The RAVI Registry: A Prospective, Multi-Center, Observational Study of Radial Access Embolization Procedures Using HydroPearl Microspheres
Conditions: Uterine Fibroid, Arteriovenous Malformations, Hypervascular Tumors, Benign Prostatic Hyperplasia
Sponsor: Terumo Medical Corporation

Clinical Investigational Plan
The RAVI Registry 
Protocol Number:  TIS2019-02 
Version 2.0 
  
15 Jan 2021                              CONFIDENTIAL 
Page 1 of 37 
 
Protocol Title
The RAVI Registry: A Prospective, Multi-Center, Observational Study of Radial 
Access Embolization Procedures using HydroPearl Microspheres
SPONSOR
Terumo Medical Corporation
265 Davidson Avenue 
Somerset, NJ 08873 
USA 
 
Study Number:  TIS2019-02 
Version Number:  2.0 
Version Date:  15-Jan-2021 
 
 
Confidentiality Statement: 
This protocol, its contents, and the information relating to it are the proprietary 
property of Terumo Medical Corporation. All information is to be kept confidential. 
 

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Protocol Number:  TIS2019-02 
Version 2.0 
  
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Table of Contents 
A.
Summary Of Revisions..................................................................................5
B. 
Protocol Approval Page ................................................................................. 6
C.
Study Roles and Responsibilities...................................................................7
D. Investigator Approval and Agreement ............................................................ 9
E. 
Study Synopsis ............................................................................................ 10
F.
List of Abbreviations and Definition of Terms............................................... 14
1
Background.................................................................................................. 15
1.1
HydroPearl microspheres and Indications For Use................................17
1.2 
Summary of Clinical Studies .................................................................. 18
2
Study Design, Sample Size and Duration.................................................... 18
2.1 
Study Design ......................................................................................... 18
2.2 
Sample Size ........................................................................................... 18
2.3 
Study Duration ....................................................................................... 18
3
Study Objective and Evaluations ................................................................. 18
3.1 
Study Objective ...................................................................................... 18
3.2 
Evaluations ............................................................................................ 18
3.2.1 Primary Evaluations ............................................................................... 19
3.2.2 Additional Evaluations ........................................................................... 19
4
Study Design ............................................................................................... 21
4.1 
Eligibility Criteria .................................................................................... 21
4.1.1 Inclusion Criteria .................................................................................... 21
4.1.2 Exclusion Criteria ................................................................................... 22
4.2 
Subject Enrollment ................................................................................. 22
5
Ethics........................................................................................................... 22
5.1 
Role of the Sponsor ............................................................................... 22
5.2 
Role of Clinical Research Organization ................................................. 22
5.3 
Ethics Review ........................................................................................ 23
5.4 
Ethical Conduct of the Study .................................................................. 23
5.5 
Written Informed Consent...................................................................... 23
5.6 
Subject Data Protection ......................................................................... 24
5.7 
Subject Withdrawal ................................................................................ 24
5.8 
Discontinuing Subject Participation ........................................................ 24
6
Device Supply Information........................................................................... 25
6.1 
Documentation ....................................................................................... 25

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6.2 
Malfunctioning / Failed Device ............................................................... 25
7
General Procedures.....................................................................................25
7.1 
Screening/ Baseline Visit ....................................................................... 25
7.2
Procedure ..............................................................................................25
7.3 
Device Set-up and Preparation .............................................................. 28
7.4
Blood Tests............................................................................................28
7.5 
Concomitant Medical Therapy ............................................................... 28
7.6
Follow-up Procedures............................................................................28
7.6.1 Discharge Visit ....................................................................................... 28
7.6.2 30 Day Visit (± 14 days).........................................................................28
7.6.3 180 Day Visit (± 30 days)....................................................................... 29
7.6.4 365 Day Visit (± 60 days) ....................................................................... 29
7.7 
Clinical Data Collection .......................................................................... 29
8
Adverse Events ............................................................................................ 29
8.1 
Definitions .............................................................................................. 30
8.2 
Anticipated Adverse Events (AEs) ......................................................... 30
8.3 
Follow-up of Adverse Events ................................................................. 31
8.4 
Causality Rating ..................................................................................... 31
8.5 
Severity of Adverse Events .................................................................... 31
8.6 
Adverse Event Monitoring...................................................................... 32
9
Risk Assessment ......................................................................................... 32
9.1 
Risk Management Procedure ................................................................ 32
9.2
Potential Benefits...................................................................................33
10 Monitoring.................................................................................................... 33
11 Image Analysis ............................................................................................ 34
12 Device Failure and Malfunction.................................................................... 34
13 Statistical Methods....................................................................................... 34
13.1 Sample Size Determination ................................................................... 34
13.2 General Considerations ......................................................................... 34
13.2.1
Study Visit ....................................................................................... 35
13.2.2
Visit Windows .................................................................................. 35
13.3 Analysis Populations .............................................................................. 35
13.4 Poolability Analysis ................................................................................ 35
13.5 Handling of Missing Data ....................................................................... 36
13.6 Subject Disposition ................................................................................ 36

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13.7 Analysis of Study Evaluations ................................................................ 36
13.8 Protocol Deviations................................................................................36
13.9 Changes to Planned Analyses ............................................................... 36
Appendix 1
References...................................................................................36
 
 
 

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A. Summary Of Revisions 
Version
Date
Description of change and rationale
1.0
13-Sep-2019
Initial Release
2.0
15-Jan-2021
Addition of BPH indication 
Statistical updates and clarifications 
Remove potential AEs for consistency with standard of care 
registry study 
Extended expected enrollment time due to COVID-19 delays 
Minor typo and grammar corrections  
Addition of 365-day visit 
Minor changes to comply with EU (Europe) regulations
Page Section Intentionally Blank 
 

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B. Protocol Approval Page
Study Title:
The RAVI Registry:  A Prospective, Multi-Center, Observational 
Study of Radial Access Embolization Procedures using 
HydroPearl Microspheres
Study Number: 
TIS2019-02
PROTOCOL APPROVAL SIGNATURES AND DATES: 
Hinna Shahid, MD, Clinical Project Manager  
 
      
                    Date
Terumo Medical Corporation
Robert Gash, Director of Clinical Research & Operations
                             Date  
 
Terumo Medical Corporation
01/29/2021

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C. Study Roles and Responsibilities 
 
Principal Investigator: 
Marcelo Guimaraes, MD 
 
 
Sponsor Contact: 
 
Hinna Shahid, MD 
Clinical Project Manager 
Terumo Medical Corporation 
265 Davidson Avenue 
Somerset, NJ 08873 
Phone:  201-398-3283 
 
CRO:  
 
 
 
MedTrials, Inc 
2727 Cole Avenue 
Suite 825         
Dallas, Texas 75204 
www.medtrials.com 
Phone 1-214-630-0288 
 
Proprietary Notice: 
This document contains mainly unpublished data and is 
the sole property of the Sponsor. Therefore, it is provided 
to you in strict confidence as an investigator, potential 
investigator, or consultant. The information may be 
reviewed by you, your staff, and your institutional review 
board/independent ethics committee. It is understood that 
this information will not be disclosed to others without 
written authorization from the study Sponsor except to the 
extent necessary to obtain informed consent from those 
persons in whom the investigational device may be 
implanted. 
 
Ethics Statement: 
The study will be completed in accordance with applicable 
regulations and standards to provide public assurance that 
the rights, safety, and well-being of study subjects are 
protected, consistent with the principles that have their 

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origin in the Declaration of Helsinki. This clinical 
investigation will be conducted in compliance with Good 
Clinical Practice (GCP), ISO 14155 and MDR (EU) 
2017/745. 
 
 

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D. Investigator Approval and Agreement 
 
PROTOCOL SIGNATURE PAGE 
 
The signature below constitutes the receipt, review and understanding of the protocol 
entitled, “The RAVI Registry: A Prospective, Multi-Center, Observational Study of Radial 
Access Embolization Procedures Using HydroPearl Microspheres” and any attachments, 
and provides the necessary assurances that this study will be conducted according to all 
stipulations of the signed Clinical Trial Research Agreement (CTRA), protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable U.S. federal and European regulations (MDR (EU) 
2017/745).    
 
 
 
________________________________________                          _________________                              
Investigator Signature 
 
 
 
Date  
______________________________________________________________________ 
Investigator Name (please print) 
______________________________________________________________________ 
Investigator Institution (please print) 
 

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E. Study Synopsis 
Study Title
The RAVI Registry: A Prospective, Multi-center, Observational Study of 
Radial Access Embolization Procedures Using HydroPearl 
Microspheres. 
Study Number
TIS2019-02
Study Sponsor
Terumo Medical Corporation 
265 Davidson 
Somerset, NJ 08873 
USA 
Study Objective 
The objective of this registry study is to assess the procedural success 
and complication rates in real-world patients undergoing HydroPearl 
embolization procedures via radial access.  
Study Design
Multicenter, prospective, non-randomized post-market registry
Procedure(s):
Embolization of hypervascular tumors and arteriovenous 
malformations, including uterine fibroids and prostate artery 
embolizationfor symptomatic benign prostatic hyperplasia, via radial 
access.  
Subject Population
Up to 100 subjects with procedures planned using radial artery access
Study Duration
Study enrollment is expected to take up to 18 months. Primary 
endpoint data will be collected at 30 days post-procedure, 180 days 
post-procedure, and 365 days post-procedure.   
Primary Study 
Evaluations 
1.
Procedural success defined as completing the planned procedure 
without femoral access bailout 
2. Technical success defined as delivery of HydroPearl to the target 
vessel and slowing the blood flow with microsphere embolization.  
3. Freedom from Major Adverse Events within 30 days of procedure, 
defined as:  
a. Death 
b. MI 
c. Stroke 
4. Freedom from radial access related complications at 30 days, 
defined as:  
a. Radial artery occlusion (reverse Barbeau and/or 
Ultrasound, per site standard of care) 
b. Hand ischemia 
c. Arteriovenous fistula 
d. Pseudoaneurysm 
e. Any complication requiring surgical and/or endovascular 
intervention within 30 days of index procedure 
Additional 
Evaluations 
1.
Incidence of Radial Artery Occlusion Complications at any time 
a. Arteritis 

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b.
Cellulitis
c. Ecchymosis 
d. Pain at puncture site 
e. Hematoma 
2. Quality of Life and Health Economics 
3. Procedural endpoints: 
a. Blood loss 
b. Patient radiation exposure  
c. Contrast volume 
d. Time to hemostasis 
e. Total procedural time 
f. Time to discharge 
g. Operative time 
h. Radial cocktail components and frequency of 
administration 
4. Access endpoints:  
a. Radial artery spasm  
b. Time to discharge  
c. Radial access pain VAS 
5. Closure endpoints 
a. Time to hemostasis 
b. Time to ambulation 
Procedure 
Evaluations 
1.
Tumor type
2. Number and size of tumors / fibroids 
3. Post embolization syndrome 
4. UFE:  
a. If post-op MRI is obtained per standard of care: 
Effectiveness of HydroPearl measured by MRI. 
i. Infarction is characterized by complete 
(100%), 90-99%, 50-89%, or less than 50%.   
ii. Uterine Volume 
iii. Dominant Fibroid Volume 
b. EQ-5D 
c. UFS-QoL 
d. Return to normal activities  
e. Pain VAS 
f. Symptoms including bleeding and bulk 
g. Pregnancy intention and occurrence 
5. Prostate Artery Embolization:  
a. IPSS with Quality of Life 
b. EQ-5D 
c. Return to normal activities  
d. Pain VAS 

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e.
Qmax
f. Prostate volume 
6. Liver Tumor Embolization: 
a. Tumor response (CR, PR, SD, PD) 
b. EQ-5D 
c. Return to normal activities 
d. Pain VAS 
e. Disease stage 
7. Other Hypervascular tumors 
a. Infarction 
b. Return to normal activities  
c. Pain VAS 
8. Arteriovenous malformations: 
a. EQ-5D 
b. Return to normal activities  
c. Pain VAS 
Inclusion Criteria
1.
2. Subject is scheduled for an embolization procedure for treatment 
with HydroPearl microspheres via radial access. 
3. Subject is willing and able to complete follow-up requirements 
4.
Subject is willing and able to sign a written Informed Consent form 
prior participating in the registry.  
Exclusion Criteria 
1.
Unable to have a procedure with radial access for any reason.
2. Participating in another clinical study which, in the opinion of the 
investigator, could impact the results of this registry.  
3. Pregnant or planning to become pregnant during the study.  
Statistical Analysis 
Endpoints will be reported with descriptive statistics as well Kaplan-
Meier survival curves where appropriate.   
Sub-group analyses include, but are not limited to:  
 
UFE procedure 
 
PAE procedure 
 
Liver embolization procedure 
 
Other hypervascular tumors procedure 
 
AVM embolization procedures 
Imaging 
Assessments 
Imaging datasets will be conducted for baseline, procedure, and 
follow-ups per site standard of care and results entered into eCRF.  
Images will not be collected or archived by the Sponsor.  
Safety
The Principal Investigator at each site will be responsible for reviewing 
and following any adverse events per site standard of care.  
Data Quality
Electronic case report forms will be used to collect data evaluations in 
this registry.   

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Source data verification will be completed during periodic on-site 
monitoring visits.  The frequency of on-site visits will be specified in 
the study monitoring plan.   
Schedule of Events 
Assessment 
Screening 
/ 
Baseline 
Procedure 
Discharge 
30 Day 
Follow-up 
±14 days 
180 Day 
and 365 
Day 
Follow-ups 
±30 days
Informed Consent
X
Eligibility Criteria
X
Medical 
History/Demographics
X
Pregnancy Test 
X 
 
 
Blood Tests (if 
available)
X 
X 
X 
X 
X 
Imaging (if available)
X 
X 
X
X
X
Physical Exam 
X 
 
X 
X
X
Procedural, access, 
closure evaluations 
X 
 
 
 
QoL questionnaires 
and return to normal 
activities
X 
 
X 
X 
X 
Concomitant 
Medications 
(Anticoagulation / 
Antiplatelets Only)
X 
X 
X 
X 
 
Device Related Adverse 
Events 
X 
X 
X 
X 

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F. List of Abbreviations and Definition of Terms
AE: 
Adverse Event 
AV: 
Arteriovenous 
BMI:  
Body Mass Index 
BPH:  
Benign Prostatic Hyperplasia 
CEC: 
Clinical Events Committee 
CFR: 
Code of Federal Regulations 
CIP: 
Clinical Investigational Plan, also referred to as (study) protocol 
CRO: 
Clinical Research Organization 
CTRA: 
Clinical Trial Research Agreement 
eCRF: 
Electronic Case Report Form 
EQ-5D: 
EuroQol Group standardized measure with 5 dimensions   
HIPAA: 
Health Care Portability and Accountability Act 
ICF:   
Informed Consent Form 
ICH: 
International Conference on Harmonization 
IFU: 
Instructions for Use 
IRB/EC: 
Institutional Review Board/Ethics Committee 
IPSS:  
International Prostate Symptom Score  
MI: 
Myocardial Infarction 
mRECIST:     Modified Response Evaluation Criteria in Solid Tumors 
PAE:  
Prostate Artery Embolization  
PG:  
Performance Goal 
QoL:  
Quality of Life 
SAE: 
Serious Adverse Event 
SDV : 
Source Document Verification 
UADE: 
Unanticipated Adverse Device Effect 
UFE 
Uterine Fibroid Embolization 
UFS-QOL:  
Uterine Fibroid Symptom Quality of Life Questionnaire  
VAS 
Visual Analog Scale  
 
 

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1
Background 
The transradial approach to percutaneous interventions has generated intense interest over 
the past decades. Initially researched in the context of percutaneous coronary interventions 
(PCI), early reports of successful transradial access (TRA) included coronary angiography in 
1989 (Campeau, 1989) and the first successful TRA coronary angioplasty and stent 
implantation in the years 1992 and 1993, respectively. (Kiemeneji & Laarman, 1993). 
Further studies of TRA for PCI have consistently demonstrated its benefits as compared to 
femoral access, including decreased bleeding, access site complications and post-
procedure recovery time, and increased patient satisfaction and cost effectiveness. (Rao, 
Cohen, Kandzari, Bertrand, & Gilchrist, 2010) . Limitations to the transradial approach have 
been recognized, such as a learning curve which must be overcome by new operators, 
limitations of available equipment suitable for radial use, and relatively rare complications 
such as localized access site hematoma. Radial artery occlusion is reportedly rare and upon 
occurrence is often asymptomatic due to collateral perfusion supplied by the ulnar artery. 
(Fischman, Swinburne, & Patel, 2015). 
The benefits of transradial access are considered by many physicians to outweigh these 
drawbacks, leading to the steady uptake of TRA for PCI; an estimated 16% of PCI 
procedures in the US were conducted transradially in the year 2012, up from 1.2% in 2007. 
Within the previous decade, additional support for TR-PCI has been generated by multiple 
prospective, randomized trials, including the RIFLE, RIVAL and MATRIX trials which have 
consistently demonstrated decreased access site bleeding and net adverse events. 
(Fischman, Swinburne, & Patel, 2015). The expanding body of evidence favoring transradial 
access for PCI prompted physicians to branch beyond the coronary space to transradial 
access for visceral and peripheral arterial interventions, (Rao, Cohen, Kandzari, Bertrand, & 
Gilchrist, 2010) and more recently, for interventional radiology procedures, such as 
embolization of hypervascular tumors, including uterine fibroids and liver tumors ( (Yamada, 
et al., 2018)). 
Uterine fibroid embolization, traditionally achieved via femoral access, is considered by the 
American College of Obstetrics and Gynecology as a safe, minimally invasive primary 
treatment for symptomatic uterine fibroids. (Keung, Spies, & Caridi, 2018) . The first reported 
series of UFE achieved via radial access dates to 2014, where Resnick, et al. (2014) 
conducted UFE on 29 patients at a single institution with a 100% success rate. No 
immediate major or minor complications were observed in any patients, and radial artery 
patency was evident in all patients at one month follow up. (Resnick, et al., 2014). Recently, 

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Gjoreski, et al. (2019) directly compared the safety and feasibility of UFE when achieved 
through radial as opposed to femoral access. In this retrospective study, 13 femoral 
procedures and 11 transradial procedures all yielded a 100% success rate with no 
significant difference in access site related and overall adverse events noted between 
cohorts. Procedure and fluoroscopy times were reportedly shorter in the radial group; a 
mean procedure time of 60.3 minutes was associated with the radial group as compared to 
72.4 minutes in the femoral cohort, and mean fluoroscopy time was 21.1 minutes and 25.3 
minutes in the radial and femoral cohorts, respectively. (Gjoreski, Gjoreski, & Nancheva, 
2019). 
The development of transradial access for embolization of hepatic tumors can be traced 
back to a 2003 report by Shiozawa et al. (2003) which described transcatheter arterial 
chemoembolization (TACE) in 327 patients, 177 of which were accessed radially and 150 
via femoral access. Therapeutic efficiency was observed in both cohorts, with a lower 
complication rate in the radial cohort (4.6%) compared to the femoral (12.7%). (Shiozawa, et 
al., 2003).  In addition to chemoembolization, radial access has also been utilized for 
radioembolization of hepatic tumors. A study by Fischman, et al. published in 2016 
described 30 procedures conducted in 26 patients which supported the safety and 
tolerability of TRA for hepatic artery embolization. In this study, 14 TACE procedures, 14 
Y90 procedures and 2 bland embolization procedures yielded a 100% technical success 
rate with no major AEs reported at one month follow up. (Fischman, et al., 2013) . In a 318 
patient study, a total of 329 planning angiograms and 245 Y90 embolization procedures 
resulted in technical success in 97.7% of cases, superficial bruising observed in 2.3% of 
cases, and a radial artery occlusion rate of 1.6%. (Bishay, et al., 2016) . 
A study by Kis and colleagues, comparing the feasibility of transradial vs transfemoral 
access for hepatic radioembolization, demonstrated 100% technical success in both radial 
and femoral cohorts, totaling 64 procedures in 50 patients. Direct savings in cost and time 
were noted in the radial group; approximately $100 and 1-hour decrease post procedure 
stay was observed on a per procedure basis. Despite a caveat noted in this study 
surrounded the technical challenges associated with radial access which led to longer 
fluoroscopy time and greater radiation doses, the authors recommended radial access as 
the primary choice in selected patients, such as those with low platelet count and/or morbid 
obesity. (Kis, Mills, & Hoffe, 2016) The association between increased radiation exposure 
and fluoroscopy time with radial access was challenged in a later study, in which 124 
intraarterial procedures were performed on 55 liver cancer patients, which demonstrated 

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significantly less radiation exposure to operators using radial artery access, and similar 
contrast agent volume and patient radiation exposure between groups. This randomized, 
prospective study was primarily conducted in order to assess patient access preference for 
intraarterial liver cancer therapies; of 36 patients who experienced at least one radial and 
one femoral access procedure, 81% preferred TRA compared to 19% who preferred TFA. 
(Yamada, et al., 2018) 
A recent paper from an Italian University hospital from a study of 60 pts treated with TACE 
for HCC reported 0% of cross-over rate from trans-femoral access (TFA) to trans-radial 
access (TRA). A positive association between operator experience and time spent for 
fluoroscopy, puncture, procedure and total examination was noted. A negative relationship 
between TRA and contrast volumes and radiation exposure were also reported. A higher 
percentage of pts treated with TFA reported post-procedural complains at the puncture site 
and limitations in performing basic activities. The operator learning curve was estimated to 
be low, with an estimated threshold of 20 procedures. (Iezzi, et al., 2019) 
The largest study involving safety and feasibility of transradial access for non-coronary 
interventions includes both UFE and hepatic artery embolization among other visceral 
interventions. In this single center study, 936 patients undergoing 1,512 consecutive TRA 
procedures were retrospectively analyzed. Of these procedures, UFE accounted for 116, 
and TACE, Y90 mapping and Y90 infusion accounted for 485, 391 and 293 procedures, 
respectively. Combined analysis indicated a technical success rate of 98.2%. Major 
complications, including one pseudoaneurysm and one seizure, were reported at 0.13%, 
and minor complications, including hematomas, RAO, RAS and arm pain, were observed in 
2.38% of cases. Twenty-seven cases, representing 1.8%, required crossover to 
transfemoral access. The favorability of these results towards radial access led authors to 
pronounce TRA as a promising alternate primary access site in a variety of peripheral 
vascular interventions.  (Posham, et al., 2016) 
 
1.1 HydroPearl microspheres and Indications For Use 
HydroPearl microspheres are indicated for use in arteriovenous malformations and 
hypervascular tumors, including uterine fibroids, and for prostate artery embolization for 
symptomatic benign prostatic hyperplasia (BPH).  

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1.2
Summary of Clinical Studies
No clinical studies using HydroPearl have been published, although a small retrospective 
study of 17 PAE patients treated with HydroPearl for BPH was presented at the Spectrum, 
an annual conference for IR (interventional radiology) oncological diseases.
 
2
Study Design, Sample Size and Duration 
2.1 Study Design
This is a prospective, multi-center, non-randomized registry to record the real-world safety 
and efficacy of the HydroPearl microspheres for arteriovenous malformations and 
hypervascular tumors including uterine fibroids, and for embolization prostatic arteries for 
symptomatic benign prostatic hyperplasia (BPH).  
 
2.2 Sample Size
Up to 10 sites in the US and EU are expected to participate in the study with 100 subjects 
enrolled.  Each study site will be limited to 30% of total patient population.  
The target population is comprised of subjects scheduled for embolization procedures with 
HydroPearl microspheres used on-label via radial access.  
 
2.3 Study Duration 
Study enrollment is expected to occur over an 18-month period. Follow-up will continue for 
each subject through 365-days post-procedure. 
 
3
Study Objective and Evaluations
 
3.1 Study Objective 
The objective of this registry study is to assess the technical and procedural success and 
complication rates in real-world patients undergoing embolization procedures with 
HydroPearl microspheres via radial access. 
 
3.2 Evaluations 
This clinical study will assess the primary and secondary evaluations as described below.  

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3.2.1 Primary Evaluations
Primary Safety Evaluation: 
The primary safety evaluation is freedom from major adverse events and radial access 
complications within 30 days post-procedure.   
Major Adverse Events are defined as:  
1. Death 
2. MI 
3. Stroke 
Radial Access related complications are defined as:  
1. Radial artery occlusion 
2. Hand ischemia 
3. Arteriovenous fistula 
4. Pseudoaneurysm 
5. Any complication requiring surgical and/or endovascular intervention within 30 days 
of index procedure.  
 
 
Primary Efficacy Evaluation: 
The primary efficacy evaluations are procedural success and technical success.   
1. Procedural success is defined as completing the planned procedure without femoral 
access bailout.   
2. Technical success is defined as delivery of HydroPearl to the target vessel and 
slowing the blood flow with microsphere embolization. Embolization may be 
confirmed clinically or radiologically at the discretion of the site investigator.  
 
3.2.2 Additional Evaluations 
Additional evaluations include:  
1. Incidence of Radial Artery Occlusion Complications at any time 
a. Arteritis 
b. Cellulitis 
c. Ecchymosis 
d. Pain at puncture site 
e. Hematoma 

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2.
Quality of Life and health economics
3. Post embolization syndrome 
4. Procedural endpoints: 
a. Blood loss 
b. Patient radiation exposure  
c. Contrast volume 
d. Time to hemostasis 
e. Total procedural time 
f. 
Time to discharge 
g. Operative time 
5. Access endpoints:  
a. Radial artery spasm,  
b. Time to discharge  
6. Closure endpoints 
a. Time to hemostasis  
b. Time to ambulation 
7. Tumor type 
8. Number and size of tumors / fibroids 
9. Post embolization syndrome  
10. UFE:  
a. If post-op MRI is obtained per standard of care: Effectiveness of HydroPearl 
measured by MRI.  
i. Infarction is characterized by complete (100%), 90-99%, 50-89%, or 
less than 50%.   
ii. Uterine Volume 
iii. Dominant Fibroid Volume 
b. EQ-5D 
c. UFS-QoL 
d. Return to normal activities  
e. Pain VAS 
f. 
Symptoms including bleeding and bulk 
g. Pregnancy intention and occurrence  
11. PAE:  
a. IPSS with Quality of Life 

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b.
EQ-5D
c. Return to normal activities 
d. Pain VAS 
e. Qmax 
f. 
Prostate volume 
12. Liver Tumor Embolization: 
a. Tumor response (mRECIST - CR, PR, SD, PD)  
b. EQ-5D 
c. Return to normal activities 
d. Pain VAS 
e. Disease stage 
13. Other Hypervascular Tumors  
a. Infarction 
b. Tumor Response (mRECIST – CR, PR, SD, PD) 
c. Return to normal activities 
d. Pain VAS 
14. Arteriovenous malformations: 
a. EQ-5D 
b. Return to normal activities 
c. Pain VAS 
 
4
Study Design
This is a prospective, multi-center, registry study to assess the procedural success, 
technical success, and complication rate of radial access procedures using HydroPearl 
microspheres.  
 
A subject is considered enrolled into the study once the guidewire is inserted into the radial 
artery.  
 
4.1 Eligibility Criteria
4.1.1 Inclusion Criteria
Subject must meet all the following inclusion criteria to be enrolled in the study:  
1. 
 

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2.
Subject is scheduled for a procedure for treatment with HydroPearl microspheres 
using radial access. 
3. Subject is willing and able to complete follow-up requirements 
4. Subject is willing and able to sign a written Informed Consent form prior to 
participating in the registry.  
 
4.1.2 Exclusion Criteria
Subjects will not be permitted to participate in the study if they meet any of the 
following exclusion criteria: 
 
1. Unable to have a procedure with radial access for any reason. 
2. Participating in another clinical study which, in the opinion of the investigator, could 
impact the results of this registry.  
3. Pregnant or planning to become pregnant during the study.  
 
4.2 Subject Enrollment
Up to 10 sites in the US and EU are expected to participate in the study with up to 100 
subjects enrolled.  
 
5
Ethics
5.1 Role of the Sponsor
The Sponsor has the overall responsibility for the conduct of the study, including assurance 
that the study meets all regulatory requirements. In this study, the Sponsor will have certain 
direct responsibilities and will delegate other responsibilities to the Clinical Research 
Organization (CRO). The Sponsor will conduct all its responsibilities in compliance with GCP 
and any applicable regulations.  
 
5.2 Role of Clinical Research Organization 
The Clinical Research Organization (CRO) will support the data management which 
includes, but is not limited to, informing the Sponsor of any unanticipated adverse device 
effects (UADEs) and serious adverse events (SAEs) as appropriate. The CRO will conduct 
all its responsibilities in compliance with the Code of Federal Regulations (CFR).  
 

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5.3
Ethics Review
The final study protocol and written Informed Consent Form must be approved in writing by 
an Institutional Review Board (IRB) and/or Ethics Committee (EC). The principal investigator 
is responsible for informing the IRB/EC of any amendments to the protocol in accordance 
with local requirements. In addition, if any advertising is used to recruit subjects to the study, 
the IRB/EC must approve prior to use. The protocol must be re-approved by the IRB/ EC 
annually, as local regulations require and where applicable.   
Progress reports and notification of serious, unexpected adverse events will be provided to 
the IRB/EC according to local regulations and guidelines. 
5.4 Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with the ICH/GCP, ISO 14155 and MDR (EU) 
2017/745. and applicable regulatory requirements. 
 
5.5 Written Informed Consent
Written Informed Consent must be obtained prior to any study-related procedures*. The site 
principal investigator will ensure that proper informed consent is provided, including 
ensuring the subject is given full and adequate oral and written information about the nature, 
purpose, possible risks and benefits of the study. Subjects must also be notified that they 
are free to withdraw from the study at any time. The subject must be given the opportunity to 
ask questions and adequate time to consider the information provided. The site principal 
investigator will ensure that the subject has met all eligibility criteria prior to enrollment in the 
study. 
The site principal investigator must store the original, signed written ICF per site specific 
procedures.  A copy of the written ICF (paper or electronic) must be given to the subject. 
Any modifications made to the ICF must first be approved by the Sponsor and IRB/EC.   
 
*Pre-procedure assessments considered standard of care completed prior to obtaining 
informed consent do not need to be repeated if performed within 90 days of the procedure 
unless the investigator feels it is medically necessary. 
 

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5.6
Subject Data Protection
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
written Informed Consent Form must include a subject authorization to release medical 
information to the study Sponsor and/or allow the Sponsor or their designate, any regulatory 
authority, and IRB access to subject’s medical information that includes all hospital records 
relevant to the study, including subjects’ medical history. 
In accordance with General Data Protection Regulation (EU) 2016/679 of the European 
Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard 
to the processing of personal data and on the free movement of such data (General Data 
Protection Regulation), the written Informed Consent form must include a subject 
authorization to release medical information to the study Sponsor and or allow the Sponsor or 
their designate, a regulatory authority, or EC access to subject’s medical information that 
includes all hospital records relevant to the study, including subjects’ medical history. 
To protect the patient’s identity, a unique patient identification code will be assigned by the 
investigator to each trial patient and used instead of patient’s name when the investigator 
reports adverse event and/or other trial related data. Thus, this number, rather than the 
patient’s name, will appear on all documents and will be cross-referenced by the patient’s 
date of birth. Personal information will be treated as confidential, but may need to be reviewed 
by the PIs, the ethics committee and regulatory authorities. 
In order to be compliant with any country-specific laws, all relevant submissions, to the 
respective authorities will be done and the corresponding approval will be obtained before 
collection of any data considered to be sensitive, such as: ethnic origin, race, full date of birth 
etc 
 
5.7 Subject Withdrawal
Subject participation in the study is voluntary. Subjects may withdraw their consent from 
participation in the study at any time. A subject may withdraw completely or may withdraw 
but leave the authorization to access their medical records in compliance with local 
regulations. Should a subject leave the study for any reason, the investigator will document 
the reason if known, and report in the study database.   
 
5.8 Discontinuing Subject Participation
A subject’s participation in the study may be terminated for the following reasons: 

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1.
Serious or severe adverse event or unanticipated adverse device effect.
2. Termination of study by the Sponsor. 
 
3. Investigator determination that continued participation is not in the best interest of 
the subject.  
4. Subject withdrawal of consent at any time. 
 
6
Device Supply Information 
6.1 Documentation 
This is a registry study observing on-label use of HydroPearl microspheres; therefore, all 
product will be obtained from the commercial stock at each study site for clinical use.  All 
product information should be recorded in source documents and the study eCRF.  
 
6.2 Malfunctioning / Failed Device
If a Terumo device has malfunctioned and/or failed, the investigator must follow the standard 
institutional policies for reporting complaints. In addition, the device failure should be 
reported in the eCRF.  
 
7
General Procedures
7.1 Screening/ Baseline Visit
Prior to the procedure, subjects must sign the informed consent form, meet all the inclusion 
and none of the exclusion criteria.  The screening visit will follow each study site’s standard 
of care and typically consists of a review of medical history and demographics, blood tests, 
imaging, review of concomitant medications, and pregnancy test if appropriate.  
 
7.2 Procedure 
Subjects that meet the eligibility criteria and have signed the informed consent will have their 
scheduled procedure performed in accordance with investigator/site standard practices.  
Any on-label use of HydroPearl microspheres are permitted this study; that is, treatment of 
arteriovenous malformations and hypervascular tumors including uterine fibroids.  
 

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Table 2:  Schedule of Events
Assessment
Screening / 
Baseline 
Procedure
Discharge
30 Day 
Follow-up 
±14 days
180 Day 
Follow-up 
±30 days
365 Day 
Follow-up 
±30 days
Informed Consent
X
Eligibility Criteria 
X 
 
 
 
Medical History/Demographics 
X 
 
 
 
Pregnancy Test ¶ 
X
Blood Tests, including platelets and INR (if available) *
X 
X 
X 
X
X
X
Embolized target organ Imaging (if available) 
X 
X 
X 
X
X
X
Physical Exam
X
X
X
X
X
Procedure, Access, Closure Evaluations
X
Quality of Life questionnaires and return to normal activities
X 
 
X 
X
X
X
Concomitant Medications (Intra-op and Anticoagulation / 
Antiplatelets Only)
X
X
X
X
Device Related Adverse Events 
 
X
X
X
X
X
¶ Pregnancy test if female of child-bearing potential (collected prior to procedure according to site standard of care)
* Blood Tests include Complete Blood Count (CBC), Platelet Count, Serum Creatinine, Hemoglobin (HGB), Blood Urea Nitrogen (BUN), Hematocrit (HCT) and 
Prothrombin time/INR, only as collected per standard of care 
 Device related adverse events should be recorded during the entire course of the study from time of enrollment through end of 180 Day Follow-up visit.   

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7.3 Device Set-up and Preparation
Please refer to the IFU for guidance. 
7.4 Blood Tests 
Blood samples will be collected and analyzed per each site standard of care.  Specific blood 
tests are not required per protocol; examples of typical tests are listed, but only need to be 
reported if collected per standard of care.  
7.5 Concomitant Medical Therapy
Subjects enrolled in this study should be medicated according to investigator’s standard of 
care prior to, during, and after the procedure. 
 
Intraoperative medications and any anticoagulant / antiplatelet medications should be 
recorded on the appropriate eCRF.  Other concomitant medications will not be collected for 
this study.  
 
7.6 Follow-up Procedures
Subjects will be evaluated prior to discharge, 30 days post-procedure,180 days post-
procedure, and 365 days post-procedure. All follow-up visit dates will be calculated based 
on a 30-day calendar.  
 
7.6.1 Discharge Visit
The subject may be discharged when clinically stable, at the discretion of the investigator.  
7.6.2 30 Day Visit (± 14 days)
All study sites will be asked to collect follow-up data per each subject at 30 days post-
procedure. Study reported evaluations are not required except for the quality of life 
questionnaire; otherwise all data collected will be per standard of care.  A typical follow-up 
visit may include blood tests, imaging, physical exam, review of concomitant medications 
and any device related adverse events.  
 

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7.6.3 180 Day Visit (± 30 days)
All study sites will be asked to collect follow-up data for each subject at 180 days post-
procedure, per site standard of care.  Study reported evaluations are not required except 
for the quality of life questionnaire; otherwise all data collected will be per standard of care.  
A typical follow-up visit may include blood tests, imaging, physical exam, review of 
concomitant medications and any device related adverse events.  
7.6.4 365 Day Visit (± 60 days)
All study sites will be asked to collect follow-up data via telephone or visit for each subject 
at 365 days post-procedure.  If a clinic visit is standard of care at 365 days, data from the 
visit will be collected.  If a clinic visit is not standard of care, follow-up information for this 
visit will be collected via telephone.  This 365-day visit will conclude the subject’s 
participation in the study. 
 
7.7 Clinical Data Collection
Information about subject demographics, eligibility requirements, procedure, specific 
concomitant mediations as well as complications and/or device related adverse events will 
be collected on the eCRFs provided by the Sponsor. The eCRFs should accurately reflect 
data contained in the subject’s medical records (i.e. source documents). 
 
8
Adverse Events
Subject complications will be monitored via the reporting of device related adverse events 
occurring from the time of enrollment (insertion of guidewire into radial artery) through study 
completion (withdrawal for any reason or completion of 365-day follow-up visit). For this 
registry, adverse events collected will be limited to any events possibly, probably or 
definitely related to a Terumo device, as described below in Section 8.2.   
 
Where an adverse event has, by its nature, a prolonged course, the event will be considered 
a single event and not multiple events.  
 
The investigator is not required to actively seek adverse events from a subject once a 
subject has exited the study. If the investigator learns of any device related adverse event at 

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any time after a subject’s exit from the study, the investigator should promptly report it to the 
Sponsor. 
8.1 Definitions 
An adverse event (AE) is defined as an unwanted medical occurrence in a subject. This 
definition does not imply that there is a relationship between the AE and the device 
under investigation. This can include, but is not limited to, a change in the subject’s 
health status from baseline that is related to the disease process, interventional 
procedures, investigational device, and/or side effects to medications.   
An adverse device effect is defined as those adverse events that are caused by, or 
related to, the device. 
A serious adverse event (SAE) is an adverse event that led to a death or led to a 
serious deterioration in the health of a subject that: 
1. Resulted in a life-threatening illness or injury, 
2. Resulted in a permanent impairment of a body structure or body function, 
3. Required in-subject hospitalization or prolongation of existing 
hospitalization, 
4. Resulted in medical or surgical intervention to prevent impairment to body 
structure or a body function, or 
5. Led to fetal distress, fetal death or a congenital abnormality or birth 
defect.   
 
Each AE will be assessed by the site investigator to determine whether it is serious or 
non-serious.  (Note:  Seriousness is different from severity; severity is used to describe 
the intensity of an event experienced by the subject).   
 
A serious adverse device effect is an adverse event that is both serious and device 
related. 
8.2 Anticipated Adverse Events (AEs) 
All expected adverse events are listed in each device’s IFU.  Potential complications 
associated with interventional procedures, access, and device are described per each site’s 

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standard of care pre-procedure consenting. Since this observational registry does not include 
any investigational devices or procedures, anticipated AEs are only specified in the IFUs, not 
in the protocol.  
There may be additional unforeseen adverse events.  
8.3 Follow-up of Adverse Events
All device related adverse events observed from the time of enrollment throughout the 
duration of the study must be reported on the eCRF. All device related adverse events will 
be followed until resolution or stabilization of symptoms through study completion and/or the 
subject withdraws consent. Resolution means that the subject has returned to a baseline 
state of health. Stabilization means that the investigator does not expect any further 
improvement or worsening of the adverse event.   
 
8.4 Causality Rating
The causal relationship of an adverse event to the device will be rated as follows: 
Possible:  An event that is unlikely caused by using the device. An alternative explanation - 
e.g., concomitant drug(s), concomitant disease(s) - is inconclusive. The relationship in time 
is reasonable; therefore, the causal relationship cannot be excluded. 
Probable:   An event that might be due to the use of the device. An alternative explanation is 
less likely - e.g., concomitant drug(s), concomitant disease(s). The relationship in time is 
suggestive of a direct relationship to the device. 
Definitely:  An event that is attributed to the use of the device. The event cannot be 
reasonably explained by an alternative explanation - e.g., concomitant drug(s), concomitant 
disease(s). 
8.5 Severity of Adverse Events 
The severity of adverse events will be rated as follows: 

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Mild
An adverse event that is tolerated by the subject, causes minimal discomfort 
and does not interfere with everyday activities, does not need medical 
treatment or intervention. 
Moderate
An adverse event that is sufficiently discomforting to interfere with normal 
everyday activities; intervention may or may not be needed.
Severe
An adverse `event that prevents normal everyday activities; treatment or 
other intervention usually needed. 
8.6 Adverse Event Monitoring  
Adverse events will be reviewed and assessed by the principal investigator at each site.  
Treatment for adverse events will be per standard of care as determined by the site 
investigator.  Device related adverse events reported in the eCRF will be processed in the 
standard compliant fashion for the manufacturer.  
 
9
Risk Assessment 
 
9.1 Risk Management Procedure
Subjects will be monitored for the duration of the study. Risks will be mitigated through 
selection of qualified physicians, appropriate training, and study monitoring ensured by the 
following: 
 
Investigators who participate in the study will be experienced and skilled in radial 
access for visceral interventions.  Additionally, investigators, in conjunction with the 
investigational site, will have adequate resources for participation in a registry 
study. 
 
Each investigator will ensure oversight and approval of the study by their IRB/EC 
prior to initiation of the study at their site. 
 
The investigator and study personnel will be trained on the study protocol.  
 
Subjects will be carefully evaluated against the eligibility criteria prior to entering the 
study to ensure that their diagnosis and medical status are appropriate for 
participation. 

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Subjects will be monitored throughout the follow-up period as defined in the study 
protocol. Subjects will have visits with the investigator or designee to review the 
subjects’ status. 
 
9.2 Potential Benefits 
Subjects enrolled in this clinical study will be monitored closely throughout the study and 
have regular assessments according to the investigator’s standards of care. The data 
collected during the clinical study will provide further understanding of procedural and 
technical success of radial access for HydroPearl procedures.  
 
10 Monitoring
Data will be collected using eCRFs for this study. Sites will enter data directly into the 
eCRFs via a web-based system. Sponsor representatives (study monitors) will schedule 
periodic, on-site visits to review source data and compare to eCRFs. 
 
Study monitors will work in accordance with Sponsor standard operating procedures (SOPs) 
and the Study Monitoring Plan.  
 
At the site, monitors will perform and verify the following: 
 
The adequacy and experience of the study center including Sponsor notification of 
any problems relating to facilities, technical equipment or medical staff 
 
Written Informed Consent has been obtained from all subjects prior to any study 
related procedures being performed and that data is recorded correctly and 
completely 
 
Source Document Verification (SDV):  comparing data in the eCRFs to ensure they 
correspond with applicable source data, and to inform the Sponsor and investigator 
of any discrepancies, errors or omissions 
 
Ensure adherence to the protocol and applicable regulations at the site and notify 
the Sponsor promptly of any deviations  
 
Evaluate subject compliance and support subject retention efforts at the site 
 

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11 Image Analysis 
Imaging, if completed, will be analyzed per standard of care at each site and results 
reported in eCRF; however, images will not be collected nor archived by the Sponsor.  
12  Device Failure and Malfunction
A device failure has occurred when the device is used in accordance with the IFU, but does 
not perform as described in the IFU, and negatively impacts treatment of the study subject.  
 
13 Statistical Methods  
13.1 Sample Size Determination
. This observational study is not testing a hypothesis; therefore, no power calculations were 
completed.  The stated sample size will provide a reasonable assimilation of safety of the 
device and will allow detection of rare major complication with a reasonable probability.  
That is, a sample size of 100 evaluable patients would provide greater than 80% probability 
of observing 1 or more major complications that may occur at a population rate of 1.6% or 
more.
13.2 General Considerations
Evaluations will be reported with descriptive statistics including 95% confidence intervals. 
Continuous endpoints will report the mean and standard error, median, min, and maximum 
values. Categorical endpoints will be summarized by proportion of each category. Time-to-
event endpoints will be summarized via Kaplan-Meier survival analyses, along with median 
and associated 95% interval. The associated Kaplan-Meier curves will be displayed as 
appropriate. 
 
Sub-group analyses include, but are not limited to:  
 
UFE treatment procedure 
 
Hypervascular benign and malignant liver treatment procedures 
 
AVM procedures 
 
PAE treatment procedure  
 
 

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13.2.1 Study Visit  
The Study Visit Day 0 is the date of the index procedure. Day in study will be calculated 
relative to the index procedure as follows: 
Study Day = Assessment Date – Index Procedure Date 
 
For each subject, duration in study will be based on last study contact date which is the 
latest date of all follow-up visits, assessments, adverse event onset or resolution, and study 
exit including date of death. 
 
Duration variables will be calculated as follows: 
Duration Days =  End Date – Start Date   
 
13.2.2 Visit Windows 
Unless otherwise specified, visit assessments will be analyzed for each analysis time point 
according to the visit entered in the eCRF. 
 
13.3 Analysis Populations
Analyses for primary and secondary evaluations will be based on the Primary Analysis Set, 
defined as all enrolled subjects (i.e., those who signed the informed consent form and meet 
all protocol eligibility criteria) who are treated. 
 
13.4 Poolability Analysis 
All investigational sites will follow the requirements of the study protocol and standardized 
data collection procedures. The primary evaluations will be presented separately for each 
site using descriptive statistics. Poolability of the primary evaluations across investigational 
sites will be evaluated using a regression model with fixed effects for site. Sites enrolling 
less than 5 subjects will be combined to form one-quasi site.  If the p-value for the site effect 
is < 0.15, additional exploratory analyses will be performed to understand any variations in 
outcomes by site.   
 

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13.5 Handling of Missing Data
All data will be collected when possible to limit the amount of missing data. Site study 
coordinators will work with the site principal investigator to collect accurate patient data. The 
number of missing data will be reported.  Only observed cases will be considered.  
13.6 Subject Disposition
Subjects who sign an informed consent form, but do not meet all protocol eligibility criteria 
(i.e., screening failure), will be excluded from the statistical analyses. 
13.7 Analysis of Study Evaluations
Study success is defined as sample size enrolled with minimal missing data to allow for 
robust descriptive statistics. No formal hypothesis tests will be performed; endpoints will be 
summarized with descriptive statistics.
13.8 Protocol Deviations
Deviations from the procedures outlined in the study protocol will be reported by study sites 
on eCRFs.  Protocol deviations will be summarized for all deviations and by type with event 
counts and number of subjects with at least one deviation. 
 
13.9 Changes to Planned Analyses 
Any changes to planned statistical analyses determined necessary prior to performing the 
analyses will be documented in an amended protocol and approved prior to the analysis 
when possible. 
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Results and Technique. American Journal of Roentgenology, 207(5), 1112-1121.
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FIschman, A. M., Resnick, N. J., Fung, J. W., Patel, R. S., Lamberson, N. B., Ort, M., . . . 
Lookstein, R. A. (2013, April). Transradial approach for hepatic arterial 
embolization: initial results and technique. Journal of Vascular and Interventional 
Radiology, 24(4), S93-S94.

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Fischman, A. M., Swinburne, N. C., & Patel, R. S. (2015). A Technical Guide Describing the 
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Keung, J. J., Spies, J. B., & Caridi, T. M. (2018). Uterine artery embolization: A review of 
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Kiemeneji, F., & Laarman, G. J. (1993). Percutaneous transradial artery approach for 
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initial experience and comparison to transfemoral access. Diagnostic and 
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Posham, R., Biederman, D. M., Patel, R. S., Kim, E., Tabori, N. E., Nowakowski, F. S., . . . 
Fischman, A. M. (2016). Transradial Approach for Noncoronary Interventions: A 
Single-Center Review of Safety and Feasibility in the First 1,500 Cases. Journal of 
Vascular and Interventional Radiology, 27, 159-166. 
Rao, S. V., Cohen, M. G., Kandzari, D. E., Bertrand, O. F., & Gilchrist, I. C. (2010). The 
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Cardiology, 55(20), 2187-2195.
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443-447.
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(2003). Transradial Approach for Transcatheter Arterial Chemoembolization in 
Patients With Hepatocellular Carcinoma: Comparison with Conventional 
Transfemoral Approach. Journal of Clinical Gastroenterology, 37(5), 412-417. 
Yamada, R., Bracewell, S., Bassaco, B., Camacho, J., Anderson, M. B., Conrad, A., . . . 
Guimaraes, M. (2018). Transradial Versus Transfemoral Arterial Access in Liver 
Cancer Embolization: Randomized Trial to Assess Patient Satisfaction. Journal of 
Vascular and Interventional Radiology, 29(1), 38-43.