35 
bifurcation aneurysms, known for a higher tendency for recurrence, when treated with Hydrocoil and 
demonstrated an initial complete occlusion rate of 82.9% and at 6 months follow-up the overall recanalization 
rate was 11.4%. 
Several other studies have examined hydrogel coils and the rates of initial complete occlusion have 
varied between 28% to 75% with recurrence rates between 11% and 28.1%.14,15 Tables 1 and 2 summarize the 
most relevant papers and their findings on occlusion rates, recanalization, retreatment, complications, 
morbidity and mortality rates. As a point of reference, the overall retreatment rate in the International 
Subarachnoid Aneurysm Trial (ISAT) was 17.4%, with an early retreatment rate of 8.8% and a late retreatment 
rate of 9.0%.16 The cut-off point between early and late retreatment was 3 months.16 

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Aneurysms showing the highest degree of occlusion and packing density (PD) are thought to be the best 
protected against recanalization and potential re-treatment.7,10,11,17-22 Cloft et al.9 studied the packing density of 
11 aneurysms treated with HydroCoil compared to 11 historical controls that were treated with bare platinum 
coils. Most of these were small aneurysms (all 3.5-8.5mm) and mean packing density for the HydroCoil was 
found to be 73% versus 32% for bare platinum coils. Gaba et al.11 calculated a theoretical volumetric 
percentage occlusion (VPO) and found that it was significantly higher in Hydrocoil than in inert bare platinum 
coils for all aneurysm sizes. The HydroCoil Endovascular Aneurysm Occlusion and Packing Study (HELPS) 
was a prospective, randomized, controlled trial that compared results from the HydroCoil system to results 
from bare platinum coils. The 500-patient, independently-run, multicenter, multinational 18-month trial was the 
first comparative study completed since the ISAT was presented in 2002. The angiographic results of the 
HELPS trial showed that there was a statistically significant decrease (8.6%) in major aneurysm recurrence 
rates in the HydroCoil system arm as compared to the bare platinum control arm.7  
In addition to HELPS, one other trial is underway. The trial entitled “Patients Prone to Recurrence after 
Endovascular Treatment”, or “PRET”, is a large multi-center prospective randomized trial that aims to compare 
hydrogel coils and platinum coils in the treatment of large aneurysms that have a high-risk of recurrence. PRET 
intends to recruit 250 patients with large aneurysms (≥10mm) and 250 patients with recurrent aneurysms at 
23-40 centers.  The clinical impact will be of major significance if substantial differences are found in the 
outcome of this randomized controlled trial. PRET was initiated prior to the development and introduction of the 
HydroFrame, however, which necessitated the mixing of hydrogel coils with platinum coils in the hydrogel 
group. With the development and introduction of the hydrogel framing coil (the HydroFrame) it will be possible 
to initiate a prospective randomized, multicenter trial to evaluate the effectiveness of packing an aneurysm 
exclusively with the HydroCoil® Embolic System (Hydrogel Group) with comparison to the current gold-
standard of endovascular aneurysm treatment using bare platinum coils (Platinum Group).  
4 
Study Objectives 
4.1 
Study Hypothesis 
The HydroCoil Embolic System allows for a higher packing density, higher initial occlusion, lower 
recanalization, and lower retreatment rates. 
 
4.2 
Primary Endpoint 
The primary purpose of the HEAT study is to compare clinical and angiographic outcomes in patients 
receiving the HydroCoil Embolic System (Hydrogel framing, filling and finishing coils) versus patients receiving 
Platinum framing and filling coils. The primary outcome is aneurysm recurrence defined as any progression on 
the Raymond aneurysm occlusion scale anytime during follow-up (for further details, see section 6.4). 
4.3 
Secondary Outcomes 
 
Packing density as measured by the volumetric filling of the aneurysm 
 
Rate of initial complete occlusion 
 
Procedure and/or device-related morbidity and mortality 
 
Clinical outcome at 18 to 24 months as assessed using the modified Rankin Scale 
 
Re-treatment rates 
 
Hemorrhage from target aneurysm during follow-up 
 
Aneurysm occlusion stability 
 
Major versus minor recurrence 
 

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4.4 
Safety Outcomes 
 
Peri-aneurysmal edema  
 
Aseptic meningitis 
 
Thromboembolic events 
 
Vasospasm 
 
Ventricular Enlargement 
 
Hydrocephalus 
 
Aneurysm Rupture  
 
Parent Vessel Occlusion 
 
5 
Clinical Study Design 
 
5.1 
Study Design 
This is a randomized, controlled, multicenter, international post-market clinical trial. All devices used in 
this study are FDA and HPB (Health Protection Branch) approved. Eligible Subjects with intracranial 
aneurysms amenable to endovascular treatment and who consent to study participation will be randomly 
assigned 1:1 to either treatment arm:   
 
The HydroCoil Embolic System (“Hydrogel Group”), or  
 
Bare platinum coils (“Platinum Group”)  
 
Both arms are standard of care. The patient will receive either Hydrogel or bare platinum coils in each 
respective arm. No other bioactive coils, including 1st generation coils or liquid embolics, can be utilized. In the 
Hydrogel arm, up to 10% of total coil length using bare platinum is allowed if deemed necessary by the 
investigator. Any type of bare platinum coil may be utilized. Assist-devices can be used at the discretion of the 
investigator.  
 
5.2 
Study Duration and Enrollment 
The duration of the open enrollment phase will be 24 months or until the required number of patients are 
enrolled. Each patient will have a post-procedure follow-up of at least 18 months. 
The number of Subjects to be enrolled, and randomized, in the study is up to 600. This sample size 
calculated to provide sufficient statistical power to show the anticipated difference in initial occlusion and 
recurrence rates between the 2 study arms (see section 9 for detailed statistical analysis). Patients will be 
recruited from up to 50 national and international centers. Each Investigational Site will be expected to enroll at 
least 20 Subjects. Each site must meet the eligibility criteria. 
A multidisciplinary approach is expected from each qualified study center. The Neurovascular teams 
should include the appropriate specialties for the proper conduct of the study e.g., neurointerventionalist(s), 
experienced in intracranial aneurysm coiling, neurosurgeon(s), and study coordinator(s). In addition, the 
treating physician must meet a minimal level of expertise consisting of at least 5 successful intracranial 
aneurysm coiling procedures utilizing the HydroCoil Embolic system prior to enrolling patients into the study. 
Each site must provide written approval from their reviewing Institutional Review Board (IRB) and all 
other required regulatory documentation prior to consenting and enrolling the first Subject. 

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5.3 
Selection and Screening of Subjects 
The study population for this clinical trial will be comprised of patients who have been diagnosed with 
intracranial aneurysms. In addition, these patients must satisfy all study inclusion and exclusion criteria. The 
trial will prospectively enroll and randomize up to 600 Subjects in a 1:1 ratio within only one stratification factor: 
participating site. The investigator or an approved member of the research team will review the patient’s 
medical history for study eligibility and will fully inform any potential candidates about the purpose of the study. 
The difference between both types of coiling systems will be described and the potential risks and benefits will 
be explained in detail to each study candidate. Patients who voluntarily agree to participate in the trial will be 
asked to sign and date the Informed Consent Form (ICF). In the event a patient is unfit to provide signed 
informed consent (e.g. drowsy/confused), his/her Legally Authorized Representative (LAR) can sign the 
consent form. Once enrolled into the study, each participant will be assigned a study number. Patient names or 
identifiers will not be used on any study related documents. An electronic case report form (eCRF) will be 
completed at the end of each procedure and after each study related follow-up. Only the Principal Investigator 
of the study (Dr. Bendok) and authorized members of the Sponsor including study monitors and auditors will 
have full access to the eCRF. Information from the eCRF will be entered into a secure, password protected 
study database. The Funder and its employees will have read-only access to collected eCRF study data, as 
provided by Northwestern, solely for review and adjudication of information related to any AE, SAE,  ADE and 
UADE (as such terms are defined below) for legal and compliance purposes. 
If a subject becomes pregnant while participating in this study, any angiographic follow-up will be done 
using non-contrast MRA as per standard of care. 
 
5.3.1 Informed Consent 
Prior to Subject participation in this study, the study team must obtain written IRB approval for the 
protocol and the Informed Consent Form (ICF). Once the patient’s potential eligibility has been determined, the 
investigator or an IRB approved member of the research team will discuss the study and ask the patient if they 
are interested in participating in the study. The study will be explained to the patient in lay terms or at the level 
of patient understanding. The differences in coiling types will be explained in full detail. The approved ICF must 
be signed prior to performing study related assessments. The subject will be given a copy of the signed and 
dated ICF. The informed consent process must be documented and placed in the subject binder. Failure to 
obtain a signed ICF prior to the procedure constitutes a protocol deviation. It must be clear to subjects that they 
may withdraw from the study at any time and for any reason without penalty. It will be made clear to study 
participants that withdrawal from the study will not adversely affect their medical treatment and they will 
continue to receive therapy as indicated by their physician. Data from subjects obtained prior to withdrawal 
may be used for statistical analysis but no further data will be obtained. 
 
5.3.2 Inclusion Criteria 
Candidates for this study must meet the following criteria to be enrolled in the study (A “NO” answer excludes 
the subject):   
1. Patient is between 18 and 75 years of age (inclusive). 
2. Patient has a documented untreated intracranial saccular aneurysm 3-14 mm diameter angiographic 
lumen, ruptured or unruptured, suitable for embolization with coils. 
3. For ruptured aneurysms, patients presenting with a Hunt and Hess Grade 1-3 or improving to such a 
grade before treatment. 

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4. Any type of bare platinum coils and HydroCoil Embolic System are treatment options (all shapes 
allowed). 
5. Patient or next of kin or person with appropriate power of attorney has provided written informed 
consent. 
6. Patient is willing and available for study follow-up visits. 
7. Patient has not been previously entered into this Study. 
5.3.3 Exclusion Criteria 
Candidates will be ineligible for enrollment in the study if any of the following conditions apply (A “YES” answer 
excludes the subject): 
1. 
Inability to obtain informed written consent. 
2. Patient is < 18 or > 75 years old. 
3. Target aneurysm is not saccular in nature (mycotic, fusiform, dissecting). 
4. Target aneurysm is > 14 mm maximum luminal dimension, < 3 mm maximum luminal dimension. 
5. Target aneurysm has been previously clipped or coiled. 
6. Target aneurysm is in the physician's estimate unlikely to be successfully treated by endovascular 
techniques. 
7. Patient has known hypersensitivity to platinum, nickel, stainless steel or structurally related compounds 
or hydrogel as found in the HydroCoil Embolic System and/or bare platinum coils. 
8. Baseline Hunt and Hess scale 4 or 5 for ruptured aneurysms. 
9. Intended use of a flow diverting stent (e.g. pipeline) 
10. Subject has concurrent intracranial pathology, e.g. 
 
Moyamoya disease 
 
Vasculitis documented by biopsy results 
 
AVMs 
 
AV fistulas 
 
Significant atherosclerotic disease (i.e. symptomatic and or >50% narrowing of the parent 
arteries necessary to traverse in order to coil the target aneurysm) 
 
Intracranial Hematoma (unrelated to the target aneurysm) 
 
Brain tumors 
 
Vascular tortuosity and other conditions preventing access to target aneurysm 
11. Subject has serious co-morbidities that could confound the study results: 
 
Uncontrolled hypertension 
 
Uncorrectable coagulation abnormality 
 
Contraindications for heparin, aspirin or clopidogrel 
 
Uncontrolled Diabetes Mellitus 
 
Organ failure of kidney, liver, heart, or lung 

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 
Myocardial infarction within the past 6 months 
 
Cancer likely to cause death within 2 years or less.  
12. Subject history indicates high risk of non-compliance (e.g., substance abuse, psychosocial issues, 
etc.) 
13. Subject has a known history contraindicating contrast dye or iodine that cannot be pre-medicated 
prior to coiling procedure (vs. sensitivity which can be safely controlled by antihistamine, steroid, etc.). 
Medical clearance will be needed for this issue. 
14. Patients who are unable to complete scheduled follow up assessments at the enrolling center due to 
limited life expectancy (<2 years), co-morbidities or geographical considerations 
15. Subject is currently breast feeding, pregnant or plans to become pregnant in the next 2 years. 
16. Major surgical procedure or trauma within 30 days prior to randomization. 
17. The patient is currently enrolled in another clinical study (device or drug). 
18. More than one aneurysm needs to be treated at the same time. 
 
6 
Subject Enrollment, Procedures, and Follow-Up 
 
6.1 
Screening and Consent 
Eligibility will be assessed once the neurovascular team makes a decision on endovascular treatment of 
an aneurysm.  A local site log of all eligible patients will be kept and a copy returned to the coordinating site 
(Northwestern University) when requested by the study monitor. 
If a patient fulfills the inclusion and exclusion criteria, an authorized member of the research team will 
discuss the trial and provide the patient or his/her LAR with the informed consent form. The patient or LAR will 
be provided adequate time to consider participation in the trial and the research team will answer all questions 
regarding the trial. A copy of the consent will be retained in the patient’s medical record, one will be given to 
the patient, and the original will be retained by the local site. 
All patients who meet the eligibility criteria and give written informed consent are eligible for enrollment 
into the study which occurs at the time of randomization  
Screen failures are defined as a subject consented and screened for enrollment, but not ultimately 
enrolled on the day of randomization; provided that the failure to enroll was attributable to the subject’s failure 
to meet the inclusion or exclusion criteria listed in the protocol. 
Screen failures and subjects who electively withdraw from the study will be dropped from any further 
follow-up and statistical analysis of this study. The original ICF and any data collected up until the date of 
withdrawal will be maintained in the clinical site’s study files and their number will not be used again in the 
study. 
 
 

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6.2 
Baseline Assessments (up to 30 days prior to procedure) 
The following information will be assessed and documentation will be maintained as source records at 
the study site: 
 
Neurological assessment of the subject and evaluation of symptoms will be performed by an 
experienced neurosurgeon, neurointerventionalist or authorized designee. In the case of a ruptured 
aneurysm, the severity of symptoms is to be administered and assessed by authorized and certified 
research staff using both the National Institutes of Health Stroke Scale (NIHSS) and the Hunt and 
Hess scale (Table 3).. 
 
The Subject’s modified Rankin Scale (mRS) assessment score will also be collected for the eCRF to 
reflect baseline functional status 
 
SF-36 questionnaire to assess general quality of life (for ruptured cases when the subject is impaired 
and unable to complete the SF-36 questionnaire, this can be completed by the subject prior to 
discharge) 
 
Medical History 
 
Current medications history including anti-platelet and anti-coagulation drugs 
 
Physical Examination 
 
Laboratory values to include hemoglobin (Hg), platelet count (Plt), prothrombin time (PT), partial 
thromboplastin time (PTT), international normalized ratio (INR), and creatinine (Cr).A pregnancy test 
is required if the subject is female with child-bearing potential. Any female of child-bearing potential 
who has not been diagnosed with menopause or any other clinical condition that would prohibit 
conception and/or has not undergone any kind of surgery that would prohibit conception (e.g. total 
hysterectomy or bilateral oophorectomy) should receive a pregnancy test prior to enrollment. 
 
 
A CT scan or MRI may be used to evaluate study Subject eligibility. However, this imaging is not 
required to be recorded on the eCRF nor is the imaging CD required to be sent to the Imaging Core 
Lab or Sponsor. 
Once the consent form has been signed, all subjects should complete the baseline assessments 
discussed in Section 7.2 and the Schedule of Assessments (Table 4). 
 
6.2.1 Clinical and radiographic evaluation 
A pre-treatment clinical assessment will be performed by the treating physician or designee and a mRS 
score should be obtained. The NIHSS and Hunt and Hess scale scores will be recorded for those patients 
presenting with ruptured aneurysms and/or SAH. The patient’s medical co-morbidities will also be recorded for 
study analysis. Results of a pre-embolization brain angiography, MRA or CTA may be recorded and submitted 
to the Imaging Core Lab and Sponsor if imaging was performed within 30 days prior to enrollment (optional). 
Measurement of the three (3) aneurysm dimensions of interest (height, length, and width), its neck size and 
maximal diameter will be recorded as well as any additional relevant radiographic features (e.g. partial 
thrombosis, peri-aneurysmal edema, etc.). 
For conventional angiography, two 10 mm silicon-coated spherical ball bearings must be used for each 
enrolled subject during procedural angiography (immediately pre- and post-coiling) as well as during any 
subsequent follow-up angiograms to make measurements as standardized as possible. One ball bearing will 
be placed on the forehead and the second in the periauricular area ipsilateral to the aneurysm. Image 
intensifiers will be placed as close to the head as possible. A 4-axis orthogonal view of the aneurysm will be 
obtained.  

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Imaging data will be recorded on the Imaging eCRF. Imaging CDs will be sent to the Imaging Core Lab 
and the Sponsor, Northwestern University. In the event ball bearings are not used during procedural 
angiography, the Sponsor may require submission of baseline imaging including CTA or MRA to enable the 
Imaging Core Lab to more accurately obtain measurements. 
 
Please see Table 7 which outlines the imaging schedule. 
 
 
6.3 
Randomization 
Subjects who meet study inclusion and exclusion criteria and who have signed an informed consent form 
will be randomized through the study’s Electronic Data  Capture (EDC).Randomization will be performed 
through the EDC on the day of the coiling procedure. This must be completed once pre-coiling imaging has 
been reviewed and immediately before endovascular coiling begins. At this time, the Subject will be given a 
unique study identification number generated by the EDC.  This number should be used on all study 
documents so that data is reported anonymously to protect subject confidentiality and patient health 
information (PHI).  Patients will be randomized 1:1 to one of two study arms: 1) The HydroCoil® Embolic 
System (“Hydrogel Group”) or 2) bare platinum coils (“Platinum Group”).  
Patient safety is a priority.  In the event the treating investigator deems it clinically necessary to switch a 
subject randomized to the Hydrogel arm to the platinum coils arm for safety reasons, the crossover should be 
documented as a protocol deviation in the eCRF. However, the subject will continue to be followed and will 
receive all study-related procedures as per protocol. Similarly, if the investigator switches a subject, 
randomized to the bare platinum arm to the Hydrogel arm or uses more than 10% platinum coils (based on 
length) in a subject randomized to the Hydrogel arm, the same procedures will be followed. The reason(s) for 
the preference of one type of coils over the other will be documented in the eCRF.  
If during the course of the treatment the investigator decides to perform staged coiling or to use a flow-
diverting stent (e.g. pipeline), a protocol deviation should be documented in the eCRF and the subject should 
continue to be followed as per protocol. 
If during the course of the treatment the investigator decides to switch to open surgery or decides not to 
treat the aneurysm at all, a protocol deviation should be documented and subjects should continue to be 
followed according to standard of care (i.e. as per site management protocol). The reason for the preference of 
surgery or no treatment over coiling will be documented on the eCRF. 
6.4 
Angiographic occlusion evaluation 
 
 Angiographic aneurysm occlusion rate will be assessed using 2 scales. The first is based on the new 
reporting standards described by Meyers et al. (grades 0 to 5).23 This reporting system will be used by the 
Imaging Core Lab only for study and validation purposes. It is comprised of 6 grades: (Figure 1) 
‐ Grade 0: complete and total aneurysm occlusion 
‐ Grade 1: ≥ 90% volumetric aneurysm occlusion 
‐ Grade 2:  70% to 89% volumetric aneurysm occlusion 
‐ Grade 3: 50% to 69% volumetric aneurysm occlusion 
‐ Grade 4: 25% to 49% volumetric aneurysm occlusion 
‐ Grade 5: < 25% volumetric aneurysm occlusion 

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The second scale will be the Raymond scale24 (complete, residual neck and residual aneurysm) (figure 
2). This scale will be used by the Imaging Core Lab and the investigator at each participating site to report 
aneurysmal occlusion rates. 
 
 
 
 In the event of recanalization*, the treating physician will be asked to grade the recurrence by 
answering the following questions: 
 
1- Can the aneurysm be retreated? YES or NO 
 
2- Should the aneurysm be retreated? YES or NO 
 
3- If answers to both questions are YES, the treating physician will be asked to indicate the most 
appropriate subsequent treatment option (i.e. recoiling, clipping, stent-coil, flow diverter stent, or parent 
artery occlusion). 
 
*As part of the Imaging Core Lab’s evaluation of the submitted imaging, they will also perform the 
above assessments for study purposes, but will do so while being blinded to the treating physician’s 
grading and assessment. The Imaging Core Lab will be unblinded to the rupture/unruptured status of 
the aneurysm as this may affect their decision making process in case retreatment is warranted. 
 
6.5 
Packing density measures 
 The packing density calculations will be based on total coil length, coil volume, and aneurysm volume. 
The following equation will be used to calculate the packing density per coiling procedure: 
 
 
Packing density = Total Coil Volume   x 100          
                               Aneurysm Volume 
 
The coil volume calculation assumes a cylindrical shape of the coil:  
 
     Coil Volume = π x Dc2 x L                                  
                                                           4                        
 
         Dc: Coil outer diameter 
L: Coil length 
 
The aneurysm volume will be calculated using the following equation: 
  
Aneurysm Volume = 4/3 pi(a/2)(b/2)(c/2) 
                                           
a, b, and c are the aneurysmal height, length and width in millimeters. 
In order to keep measurements as uniform as possible, the Imaging Core Lab will provide the aneurysm 
volume and the treating physician will provide the total coil volume as the Imaging Core Lab will be blinded to 
the type of coils used.  
 

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6.6 
Treatment protocol 
6.6.1 Coiling procedure 
Coiling will be performed according to the standards of each institution. The choice of catheters and 
guide-wires will not be dictated. The investigator will also have the choice to use assist devices (balloon and/or 
stents). The use of assist devices will be recorded on the Procedure eCRF. No flow diverter stents are to be 
utilized in this study. Coiling will be done in a one-step procedure. Every attempt should be made to treat with 
as much of the randomized coil type as possible to achieve optimal occlusion. Use of any bioactive or non-
HES 2nd generation coils (e.g. Matrix, EV3 or Cerecyte) and/or use of liquid embolic materials is not allowed. 
Use of such devices will be considered a protocol deviation but the subject will continue to be followed 
according to HEAT protocol.  
The use of Antiplatelet therapy is left to the discretion of the treating physician. Antiplatelet therapy type 
and dosing should be recorded on the eCRF. Timing of anticoagulation and ACT during the procedure should 
be documented on the eCRF.    
For the Platinum group, any type of FDA or HPB approved or cleared (as applicable) bare platinum coils 
can be used. For the Hydrogel group, the investigator will use any type of FDA or HPB approved or cleared (as 
applicable) second generation HydroCoil Embolic System product (which includes HydroSoft, HydroFrame, 
HydroFill and future FDA or HPB approved hydrogel products). For subjects randomized to the Platinum arm, 
treatment should involve exclusive use of bare platinum coils. For subjects randomized to the Hydrogel arm, 
treatment should involve exclusive use of HES products with up to 10% of total coil length using bare platinum 
allowed.  
   
After the procedure, digital copies of the pre and post-coiling angiograms with AP and lateral working 
projections will be sent to the Imaging Core Lab for independent evaluation and analysis. A copy will also be 
sent to the Sponsor, Northwestern University. The images will be de-identified and the CD/DVD will be labeled 
with the subject’s assigned study identification number, imaging type, and date of imaging.  
 
6.7 
Post-procedure follow-up: Day 1 post-coiling 
On day 1 post-coiling, clinical and neurological assessment of the subject is performed and documented 
on the eCRFs. This visit involves a mRS assessment for all subjects and NIHSS and Hunt & Hess scale 
assessments for subjects presenting with a ruptured aneurysm.  
 
6.8 
Immediate follow-up visit: Between 3 to 28 Days post-coiling 
The immediate post-coiling follow-up will consist of a clinical assessment and specifically a neurological 
exam. This visit involves a mRS assessment for all subjects and NIHSS and Hunt & Hess scale assessments 
for subjects presening with a ruptured aneurysm. The investigator or an authorized member of the research 
team will assess for any new or unresolved adverse events. The need for cerebral imaging will be assessed 
and performed according to the standard of care at each institution to evaluate aneurysm occlusion and to 
study the early recanalization rate. If the length of hospitalization post-procedure equals or exceeds 3 days, 
then the 3 to 28 day follow-up will also be considered as the discharge follow-up and it will be marked as such 
on the eCRF. If a 3-28 day visit is not standard of care at a site, the mRS score and review of adverse events 
can be obtained via phone.  
 

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6.9 
Early follow-up Visit: Between 3 months to 12 months post-coiling 
Clinical and neurological assessments will be performed. The neurological examination will include the 
mRS. The investigator or an authorized member of the research team will assess for any new or unresolved 
adverse events. A digital subtraction cerebral angiogram will be performed. MRA can be performed instead of 
or in addition to the angiogram if considered standard of care at the institution. Quality of life will be assessed 
with the SF-36 questionnaire. For subjects enrolled with ruptured aneurysms, an NIHSS score will also be 
obtained. 
 
6.10 Final follow-up Visit: Between 18 to 24 months post-coiling 
Clinical and neurological assessments will be performed. The neurological examination will include the 
mRS. The investigator or an authorized member of the research team will assess for any new or unresolved 
adverse events. A digital subtraction cerebral angiogram will be performed. MRA can be performed instead of 
or in addition to the angiogram if considered standard of care at the institution. Quality of life will be assessed 
with the SF-36 questionnaire. For subjects enrolled with ruptured aneurysms, an NIHSS score will also be 
obtained. 
 
6.11 Unscheduled Follow-up Visit 
Should an unscheduled follow-up visit occur, the reason for the visit should be clearly marked in the 
eCRF. In the event there is a change in the clinical neurological status due to an adverse event/serious 
adverse event, the mRS score should be assessed and entered in the eCRF. If the subject presents with a 
hemorrhage, the NIHSS and Hunt and Hess scores should be assessed and entered in the eCRF. The 
investigator or an authorized member of the research team should assess and report any unresolved or new 
adverse events. If imaging is ordered to assess occlusion or recurrence of the aneurysm, the Imaging eCRF 
must be completed and the imaging CD should be sent to the Imaging Core Lab and the Sponsor, 
Northwestern University.  If imaging is performed for purposes other than to assess occlusion or recurrence, 
the Imaging eCRF does not need to be completed and no CD is required for submission.  
6.11. 1   Re-treated Subjects 
 
For subjects who are retreated, please complete the Unscheduled follow-up visit. If a subject is 
retreated by coiling or stent-coil, sites will need to send the images to both the IMAGING CORE LAB and 
Sponsor. 
 
 
For subjects who were retreated prior to their 18-24 Month follow-up visit, please follow the above 
depending on how the subject was treated. 
 
6.12 Schedule of Assessments 
A summary of the study related assessments as outlined above is described in Table 4. 
 
6.13 Study Completion 
Once a subject completes all study follow-up visits which include the 18 to 24 month visit, the Final 
Follow-Up  eCRF must be completed. During the course of the study, it is possible that subjects will be 

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withdrawn from the study prior to completing the final 18 to 24 months visit. Factors leading to Subject 
withdrawal may include, but are not limited to the following: 
 
Subject Withdrawal - A Subject may voluntarily withdraw from the study at any time for any reason, 
whether disclosed or undisclosed, without affecting their future medical treatment or benefits. In 
addition, if a patient refuses follow-up examinations and evaluations the investigator may remove 
her/him from the study after appropriate notice. 
 
Subject Lost to Follow-Up – If the subject does not show up to the planned follow-up visits, 
attempts should be made to contact her/him. If after at least three (3) attempts the subject remains 
unreachable, she/he may be withdrawn from the study. The research team must document at least 
three contact attempts before declaring a subject as lost to follow-up.   
 
Subject Death - When a Subject dies, the ADVERSE EVENT and STUDY EXIT eCRFs must be 
completed immediately (within 24 hours of the event). If available, documents such as the death 
summary, the autopsy report and a copy of the death certificate shall be provided to the principal 
investigator of the site and the Sponsor, Northwestern University, and the funder, MicroVention. 
Personal identifiers should be removed from any documentation provided. The site’s IRB shall also 
be notified promptly. 
If a subject was withdrawn for any of the above mentioned reasons, the Study Exit eCRF form must be 
completed.  
7 
Management of Adverse Events 
 
7.1 
Definitions 
An Adverse Event (AE) is any undesirable clinical event occurring to a subject enrolled in the trial, 
whether or not it is considered related to the investigational product. This includes a change in a patient's 
clinical condition including changes in neurological status or laboratory results that has or could have a 
deleterious effect on the patient's health or well-being.  
An Adverse Device Effect (ADE) is any AE related to the deployment of any coil type.  
A Serious Adverse Event (SAE) or a Serious Adverse Device Effect (SADE) is an event that:  
 
Results in death 
 
Is life threatening  
 
Is disabling  
 
Requires initial or prolonged hospitalization (does not include planned hospitalization) 
 
Requires intervention to prevent permanent impairment / damage 
An Unanticipated Adverse Device Effect (UADE) 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 investigational plan, or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare 
of subjects. 
 
See Figure 3 for a classification of adverse events. 

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7.2 
Reporting of Adverse Events 
For this post-market study, only AE/SAEs that are related to the procedure, device or a change in 
neurological status should be captured on eCRFs and in the Subject’s medical records, for both treatment 
arms. In case of occurrence of any SAE and/or UADE, the site’s principal investigator shall promptly submit a 
report along with any other required documentation to the Sponsor, Northwestern University and funder, 
MicroVention, Inc and follow site-specific IRB procedures.  
  
 
If there is a serious adverse event, the clinical study site will report such to the Sponsor, Northwestern 
University and the funder, MicroVention, Inc within 24 hours of learning the event.  
 
 
If there is an unanticipated adverse device effect, the Principal Investigator will submit a report to the 
Sponsor, Northwestern University and the funder, MicroVention, Inc and to the reviewing IRB as soon as 
possible, but not later than 10 working days after the investigator learns of the effect. 
  
All other reportable events should be reported no later than 10 working days after the investigator or 
site first become aware of the adverse event in question. 
 
The adverse event report should at least include the following parameters:  
 
Date of event and time 
 
Type of event (E.g., AE, SAE, UADE) 
 
Narrative 
 
Duration of adverse event or adverse device effects (start-end) 
 
Treatment 
 
Outcome/Resolution Status 
The principal investigator and the principal investigator of the site shall present any additional information 
or documentation (e.g. imaging results) to the DSMB and steering committee if required by these committees. 
 
 
7.3 
Expected Risks 
Known risks associated with aneurysm coiling are as follows: 
 
Aseptic meningitis 
 
Inflammation 
 
Thromboembolic events 
 
Stroke 
 
Vasospasm 
 
Hydrocephalus 
 
Aneurysm Rupture  
 
Coil protrusion into parent vessel  
 
Parent Vessel Occlusion 
 
Premature coil detachment (coil breakage due to technical device malfunction) 
 
Death 
 
 

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8 
Ethics and Regulatory Considerations 
 
8.1 
Subject Information and Consent Procedures 
The Investigator, study coordinator or any other member of the research team approved by the IRB will 
obtain written informed consent from the patient or his/her LAR before subjecting her/him to study assessment 
procedures. The Subject will be clearly informed that the principal investigator, study coordinator and study 
monitor of the coordinating site (Northwestern University) will have access to personally identifiable information 
for the purposes of monitoring data against source documentation. However, only de-identified data is entered 
into the study database.  
Each site participating in this study will have their own consent form that must be approved by their IRB. 
In addition, a study consent form approved by the primary site IRB will be provided to each clinical site. Only 
the local participating site consent form should be signed prior to enrollment and treatment. The coordinating 
site must receive and approve each participating site’s ICF. Each Investigational site must provide to the 
Sponsor or Principal Investigator a copy of its IRB approved ICF, renewed approvals and signed patient 
consents, as appropriate, for the duration of the study. 
The original, signed and dated ICF should be retained in the Subject’s study records, and a copy 
provided to the Subject. Documentation of the informed consent process should also be retained in the 
subject’s study records. 
8.2 
IRB Approval 
The Investigator or the study coordinator is responsible for submitting the study protocol and any 
changes issued by the Sponsor during the course of the study for IRB approval prior to any Subject enrollment 
and amendments taking effect as well as obtain renewals at periods determined by the IRB for the duration of 
the study.  
9 
Statistical Methods 
Primary analysis of primary and secondary outcomes will be based on the intent-to-treat (ITT) principle. 
Secondary analyses will examine differences based on per protocol principles, as well as a detailed analysis of 
missing data, should there be any (see below). 
9.1 
Sample Size Estimation 
 For univariate associations, using a two-sided two-sample test of proportions (Chi-square test), Table 5 
shows the effect sizes one would be able to detect for given baseline rates (assuming 1:1 randomization and 
5% type I error rate) at 80% power. 
Using multiple logistic regression to predict recurrence (baseline rate in Platinum group of 33%), the 
sample of 600 patients would provide 80% power to detect an odds ratio between 0.60 and 0.47, depending on 
the r-squared of the other covariates to coils (between 0-0.2; note r-squared of 0 corresponds to hydrogel rate 
of 22.8% as in the univariate analysis). Likewise, for complete occlusion (baseline rate of .556), a sample of 
600 provides 80% power to detect odds ratios between 1.60-1.70, depending on the r-squared of the other 
covariates to coils (between 0-0.2; note r-squared of 0 corresponds to hydrogel rate of .678 as above).  
Similarly, for recanalization, one would have 80% power to detect odds ratios between 0.613-0.577 (n=600). 
 
 
 

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9.2 
Statistical Analysis Plan 
9.2.1 
Primary endpoints: 
Chi-square tests (simple logistic regression) will be used to determine if rates of recurrence differ by coil 
type. Additionally, multiple logistic regression models will be used to examine those rates while adjusting for 
various covariates, including, but not limited to: site, age, gender, aneurysm size, neck size, packing density 
and rupture status. Models will be fit to examine potential interactions between covariates and randomization 
group in predicting outcomes; and final models will be fit depending on statistical and clinical significance of the 
covariates to the outcome as well as any change in the relationship between the randomization group and 
outcome. Analyses will be presented both as univariate and adjusted Odds Ratios and corresponding [Wald] 
95% Confidence intervals.  
While the study has been designed to minimize any missing data due to this being a longitudinal study, 
the potential for missing data or loss to follow-up is present. Patterns of missing data and dropout will be 
examined to determine if complete case analysis or available data analyses are appropriate or if imputation 
methods will need to be incorporated.  Should a complete case analysis be appropriate, PROC LOGISTIC will 
be used to analyze these binary outcomes; otherwise PROC GLIMMIX will be used for an available data 
analysis. If imputation methods are called for, PROC MI and PROC MIANALYSE will be used and results 
presented. All analyses will be run at a type I error rate of 5% using SASv9.2, Cary, NC. 
   
9.2.2 
Secondary endpoints: 
The rates of initial complete occlusion, partial occlusion, recanalization, retreatment, or hemorrhage from 
the target aneurysm during follow-up (and other binary outcomes) will be analyzed similar to the primary 
endpoints. Packing density will be analyzed by comparing means or medians (depending on the underlying 
distribution) between groups. Additionally, this will be compared using linear regression models (PROC REG or 
PROC MIXED, as above) adjusting for potential confounders including site, age, gender, aneurysm and neck 
size, and rupture status.  Clinical outcomes and quality of life will be compared between groups using models 
appropriate for repeated measures (generalized linear mixed models). This will take into account changes in 
these outcomes over time as well as the 18-month evaluation and can accommodate some missing data as it 
does not require only complete cases be used but rather uses an available data analysis. Again univariate and 
multivariate results (means and 95% Confidence intervals) will be presented. 
 
9.3 
Demographics by race/ethnicity 
This is an international study. Since intracranial aneurysms are more prevalent in females than in males, it 
is anticipated that there will be a higher relative percentage of females represented in the study population. 
 
10 
Records and Reports 
 
10.1 Records 
Each study site will maintain eCRF and source study records for monitoring and/or audit purposes for the 
latter of: 
 
At least five (5) years after study completion; or 
 
For the period required by the local governing authority and reviewing IRB 

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These records also include the following:  
 
Correspondence with the Sponsor, the Funder, the Imaging Core Lab, the DSMB, the steering 
committee, the various committees and other investigators 
 
Patient Records, including ICFs and supporting documents in addition to the eCRF 
 
Most current version of the study protocol with dates and details of reasons for any deviations 
from the protocol 
 
Reports of any adverse events, serious adverse event or adverse device effects 
 
A copy of all approvals related to the clinical investigation 
 
The approved, blank ICF and blank CRFs 
 
Certification that the investigational plan has been approved by the IRB from each site 
 
Signed sub-site agreements with the Sponsor, the site and principal investigator of the site.  
The site principal investigator and the study coordinator will be responsible for archiving the data for the 
periods mentioned above. If the data is to be archived at an off-site, the IRB will be notified and the principal 
investigator and the study coordinator will be responsible for keeping it confidential. The Sponsor will have full 
access to this data, and the Funder will have read-only access to this study data, as provided by Northwestern, 
solely for review and adjudication of information related to any AE, SAE, ADE, SADE and UADE (as defined in 
section 7.1) for legal and compliance purposes 
 
10.2 Reports 
Investigators at participating sites are required to submit reports in conformance with the regulations 
mentioned throughout this protocol. 
 
10.3 Protocol deviation 
Any deviation from the protocol should be reported within 10 days to the Sponsor and clearly 
documented. Each site will be responsible for reporting any protocol deviation to their IRB according to their 
institution’s standards. 
  If the investigator finds that the aneurysm characteristics require a deviation from the protocol, he/she 
must contact the principal investigator of the site as soon as possible and the principal investigator of the site 
or investigator shall submit a report as to why this decision was made. Any protocol deviation must be clearly 
documented in the eCRF. 
 
11 
Data Management 
All required data for this study will be collected on appropriate source medical records and source  
documents for entry into the EDC within 5 days of the subject visits. A database lock timeline will be created to 
ensure proper and timely collection of data from all sites (this will be done every 3 months). 
 
 
 

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12 
Monitoring of the study and Quality Control 
 
12.1 Medical Monitoring by DSMB 
All SAEs and ADEs will be reported to and evaluated by the DSMB members for a potential relationship 
to the study device or procedure as set forth in Section 7.2. All AEs will be evaluated by the investigational site 
and the principal investigator of the site, and they will follow site specific IRB procedure with respect to AEs. 
The principal investigator of the site will complete the eCRF and notify the Sponsor and Principal Investigator 
with respect to AEs in accordance with Section 7. 
 
12.2 Data Collection and Monitoring 
Each site’s study coordinator will collect and document data in hospital and clinic charts. eCRF data will 
be entered in anonymous form into the secure web-based and password-protected database within 5 days of 
each subject study visit. Only the investigator, study coordinator and other designated authorized research 
personnel will have access to the database. Each participating site will have access to only its own data. In 
addition, the Sponsor, the Principal Investigator, monitor and the study coordinator of the Sponsor’s site will 
have access to the entire database with full rights to act as the administrator of the database. 
 
Data verification occurring during monitoring visits will involve the review of the subject’s medical record 
(for study specific visit dates only) and source documents. These source documents should only be used in 
instances where the subject’s medical record does not contain the data required for study. These forms should 
be signed and dated by study personnel collecting the data at the time of collection.  
Completed eCRFs in final form may be printed and filed in hardcopy for archiving if required by the local 
governing authority. All data will be exported and stored on appropriate electronic media by the Principal 
Investigator and to study biostatistician for analyses.   
The Principal Investigator of each site is responsible for data integrity at the site and will review and 
electronically sign all Patient Selection, Adverse Event, Protocol Deviation, Imaging and Study Exit eCRFs. 
The clinical site will be monitored routinely by the Sponsor and by a trained study coordinator and/or 
monitor for adequate enrollment, timeliness of data submission, and compliance with the investigational plan 
and applicable local and federal regulations. If the site in question fails to show compliance with the above 
mentioned, the site investigator will be contacted by the principal investigator, and if corrective actions are not 
taken to resolve the issues, the clinical site may be withdrawn from the study. 
 
12.3 Site Compliance / Deviations 
In order to optimize correct and detailed records, all eCRFs should be entered in the web-based 
database as indicated in Table 6. 
In some cases, a site investigator may want to include and randomize a potential Subject who meets all 
but one Inclusion/Exclusion criterion. The investigator will present the case and report their medical opinion to 
the Sponsor, Principal Investigator and, if appropriate, the DSMB for consideration. If the prospective deviation 
is approved then the Subject may be enrolled in the study. This protocol deviation will be documented in the 
subject’s eCRF. 

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13 
Financial and Insurance Matters 
As all devices used in this trial are FDA or HPB approved, the coiling procedures are considered 
Standard of Care and shall be the patient’s responsibility (insurance or self-pay). Any follow-up assessments 
that are protocol driven and not standard of care shall be covered under study agreement.  
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1086. 
21. 
Deshaies EM, Adamo MA, Boulos AS. A prospective single-center analysis of the safety and efficacy of 
the hydrocoil embolization system for the treatment of intracranial aneurysms. J Neurosurg. Feb 
2007;106(2):226-233. 
22. 
Kang HS, Han MH, Lee TH, et al. Embolization of intracranial aneurysms with hydrogel-coated coils: 
result of a Korean multicenter trial. Neurosurgery. Jul 2007;61(1):51-58; discussion 58-59. 
23. 
Meyers PM, Schumacher HC, Higashida RT, et al. Reporting standards for endovascular repair of 
saccular intracranial cerebral aneurysms. AJNR Am J Neuroradiol. Jan 2010;31(1):E12-24. 
24. 
Roy D, Milot G, Raymond J. Endovascular treatment of unruptured aneurysms. Stroke. Sep 
2001;32(9):1998-2004. 
 

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Table 1. Major hydrogel coil studies - initial results 
 
Author 
and 
year 
Type of study 
Number of 
aneurysms 
treated 
Aneurysm size 
Ruptured 
vs. 
Unruptured 
Mean 
Neck size 
 
Initial 
Complete 
Occlusion 
Residual 
Neck 
Residual 
aneurysm 
% hydrocoil 
used 
Berenstein 
et 
al. 2006 
Retrospective 
Single center 
104 
S/S: 42 
S/W: 27 
L: 32 
G: 3 
48 vs. 56 
- 
34% 
35% 
32% 
45.5% 
Cloft 
et 
al. 
2006 (HEAL) 
Prospective 
Multicenter 
Registry 
191 
Mean: 8 mm 
71 vs. 120 
4.3mm 
48.7% 
41.4% (near-
complete) 
9.9% 
Frame: 
Platinum coil  
Fill: HydroCoil
Gaba 
et 
al. 
2006 
Prospective 
50 
S ( 5mm): 17 
M (6 - 10 mm): 26 
L (11 - 20 mm): 5 
31 vs. 19 
- 
58% 
36% 
6% 
71.8% 
Deshaies et al. 
2007 
Prospective 
67 
S: 30 
L: 27 
VL: 7 
G: 3 
35 vs. 32 
- 
43% 
35% 
22% 
- 
Fanning et al. 
2007  
Prospective 
observational 
100 
<7 mm:42 
7 -15 mm: 52 
16 - 25 mm: 6 
64 vs. 36 
 4mm: 40 
28% 
54% 
(>95% 
occluded) 
18% 
42.5% 
Kang 
et 
al. 
2007 
Prospective 
Multicenter  
80 
S :58 
L (10 mm): 22 
32 vs. 48 
- 
75% 
17.5% (near-
complete) 
7.5% 
46 to 74% of 
followed-up 
aneurysms 
White et al. 
2008 (HELPS) 
Randomized 
Controlled 
trial 
495 
(249 
randomized 
to 
the 
Hydrogel 
group) 
Mean: 6.5 mm 
2 - 4.9 mm: 42 
5 - 9.9 mm: 144 
10 - 24.9 mm: 63 
139 vs. 110 
- 
47.3% 
31.3% (near-
complete) 
21.4% 
- 
Gunnarsson et 
al. 2009 
Retrospective 
200 
S (<10mm): 125 
L (10 - 25 mm):75 
104 vs. 96 
- 
53.8% 
29.6% 
16.6% 
58% 
 
 
Table 2. Major Hydrogel coil studies - follow up results 
Author 
and 
year 
Complications/ 
Morbidity 
Mortality 
% followed up 
 
Mean 
Follow-up 
(Months) 
Recanalization 
Retreatment
Berenstein et 
al. 2006 
14 / 5.8% Immediate 
post- 
procedure 
Morbidity 
0% 
(Immediate post-
procedure) 
51% 
10.3 
21% 
- 
Cloft et al. 
2007 (HEAL) 
10.9% 
(Immediate 
post-
procedure) 
 
- 
135/191 
(70.6%) 
3-6 
28.1% 
- 
Gaba et al. 
2006 
4% 
2 (4.4 %) 
84% 
12.3 
17% 
10% 
Deshaies 
et 
al. 2007 
32.8% 
- 
90% 
12 
15% 
- 
Fanning et al. 
2007 
12% / 6.4% morbidity 
1.1% 
63% 
7.5 
14.3% 
4.8% 
Kang et al. 
2007 
16 procedure related-
events 
0% 
68% 
 6 mo: 54 aneurysms 
 12 mo: 13 aneurysms
11% 
- 
White et al. 
2008 
(HELPS) 
70  
(Procedural Adverse 
events) 
3.6% 
- 
- 
- 
- 
Gunnarsson 
et al. 2009 
15% 
complication  
(6% 
leading 
to 
permanent morbidity 
or mortality) 
 
60.5% 
16.3 
21.5% 
10.7% 

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      25 
 
Table 3. Hunt and Hess classification of SAH 
 
Grade 
Description 
1 
Asymptomatic, or mild H/A and slight nuchal rigidity 
2 
Cr. N. palsy (e.g. III, VI) moderate to severe H/A, nuchal rigidity 
3 
Mild focal deficit, lethargy, or confusion 
4 
Stupor, moderate to severe hemiparesis, early decerebrate rigidity 
5 
Deep coma, decerebrate rigidity, moribund appearance 
Add one grade for serious systemic disease (e.g. HTN, DM, severe atherosclerosis, COPD) or severe 
vasospasm on arteriography. 
 
 
Table 4. Schedule of assessment   
1 For Subjects enrolled with ruptured aneurysms  
2 According to standard of care of each institution.  
3 For Subjects with ruptured aneurysms who are unable to complete the SF-36 prior to procedure, the SF-36 can be 
completed prior to subject discharge following procedure. 
 
 
 
 
 
 
 
 
 
HydroCoil Embolic System Clinical 
Trial 
Screening 
& Baseline
Procedure 
Post-
procedure 
Follow-up 
Immediate 
Follow-Up 
Early 
Follow-Up 
Final 
Follow-Up 
Schedule of Events 
Up to 30 
days prior to 
surgery 
Day 0 
Day 1 
3-28 Days 
3-12 Months 
18-24 
Months 
Review Inclusion/Exclusion 
X 
 
 
 
 
 
Data Entry, Validation, Query 
Resolution 
X 
X 
X 
X 
X 
X 
Obtain Informed Consent 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
Demographic Data 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Hunt & Hess Scale1 
X 
X 
X 
 
 
 
Modified Rankin Score 
X 
X 
X 
X 
X 
X 
NIH Stroke Scale (NIHSS)1 
X 
X 
X 
 
X 
X 
SF-36 
X3 
 
 
 
X 
X 
Angiogram 
X 
X 
 
 
X 
X 
MRA 
X2 
 
 
 
X2 
X2 
Final Visit Assessment 
 
 
 
 
 
X 

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      26 
 
 
 
 
Table 5. Effect Sizes for outcomes with N=600, with 80% power 
 
Outcome 
baseline 
(platinum) 
rates 
 
Hydrocoil rates 
% change 
Recurrence 
33.0% 
22.8% 
-30.9% 
Complete occlusion 
55.6% 
66.7% 
20% 
 
47.6% 
59.0% 
23.9% 
Complete 
or 
nearly 
complete 
occlusion 
85.5% 
92.6% 
8.4% 
Retreatment 
17.4% 
9.6% 
-44.8% 
 
 
 
 
Table 6. Electronic Data Entry Timelines 
 
 
eCRF 
Timeline 
Adverse Event eCRF  
In the event of a serious adverse event, 
complete the AE CRF on the web-based 
database and fax report within 24 hours of 
learning of the event to the Sponsor and 
Funder.  Comply with local reviewing IRB 
reporting rules.  
In the event of an unanticipated adverse 
device effect, complete the AE CRF on 
the web-based database and fax report as 
soon as possible, but no later than 10 
working days after the investigator first 
learns of the effect to the Sponsor and 
Funder.  Comply with local reviewing IRB 
reporting rules. 
All other eCRFs 
Within 5 business days of subject 
discharge or follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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      27 
 
 
 
 
Table 7:  Required Imaging Schedule 
HydroCoil 
Embolic System 
Clinical Trial 
Screening & 
Baseline 
Surgery 
Post-
Procedure 
Follow-up 
Immediate 
Follow-up 
Early 
Follow-up 
Final Follow-up 
Schedule of 
Events 
Up to 30 days 
prior to 
surgery 
Pre-Coil 
Post-Coil 
Day 1 
3-28 Days 
3-12 
Months 
18-24 Months 
Angiogram 
 
X 
X 
 
 
X 
X 
MRA 
 
 
 
 
 
X² 
X² 
² According to standard of care at each institution 
 
Please note that if an angiogram, MRA or CTA is performed 30 days before surgery, the Imaging eCRF 
should be completed and the CD shipped to the core lab and Northwestern University.  This imaging is 
optional and is not required for the study. 
Results of MRIs or CTs are not needed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 1. Aneurysm occlusion grading system as reported by Meyers et al.23  
 
 
 
 
Figure 2. Raymond angiographic classification of residual coiled aneurysm. 
 

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Figure 3:  Classification of Adverse Events 
 
 
 
                   yes 
 
 
 
 
 
 
 
 
 
no 
 
 
 
 
 
 
 
 
 
 
      
 
           yes 
 
 
 
 
 
 
 
 
 
        no 
 
 
 
     no 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    yes 
 
           yes 
 
         
 
 
 
 
 
 
 
 
 
 
 
 no 
 
 
 
 
 
 
 
           yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 no 
 
 
 
 
 
 
 
 
 
 
 
 
 
             yes 
 
A. Complaint or Untoward medical 
occurrence   
(i.e., adverse event) 
B.  Subject? 
Non-medical 
complaint 
C. Device, 
comparator or 
procedure related 
Serious? 
Adverse Event 
(AE) 
D. Serious? 
Adverse Device Effect 
(ADE) 
Serious Adverse Event 
(SAE) 
 E. Unanticipated? 
Serious Adverse Device Effect 
(SADE) 
Unanticipated Serious Adverse Device 
Effect 
(USADE)