LC Bead LUMI for Prostatic Artery Embolization: A Pilot Study
Phase: NA
Conditions: BPH
Sponsor: University of North Carolina, Chapel Hill

 
LC Bead LUMI for Prostatic Artery Embolization: A Pilot Study 
 
 
NCT number NCT03372096 
Document Date July 19, 2019 
 

Page 1 of 22 
 
 
 
 
 
 
 
 
 
Protocol Title: 
LC Bead LUMI for Prostatic Artery 
Embolization: A Pilot Study 
 
 
Principal Investigator: 
Ari J Isaacson, MD 
 
Co-Investigators: 
 
Sandeep Bagla, MD 
 
 
Mathew Raynor, MD (Urologist) 
 
Biostatistician 
 
Thad Benefield, MS 
 
 
Medical Device: 
LC Bead LUMI  
 
IDE Number:  
 
G170232 
 
Version Date:  
 
July 19, 2019 
 
Version: 
 
 
 1 
 

Page 2 of 22 
Table of Contents 
 
1.0 
Introduction 
1.1 
Study Conduct 
1.2 
Background 
1.3 
Medical Device 
1.3.1 Name of Investigational Device 
1.3.2 Intended Use of the Investigational Device 
1.3.3 Description of the Investigational Device 
1.4 
Preclinical Data 
1.5 
Clinical Data to Date 
1.6 
Similar Approved Devices 
2.0 
Study Objectives 
3.0 
Study Design  
3.1 
General Design 
3.2 
Primary Study Endpoints 
3.3 
Secondary Study Endpoints 
3.4 
Primary Safety Endpoints 
4.0 
Subject Selection and Withdrawal 
4.1 
General Characteristics of the Proposed Subject Population 
4.2 
Anticipated Number of Research Subjects 
4.3 
Inclusion Criteria 
4.4 
Exclusion Criteria 
4.5 
Subject Recruitment and Screening 
4.6 
Early Withdrawal of Subjects 
4.6.1 Criteria for removal from study 
4.6.2 Follow-up for Withdrawn Subjects 
5.0 
Study Treatment or Diagnostic Product Procedures 
5.1 
Description 
5.2 
Method for Assigning Subject to Treatment Groups 
5.3 
Subject Compliance Monitoring 
5.4 
Prior and Concomitant Therapy 
5.5 
Blinding of Study  
5.6 
Receiving, Storage, Dispensing and Return 
5.6.1 Receipt of Investigational Device Supplies 
5.6.2 Storage 
5.6.3 Dispensing 
5.6.4 Return or Destruction of Investigational Device 
6.0 
Study Procedures 
6.1 
Pre-study Visit (Urology Clinic) 
6.2 
Visit 1 (Vascular Interventional Radiology Clinic) 
6.3 
Visit 2 PAE 
6.4 
Visit 3 (1 Month Follow-Up) 
6.5 
Visit 4 (3 Month Follow-Up) 
6.6 
Visit 5 (6 Month Follow-Up) 
6.7 
Visit 6 (12 Month Follow-Up) 
6.8 
Follow-up Phone Call 
6.9 
Study Procedure Flow Chart 
7.0 
Safety and Effectiveness Assessments 

Page 3 of 22 
7.1 
Safety Assessments 
7.2 
Effectiveness Assessments 
8.0 
Statistical Plan 
8.1 
Sample Size Determination 
8.2 
Statistical Methods 
8.3 
Subject Population(s) for Analysis 
8.4 
Interim analysis 
9.0 
Risk Analysis 
9.1 
Anticipated Risks 
9.2 
Adverse Event Definitions 
9.3 
Recording of Adverse Events 
9.4 
Causality and Severity Assessment 
9.5 
Reporting of Adverse Effects and Unanticipated Problems 
9.5.1 Reporting of adverse Effects to the FDA 
9.5.2 Reporting Adverse Effects to the Responsible IRB 
9.6 
Stopping Rules 
9.7 
Medical Monitoring 
9.7.1 Data and Safety Monitoring Plan 
9.7.2 Data and Safety Monitoring Board 
10.0 
Data Handling and Record Keeping 
10.1 
Confidentiality 
10.2 
Source Documents 
10.3 
Case Report Forms 
10.4 
Record Retention 
10.5 
IRB Documentation 
11.0 
Study Monitoring, Auditing and Inspecting 
11.1 
Study Monitoring Plan 
11.1.1 Locations 
11.1.2 Study Staff Responsibilities and Training 
11.1.3 Quality Assurance and Quality Control 
11.1.4 Safety Monitoring 
11.1.5 Monitoring Activities 
11.1.6 Study Closure 
11.2 
Auditing and Inspecting 
12.0 
Ethical Considerations 
12.1 
Institutional Review Board (IRB) Approval 
12.2 
Ethical and Scientific Conduct of the Clinical Research Study 
12.3 
Subject Informed Consent 
13.0 
Study Finances 
13.1 
Funding Source 
13.2 
Conflict of Interest 
13.3 
Subject Stipends or Travel Reimbursements 
14.0 
Publication Plan 
15.0 
References 
16.0 
Attachments 
 
 

Page 4 of 22 
 
1.0 Introduction 
1.1 Study Conduct 
This study will be conducted in compliance with the protocol approved by the 
Institutional Review Board, and according to Good Clinical Practice standards. No 
deviation from the protocol will be implemented without the prior review and approval 
of the IRB except where it may be necessary to eliminate an immediate hazard to a 
research subject. In such case, the deviation will be reported to the IRB according to its 
policies and procedures. 
 
1.2 Background 
Over the past 5 years, data has emerged from numerous countries supporting the safety 
and efficacy of prostatic artery embolization (PAE) for the treatment of lower urinary 
tract symptoms (LUTS) in the setting of benign prostatic hyperplasia (BPH) (1). In 
response, the Food and Drug Administration (FDA) recently granted a de novo 
classification to Merit Medical Systems to expand the indications for Embosphere 
Microspheres to include PAE for the treatment of BPH. Moreover, it has given 510(k) 
clearance for Embozene Microspheres. 
 
LC Bead LUMI is a spherical polyvinyl alcohol embolic particle that has become 
available for clinical use over the last two years. It is unique among embolic particles in 
that it is innately radiopaque. It is a reengineered iteration of LC Bead that now includes 
iodine moieties to provide radiopacity (2). A disadvantage of the new molecular structure 
is that it has a shorter suspension time and less compressibility (2). These factors can lead 
to clumping and sub-optimal proximal embolization.  
 
While PAE is clinically effective in as many as 75% of patients at 2-year follow-up (3), 
there is still uncertainty as to the reasons for failure. Additionally, although they are rare, 
several major complications have occurred as a result of non-target embolization during 
PAE (1). Because LUMI is inherently radiopaque, its distribution can be imaged on post-
embolization conventional or cone beam computed tomography (CT). If used for PAE, 
these scans could provide information about completeness of prostate embolization as 
well as the presence of non-target embolization, leading to improved embolization 
techniques and patient selection. Before these avenues can be investigated, it must be 
determined if PAE can be performed effectively and safely with LC Bead LUMI. 
 
1.3 Medical Device 
 
1.3.1 Name of Investigational Device 
LC Bead LUMI (M0 or M1 bead sizes are acceptable for use in this trial) 
 
1.3.2 Intended Use of the Investigational Device 
LC Bead LUMI will be used for prostatic artery embolization in patients with 
BPH. 
 
1.3.3 Description of the Investigational Device 
LC Bead LUMI is a spherical polyvinyl alcohol embolic particle that incorporates 
radiopaque moieties (2).  Once a catheter has been fluoroscopically guided into the 
target vessel, the beads are then injected, causing obstruction at the arteriole level 

Page 5 of 22 
until the desired degree of embolization has occurred. We do not anticipate any 
changes in our use of the microspheres during the study. 
 
1.4 Preclinical Data 
LC Bead LUMI has undergone in vitro testing to evaluate its duration of suspension 
in solution, density in solution and deliverability through a catheter, as well as it 
degree of opacity on fluoroscopy and CT (2). In vivo testing in a rabbit VX2 tumor 
model demonstrated high visibility of the particles after embolization on fluoroscopy 
and cone beam CT (2). Similar in vivo testing was done in a swine model also 
demonstrating visibility under fluoroscopy and CT (4). Further swine liver model 
testing revealed that LC Bead LUMI is effective for embolization resulting in 
predictable ischemia/necrosis and excellent long-term biocompatibility (2). 
 
1.5 Clinical Data to Date 
There is no published data available for PAE with LC Bead LUMI. There is a case 
series reporting safe, successful use of LC Bead LUMI for the treatment of liver 
cancer in humans (5). There is also data supporting the safe and effective use of a 
closely related embolic (Bead Block-also a spherical polyvinyl alcohol embolic 
particle manufactured by BTG) for PAE (6). 
 
1.6 Similar Approved Devices 
To date there are 2 embolic devices that are approved for the indication of PAE, 
Embospheres and Embozene Microspheres.  Embospheres was approved with a de 
novo classification request (see 
https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN160040.pdf).  Embozene 
Microspheres received 510(k) clearance (see 
https://www.accessdata.fda.gov/cdrh_docs/pdf18/K180102.pdf).   
 
1.6.1 Safety and Efficacy of Embospheres 
Based on a phase 3 multicenter clinical trial, the procedure using Embospheres was 
efficacious as 100% of subjects treated with PAE achieved a decrease of 3 or greater 
in IPSS.  There were a total of 123 adverse event sin the PAE group, of which 86% 
were classified as mild.  Serious adverse events in PAE patients were limited to 
urinary retention, sepsis, fever, UTI, rigors, and nausea in one patient each. A second 
study has included 2 patients at the time of the FDA filing.  These 2 patients saw 
success in IPSS scores with no adverse events reported.  A third trial also saw 
improvement in 4 patients at the time of FDA filing without any occurrence of 
reported adverse events. 
 
A review of retrospective patient information for 286 patients also demonstrated 
efficacy of PAE with 97% of subjects demonstrating a reduction of IPSS of 3 or 
greater at 9-16 months.  A total of 85% of total patients experience an adverse event 
with the majority being post-PAE syndrome, which is mild pain in the perineum, 
retropubic area, and/or urthra; fever; nausea (74.1%).  Serious adverse events 
occurred in 1%.  
 
1.6.2 Safety and Efficacy of Embozene Microspheres 
Embozene is similar in size and material composition to Embospheres.  This device 
also has similar indications for use.  While there are some slight differences in the 

Page 6 of 22 
two products, they do not affect the overall safety and efficacy of Embozene 
Microspheres.   
 
Safety and efficacy was evaluated for Embozene Microspheres in a total of 38 
patients that underwent PAE for the treatment of BPH in a prospective, single center 
study.  Of these patients, 81.8% saw a reduction of at least 3 points of IPSS within 12 
months.  A total of 47% of patients demonstrated symptomatic improvement over 
baseline at 12 months.  There was also evidence of a reduction in the size of the 
prostate following the PAE procedure.  Overall, the study revealed a 100% success 
rate without incidence of non-targeted embolization.  In regards to safety, the study 
revealed that PAE was safe as there was only an incidence of adverse events in 39.5% 
of patients, with no serious adverse events reported.  The study did not report any 
incidence of post-PAE syndrome.   
 
2.0 Study Objectives 
The purpose of this pilot study is to determine preliminary estimates of the 
parameters related to the distribution of the study endpoints including: IPSS and QoL 
score changes, Qmax changes, PVR changes, percent prostate infarction and presence 
of non-target embolization.   
 
3.0 Study Design  
3.1 General Design 
This will be an open label pilot study with a small population undergoing an 
intervention to determine initial safety and potential for efficacy as measured by 
improvement of LUTS and decrease in prostate size 
 
3.2 Primary Study Endpoint 
Reduction in IPSS at 6 months 
 
3.3 Secondary Study Endpoints 
1. Improvement of QoL score at 6 months 
2. Improvement of uroflowmetry (Qmax, PVR) at 6 months 
3. Reduction of prostate volume at 6 months 
4. Percentage of prostate infarcted at 6 months 
5. Incidence of non-target embolization at 6 months 
6. Incidence of minor complications at 6 months 
7. Improvement in IIEF at 6 months 
 
3.4 Primary Safety Endpoints 
1. Incidence and classification of major device related complications using Clavien-
Dindo classification system at 6 months 
3.5 Secondary Safety Endpoints 
1. Incidence and classification of minor device related complications using Clavien-
Dindo classification system at 6 months 
 
4.0 Subject Selection and Withdrawal 
4.1 General Characteristics of the Proposed Subject Population 
Study subjects will be men with moderate severe LUTS refractory to medication with 
measured prostate gland size >50 grams. 

Page 7 of 22 
 
4.2 Anticipated Number of Research Subjects 
Enrollment into the investigation will be defined as providing informed consent for 
study participation per IRB policies.  
 
Twenty subjects will be enrolled and all are anticipated to complete the study. 
 
4.3 Inclusion Criteria 
1. Male 
2. Age > 40 
3. Prostate gland >50 grams as measured by pre-procedural CT 
4. Have previously taken BPH medication for 6 months without desired improvement 
of LUTS or has started medication and stopped due to unwanted side effects 
5. Moderate to severe LUTS as defined by IPSS score >18 
6. Peak urine flow rate (Qmax) <12 ml/sec 
7. Capable of giving informed consent 
8. Life expectancy greater than 1 year 
 
4.4 Exclusion Criteria 
1. Severe vascular disease 
2. Uncontrolled diabetes mellitus 
3. Immunosuppression 
4.  Neurogenic bladder and/or sphincter abnormalities secondary to Parkinson’s 
disease, multiple sclerosis, cerebral vascular accident, diabetes, etc. 
5. Complete urinary retention 
6. Impaired kidney function (serum creatinine level > 1.8 mg/dl or a glomerular 
filtration rate < 60 as approximated using serum creatinine levels) unless anuric and 
on dialysis. 
7. Confirmed or suspected bladder cancer 
8. Urethral strictures, bladder neck contracture, or other potentially confounding 
bladder pathology 
9. Ongoing urogenital infection 
10. Previous pelvic radiation or radical pelvic surgery 
11. Confirmed or suspected malignancy of the prostate based on DRE, TRUS or PSA 
(> 10 ng/ml or > 4.0 ng/ml and < 10 ng/ml with free PSA < 25% of total PSA without 
a negative biopsy). 
12. Uncorrectable coagulopathy including INR > 1.5 or platelets < 50,000 
13. Contrast hypersensitivity refractory to standard medications (antihistamines, 
steroids) 
 
4.5 Subject Recruitment and Screening 
Subjects will be recruited from the urology and vascular & interventional clinics at 
the University of North Carolina Hospital as well as at outlying clinics staffed by 
UNC Urology. A second site, Vascular Institute of Virginia, will also recruit patients 
from interventional radiology and urology clinics in the Northern Virginia Area. 
 
4.6 Early Withdrawal of Subjects 
4.6.1 Criteria for Removal from Study 

Page 8 of 22 
Subjects will be withdrawn from the study if a major complication occurs that 
prevents completion of PAE or the ability to complete the follow up visits. 
Patients may also withdraw at any point at their discretion.  Data will be 
included with an intent to treat analysis. Reasons for study withdrawal will be 
recorded. 
 
4.6.2 Follow-up for Withdrawn Subjects 
If a subject withdraws from the study, any recorded data will still be included 
in the analysis. Subjects will only be replaced if they withdrew prior to 
undergoing PAE. 
 
5.0 Study Treatment or Diagnostic Product Procedures 
5.1 Description  
Subjects will be advised to stop taking their BPH medications two weeks prior to 
PAE. Though this is advised, it is not required if they cannot tolerate cessation.  They 
will be given a dose of antibiotics on the day of the procedure and continue with oral 
antibiotics for seven days after the procedure. Additionally, non-steroidal anti-
inflammatory medication will be administered mid-procedure. The patients will be 
given the choice of receiving intravenous anxiolytic and analgesic medication during 
procedure or proceeding with local anesthetic only. 
 
Ultrasound-guided access into common femoral artery or radial artery will be 
obtained. An intra-arterial sheath will be placed. Through this sheath a diagnostic 
catheter will be used to perform pelvic angiography. Based on these images and CT 
angiography obtained before the procedure, a microcatheter will be fluoroscopically 
guided into the prostatic artery. LC Bead LUMI will then be injected under 
fluoroscopic guidance to prevent reflux and non-target embolization. Injection will 
continue until there is stasis. The catheter will then be guided into the contralateral 
prostatic artery and repeat embolization will be performed until stasis. If necessary, 
extraprostatic arterial anastomoses will be embolized with a coil or a gel-foam 
pledget to protect against non-target embolization. The catheter and sheath will then 
be removed and hemostasis will be achieved with compression or an intra-arterial 
closure device. The subject subsequently will be discharged home the same day or the 
following day. 
 
It is anticipated that less than 4 milliliters of LC Bead LUMI will be required for 
bilateral embolization. LC Bead LUMI currently have FDA approval for 
embolization of hypervascular tumors and arterio-venous malformations. 
 
5.2 Method for Assigning Subject to Treatment Groups 
Because this is a pilot study to assess feasibility, all subjects will receive the study 
intervention (PAE). 
 
5.3 Subject Compliance Monitoring 
Study coordinators and physicians will inquire of the subjects to determine when they 
have stopped taking their BPH medications prior to the procedure. Additionally, the 
subjects will be asked if they completed all seven days of their post-procedural 
antibiotic regimen. 
 

Page 9 of 22 
5.4 Prior and Concomitant Therapy 
The subjects will be required to have been on medical therapy for BPH for at least six 
months prior to undergoing PAE. They will be advised to stop the BPH medications 
two weeks prior to undergoing PAE. They will be asked to discontinue BPH 
medication after PAE.  Some patients may require maintenance of their BPH 
medications pending alternative therapy. Such medications include prescription and 
over-the-counter drugs.  If potentially confounding medications are clinically 
appropriate to be taken concurrent with the study, dosage should not change during 
the study period unless medically necessary. 
 
5.5 Blinding of Study  
As a pilot study to assess feasibility, all subjects will receive PAE.  Therefore, neither 
the study physicians nor patients will be blinded to the treatment protocol.   
 
5.6 Receiving, Storage, Dispensing and Return 
 
5.6.1 Receipt of Investigational Device Supplies 
LC Bead LUMI will be stored within the Vascular and Interventional 
Radiology procedural suite. 
 
5.6.2 Storage 
LC Bead LUMI must be stored in a cool, dark, dry place in their original 
packing. 
 
5.6.3 Dispensing 
LC Bead LUMI are routinely used in VIR.  No study specific dispensing 
techniques will be used. 
 
5.6.4 Return or Destruction of Investigational Device 
The Institution and Sponsor-Investigator shall, return any such Product to 
Company promptly if requested by the Company upon the completion or 
termination of the Study for which such Product was being utilized, or promptly 
dispose of or destroy, as the Company may reasonably direct, all of its remaining 
stocks of Product. Risk of loss to any such Product shall reside with the 
Institution. Institution shall reimburse Company for any loss of or damage to any 
Product provided by Company under this Agreement due to the negligence of 
Institution or Sponsor-Investigator, ordinary wear and tear excepted. The 
Institution and Sponsor-Investigator shall not use any Product provided by 
Company under this Agreement for any purpose whatsoever except as is 
necessary for the conduct of the Study. 
6.0 Study Procedures 
 
6.1 Pre-Study Visit 
Possible enrollees will have already undergone a standard TURP/OP work-up, which 
typically includes a history, physical exam, urine flow rate recording (Qmax), post-
void residual urine volume assessment (PVR), and imaging to measure prostate size. 
These workups also generally include the following laboratory testing-- UA, PSA, 
CBC, INR, and chemistry.  
 

Page 10 of 22 
6.2 Visit 1 (Vascular Interventional Radiology Clinic) 
If a patient qualifies to be a subject in the study based on the inclusion and exclusion 
criteria listed in section 4.3 and 4.4, the study coordinator will be notified.  The 
coordinator will review the study with the patient and obtain written informed 
consent. Once the subject is enrolled in the study, he will be seen by one of the co-
investigators in either UNC or VIV IR clinic. The procedure will be again described 
to the patient and any questions will be answered. International Prostate Symptoms 
Survey (IPSS), International Index of Erectile Function (IIEF) and Quality of Life 
(QOL) questionnaires will be completed if not done during the pre-study work-up. A 
CT of the pelvis without contrast will be ordered and obtained prior to visit 2 for 
baseline evaluation of the prostate unless the patient has one from the prior 6 months.  
If the patient had a CT of the pelvis within the past 6 months, this CT will be used. 
 
6.3 Visit 2 (PAE) 
PAE will be performed as described in part 5.1 above within 4 weeks of Visit 1. The 
day following the procedure, the subject will be contacted by telephone to inquire 
about symptoms that could be the result of the procedure. In addition, they will be 
given a pager number to reach a physician 24 hours a day to report any adverse 
symptoms and receive medical advice. 
 
6.4 Visit 3 (1 Day Follow Up) 
Subjects will be contacted by study personnel the day after PAE to inquire about 
delayed onset complications. 
 
6.5 Visit 4 (3 Month Follow-Up) 
Subjects will return 90 +/- 7 days after PAE to complete IPSS, IIEF, and QOL 
questionnaires; to have Qmax and PVR measured; and to have a follow up CT of the 
pelvis to evaluate for non-target embolization and PV changes as well as percent 
prostate infarction.  
 
6.6 Visit 5 (6 Month Follow-Up) 
Subjects will return 180 +/- 7 days after PAE to complete IPSS, IIEF, and QOL 
questionnaires and to have Qmax and PVR measured. 
 
6.7 Visit 6 (12 Month Follow-Up) 
Subjects will return 360 days +/- 14 days after PAE to complete IPSS, IIEF, and QOL 
questionnaires and to have Qmax and PVR measured. 
 

Page 11 of 22 
6.8 Study Procedure Flow Chart 
  
 
7.0 Safety and Effectiveness Assessments 
7.1 Safety Assessments 
Subjects will be observed for several hours after PAE to monitor for immediate 
complications to include bleeding, infection and acute ischemia of the rectum and 
bladder. Subjects will be contacted by study personnel the day after PAE to inquire 
about delayed onset complications. The subjects will also be given a phone number 
that they can call to reach a nurse if they believe they have developed a complication 
of the procedure. 
Pre-study from work-up from Urology or IR Clinic 
Pre-study work up generally includes history, physical, urine flow rate, residual urine 
volume, urodynamic testing, imaging for size measurement, UA, CBC, Chem, PSA and 
biopsy if indicated 
VIR Clinic 
Pre-procedural counseling, IPSS, IIEF and QOL questionnaires (if not obtained during 
pre-study work-up), Pelvic CT 
PAE 
3 Month Follow-Up 
CT, PVR, Qmax and IPSS, IIEF, and QOL questionnaires 
6 Month Follow-Up 
PVR, Qmax and IPSS, IIEF, and QOL questionnaires 
12 Month Follow-up  
PVR, Qmax and IPSS, IIEF, and QOL questionnaires 
1 Day Follow Up 

Page 12 of 22 
 
 
7.2 Effectiveness Assessments 
Technical success will be defined as bilateral prostatic artery embolization. This will 
be determined during the procedure. Clinical success will be defined by a reduction of 
IPSS of  ≥ 25% and reduction of QoL by ≥2 . The size of the prostate will be 
measured by CT at 3 the follow-up visit. IPSS, QoL, IIEF, PVR and Qmax will be 
measured at 3, 6 and 12-month follow-ups. 
 
8.0 Statistical Plan 
8.1 Sample Size Determination 
Twenty subjects will be enrolled into this pilot study. Because there is no previous 
study reporting results for PAE with LC Bead LUMI, this pilot study will provide 
sample size data for a larger trial with adequate power. Due to budgetary constraints, 
we have selected a sample size of 20 participants. Given our sample size, and using 
parameters determined from prior studies, we expect to have 3.60% precision for the 
estimate of percent change in IPSS score from baseline to 6 month follow-up.(1)   
 
8.2 Statistical Methods 
Fractions and percentages will be used to describe technical and clinical success rates 
as well as major, minor and specific complication rates. Descriptive statistics 
including means and standard deviations will be used to summarize both discrete 
questionnaire scores and continuous values for prostate size, Qmax, and PVR for the 
3-12 month follow-up period. Prostate size is only measured before the procedure and 
3 months after the procedure.  Percent change will be calculated between the baseline 
and final values. Continuous measures will be described using 95% confidence 
intervals.  Feasibility for a future trial will be assessed using retention rates at each 
visit.   Retention rates will be used to plan sample sizes for future studies.   
 
Any deviations from the previously described statistical plan will be described and 
justified in a protocol amendment and/or in the final report submitted to the IDE 
application. 
 
8.3 Subject Population(s) for Analysis 
All subjects’ data will be included for analysis even if follow up data is incomplete. 
Every attempt will be made to ensure that there is as little missing data as possible 
including reminder phone calls and follow-up phone calls if a subject misses a visit. 
 
8.4 Interim Analysis 
No interim analysis is planned. 
 
9.0 Risk Analysis 
 
9.1 Anticipated Risks 
A recent meta-analysis of PAE data from 662 patients in nine studies reported only 
two major complication (0.3% major complication rate) involving bladder ischemia 
requiring surgery and severe urinary sepsis requiring hospitalization. Among minor 
complications transient rectalgia and/or dysuria (9.1%), acute urinary rentention 
(7.9%) and transient hematuria (4.4%) were the most common (1). 

Page 13 of 22 
 
9.2 Adverse Event Definitions 
Adverse events, Serious Adverse Events and Product Malfunctions  
An adverse event (AE) is defined as any untoward or unfavourable medical 
occurrence in a human patient or clinical trial subject administered a medicinal 
product, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the patient’s 
participation in the research, and which does not necessarily have a causal 
relationship with this treatment (study medication, application of the study device, 
etc.) or study participation. It includes all adverse events regardless of seriousness or 
relatedness.  
 
A serious adverse event (SAE) is defined as an adverse event that  
a) Results in death 
b) Led to a serious deterioration in health that either: 
I. 
Results in a life-threatening illness or injury, or 
II. 
Results in a permanent impairment of a body structure or a body function, 
or 
III. 
Requires in-patient hospitalization or prolongation of existing 
hospitalization, or 
IV. 
Results in medical or surgical intervention to prevent life threatening 
illness or injury or permanent impairment to a body structure or a body 
function.  
V. 
Results in a persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions. 
c) Led to fetal distress, foetal death or a congenital abnormality or birth defect 
 
A product malfunction is defined as a failure of the device to meet its performance 
specifications, essential function or otherwise perform as intended. Performance 
specifications include all claims made in the labelling for the device. The essential 
function of a device refers not only to the device's labelled use, but for any use widely 
prescribed within the practice of medicine. 
 
Reporting of Adverse Events, Serious Adverse Events and Device Malfunctions 
The Institution and/or the Sponsor-Investigator shall report all and any serious 
adverse events, product malfunctions or quality complaints (regardless of causality) 
that they become aware of in relation to the Product and/or the investigation to BTG.  
 
All reports will be exchanged in English and Sponsor-Investigator will also provide 
BTG with such information and reasonable assistance as may be requested by BTG to 
allow BTG to comply with their obligations.   
 
The Institution and/or the Sponsor-Investigator shall report all SAEs and incidents 
impacting patient safety to pharmacovigilance@btgplc.com.  
 
SAEs 
The Sponsor-Investigator will report SAEs within one business day to enable BTG to 
comply with their obligations as the device manufacturer, under applicable laws and 
regulations. 

Page 14 of 22 
All reports will contain the following, if available: 
• Study title and name of the Sponsor-Investigator.  
• Patient number 
• Adverse event number 
• Date of event occurrence/date notified 
• Product details 
o Product name/ part number 
o Size / dose  
o Batch / lot number 
• Adverse event details along with comprehensive event description  
• Action(s) taken to treat or resolve the event 
• Outcome 
• Investigators opinion of causality of event i.e. related to 
o Drug  
o Device 
o Procedure 
• Product returned to BTG if applicable 
 
Device Malfunctions 
The Institution and/or the Sponsor-Investigator shall report all device malfunctions 
and/or quality complaints to within one business day of becoming aware of the issue.  
 
9.3 Recording of Adverse Events 
Research subjects will be questioned about adverse effects by telephone the day 
following the procedure. In addition they will be given a pager number to reach a 
physician 24 hours a day to report adverse effects and receive medical advice. The 
subjects will also be questioned about possible adverse effects at each follow-up visit. 
 
All observed or volunteered adverse effects (serious or non-serious) and abnormal 
test findings, regardless of treatment group, if applicable, or suspected causal 
relationship to the investigational device or, if applicable, other study treatment or 
diagnostic product(s) will be recorded in the subjects’ case histories.  For all adverse 
effects, sufficient information will be pursued and/or obtained so as to permit 1) an 
adequate determination of the outcome of the effect (i.e., whether the effect should be 
classified as a serious adverse effect) and; 2) an assessment of the casual relationship 
between the adverse effect and the investigational device or, if applicable, the other 
study treatment or diagnostic product(s).    
 
Adverse effects or abnormal test findings felt to be associated with the investigational 
device or, if applicable, other study treatment or diagnostic product(s) will be 
followed until the effect (or its sequelae) or the abnormal test finding resolves or 
stabilizes at a level acceptable to the investigator-sponsor. 
 
An abnormal test finding will be classified as an adverse effect if one or more of the 
following criteria are met: 
 
• The test finding is accompanied by clinical symptoms 

Page 15 of 22 
• The test finding necessitates additional diagnostic evaluation(s) or 
medical/surgical intervention; including significant additional concomitant 
drug treatment or other therapy  
o Note: simply repeating a test finding, in the absence of any of the other 
listed criteria, does not constitute an adverse effect.   
• The test finding leads to a change in study protocol or discontinuation of 
subject participation in the clinical research study 
• The test finding is considered an adverse effect by the Sponsor-Investigator. 
 
9.4 Causality and severity assessment 
The investigator-sponsor will promptly review documented adverse effects and 
abnormal test findings to determine 1) if the abnormal test finding should be 
classified as an adverse effect; 2) if there is a reasonable possibility that the adverse 
effect was caused by the investigational device or, if applicable, other study treatment 
or diagnostic product(s); and 3) if the adverse effect meets the criteria for a serious 
adverse effect. 
 
If the investigator-sponsor’s final determination of causality is “unknown and of 
questionable relationship to the investigational device or, if applicable, other study 
treatment or diagnostic product(s)”, the adverse effect will be classified as associated 
with the use of the investigational device or study treatment or diagnostic drug 
product(s) for reporting purposes.  If the investigator-sponsor’s final determination of 
causality is “unknown but not related to the investigational device or, if applicable, 
other study treatment or diagnostic product(s)”, this determination and the rationale 
for the determination will be documented in the respective subject’s case history. 
 
9.5 Reporting of Adverse Effects and Unanticipated Problems 
 
9.5.1 Reporting of adverse reactions to the FDA 
The investigator-sponsor will submit a completed FDA Form 3500Ato the FDA’s 
Center for Devices and Radiological Health for any observed or volunteered adverse 
effect that is determined to be an unanticipated adverse device effect.  A copy of this 
completed form will be provided to all participating sub-investigators. 
 
The completed FDA Form 3500Awill be submitted to the FDA as soon as possible 
and in no event, later than 10 working days after the investigator-sponsor first 
receives notice of the adverse effect. 
 
If the results of the sponsor-investigator’s follow-up evaluation show that an adverse 
effect that was initially determined to not constitute an unanticipated adverse device 
effect does, in fact, meet the requirements for reporting; the investigator-sponsor will 
submit a completed FDA Form 3500Aas soon as possible, but in no event later than 
10 working days, after the determination was made. 
 
For each submitted FDA Form 3500A, the sponsor-investigator will identify all 
previously submitted reports that that addressed a similar adverse effect experience 
and will provide an analysis of the significance of newly reported adverse effect in 
light of the previous, similar report(s). 
 

Page 16 of 22 
Subsequent to the initial submission of a completed FDA Form 3500A, the 
investigator-sponsor will submit additional information concerning the reported 
adverse effect as requested by the FDA. 
 
9.5.2 Reporting Adverse Events to the Responsible IRB 
In accordance with applicable policies of the University of North Carolina 
Institutional Review Board (IRB), the investigator will report, to the IRB, any 
observed or volunteered adverse effect that is determined to be (1) unexpected; (2) 
related or possibly related to the research; and (3) involves increased or greater risk of 
harm to participant(s) or others than was previously known or approved by the IRB. 
Adverse effect reports will be submitted to the IRB in accordance with the IRB 
policies and procedures.  
 
9.6 Stopping Rules 
The study will be stopped if there is greater than one major complication as defined 
by the Society of Interventional Radiology Classification System for Complications 
by Outcome (7). 
 
9.7 Medical Monitoring 
9.7.1 Data and Safety Monitoring Plan 
Safety Monitoring will be performed by a licensed physician who is not a study 
investigator. The CRFs and any relevant source documents will be sent to the medical 
safety monitor (as above) who will review them after treatment is complete for 
subject 1, 5, 10 and 20. 
 
Complications will be assessed by the PI, categorized into major and minor categories 
and recorded on the CRF. CRFs and appropriate source documents will be made 
available to this individual for bi-monthly (every 2 months) review to ensure 
completeness of data collection. Any discrepancies will be immediately addressed by 
the PI.  All adverse events will be recorded and then summarized for inclusion in the 
final manuscript.  
 
Data monitoring will be performed by an individual who is not a study investigator. 
CRFs and appropriate source documents will be made available to this individual for 
bi-monthly review to ensure completeness of data collection. Any discrepancies will 
be immediately addressed by the PI. 
 
9.7.2 Data and Safety Monitoring Board 
Because this is a pilot study with only 20 subjects, no DSMB will be used for this 
study.  Data and safety monitoring will be conducted by individuals who are not 
investigators on this study. 
 
10.0.1 Data Handling and Record Keeping 
10.1Confidentiality 
Information about study subjects will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Consistent with these regulations a signed authorization will be obtained 
that informs each subject of the following:   

Page 17 of 22 
• 
What protected health information (PHI) will be collected from subjects in 
this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their 
PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior to 
the revocation of subject authorization.  For subjects that have revoked authorization 
to collect or use PHI, attempts should be made to obtain permission to collect at least 
vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
10.2 Source Documents 
The study case report form (CRF) is the primary data collection instrument for the 
study.  All data requested on the CRF must be recorded.  All missing data must be 
explained.  If a space on the CRF is left blank because the procedure was not done or 
the question was not asked, write “N/D”.  If the item is not applicable to the 
individual case, write “N/A”.  All entries should be printed legibly in black ink.  If 
any entry error has been made, to correct such an error, draw a single straight line 
through the incorrect entry and enter the correct data above it.  All such changes 
must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, 
then initial and date it. 
 
Copies of completed CRFs with subject IDs will be scanned and sent to the lead 
study coordinator at UNC for entry in the study database.  CRFs should be sent 
within 5 business days to ensure timely entry. 
 
10.3 Case Report Forms 
The case report forms will be collected by the principal investigator and will be 
reviewed monthly for accuracy and completion. 
 
The study case report form (CRF) is the primary data collection instrument for the 
study.  All data requested on the CRF must be recorded.  All missing data must be 
explained.  If a space on the CRF is left blank because the procedure was not done or 
the question was not asked, write “N/D”.  If the item is not applicable to the 
individual case, write “N/A”.  All entries should be printed legibly in black ink.  If 
any entry error has been made, to correct such an error, draw a single straight line 
through the incorrect entry and enter the correct data above it.  All such changes 
must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, 
then initial and date it. 
 
The coordinator at each site will complete the first CRF together with one of the Co-
PIs to verify that it is completed correctly. Then, we will verify a randomly selected 
25% of all source docs at the conclusion of data collection.  Randomization will 
occur on a visit level and not per patient.  The randomization for this verification will 
be generated using a random number generator in Excel. 

Page 18 of 22 
 
10.4     Record Retention 
It is the investigator’s responsibility to retain study essential documents during the 
investigation and for a period of 2 years after the latter of the following two dates: 
The date on which the investigation is terminated or completed, or the date that the 
records are no longer required for purposes of supporting a premarket approval 
application or a notice of completion of a product development protocol.  These 
documents should be retained for a longer period if required by an agreement with 
the sponsor.  In such an instance, it is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.  
 
Research records and original signed consent forms are to be retained by principal 
investigator for at least 6 years if the form includes authorization for use of private 
health information.   Investigators may need to retain these documents for a longer 
period if required by an agreement with a sponsor or per other applicable regulatory 
requirements.  The 6 year minimum retention of authorizations complies with the 
privacy regulation requirements. 
 
10.5    IRB Documentation 
The principal investigator and research coordinator will be responsible for 
maintaining IRB correspondence. IRB approved forms maintained as part of the 
study will include the subject consent form and the HIPAA authorization form. 
 
11.0 Study Monitoring, Auditing and Inspecting 
11.1 Study Monitoring Plan 
11.1.1   Locations 
Initial enrollment will occur at a UNC Urology clinic (within the main 
hospital or off-site) or at VIR clinic within the main hospital. PAE will be 
performed within the VIR department of UNC Hospital, a facility that has an 
on-call emergency response team, an emergency department, intensive care 
units and a full surgical operating suite. Follow up imaging, tests and 
questionnaires will occur in UNC Hospital. 
 
 
11.1.2   Study Staff Responsibilities and Training 
CITI Training: 
The investigators and all staff involved in the study will have completed their 
required Collaborative IRB Training Initiative (CITI) in the protection of 
human research subjects and Good Clinical Practice training.  
 
Drs. Isaacson or Bagla (all fellowship trained interventional radiologists) will 
be the only primary operators for each of the PAE’s. Dr. Isaacson has 
performed approximately 400 arterial embolization procedures with 190 prior 
PAEs. Dr. Bagla has performed approximately 900 arterial embolization 
procedures with approximately 350 prior PAEs.  
 
Dr. Raynor (board certified urologists) will oversee urologic work-up of 
potential subjects as well as urologic care of any AEs requiring treatment. 
 

Page 19 of 22 
 
11.1.3   Quality Assurance and Quality Control 
The research coordinator will monitor the study files on a monthly basis to 
ensure the appropriate regulatory and IRB documentations are on file and up 
to date. The research coordinator will also be responsible for ensuring proper 
study documentation in order to verify compliance with Institutional policy, 
IRB, FDA and GCP guidelines in the following areas: Informed consent, 
Protocol, Source Documents and Electronic Case Report Forms. 
 
11.1.4   Safety Monitoring 
The research coordinator will complete the appropriate report form and logs; 
assist the PI to prepare reports and notify the IRB, FDA, and/or medical 
monitor of all Unanticipated Problems/SAE’s. 
 
The research coordinator and Principal Investigator will confirm that all 
Adverse effects (AE) are correctly entered into the AE log by the coordinator; 
be available to answer any questions that the coordinators may have 
concerning AEs; notify the IRB and FDA of all Unanticipated Problems/SAEs 
and AEs as appropriate. All assessments of AEs will be made by a licensed 
medical professional who not investigator on the research and acting as a 
safety monitor for the study. 
 
The research coordinator will confirm that the AEs are correctly entered into 
the AE log. The Monitor will confirm that the adverse events are consistent 
with the source documents and are reported to the appropriate regulatory 
bodies, as required. 
 
11.1.5 Monitoring Activities 
A safety monitor who is not a study investigator will conduct bimonthly safety 
monitoring. Adverse events will be documented and reported as described 
above. 
 
The following issues will be addressed quarterly or more frequently as 
necessary: 
• Verify receipt of all documents and supplies needed to conduct study 
• Informed consent obtained for each participant 
• CRF completion 
• Investigational product accountability 
• Check and review of the regulatory binder and all essential documents 
• Clinical supply inventory 
• SAE reporting 
• Enrollment issues and targets 
• Protocol amendment and their approval by the IRB 
• Significant protocol deviations 
• Personnel changes 
• Updated regulatory documentation 
• Any other issue as deemed important to the conduct of the study 
 
11.1.6 Study Closure 

Page 20 of 22 
Upon study closure a final evaluation of the data will ensure that all forms are 
present and complete. The data, scanned copies of the consent forms and 
questionnaires and all IRB correspondence will be maintained in digitally 
secure location under the supervision of the research coordinator. Any paper 
copies will be shredded. All subjects will be contacted via phone to thank 
them for their participation and to discuss the study findings as well possible 
additional treatment options. 
 
11.2 Auditing and Inspecting 
 
The investigator will permit study-related monitoring, audits, and inspections by the 
Research Quality Assurance Office, IRB, the sponsor, and government regulatory 
bodies, of all study related documents (e.g. source documents, regulatory documents, 
data collection instruments, study data etc.).  The investigator will ensure the 
capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
12.0 Ethics 
This study will be conducted in compliance with the protocol approved by the 
Institutional Review Board, the relevant federal regulations, and IRB policies and 
procedures and according to Good Clinical Practice standards. No deviation from the 
protocol will be implemented without the prior review and approval of the IRB 
except where it may be necessary to eliminate an immediate hazard to a research 
subject. In such case, the deviation will be reported to the IRB according to its 
policies and procedures. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for 
review and approval by the IRB for the study.  The formal consent of all subjects will 
be sought using the IRB-approved consent form. Before a subject undergoes any 
study procedure, an informed consent discussion will be conducted and written 
informed consent obtained with a consent form signed by the subject or legally 
acceptable surrogate if applicable. An investigator-designated research professional 
will obtain written informed consent from subjects. All subjects will be given a 
signed copy of the informed consent form. 
 
13.0 Study Finances 
13.1 Funding Source 
This study is funded by a grant from Biocompatibles, UK LTD. 
 
13.2 Conflict of Interest 
Any investigator who has a conflict of interest (COI) with this study as defined by the 
policies of the University of North Carolina will have the conflict reviewed by a 
properly constituted Conflict of Interest Review Committee with a committee-
sanctioned conflict management plan that has been reviewed and approved by the 
IRB prior to participation in this study.  All University of North Carolina 
investigators will follow the University conflict of interest policy. 
 
13.3 Subject Stipends or Travel Reimbursements 

Page 21 of 22 
Subjects be reimbursed for travel/parking expenses as well as for their time during 
study visits. 
 
14.0 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided by the sponsor for the purposes of 
performing the study, will be published or passed on to any third party without the 
consent of the study sponsor. Any investigator involved with this study will be 
obligated to provide the sponsor with complete test results and all data derived from 
the study. 
 
15.0 References 
1. 
Uflacker A, Haskal ZJ, Bilhim T, Patrie J, Huber T, Pisco JM. Meta-Analysis of 
Prostatic Artery Embolization for Benign Prostatic Hyperplasia. J Vasc Interv Radiol. 
2016. 
2. 
Duran R, Sharma K, Dreher MR, Ashrafi K, Mirpour S, Lin M, et al. A Novel 
Inherently Radiopaque Bead for Transarterial Embolization to Treat Liver Cancer - A 
Pre-clinical Study. Theranostics. 2016;6(1):28-39. 
3. 
Gao YA, Huang Y, Zhang R, Yang YD, Zhang Q, Hou M, et al. Benign prostatic 
hyperplasia: prostatic arterial embolization versus transurethral resection of the prostate--
a prospective, randomized, and controlled clinical trial. Radiology. 2014;270(3):920-8. 
4. 
Dreher MR, Sharma KV, Woods DL, Reddy G, Tang Y, Pritchard WF, et al. 
Radiopaque drug-eluting beads for transcatheter embolotherapy: experimental study of 
drug penetration and coverage in swine. J Vasc Interv Radiol. 2012;23(2):257-64 e4. 
5. 
Levy EB, Krishnasamy VP, Lewis AL, Willis S, Macfarlane C, Anderson V, et al. 
First Human Experience with Directly Image-able Iodinated Embolization Microbeads. 
Cardiovasc Intervent Radiol. 2016;39(8):1177-86. 
6. 
Pisco JM, Bilhim T, Pinheiro LC, Fernandes L, Pereira J, Costa NV, et al. 
Medium- and Long-Term Outcome of Prostate Artery Embolization for Patients with 
Benign Prostatic Hyperplasia: Results in 630 Patients. J Vasc Interv Radiol. 
2016;27(8):1115-22. 
7. 
Sacks D, McClenny TE, Cardella JF, Lewis CA. Society of Interventional 
Radiology clinical practice guidelines. J Vasc Interv Radiol. 2003;14(9 Pt 2):S199-202. 
 
 
 

Page 22 of 22 
 
16.0 Appendices  
 
 
Figure 1. Time and Events Table 
TIME TABLE 
Pre-
Study 
Standard 
of Care 
Visit 1 
Visit 2 
Visit 3  
(3 month 
follow-up) 
Visit 4 
(6 month 
follow-up) 
Visit 5 
(12 month 
follow-up) 
History and 
Physical Exam 
X 
 
 
 
 
 
Qmax 
X 
 
 
X 
X 
X 
PVR 
X 
 
 
X 
X 
X 
Prostate volume 
measurement 
X 
 
 
X 
 
 
PSA 
X 
 
 
 
 
 
PAE 
 
 
X 
 
 
 
IPSS 
questionnaire 
 
X 
 
X 
X 
X 
IIEF 
questionnaire 
 
X 
 
X 
X 
X 
QOL 
questionnaire 
 
X 
 
X 
X 
X 
CT  
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Study Device (LC Bead LUMI)