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PROTOCOL AVF 10 Feb 2017 version A 2

PHIL evaluation in the endovascular treatment of intracranial dural AVF

European multi-center, observational, prospective, single arm and open label study.

AVFRegistryPHILprotocol10Feb2017versionA Page2

Tableofcontents31

SUMMARY...............................................................................................................................................332

1. INTRODUCTION...................................................................................................................1033

2. MEDICAL DEVICE INFORMATION................................................................................2134

3.0. Study Design........................................................................................................................2235

3.1. Study Patients......................................................................................................................2236

3.2. Study Schedule Table..........................................................................................................2237

4. STUDY OBJECTIVES...........................................................................................................2338

4.0. Primary endpoint................................................................................................................2339

4.1. Secondary endpoints...........................................................................................................2340

5. ASSESSMENT CRITERIAS.................................................................................................2341

5.0. Main Criteria Assessment..................................................................................................2342

5.1. Secondary Criteria Assessments........................................................................................2443

6. DATA TO BE COLLECTED PER SCHEDULED VISITS................................................2444

6.0. Selection...............................................................................................................................2445

6.1. Inclusion...............................................................................................................................2546

6.2. Procedure.............................................................................................................................2647

6.3. Discharge..............................................................................................................................2848

6.4. 1 Month Follow up..............................................................................................................2849

6.5. 3-6 Months Follow up.........................................................................................................2950

7. CLINICAL SITE.....................................................................................................................3051

8. STUDY DURATION..............................................................................................................3052

9. PATIENT SELECTION.........................................................................................................3053

9.0. Inclusion criteria.................................................................................................................3054

10. STATISTICAL ANALYSIS PLAN.......................................................................................3055

10.0. Statistical Analysis..........................................................................................................3156

10.1. Population size.................................................................................................................3157

10.2. Invalid, Unused and Missing data..................................................................................3158

10.3. Minimizing bias strategy................................................................................................3259

11. END OF STUDY PARTICIPATION....................................................................................3260

12. ADVERSE EVENTS...............................................................................................................3261

13. PROTOCOL DEVIATIONS..................................................................................................3362

14. QUALITY CONTROL...........................................................................................................3363

15. ETHICS AND REGULATIONS............................................................................................3464


16. STUDY DOCUMENTATION AND DATA RETENTION.................................................3465

17. DATA ANALYSIS and REPORTS.......................................................................................3466

17.0. Access to the data and source documentation...............................................................3467

17.1. Study Report....................................................................................................................3568

17.2. Presentation and publication rules................................................................................3569

18. RISKS AND BENEFITS........................................................................................................3570

18.0. Risks.................................................................................................................................3571

18.1. Benefits.............................................................................................................................3572

19. APPENDIX..............................................................................................................................3573

19.0. Patient Informed Consent Form....................................................................................3574

19.1. Clinical sites list...............................................................................................................3575

19.2. Cognard & al. Classification..........................................................................................3576

19.3. Bibliography....................................................................................................................3677

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SUMMARY 92

ProtocolSummary93

Titleandstudydesign: PHIL evaluation in the endovascular treatment of intracranial dural

AVF

European multi-center Study, observational, prospective, single arm

and open label.

Device: PHIL® Liquid Embolic System

(PHIL-25, PHIL-30, PHIL-35)

PHIL device, is CE marked for the evaluated indication

Studyobjective: Safety evaluation at 1 month after each embolization, 3-6 months

after last embolization and efficacy 3-6 months after the last

embolization treatment of dAVF with PHIL used with or without

other embolization products (cyanoacrylate glue, coils, balloon, etc.).

Primaryendpoint: • Safety: Number of adverse events (resulting in death or not)

at 1 month after each embolization and neurological

assessment (mRS) 1 monthsafter each embolization

compared to baseline

• Angiographic Efficacy: The cure rate by Angiographic

assessment at 3-6 months after last embolization

• Clinical efficacy: clinical course of the patient assessed as

(Stable / improved / deteriorated) at 3-6 months after last

embolization compared to baseline

Secondaryendpoints: • Safety: Number of adverse events (resulting in death or not)

3-6 months after last embolization and neurological

assessment (mRS) performed by a Independent neurologist

3-6 months after last embolization compared to baseline

• Improvement in the quality of life of the patient (QOL EQ

5D assessment) and changes in patients symptoms (Stable /

improved / deteriorated) present at baseline versus at 3-6

months after last embolization


Studypopulation: Selection Phase: All patients with an intracranial dAVF requiring

treatment that has not been previously treated (regardless of the

intended mode of treatment and who provide appropriate consent).

Patient population: All patients with an intracranial dAVF that has

not been previously treated and will be treated by embolization with

PHIL® used with or without other embolization products and who

provide appropriate consent. At the end of the screening visit these

patients will be documented into a screening log.

Patientenrollment: Up to 16 institutions will enroll up to 60 subjects.

Each center will include a minimum of 4 patients.

Samplesize: 60 patients

With a sample size of 55 patients, we will be able to estimate the

success rate with a 95% confidence interval size of ±10.0%

considering the observed success rates in a previous study (83%)

(Cognard and al.). Thus, the lower bound of the 95% confidence

interval will be higher than the lowest estimation found in the

literature (Lv and al. 61%).

In addition, even with 10% loss to follow-up patients, this sample

size (N=60) ensures an accuracy of at least ±10% for observed

parameters.

Studyduration: The duration of the study will be determined by the time required to

recruit 60 consecutive patients within 16 investigational centers. As

the centers may not be activated simultaneously, the total period of

inclusion is estimated at 12 months.

The majority of dAVFs treated by embolization are treated in one or

two sessions. As this is an observational study in which all patients

will be followed 3 to 6 months after the last embolization by PHIL®

as part of a therapeutic path in which the number of embolizations

and the time between sessions can be variable, the expected

approximate study duration is 24 months.


Inclusioncriteria: • Patient or patient’s legally authorized representative has received

information about data collection and has signed and dated an

Informed Consent Form

• Patient has an intracranial dAVF that can be treated by

embolization with PHIL® used with or without other embolization

products except other non-adhesive liquid embolization products

(i.e. Onyx or Squid)

• Patient is at least 18 years of age.

Exclusioncriteria: • - Patient has multiple dAVFs to be treated

• - Patient participates in a study evaluating another medical device,

procedure, or medication during the course of dAVF treatment and

follow up per this study protocol

• - Patient does not give consent to the collection and processing of

data required for centralized monitoring

• (For patients who refused collection of their personal data or

meeting an exclusion criteria only, their age, sex, the reason for

non-inclusion and the date of screening will be documented in a

screening log.)

-Any condition that could prevent patient follow up

Followup: Per each study center’s standard of care follow up paradigm

Independentcentral

review:

Centralized review of laboratory tests (Core Lab): An independent

committee will evaluate the angiographic / MRA assessments at the

following times:

• Before the first embolization session, in order to assess the

dAVF anatomy.

• At the end of the treatment, after the last embolization

session.

• At 3-6 months post last embolization (imaging control).


Clinical events Committee (CEC):

This independent committee will evaluate any adverse events (serious

or not) per/post-procedure throughout the study duration. Any AEs

will be evaluated as serious or not and their relationship to the device

and / or procedure will be evaluated throughout the study.

Statisticalmethod: All patients included and treated with PHIL® during the study will

be analyzed (ITT).

Categorical variables will be described by their frequency

distribution and ranges bilateral 95% confidence. Continuous

variables will be described by their average, minimum standard

deviation, maximum, median and quartiles.

Variables (3-6 months cured (yes / no) or improvement of mRS at 1

month (yes / no)) will be described by their distribution frequencies

and intervals bilateral associated 95% confidence.

Relevant group comparisons will be performed using an adequate test

for the variable type:

• Person's chi-square (or Fisher's exact test if the expected

frequency in a group is smaller than five) for qualitative

variables

• Variance analyses for quantitative variables

• Variance analyses based on ranks for ordinal variables

Statistical test will be performed with a type I error risk of 5%.

The rate of events for which a date of onset has been collected will be

described survival curve according to Kaplan-Meier method and the

associated Kaplan Meier estimators will be calculated.

Regulatory: Prior to inclusion of patients, this non-interventional evaluation will

be submitted in accordance with the appropriate regulations in each

participating country, in order to obtain opinions and authorizations.

Patient information:

The patient (or his/her legal representative) must sign and date an

Informed Consent Form, prior to inclusion in the study, and be

informed of his/her rights to be able to object, if desired, to the


collection and transmission of data. In accordance with appropriate

regulation, a note containing all required information will be given to

the patient or his legal representative.

Datacollectionandstudy

management:

Data will be collected by the participating investigators in an

electronic CRF developed specifically for this evaluation. Access is

secure and limited to authorized persons.

Microvention Europe is responsible for monitoring the data

collection. To ensure data quality, a plan for monitoring visits will be

implemented.

Data from the study will be stored in a European or international

public database.

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Acronyms 95

Abbreviations Definitions

AE/SAE Adverse Event/Serious Adverse Event

AICA Anterior Inferior Cerebral Artery

CA Competent Authority

cAVM Cerebral Arterio Venous Malformation

CEC Clinical Event Committee

CE Conformité Européenne (European Conformity)

CRA Clinical Research Associate

CT/CTA Computed Tomography/Computed Tomography Angiography

CVD Cortical Venous Drainage

dAVF dural Arterio Venous Fistula


DSA Digital Subtraction Angiography

DMSO DiMethyl SulfOxide

EoS End of Study

EVOH Ethyl vinyl alcohol

ICA Internal Carotid Artery

ICF Inform Consent Form

ICH Intra Cerebral Hemorrhage

IVH Intra Ventricular Hemorrhage

LOCF Last Observation Carried Forward

MRA/MRI Magnetic Resonance Angiography/ Imaging

mRS modified Rankin Scale

NBCA N-Butyl CyanoAcrylate

NSR NeuroSurgery

PICA Posterior Inferior Cerebral Artery

RT Radio Therapy

SAS Statistical Analysis System

TIA Transient Ischemic Attack

WFNS World Federation of Neurological Surgeons

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1. INTRODUCTION 100

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Intracranial dural arteriovenous fistulas(dAVFs)are acquired transdural arteriolo-venous shunts.102

They are most often encountered in adults more than 50 years old but may also be seen in103

newborns. They present with a very wide spectrum of symptoms (pulsatile tinnitus, ocular104

symptoms, intracranial hypertension, dementia, intracranial hemorrhages, myelopathy, etc.).105

Dependingontheirvenousdrainagetheycanbeeitherbenignwithoutanyneurologicalriskforthe106

patient or on the contrary aggressive carrying a very high risk of intracranial hemorrhage. Perfect107

understandingoftheangio-architectureandvenousdrainagepatternsismandatorytoevaluatethe108

individualneurologicalriskofeachpatient.Treatmentstrategybasicallydependsonvenousdrainage109

andconsequentneurologicalrisk.110

Physiopathologyandclassification:111

dAVFs have long been regarded as a benign disease when compared to brain arteriovenous112

malformations1.However,thefirstdescriptionsofintracranialhemorrhagefromdAVFsmodifiedthis113

ideaandledtothebeliefthatalldAVFswerepotentiallyatrisk.dAVFswerefirstclassifiedaccording114

to their venous drainage in 1978 by Djindjian, Merland and Theron2and in 1995Cognardandal.3115

reviewedaseriesof205consecutivepatientsinordertocorrelateaggressiveneurologicalbehavior116

ofdAVFs to angiographic patterns. The initial classification of Djindjian, Merland, and Theron was117

consequentlymodifiedtofiveTypes(Table1and2).118

ThisseriesconfirmedstrongcorrelationbetweenTypeofvenousdrainageandneurologicalrisk.All119

patientswithTypeIdAVFshadbenignsymptoms.PatientswithTypeIIadAVFshadbenignsymptoms120

in 63% of the casesand intracranial hypertension symptoms in 37% but no bleeding. Focal121

neurologicalsymptoms,venousinfarctionorhemorrhageoccurredonlyincaseswithcorticalvenous122

drainage(TypeIIbtoV).Riskofhemorrhagewashigherincaseswithdirectcorticaldrainageandin123

caseswith ectasia on the draining vein. Type VdAVFs (Type III or IVdAVFs with associated124


perimedullarydrainage)presentedinhalfofthecaseswithprogressivemyelopathyasaspinaldAVF.125

ThisclassificationcanbeappliedtoallintracranialdAVFswhatevertheirlocation.126

Bordenetal.4proposedasimplifiedclassificationforbothspinalandcranialdAVFs:-TypeIdAVFs127

drainintoduralsinusormeningealveins,-TypeIIdrainintoduralsinusormeningealveinsbutalso128

with retrograde drainage into subarachnoid veins,-Type III drain directly into subarachnoid veins.129

Thisclassificationwasnotbasedonaclinicalseriesandnocorrelationwithaggressiveneurological130

coursewasmade.Daviesetal.5evaluatedthevalidityofthosetwoclassificationsinaseriesof102131

patientswithdAVFs.InCognard’sclassification,aggressiveclinicalpresentationwasseenin:-0%of132

TypeI,-7%ofTypeIIa,-38%ofTypeIIb,-40%ofTypeIIa+b,-69%ofTypeIII,-83%ofTypeIVand133

100%ofTypeVdAVFs.InBorden’sclassification,aggressiveclinicalpresentationwasseenin2%of134

Type I, 28% of Type II and 31% of type IIIdAVFs.We personally prefer using the Cognard135

Classification,whichmorepreciselyallowsevaluationofpatients’risksandtherapeuticdecision.136

LocationofdAVFs:137

The most frequent locationsarethe transversesinus (50%),cavernous sinus (16%),tentorium138

cerebelli(12%),andsuperiorsagittalsinus(8%).Otherfrequentlocationsincludetheanteriorcranial139

fossa, Torcular, vein of Galen and straight sinus, superior or inferior petrosal sinus, foramen140

magnum,andcondylarvein.SomecommentsmustbemaderegardingdAVFlocations:141

-dAVFscanbeobservedeverywhereonthemeningesofthecraniumandspine.142

-ArteriesfeedingthedAVFsaremeningealfeedersnormallysupplyingtheareawheretheshuntis143

located.This may influence the therapeutic strategy and make endovascular treatment difficult or144

impossible in some locationswhere feeding arteries are distal branches of internal carotid or145

vertebralarteries(anteriorcranialfossa,tentoriumcerebella,etc.).146

-TypeofvenousdrainagedependsondAVFlocation.dAVFslocatedonthewallofvenoussinuses147

(transverse/signmoid, superior sagittal, cavernous sinuses) more often drain directly into the148

affected sinus (Type I or II). On the contrarydAVFs distantfromdural sinuses always drain into149

cortical veins and are consequently at higher risk of aggressive clinical course.Therefore, the150


presenceorabsenceofaggressivesymptomsvariedwiththelocationofthedAVFbecauseanatomy151

dictatedthetypeofvenousdrainage most frequently encountered in each location. However, it is152

likewiseimportanttonotethatwhencomparingthesametypesofvenousdrainage,thelocationdid153

notinfluencetheriskofhemorrhage.154

Symptoms,clinicalpresentationandrisks:155

AlmostallthesymptomsofdAVFsarerelatedtothearterializationsofthesinus/veinsdrainingthe156

fistulas(Table3).157

Pulsatiletinnitusandotherbenignsymptoms:arethemostcommonsymptomsofdAVFs.Patients158

may also present with pain at the level of mastoid region or headaches. Vertigoisfrequently159

encountered. Most Type I or IIdAVFs of the transverse/sigmoid, Torcular and superior sagittal160

sinusespresentwithsuchsymptoms.Theymaybeencounteredinthecavernoussinusbutrarelyin161

otherlocationsandrarelyindirectcorticalvenousdrainagedAVFs(TypeIIItoV).162

Ocular symptoms:are encountered indAVFs draining into the superior/inferior ophthalmic veins163

mainlybutnotonlyinthecaseofcavernoussinusdAVFs.Reversedbloodflowintotheophthalmic164

veins producesvarious ophthalmic symptoms(chemosis, exophtalmos, cranial nerve palsy,165

intracranial pressure, diplopia, and impaired vision). Nevertheless, one should keep in mind that166

thosefistulasmaypresentwithcorticalvenousdrainageandassociatedneurologicalsymptoms.167

Intracranialhypertension(ICH):ICHhasinfactbeenfrequentlydescribedasasymptomofdAVFs.168

ThemostlikelyhypothesistoexplainintracranialhypertensioninTypeIIdAVFsisthattheincreased169

pressureinthesuperiorsagittalsinusproducesareductionoftheCSFresorption.Herebyitfollows170

that an increase in SSS pressure lowers the CSF resorption which in turn leads to increased171

intracranial pressure.Therefore,it must be kept in mind that high flow Type IIdAVFs can induce172

potentiallydevastatingintracranialhypertension.173

Dementia:SomedAVF cases showing only progressive dementia or Parkinsonism as their initial or174

main symptoms have been reported. It should be kept in mind that venous hypertensive175


encephalopathy resulting fromdAVFs should be considered as a cause of reversible dementia in176

patientswithprogressivecognitivedecline.177

Seizures,venousinfarction,hemorrhages:These“aggressive”neurologicalsymptomsonlyoccurin178

casesofdAVFswithretrogradecorticalvenousdrainage(TypeIIbtoV).VanDijketal.reportedthat179

thepersistenceofcorticalvenousdrainageyieldsanannualmortalityrateof10.4%.Excludingevents180

at presentation,the annual risk for hemorrhage or non-hemorrhagic neurological deficit during181

follow-up was 8.1% and 6.9% respectively, resulting in an annual event rate of 15%6. Duffau et al.182

reported a 35% rebleeding rate in the two weeks following the initial hemorrhage7. Davies et al.183

reporteda20%annualmortalityandmorbidityrate8.Inconclusion,dAVFswithcorticalvenousreflux184

carry a high risk of morbidity-mortality due to hemorrhagic or non hemorrhagic events both at185

presentation andin the disease course. Furthermore the risk of rebleeding is high in patients186

presenting with a hemorrhage. This suggests the need for an urgent and complete cure of those187

dAVFstoavoidbleedingorrebleeding.188

Myelopathy:Some intracranialdAVFs may present as a spinal dural fistula withthesame clinical189

symptoms and MR pattern. Thus it shouldbekeptin mind that inthecase of patients with190

progressive myelopathy and no spinal dural AVF visible on spinal angiography,a cerebral191

angiographyshouldbeperformedlookingforintracranialshunt.192

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Indicationfortreatment194

ThetherapeuticimplicationsresultingfromtheclassificationissummarizedinTable4.195

-TypeIdAVFs:aredrainingintoasinus,withanormalantegradeflowdirection.Thesefistulashave196

alwaysabenignbehaviorandpresentonlywithfunctionalsymptomssuchastinnitus,retro-auricular197

painorocularsymptoms.Nevertheless,thepermeabilityoftheothermainduralsinuseshastobe198

carefullystudiedaswellasthecerebralvenousdrainagepatterns.ThetreatmentofTypeIDAVFsis199

performed when tinnitus is disturbing. Because of the total absence of neurological risk in the200

evolutionofthesefistulasthetreatmentitselfhastobewithoutrisk.201


-TypeIIadAVFs:aredrainingintoasinuswithinsufficientorabsentanterogradevenousdrainage202

and reflux into other sinuses. The reflux is most often due to stenosis or thrombosis downstream203

fromthe fistula but may be due to high flow fistulas with normal patent sinus. These DAVFs may204

produce:-Intracranial hypertension symptoms with headaches, transient visual obscurations,205

decreasedvisualacuity,diplopiaduetoVIthcranialnervepalsywitheitherbilateralpapilledemaor206

opticdiskatrophy,-progressivedementiaor–Parkinsonism.Thegoalofthetreatmentistocurethe207

fistulaortoreducetheflowenoughinsidethefistulatoallowanormalcerebralvenousdrainageand208

intracranialpressure.209

-TypeIIbora+b:aredrainingintoasinuswithinsufficientorabsentanterogradevenousdrainage210

andrefluxintocorticalveinsand/orintocorticalveinsandsinuses.Refluxintovenoussinusesmay211

produceintracranialhypertensionduetovenouscongestion.Refluxintocorticalveinsmayproduce212

seizures, venousinfarction or subarachnoid hemorrhage and intracranial hematomas. The213

neurological risk (hemorrhagic or not) requires in these cases a cure of the fistula that must be214

completeanddurable.Inmostofthecasesthebesttreatmentissinusocclusion.215

-Type III and IV:are draining directly into cortical veins without (type III) or with (type IV) venous216

ectasia(s)andareassociatedwithahighriskofhemorrhage.Completeanddurablecureofthefistula217

isrequiredandsubtotalocclusionmayproducerebleeding.218

-TypeV:aredrainingintothespinalveins.Whatevertheclinicalpresentation(myelopathyornot)a219

completecureisrequiredduetotheneurologicalrisk.220

Ineverycase,treatmentindicationandstrategyhavetobediscussedinamultidisciplinaryapproach221

todecidethebeststrategybasedonpatientsymptomsandrisksandtypeofvenousdrainage.222

EndovascularTreatment:223

TypeIdAVFs:224

Abstaining:TypeIfistulamaynotneedtobetreatediffunctionalsymptomsarenotdisturbingand225

cerebralvenousdrainageisnormal.Nevertheless,thepatienthastobeawarethatanymodification226

ofsymptomssuchasincreasedordecreasedtinnitus,headachesorretro-auricularpain,vertigo,or227


visualobscurations, require a new medical consultation. Angio-MR orangiography has to be228

performedtodepictanychangesinthevenousdrainage.229

Onyx/PHILarterialinjectionwithsinusballoonprotection:Themostcommontreatmentperformed230

in TypeIfistula consistsofan arterial injection through meningeal feeders (usually the middle231

meningealartery)togetherwithavenousapproach(femoralorjugularvein)inordertoperforma232

venousballooninflationtoavoidOnyxmigrationwithinthesinus.Thisway,thearterialnetworkmay233

beoccludedandthepatencyofthesinusmaybeobtainedduetoballoonprotection.234

TypeII:235

These fistulas drain initially into a sinus with a reflux into other sinuses and /or cortical veins. The 236

target of embolization is the junction between arterial feeders and the sinus wall. They can be treated 237

by venous embolization with sinus occlusion using coils or by arterial embolization using glue or 238

Onyx/PHIL. Sinus occlusion with coils: The aim of venous embolization is to occlude the draining 239

sinus with coils. It almost always allows a complete cure of the fistula9, 10, 11, 12, 13 . The best indication 240

for sinus occlusion is Type IIb fistulas. These fistulas are risky and require a complete treatment. Sinus 241

and cortical veins are arterialized and not used for cerebral venous drainage. Sinus occlusion is safe. In 242

Type IIa (and even in some rare high flow Type I) fistulas, sinus occlusion can be performed. It 243

obtains a complete occlusion of the shunt when arterial embolizations often fail because of multiple 244

feeders. However, because in Type IIa and I, the sinus may be functional and used to drain the 245

temporal lobe and cerebellum, there is a higher risk of venous infarction. Venous catheterization can 246

be extremely easy when the sinus downstream from the fistula is patent. In some cases it is very 247

difficult and hazardous or impossible because the affected sinus is stenosed, compartmentalized, or 248

even occluded downstream and/or upstream from the fistula. 249

Transarterial sinus occlusion with Onyx/PHIL of Type IIa or IIb dAVFs is a new approach recently 250

published14 Cognard et al. reported this technique in cases in which venous access to the fistulous 251

sinus is difficult or impossible and transarterial sinus coil occlusion is also impossible to avoid 252

surgical puncture of the sinus. In such cases, arterial Onyx embolization may be an efficient and safe 253

alternative. Due to the ease of sinus filling from the arterial approach we can consider that type II 254


dAVFs should be treated with Onyx/PHIL arterial embolization without a previous attempt at venous 255

catheterization if it is expected to be difficult. 256

Arterial embolization with glue or Onyx: These fistulas are often fed by numerous dilated arteries 257

from both external/internal carotid or vertebral arteries’ meningeal feeders. Complete occlusion is 258

difficult to achieve from arterial embolization with glue. The Onyx / PHIL/ Squid Liquid Embolic 259

System are non adhesive agents containing a mixture of a copolymer and DMSO. The advantages of a 260

non adhesive liquid are a decreased risk of gluing the catheter and the ability to inject a larger volume 261

of agent per administration. There have been several recent reports describing the use of Onyx for 262

dAVFs15, 16. The main advantage of Onyx is the ability to administer a large volume via a long-263

duration injection through one pedicle. This results in progressive filling of the arteriovenous network 264

and veins with arterio-arterial retrograde migration of the agent, which avoids the need for multiple 265

catheterizations and embolizations. 266

Sinus recanalization, angioplasty or stent placement: Sinus thrombosis is probably the inciting 267

event of dAVF formation. In type II dAVFs, insufficient antegrade venous drainage due to sinus 268

stenosis or thrombosis produce a retrograde drainage into other sinuses or cortical veins. The idea that 269

sinus thrombosis is the origin of dAVFs and the cause of retrograde drainage led some authors to 270

propose sinus recanalization and angioplasty or stenting as a treatment of Type II dAVFs. 271

Type III to V: 272

Arterial embolization with glue or Onyx: For those direct CVR dAVFs, the old technique is arterial 273

embolization with an injection of diluted NBCA after arterial feeder distal catheterization in a wedge 274

position. The goal of embolization is to glue the origin of the draining vein. However, NBCA injection 275

can be hazardous, and the use of glue generally requires a highly experienced operator having the 276

ability to determine the appropriate glue dilution (depending on the catheter tip positioning and 277

evaluation of the flow). An injection that is too proximal and does not occlude the vein can result in 278

arterial recruitment and a persistent fistula, whereas an injection too distal may lead to migration 279

within the draining veins resulting in an increased risk of infarction or hemorrhage. Cognard et al.17 280

reported the use of Onyx in 30 dAVFs with cortical venous drainage (10 Type Iib and 20 Type III and 281

IV dAVFs). Onyx embolization resulted in complete shunt closure in 24 cases. Complete cure was 282


achieved in 23 of 25 patients who were not embolized previously and in only 1 of 5 patients who were 283

embolized previously with NBCA or coils. These findings indicate that Onyx should be used as the 284

primary treatment and that the rate of success is far lower after a previously failed embolization that 285

has closed the main feeders. The main advantage of Onyx is the ability to administer a large volume 286

via a long-duration injection through 1 pedicle. This results in progressive filling of the arteriovenous 287

network and veins with arterio-arterial retrograde migration of the agent, which avoids the need for 288

multiple catheterizations and embolizations. The more efficient access is through the middle 289

meningeal artery (even if of very small diameter), than through other more dilated feeders (occipital 290

and posterior auricular arteries). Onyx injection duration may last for more than 1 hour compared to a 291

maximum of one or two minutes with glue. Venous Onyx migration can be controlled by temporarily 292

halting its administration. There is less risk of inadvertent uncontrolled venous migration with Onyx 293

than with cyanoacrylates that can fly into the draining vein. Indeed, a few minutes after administration, 294

the initially liquid Onyx becomes pasty, and the Onyx column can be pushed progressively from the 295

catheter tip to the vein and from the vein backwards to the distal aspect of the other feeders. 296

Nevertheless, in some cases the Onyx does not reach the venous side and associated treatment by 297

Radiosurgery or surgery may be required. Regardless of the agent used, it is important to consider that 298

a complete fistula cure may produce devastating complications due to extensive thrombosis of the 299

draining veins and consequent venous infarction or hemorrhage. 300

Venous embolization with glue or Onyx: Retrograde catheterization has been done in few cases 18, 301

19It consists of a catheterization of the draining sinus followed by a microcatheterization of the vein 302

from its origin in the sinus retrograde to the fistula site. The aim is the occlusion of the origin of the 303

draining vein which produces a complete cure of the fistula. 304

1. Surgery: 305

Surgery is obviously indicated in some dAVFS with direct cortical venous drainage when the 306

endovascular approach seems too difficult and risky. Superior petrosal sinus or petrous ridge, anterior 307

fossa and tentorial dAVFs are today the best candidates for such approach. They are all type III to V 308

and they often drain in a single vein. The arterial approach is dangerous because feeders are coming 309


from meningeal arteries of the ICA or ophthalmic arteries. In very difficult cases combined 310

embolization and surgical approaches have been described. 311

2. Radiosurgery: 312

Radiosurgery is rarely proposed in the treatment strategy of dAVFs. Soderman et al. reviewed more 313

than 1600 intracranial arteriovenous shunts treated from 1978 to 2003 (25 years) in which 58 cases 314

were dAVFs20. In 41 cases with follow up angiography at 2 years, 28 cases (68%) were obliterated, ten 315

had significant flow reduction (24%) and three were unchanged. Two patients had rebleeding with 316

parenchymal hematoma at 2 and 6 months. One patient had a radiation induced complication 10 years 317

after Radiosurgery. The authors concluded that the major disadvantage of Radiosurgery is the time 318

elapsed before obliteration and the risk of persisting shunts. 319

320

Conclusion: 321

Intracranial dAVFs may produce a wide variety of symptoms. Individual risk is evaluated by a precise 322

analysis of the venous drainage. The decision to treat or not to treat is based on this analysis. 323

Treatment strategy is decided by a multidisciplinary neurovascular team and must take into account 324

the individual risk of each dAVF. Embolization is in most cases proposed as the first treatment option 325

and usually succeeds to obtain a complete and definitive cure of the dAVF. Surgery is still required in 326

some locations or in the case of embolization failure. Radiosurgery is rarely indicated because it is not 327

always efficient and because of the time required for shunt obliteration and the risk of bleeding in this 328

period. 329

The aim of this study is to evaluate the use of PHIL in the endovascular management of ICD AVFs. 330

331

332

333

334

335

336


337

338

Types Patterns of venous drainage

Type I Drainage into a sinus with a normal antegrade flow direction.

Type II Drainage into a sinus with insufficient antegrade venous drainage and

reflux:

IIa: into sinus(es) only.

IIb: into cortical vein(s) only.

IIa+b: into sinus(es) and cortical vein(s).

Type III Direct drainage into a cortical vein.

Type IV Drainage into a cortical vein with a venous ectasia.

Type V Drainage into spinal perimedullary veins.

Table 1: Classification of Djindjian and Merland according to the venous drainage. 339

340


Table 2: Drawings of the types of venous drainage according to the revised Classification of 341

Djindjian and Merland. 342

343


Venousdrainage Symptomsandrisks

Transverse/sigmoidsinus Pulsatiletinnitus

Ophthalmicveins Ocularsymptoms

Refluxintosuperiorsagittalor

straightsinus

Intracranialhypertension,dementia

Corticalveins Seizures,focaldeficits,venousinfarction,hemorrhages

Perimedullaryveins Myelopathy

Table3:Symptomsandrisksdependingonthedrainingvein/sinus.344

345

346

2. MEDICAL DEVICE INFORMATION 347

348

The PHIL® device has been CE marked since July 2014. It is intended for use in the embolization of 349

lesions in the peripheral and neurovasculature, including arteriovenous malformations and 350

hypervascular tumors. 351

The PHIL® device is a non-adhesive liquid embolic agent comprised of a co-polymer dissolved in 352

DMSO (dimethyl sulfoxide). An iodine component is chemically bonded to the co-polymer to provide 353

a radio pacifier element during fluoroscopic visualization. The PHIL® Liquid Embolic System 354

consists of a sterile, pre-filled, 1.0 mL syringe of PHIL® liquid embolic, a sterile, pre-filled 1.0 mL 355

syringe of DMSO, and microcatheter hub adaptors. A DMSO compatible delivery microcatheter that 356

is indicated for use in the neurovascular or peripheral vasculature is used to access the embolization 357

target site. The PHIL® Liquid Embolic System is available in several product formulations: PHIL

® 358

25%, PHIL® 30%, and PHIL

® 35%. PHIL

® 25% liquid embolic will travel more distally and 359

penetrate deeper into the nidus due to its lower viscosity compared to PHIL® 30% or 35% liquid 360

embolic. Final solidification occurs within five minutes for all product formulations. 361

The PHIL® device is delivered by slow, controlled injection through a microcatheter into the vascular 362

malformation under fluoroscopic control. The DMSO solvent dissipates into the blood, causing the 363

copolymer to precipitate in situ into a coherent embolus. The PHIL® device immediately forms a skin 364

as the polymeric embolus solidifies from the outside to the inside, while traveling more distally in the 365

vascular lesion. 366

367

368


3. STUDY DESIGN AND SCHEDULE 369

370

3.0. Study Design 371

372

This study is a European multi-center Study, observational, prospective, single arm and open label. 373

Each patient will be treated per hospital standard of care. 374

375

3.1. Study Patients 376

377

Any patients having an untreated dural arteriovenous fistula requiring treatment will be screened by 378

the investigational sites. Those eligible to be treated with PHIL® will be enrolled after having dated 379

and signed an informed consent form as per appropriate regulation in the participating country. 380

381

3.2. Study Schedule Table 382

383

384

Selection1/Inclusion Procedure 3 Discharge

3 1 month FU

3,6 3-6 months FU

Patient demographic

x

dAVF information x Patient informed consent

x

Inc/excl criteria x Clinical status (mRS7, WFNS2)

x7 x x7

Symptoms x xQoL x5 x

dAVF & embolized vessels info

x

Procedure x Irradiation info x Procedure complications

x

Procedure results x AE(s) x x x x xAngio control4 x

385

1 Any patient to be treated for a dAVF will be listed in a consecutive screening log (for those not enrolled in the study only 386date of screening, age, sex and reason for non-inclusion will be collected) 387

2 Only in the case of hemorrhage 388

3 To be repeated for each single procedure. (In the case of a second procedure, 1 month FU can be done just prior) 389

4 DSA preferred but MRA can performed depending on patient health status 390

5 To be performed before the patient enters the catheterization room. 391

6Optional by Phone 392

7Performed by an independent Neurologist 393


4. STUDY OBJECTIVES 394

395

4.0. Primary endpoint 396

397

Safety evaluation at 1 month after each embolization, 3-6 months after last embolization and efficacy 398

at 3-6 months after the last embolization treatment of dAVF with PHIL used with or without other 399

embolization products (cyanoacrylate glue, coils, balloon, etc.) except other non-adhesive liquid 400

embolic agents (i.e. Squid, Onyx). 401

402

4.1. Secondary endpoints 403

404

• Number of adverse events (resulting in death or not) 3-6 months after embolization alone 405

• Improvement in the quality of life of the patient as assessed by changes in symptoms present 406

at pre-treatment 3-6 months after the first and last sessions of embolization treatment (Stable / 407

improved / deteriorated) clinical course of the patient 408

409

5. ASSESSMENT CRITERIA 410

411

5.0. Main Assessment Criteria 412

413

• Clinical course of the patient assessed as (Stable / improved / deteriorated) at 3-6 months (during 414

angiography) after each embolization compared to its state at 1 months and baseline. 415

416

• Safety 1 month after the embolization procedure: 417

418

- The number of adverse events (resulting in death or not) at 1 month after each embolization. 419

Any adverse events reported in this study will be reviewed by an Independent Review 420

Committee (CEC) and neurological assessment (mRS) performed by an independent 421

neurologist 1 months after each embolization and compared to baseline. 422

423

• The cure rate at 3-6 months after the last embolization. Cure rate definition depends on the type of 424

fistula: 425

426

- Cured dAVF> IIa is defined by no venous drainage 3-6 months after the last embolization. In 427

an elderly patient, assessment can be done by MR angiography. 428

- Cured dAVF I or IIa is based on clinical improvement assessed by the patient’s self-reported 429

QOL questionnaire, progression of symptoms present pre-treatment (improved / stable / 430

deteriorated gradient) For elderly patients or if the fistula is assessed as benign, assessment 431

will be made by MR angiography. 432

433

• The last angiographic embolization evaluation after 3-6 months: The degree of occlusion of the 434

dAVF will be assessed by an Independent Imaging Core Lab versus baseline dAVF angiography and 435

classified into 3 categories: 436

437

For dAVF I or IIa: 438


- Cured 439

- Residual Shunt Type I or IIa 440

- Residual Shunt Type> IIa 441

- Failed 442

443

For dAVF> IIa: 444

- Cured 445


- Residual Shunt >IIa 447

- Failed 448

449

5.1. Secondary Assessment Criteria 450

451

• The number of adverse events (resulting in death or not) 3-6 months after embolization. Adverse 452

events reported in this study will be reviewed by an Independent Review Committee which will 453

evaluate the relationship between AEs and the device and/or procedure. 454

455

• Improvement in the quality of life of the patient as assessed by changes in symptoms present at pre-456

treatment 3-6 months after the last sessions of embolization treatment and as assessed by the EuroQoL 457

EQ-5D scale. 458

459

460

6. ASSESSMENT AND DATA TO BE COLLECTED PER SCHEDULED VISITS 461

462

6.0. Selection 463

464

Patient demography: 465

- Age 466

- Sex 467

468

Patient informed consent form: 469

470

- Date of signature 471

472

Inclusion/exclusion criteria review 473

474

All patients with an intracranial dAVF requiring treatment that has not been previously treated will be 475

screened by the investigational sites. (If the patient is not enrolled the reason will be documented.) At 476

the end of the screening visit enrolled patients will be documented into a screening log. 477

478

(For patients who refused collection of their personal data or meeting an exclusion criteria only, their 479

age, sex, the reason for non-inclusion and the date of screening will be documented in a screening 480

log.) 481


482

483

6.1. Inclusion 484

485

dAVF Information: 486

487

- Type: I, IIa, IIb, IIa + b, III, IV, V (according to the classification of Cognard et al – see 488

Appendix 19.2). 489

490

- Location of the fistula (multiple choice): 491

492

• Transverse and sigmoid Sinus 493

• Cavernous Sinus and paracavernous 494

• Petrosal sup. Or inf. Sinus 495

• Superior longitudinal Sinus 496

• Tentorial 497

• Ethmoid 498

• Vein of Galen, Straight sinus 499

• Foramen magnum 500

• Condylar Canal 501

502

503

Clinical status: 504

- mRS 505

- WFNS (in the case of hemorrhage) 506

507

Symptoms: 508

509

- Minor symptoms (tinnitus, dizziness, headache) 510

- Ocular symptoms (visual or oculomotor) 511

- Seizures 512

- Intracranial hypertension 513

- Cognitive disorders 514

- Venous infarction 515

- Intracerebral hematoma 516

- Subarachnoid hemorrhage 517

- Subdural hemorrhage 518

- Cranial nerves 519

- Myelopathy 520

521

522

523

524

If any new AE(s) occurs it will be documented. 525


526

6.2. Procedure(s) 527

528

QoL EQ 5D(to be completed before the procedure.) 529

530

No. of arteries/veins catheterized 531

532

Type of catheter: 533

534

- Scepter 535

- Ultraflow 536

- Apollo 537

- Marathon 538

- Echelon 539

- Duo 540

- Sonic 541

- other 542

543

Arteries: 544

545

- Middle Meningeal artery. 546

- Occipital artery 547

- Posterior auricular artery 548

- Accessory Meningeal artery 549

- Ascending pharyngeal artery 550

- Ophthalmic artery 551

- Post meningeal. (Vertebral) artery 552

- Meningeal branches of the internal carotid 553

- Cortical artery 554

- Superficial temporal artery 555

556

Veins: 557

558

- Inferior petrosal Sinus (IPS) 559

- Superior petrosal Sinus (SPS) 560

- Cavernous sinus 561

- Facial Veins 562

- Superior longitudinal Sinus 563

- Straight sinus 564

- Transverse/Sigmoid sinus 565

- Cortical veins 566

567

568

569

Duration of the PHIL® injection by artery / vein 570


571

Volume of PHIL® injected by artery / vein 572

573

Backflow (in cm) by artery / vein 574

575

Batch number 576

Other material used: 577

578

- Intravenous coils 579

- Arterial coils 580

- Intravenous glue 581

- Arterial glue 582

- Balloon for protection (intravenous) 583

- Injection through the balloon 584

- Balloon for reducing the flow (arterial) 585

- Other 586

587

Total dose of radiation: mGy / cm2 588

589

Procedural Complications: 590

591

• Type of complications: catheterization/catheter / injection PHIL® / the dAVF / other: 592

593

- Dissection, arterial rupture 594

- Catheter stuck, broken, occluded 595

- Migration of PHIL® in the vein (cortical veins, sinus, lung) 596

- Arterio-arterial migration 597

- Bleeding (Subarachnoid hemorrhage, parenchymal hematoma) 598


- Cerebral edema 600

601

14 Other 602

603

604

• with or without clinical sequelae 605

- Epileptic seizures 606




- Hematoma 610

- Focal neurological deficit 611

- Cranial nerve deficit 612

- Blindness or other visual impairment 613

- Other 614

615

Results of the angiographic procedure: 616


617

For dAVF I or IIa: 618

- Cured 619



- Failed 622

- Decision not to treat 623

624

For dAVF > IIa: 625

- Cured 626



- Failed 629


631

632

Further treatment: 633

634

- Radiosurgery 635

- Surgery 636

- second embolization 637

638

6.3. Discharge 639

640

If any new AE(s) occurs it will be documented. At this stage the expected AEs are: 641

642





- Hematoma 647



- Cranial nerve 650


- Other 652

653

654

655

6.4. 1 Month Follow up (Optional by Phone) 656

657


- mRS 659

- WFNS (in the case of hemorrhage) 660

661

If any new AE(s) occurs it will be documented. 662

663


This visit can be performed over the phone if a face to face visit cannot be performed 664

665

666

6.5. 3-6 Month Follow up 667

668

Angiography (DSA strongly recommended, but MR / MRA is acceptable based on patient age, 669

specific health status, etc.) 670

671

Procedure Result: 672

673

- Cured 674



- Failure 677


679

For dAVF> IIa: 680

- Cured 681



- Failure 684


Additional Proposed Treatment: 686

687

- Radiosurgery 688

- Surgery 689

- Second embolization (in this case procedure, discharge, 1 month FU and 3-6 month FU visits and 690

assessments should be repeated) 691

692


- mRS 694

Changes in the symptoms compared to baseline (Stable / improved / deteriorated) 695

If any new AE(s) occurs it will be documented. At this stage the expected AEs are: 696

697





- Hematoma 702



- Cranial nerve 705


- Other 707

708


QoL EQ 5D (assessment will be completed before the patient leaves the hospital) 709

710

711

7. CLINICAL SITES 712

713

Up to 16 sites will participate in the study representing 4 to 5 European countries. Each site will 714

demonstrate its ability to recruit at least 5 patients within one year. All sites will have demonstrated 715

significant experience with liquid embolic procedures and will have received specific training in the 716

use of PHIL®. 717

718

8. STUDY DURATION 719

720

It is expected to recruit 60 consecutive patients in approximatively one year in 16 investigational sites. 721

Follow-up for each patient is expected to take up to 12 months after the first embolization session, 722

since each patient may require up to 2 embolizations maximum and the final follow-up visit is to take 723

place 3-6 months after the last session. 724

Therefore, the overall study duration will be approximatively 2 years. 725

726

9. PATIENT SELECTION 727

728

9.0. Inclusion criteria 729

1. Patient or patient’s legally authorized representative has received information about data 730

collection and has signed and dated an Informed Consent Form 731

2. Patient has an intracranial dAVF that can be treated by embolization with PHIL® used with or 732

without other embolization products except other non-adhesive liquid embolic agents (i.e. Squid, 733

Onyx). 734

3. Patient is at least 18 years of age. 735

736

9.1. Exclusion criteria 737

1. Patient has multiple dAVFs to be treated. 738

2. Patient participates in a study evaluating another medical device, procedure, or medication during 739

the course of dAVF treatment and follow-up per the study protocol. 740

(For patients who refused collection of their personal data or meeting an exclusion criteria only, 741

their age, sex, the reason for non-inclusion and the date of screening will be documented in a 742

screening log.) 743

3. Any condition that could prevent patient follow up. 744

745

10. STATISTICAL ANALYSIS PLAN 746


747

10.0. Statistical Analysis 748

All patients included in the study will be included in the analyses (ITT). 749

Qualitative parameters are described by their frequency distribution and ranges bilateral 95% 750

confidence associated quantitative parameters by their average, minimum standard deviation, 751

maximum, median and quartiles, number of missing values. 752

Quality parameters (i.e. 3-6 months cured (yes / no) or improvement of mRS 1 month (yes / no)) 753

will be described by their distribution frequencies and intervals bilateral associated 95% 754

confidence. 755

Relevant group comparisons will be performed using an adequate test for the variable type: 756

• Person’s chi-square (or Fisher’s exact test if the expected frequency in a group is smaller than 757

five) for qualitative variables 758

• Variance analyses for quantitative variables 759

• Variance analyses based on ranks for ordinal variables 760

Statistical test will be performed with a type I error risk of 5%. 761

The rate of events for which a date of onset has been collected will be described survival curve 762

according to Kaplan-Meier method and the associated Kaplan Meier estimators will be calculated. 763

10.1. Population size 764

11. Sample size: 60 patients 765

12. With a sample size of 55 patients, we will be able to estimate the success rate with a 95% 766

confidence interval size of ±10.0% considering the observed success rates in a previous study 767

(83%) (Cognard and al.). Thus, the lower bound of the 95% confidence interval will be higher than 768

the lowest estimation found in the literature (Lv and al. 61%)21. 769

13. In addition, even with 10% loss to follow-up patients, this sample size (N=60) ensures an accuracy 770

of at least ±10% for observed parameters. 771

772

13.0. Invalid, Unused and Missing data 773

Missing data will be treated in the three following ways: 774

• The LOCF method will be used, with the last observation seen used as a reference value 775

for a missing value at the end of follow-up 776

• The basic method to exclude patients with missing data will be used 777

• The missing data will be charged through multiple imputation procedure 778


779

13.1. Minimizing bias strategy 780

781

In order to minimize bias the two following independent review committees will be established: 782

Centralized review of laboratory tests (Core Lab): An independent committee will evaluate the 783

angiographic / MRA examinations at the following times: 784

Angiography before/during the first embolization session, in order to assess the dAVF anatomy. 785

At the end of the treatment after each embolization. 786

At 3-6 months after the last embolization (imaging control). 787

Clinical events Committee (CEC): 788

This independent committee will evaluate any adverse events per-procedure and for the overall 789

study duration. It will assess the existence of a relationship with the device and/or procedure and 790

identify any Serious Adverse Events. 791

792

793

14. END OF STUDY PARTICIPATION 794

795

End of patient study participation will occur in the following cases: 796

797

• Patient consent withdrawal for any reason (if possible, the patient will be asked to 798

attend the EoS visit in order to assess his/her final safety and clinical outcomes before 799

he/she stops participation in the study) 800

• Investigator decision to stop patient participation 801

• Lost to follow up 802

• Patient death 803

• Scheduled end of the study 804

805

It will be requested of the investigator to take any action in order to avoid patients lost to 806

follow up (including calling the patient, contacting the patient’s family doctor, etc.). 807

808

15. ADVERSE EVENTS 809

Any adverse event, whether serious or not, whether symptomatic or not, per- or post-operative, 810

related or unrelated to the use of the device will be identified. Problems associated with the use of 811

the device will be communicated to the appropriate country’s authority following the procedures in 812

force. 813

Any device that is believed to have malfunctioned or have a defect must be returned to the 814

manufacturer for analysis. 815


Serious Adverse Events(SAEs) are adverse events that meet the following criteria: 816

a) led to a death, 817

b) led to a serious deterioration in health that either: 818

1) resulted in a life-threatening illness or injury, or 819

2) resulted in a permanent impairment of a body structure or a body function, or 820

3) required in-patient hospitalization or prolongation of existing hospitalization, or 821

4) resulted in medical or surgical intervention to prevent life threatening illness or injury or 822

permanent impairment to a body structure or a body function. 823

c) led to fetal distress, fetal death or a congenital abnormality or birth defect. 824

825

826

In this study, all serious adverse events must be reported to the safety officer. SAEs will also result 827

in a declaration to the appropriate countries’ authorities in accordance with procedures in force. 828

Adverse events are unanticipated when they are not included in the instructions for use of the 829

medical device. 830

If the case of an unexpected serious adverse event, the safety officer will immediately contact the 831

investigator to prepare an initial report to be forwarded to the competent authorities in the prescribed 832

procedures material-vigilance and Oversight Committee. 833

834

835

836

837

16. PROTOCOL DEVIATIONS 838

839

A study/protocol deviation occurs when the investigator or other study personnel did not conduct the 840

study according to the Clinical Investigation Plan or according to regulations. 841

The investigator will document and inform the sponsor or his mandated representative of any 842

deviations that occur at his site. If needed, he will take any reasonable corrective action in order to 843

avoid deviation repetition. 844

845

846

847

17. QUALITY CONTROL 848

Progress of research in the study centers and support issues will be performed in accordance with the 849

ethics and medical recommendations. 850

Case report form completion 851

Data from the study will be recorded by authorized study site staff on an eCRF. The information 852


reported in the medical questionnaire should be a reflection of that in the medical records of the 853

subject. 854

Data quality entered into the eCRF will be assessed during monitoring visits performed by a CRA. 855

Monitoring visits will be conducted as per standard operating procedure and the monitoring plan of the 856

company as mandated by the sponsor. 857

Data management quality check will be implemented in order to enhance data quality and consistency 858

as per standard operating procedure and the monitoring plan of the company as mandated by the 859

sponsor. 860

Quality assurance at any step of the study will be performed on a regular basis as per standard 861

operating procedure and the monitoring plan of the company as mandated by the sponsor. 862

18. ETHICS AND REGULATION 863

864

The final version of the Investigational Plan with the Patient Information document and Consent Form 865

will be submitted to an appropriately constituted EC or relevant country Competent Authority (CA) by 866

the Investigator/sponsor prior to commencement of the Study. A copy of the EC or CA 867

opinion/approval letter along with, for the EC document, the list of EC voting members will be 868

provided to the Sponsor prior to initiating the Study at any center. 869

The Investigator/sponsor will submit the appropriate documentation if any extension, renewal or 870

amendment of the EC or CA approval must be obtained. In particular Investigational Plan 871

amendments, Informed Consent Form changes or other written information provided to the patient 872

and/or Study procedures directly affecting the patient must be approved by the EC or CA in writing. 873

Each Investigator must sign the Investigational Plan Amendment before implementing the change at 874

his/her Site. 875

The Investigator/sponsor will report to the EC any new information that may affect patient safety or 876

the conduct of the Study. Written summaries of the Study status shall be sent by the Investigator to 877

the EC according to local requirements, and at least once annually. 878

Upon completion of the Study, the Investigator shall provide the EC with a brief report of the outcome 879

of the Study as required by the local EC. 880

881

19. STUDY DOCUMENTATION AND DATA RETENTION 882

Research-related documentation must be filed by each site for the appropriate period of time based 883

on its country’s regulation. The sponsor will file these documents based on the longest period of 884

time required by the regulation of any participating country. 885

The database used for statistical analysis will be archived by the entity performing the analysis. 886

20. DATA ANALYSIS and REPORTS 887

888

20.0. Access to the data and source documentation 889

890

Confidentiality of data shall be observed by all parties involved at all times throughout the clinical 891

investigation. All data shall be secured against unauthorized access. 892


The privacy of each subject and confidentiality of his/her information shall be preserved in reports and 893

when publishing any data. 894

The principal investigator or institution shall provide direct access to source data during and after the 895

clinical investigation for monitoring, audits, EC review and regulatory authority inspections. 896

897

20.1. Study Report 898

899

A final study report will be written under the sponsor’s supervision. This report will be sent to any 900

investigators and EC/CA as per regulation in force in the participating countries. 901

902

20.2. Presentation and publication rules 903

904

Microvention Europe Company owns all the data, analysis and results for the PHIL® resulting from 905

this study and no use or transmission to a third party can be made without prior consent. However, 906

each individual center is free to use and develop independently the data from the medical records of its 907

own patients. 908

909

21. RISKS AND BENEFITS 910

911

21.0. Risks 912

913

This is an observational study with no change required to standard of care. As such, there will be no 914

additional risks to patients participating in the study. 915

916

21.1. Benefits 917

918

All patients will be managed in the same way as they would have been managed if they had refused to 919

participate in the study. There is no individual benefit to participating in this study. 920

921

922

923

22. APPENDIX 924

925

22.0. Patient Informed Consent Form 926

927

Provided separately 928

929

22.1. Clinical sites list 930

931

List attached to the protocol. 932

933

22.2. Cognard & al. Classification 934


The Cognard classification is based on the direction of dural sinus drainage, the presence or absence of 935

CVD, and venous outflow architecture (nonectatic cortical veins, ectasia cortical veins, or spinal 936

perimedullary veins). 937

Type I lesions drain into the dural sinus, have an antegrade flow direction, and lack of CVD. 938

Type II lesions are subdivided into 3 subcategories: 939

Type IIa lesions drain retrogradely into a dural sinus without CVD, 940

Type IIb lesions drain antegradely into a dural sinus with CVD, 941

Type IIa+b lesions drain retrogradely into a dural sinus with CVD. 942

Types III (Direct drainage into a cortical vein without venous ectasia), IV (Direct drainage into a 943

cortical vein with ectasia >5mm and 3x larger than the diameter of the draining vein), and V (Direct 944

drainage into spinal perimedullary veins) lesions all have CVD, absent dural venous drainage, and 945

varying cortical venous outflow architecture Lack of CVD 946

947

22.3. Bibliography 948

9491[NewtonTH,GreitzT.Arteriovenouscommunicationbetweentheoccipitalarteryandtransverse950

sinus.Radiology1966;87:824-828].9512[DjindjianRMJ,TheronJ.Superselectivearteriographyoftheexternalcarotidartery.952

SpringerVerlagBerlin,New-York;1977:606-628.]9533[CognardC,GobinYP,PierotL,etal.Cerebralduralarteriovenousfistulas:clinicalandangiographic954

correlationwitharevisedclassificationofvenousdrainage.Radiology1995;194:671-680]9554[BordenJA,WuJK,ShucartWA.Aproposedclassificationforspinalandcranialduralarteriovenous956

fistulousmalformationsandimplicationsfortreatment.Journalofneurosurgery1995;82:166-179]9575[DaviesMA,TerBruggeK,WillinskyR,CoyneT,SalehJ,WallaceMC.Thevalidityofclassificationfor958

theclinicalpresentationofintracranialduralarteriovenousfistulas.Journalofneurosurgery959

1996;85:830-837]9606[vanDijkJM,terBruggeKG,WillinskyRA,WallaceMC.Clinicalcourseofcranialduralarteriovenous961

fistulaswithlong-termpersistentcorticalvenousreflux.Stroke2002;33:1233-1236]9627[DuffauH,LopesM,JanosevicV,etal.Earlyrebleedingfromintracranialduralarteriovenous963

fistulas:reportof20casesandreviewoftheliterature.Journalofneurosurgery1999;90:78-84]9648[DaviesMA,TerBruggeK,WillinskyR,CoyneT,SalehJ,WallaceMC.Thevalidityofclassificationfor965

theclinicalpresentationofintracranialduralarteriovenousfistulas.Journalofneurosurgery966

1996;85:830-837]9679[HalbachVV,HigashidaRT,HieshimaGB,MehringerCM,HardinCW.Transvenousembolizationof968

duralfistulasinvolvingthetransverseandsigmoidsinuses.Ajnr1989;10:385-392]96910[MironovA.Selectivetransvenousembolizationofduralfistulaswithoutocclusionofthedural970

sinus.Ajnr1998;19:389-391]97111[PiskeRL,CamposCM,ChavesJB,etal.Duralsinuscompartmentinduralarteriovenousshunts:a972

newangioarchitecturalfeatureallowingsuperselectivetransvenousduralsinusocclusiontreatment.973

Ajnr2005;26:1715-1722]974


12[RoyD,RaymondJ.Theroleoftransvenousembolizationinthetreatmentofintracranialdural975

arteriovenousfistulas.Neurosurgery1997;40:1133-1141;discussion1141-1134]976

13[UrtasunF,BiondiA,CasacoA,etal.Cerebralduralarteriovenousfistulas:percutaneous977

transvenousembolization.Radiology1996;199:209-217]97814[CognardC,JanuelAC,SilvaNA,Jr.,TallP.EndovascularTreatmentofIntracranialDural979

ArteriovenousFistulaswithCorticalVenousDrainage:NewManagementUsingOnyx.Ajnr2007].98015[AratA,InciS.TreatmentofasuperiorsagittalsinusduralarteriovenousfistulawithOnyx:981

technicalcasereport.Neurosurgery2006;59,169-170]98216[RezendeMT,PiotinM,MounayerC,SpelleL,AbudDG,MoretJ.Duralarteriovenousfistulaofthe983

lessersphenoidwingregiontreatedwithOnyx:technicalnote.Neuroradiology2006;48:130-134].98417[CognardC,JanuelAC,SilvaNA,Jr.,TallP.EndovascularTreatmentofIntracranialDural985

ArteriovenousFistulaswithCorticalVenousDrainage:NewManagementUsingOnyx.Ajnr2007]98618[DeasyNP,GholkarAR,CoxTC,JeffreeMA.Tentorialduralarteriovenousfistulae:endovascular987

treatmentwithtransvenouscoilembolisation.Neuroradiology1999;41:308-312]988

19[DefreyneL,VanlangenhoveP,VandekerckhoveT,etal.Transvenousembolizationofadural989

arteriovenousfistulaoftheanteriorcranialfossa:preliminaryresults.Ajnr2000;21:761-765].99020[SodermanM,EdnerG,EricsonK,etal.Gammaknifesurgeryforduralarteriovenousshunts:25991

yearsofexperience.Journalofneurosurgery2006;104:867-875].992

21[NogueiraRG,DabusG,RabinovJD,EskeyCJ,OgilvyCS,HirschJAetal.Preliminaryexperiencewith993

Onyxembolizationforthetreatmentofintracranialduralarteriovenousfistulas.AJNR.2008994

Jan;29(1):91-7.Epub2007Nov1].995

996

22.4. mRS 997

998

999

Score Description 1000

1001

0 No symptoms at all 1002

1003

1 No significant disability despite symptoms; able to carry out all usual duties and activities 1004

1005

2 Slight disability; unable to carry out all previous activities, but able to look after own affairs 1006

without assistance 1007

1008

3 Moderate disability; requiring some help, but able to walk without assistance 1009

1010

4 Moderately severe disability; unable to walk without assistance and unable to attend to own 1011

bodily needs without assistance 1012

1013

5 Severe disability; bedridden, incontinent and requiring constant nursing care and attention 1014

1015

6 Dead 1016

1017

TOTAL (0–6): _______ 1018

1019


1020

22.5. WFNS 1021

1022

World Federation of Neurological Surgeons Grading System for Subarachnoid Hemorrhage 1023

(WFNS) scale 1024

1025

Overview: 1026

The clinical grading system proposed by the World Federation of Neurological Surgeons is 1027

intended to be a simple, reliable and clinically valid way to grade a patient with subarachnoid 1028

hemorrhage. This system offers less interobserver variability than some of the earlier 1029

classification systems. 1030

1031

• Grade 1: GCS score of 15 without focal deficit 1032

• Grade 2: GCS score of 13 or 14 without focal deficit 1033

• Grade 3: GCS score of 13 or 14 with focal deficit 1034

• Grade 4: GCS score of 7-12 1035

• Grade 5: GCS score of 3-6 1036

GCS (Glasgow coma score) 1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

22.6. QoL 1047

1048

EuroQOL*EQ-5D 1049

1050

Under each heading, please tick the ONE box that best describes your health TODAY 1051

MOBILITY 1052

I have no problems in walking about 1053

I have slight problems in walking about 1054

I have moderate problems in walking about 1055

I have severe problems in walking about 1056

I am unable to walk about 1057

1058

SELF-CARE 1059


I have no problems washing or dressing myself 1060

I have slight problems washing or dressing myself 1061

I have moderate problems washing or dressing myself 1062

I have severe problems washing or dressing myself 1063

I am unable to wash or dress myself 1064

1065

USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 1066

I have no problems doing my usual activities 1067

I have slight problems doing my usual activities 1068

I have moderate problems doing my usual activities 1069

I have severe problems doing my usual activities 1070

I am unable to do my usual activities 1071

1072

PAIN / DISCOMFORT 1073

I have no pain or discomfort 1074

I have slight pain or discomfort 1075

I have moderate pain or discomfort 1076

I have severe pain or discomfort 1077

I have extreme pain or discomfort 1078

1079

ANXIETY / DEPRESSION 1080

I am not anxious or depressed 1081

I am slightly anxious or depressed 1082

I am moderately anxious or depressed 1083

I am severely anxious or depressed 1084

I am extremely anxious or depressed 1085

1086

1087


1088

1089

• We would like to know how good or bad your health is TODAY. 1090

• This scale is numbered from 0 to 100. 1091

• 100 means the best health you can imagine. 1092

• 0 means the worst health you can imagine. 1093

• Mark an X on the scale to indicate how your health is TODAY. 1094

• Now, please write the number you marked on the scale in the box below. 1095

1096

YOUR HEALTH TODAY = 1097

1098

1099

1100

1101

1102

1103

90

80

70

60

50

40

30

20

10

100

Worstimaginable

healthstate

Bestimaginable

healthstate

0

95

85

75

65

55

45

35

25

15

5

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