Prospective, Controlled Investigation of Prostate Artery Embolization With Embosphere Microspheres Compared to Transurethral Resection of the Prostate for the Treatment of Symptomatic Benign Prostatic Hyperplasia
Phase: NA
Conditions: Benign Prostatic Hyperplasia
Sponsor: Merit Medical Systems, Inc.

Protocol Title: PROSPECTIVE, CONTROLLED INVESTIGATION OF PROSTATE ARTERY EMBOLIZATION 
WITH EMBOSPHERE® MICROSPHERES COMPARED TO TRANSURETHRAL RESECTION OF THE PROSTATE 
FOR THE TREATMENT OF SYMPTOMATIC BENIGN PROSTATIC HYPERPLASIA 
 
Protocol Number: BPH-P3-12-01 
 
IDE Number: G120141 
 
Date of Protocol: April 18, 2016 
 
Protocol Version: Version 4.0 
 
NCT Number: NCT01789840 
 
Redaction Completed: May 15, 2021 

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TABLE OF CONTENTS 
Section Num
ber 
Section 
Page Num
ber 
1 
Introduction 
 4 
1.1 
Background 
 4 
1.2 
Prostate Artery Embolization (PAE) 
 
 6 
2 
Study Objectives 
10 
2.1 
Primary Objective 
10 
2.2 
Secondary Objectives 
 
10 
3 
Patient Population 
11 
3.1  
Inclusion Criteria 
11 
3.2 
Exclusion Criteria 
 
12 
4 
Study Design 
 
14 
5 
Enrollment  and Blinding 
 
15 
6 
Treatment and Assessment 
15 
6.1 
Visit -1: Screening/Baseline Visit 
15 
6.2 
Visit 1: Study Treatment Visit 
16 
6.3 
Visit 2: Month 1 Visit 
17 
6.4 
Visit 3: Month 3 Visit 
17 
6.5 
Visit 4: Month 6 Visit 
18 
6.6 
Visit 5: Month 12 Visit 
18 
6.7 
Annual Long Term Follow-Up 
 
19 
7 
Withdrawal of Patients 
 
20 
8 
Adverse Events 
20 
8.1 
Definitions 
20 
8.2 
Adverse Event Reporting 
22 
8.3 
Serious Adverse Event Reporting 
 
23 
9 
Symptom Assessments 
23 
9.1 
International Prostate Symptom Score (IPSS) 
23 
9.2 
International Index of Erectile Function (IIEF) 
 
23 
10 
Statistical Analysis 
23 
10.1 
General Considerations 
23 
10.2 
Sample Size Calculations 
24 
10.3 
Analysis Populations 
24 
10.4 
Demographic and Baseline Characteristics 
25 
10.5 
Efficacy Analysis 
25 

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Section Num
ber 
Section 
Page Num
ber 
10.6 
Safety Analysis 
29 
11 
Data Safety Monitoring Board (DSMB) 
 
31 
12 
Records and Confidentiality 
 
31 
13 
Quality Control and Assurance 
 
31 
14 
Good Clinical Practice 
 
32 
15 
Ethical Considerations 
 
32 
16 
Patient Information and Informed Consent 
 
32 
17 
Patient Confidentiality 
 
32 
18 
Protocol Compliance 
 
33 
19 
Monitoring, Verification of Data, Audit and Inspection 
 
33 
20 
Data Recording and Retention of Study Data 
 
34 
21 
Confidentiality, Publication and Disclosure Policy 
 
34 
22 
Bibliography 
 
35 
Appendix A 
Schedule of Study Events 
 
37 
Appendix B 
Study Flow Chart 
 
38 
Appendix C 
Technical Protocol for Prostatic Embolization with Embosphere 
Microspheres 
39 
Appendix D 
International Prostate Symptom Score (IPSS) 
 
42 
Appendix E 
International Index of Erectile Function (IIEF)  
 
43 
Appendix F 
Procedural Protocol for MRI of the Prostate 
 
45 
 
 
 
 

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1 Introduction 
1.1 Background:  
Benign Prostatic Hyperplasia 
The prostate is a walnut-sized gland that forms part of the male reproductive system. The gland 
is made of two lobes, or regions, enclosed by an outer layer of tissue. The prostate continues to 
grow during most of a man's life, but the enlargement does not usually cause problems until after 
age 50. Benign prostatic hyperplasia (BPH) is the most common benign neoplasm in men, with 
more than 50% of men in their sixties and as many as 90% in their seventies and eighties having 
some symptoms of BPH. As life expectancy increases, so does the occurrence of BPH. In the 
United States in 2000, there were 4.5 million visits to physicians for BPH in the US with a direct 
cost of $1.1 billion. (NIDDK; Wei 2005) 
As the prostate enlarges, the layer of tissue surrounding it stops it from expanding, causing the 
gland to press against the urethra like a clamp. The bladder wall becomes thickened and irritable, 
and begins to contract even when it contains small amounts of urine, causing more frequent 
urination. Eventually, the bladder weakens and loses the ability to empty itself, so some of the 
urine remains after voiding. In addition, the prostate can push upward against the bladder floor, 
contributing to bladder outlet obstruction. The narrowing of the urethra and partial emptying of 
the bladder cause many of the problems associated with BPH. Lower urinary tract symptoms 
(LUTS) are common complaints resulting from BPH, and approximately half of all men with a 
histologic diagnosis of BPH have moderate to severe LUTS. Symptoms include nocturia, urinary 
frequency, urgency, decreased urine flow rates, hesitancy and incomplete bladder emptying.  
Over time, urine retention may cause an increase in urinary tract infections, bladder or kidney 
damage, bladder stones, or incontinence. (NIDDK , Wei 2005)   
 
Current Treatment of BPH 
Medical treatment is usually the first line therapy for LUTS due to BPH. The two main 
categories of medications for management of BPH are alpha blockers and 5α -reductase 
inhibitors. Alpha blockers (α1-adrenergic receptor antagonists) are the most common choice for 
initial therapy. Alpha blockers used for BPH include doxazosin, terazosin, alfuzosin, tamsulosin, 
and silodosin. They work by relaxing smooth muscle in the prostate and the bladder neck, 
thereby decreasing the hindrance to urine flow. Common side effects of alpha blockers include 
orthostatic hypotension, ejaculation changes, loss of libido, impotence, nasal congestion, and 
weakness.  Men planning on undergoing cataract surgery are not good candidates for alpha 
blocker therapy because it can result in intraoperative floppy iris syndrome (IFIS). IFIS occurs in 
43-90% of men taking tamsulosin.  

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The 5α-reductase inhibitors include finasteride and dutasteride. These medications inhibit 5a-
reductase, which reduces production of DHT, one of the hormones responsible for enlarging the 
prostate. Side effects include decreased libido and ejaculatory or erectile dysfunction. Because 
they have different mechanisms of action, the two medications are sometimes used together. 
(Kacker 2011; McVary 2011) 
Patients who cannot tolerate these drugs or are refractory to treatment typically receive surgery 
or a minimally invasive therapy. In general, transurethral resection of the prostate (TURP) is still 
considered the gold standard of prostate interventions for patients that require a procedure. The 
procedure involves removing part of the prostate through the urethra with a resectoscope. The 
resectoscope uses an electrical loop to cut tissue and seal blood vessels. The most common 
adverse event is retrograde ejaculation, occurring in up to 65% of patients, followed by 
hemorrhage requiring transfusion (8%), erectile dysfunction (6.5%) urethral stricture (4%), and 
incontinence (2%). (Kacker 2011; McVary 2011) 
There are also a number of less invasive methods for reducing prostate size, including 
radiofrequency, microwave and laser therapies. All of these treatment methods involve 
introducing energy into the body and urethral access and manipulation. 
Photoselective vaporization prostatectomy (PVP), also known as GreenLight Laser, vaporizes 
prostate tissue through selective absorption by hemoglobin, which creates a TURP-like defect. A 
major advantage of PVP is that it causes coagulation during tissue vaporization so the method 
can be used for patients on anticoagulation therapy, and it is also viable for patients with acute 
urinary retention. Postoperative irritative voiding symptoms, including urge incontinence, are 
common, with an incidence over 25%, and retrograde ejaculation occurs in approximately 50% 
of patients.  
Transurethral radiofrequency needle ablation (TUNA) consists of endoscopes with attached 
needles that are inserted into the prostate to emit low-level radiofrequency energy to induce 
necrosis. The dead tissue is absorbed back into the prostate, partially reducing its size. The most 
frequent adverse events from TUNA are hematuria and urinary retention, but they are usually 
transitory. The limitation of this treatment is that the amount of prostate reduction is less than 
with some other treatments, and there is a trend toward decreased urinary improvement after 3 
years.  
Transurethral microwave thermotherapy (TUMT), similar to TUNA, uses heat to ablate tissue to 
reduce the size of the prostate. Instead of utilizing needles, TUMT employs a microwave antenna 
placed on the end of a urethral catheter to deliver the treatment. Some, but not all, models 
employ urethral cooling mechanisms to protect the urethra, bladder neck and sphincter from 
damage. Contraindications for use include implanted pacemakers, defibrillators, metallic 
implants, and “ball valve” median lobe enlargement. Chronic urinary retention is a relative 

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contraindication. Variations in procedure, the difference between high versus low energy level 
models and transurethral versus transrectal methods have led to varying results. Postoperative 
dysuria has been reported in up to 50% of patients treated with this method, and in 2000 the FDA 
warned against rare but severe complications such as penile necrosis and fistula. 
Holmium lasers initially were used for tissue ablation (HoLAP), but holmium enucleation of the 
prostate (HoLEP) became possible with the advent of mechanical morcellators. The laser 
wavelength is absorbed by water and produces vaporization of prostate tissue. Instead of ablating 
the tissue, the laser cuts off a portion of the prostate, which is then cut into smaller pieces by the 
morcellator and flushed out with irrigation fluid. It can be used for prostates as large as 300gm. 
There is little bleeding during or after the procedure, but the technical learning curve is high, 
which can result in capsular perforations, strictures and conversions to surgery. (Kacker 2011; 
McVary 2011) 
 All these technologies have the same objective—to remove prostate tissue to relieve constriction 
of the urethra or bladder outlet obstruction and reduce symptoms of LUTS. They produce 
outcomes similar to TURP, although there is not as much data on long term effectiveness as 
there is for surgery. The challenge for developing new methods of treating symptomatic BPH is 
to reduce hyperplastic tissue and achieve good long term control of LUTS while reducing 
adverse events and negative impacts on quality of life, such as ejaculatory disorders. 
1.2 Prostate Artery Embolization (PAE) 
Embolization of prostate arteries has been used for many years to control serious bleeding after 
biopsy or prostatectomy. The first published case in which it was recognized that embolization 
could have a therapeutic affect on benign prostatic hyperplasia (BPH) was by DeMeritt and 
colleagues (DeMeritt 2000). The paper reported on a patient with BPH who had such severe 
hematuria that he required transfusion, and who underwent prostate artery embolization with 
PVA particles in an attempt to stop the bleeding. As intended, the bleeding stopped immediately 
after embolization. Unexpectedly, the physicians found that the prostate size had reduce to 52% 
and 62% of its pre-embolization size at follow up visits 5 and 12 months later. This case was the 
first indication that prostate artery embolization (PAE) could be clinically effective in the 
treatment of BPH. (DeMeritt 2000) 
More recently there have been two studies in peer-reviewed journals of investigations of PAE 
using Embosphere Microspheres in animal models, and one published abstract. 
The first investigation, by Faintuch and colleagues (Faintuch SIR 2008) involved embolization 
of 6 beagles with Embosphere Microspheres. Immediately following embolization retrograde 
urethrocystography and multiphasic, multislice, contrast enhanced CT scans were obtained to 
document distribution of the microspheres, perfusion, and 3D volume analysis.  

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CTs done 1 month after treatment demonstrated good distribution of the microspheres in the 
embolized territory with no evidence of non-targeted embolization. All animals who received 
bilateral PAE showed improvement in the degree of stenosis of their prostatic urethras, and dogs 
who underwent either unilateral or bilateral PAE displayed decreased perfusion, cavitary 
necrosis and volume reduction of the prostate, with excellent histopathological and radiological 
correlation. 
Soon after Sun and colleagues (Sun 2008) published a study in which they used 16 healthy pigs 
to evaluate the technical feasibility and safety of PAE. All animals had selective angiography, 
and half then underwent embolization with Embosphere Microspheres. Three months post 
treatment the investigators evaluated the sexual function of the pigs during mating. Subsequently 
the animals were euthanized and their prostates were examined for size and histopathological 
appearance. 
The prostate artery embolization was technically successful in all eight animals without 
complications. No significant difference in sexual desire or function was noted between the two 
groups (p=0.328). After sacrifice, the mean prostate volume of the treated animals was 
statistically significantly smaller than that of the control group (p<0.001) and histopathological 
exam demonstrated that the Embosphere Microspheres had occluded the arterioles of the 
prostate. This resulted in disappearance of tissue in the surrounding area and atrophy of residual 
glandular tissue. Examination of the bladder, ureters , urethra, sigmoid colon, and rectum 
revealed no abnormalities. 
 Sun and colleagues also evaluated pathologic responses and technical safety of PAE in a canine 
model (Sun 2011). In this study 10 beagles were surgically castrated and given hormone therapy 
for 4 months to induce BPH. After 3 months of hormone administration all dogs had selective 
angiography and 7 underwent PAE with Embosphere Microspheres, with the other 3 acting as 
controls. One month later all dogs were sacrificed. 
MRI and transrectal ultrasound demonstrated that all 10 dogs developed BPH from the hormone 
therapy. The prostates of all 7 dogs that had been embolized exhibited an intraprostatic cavity 
one month after PAE, and of these, 4 animals demonstrated significant shrinkage in size. Of the 
3 embolized dogs that had an increase in prostate size, imaging and necropsy revealed huge 
cavities occupying 90-100% of the entire prostate. The prostates of the control animals displayed 
no cavitary necrosis. There were no complications associated with the PAEs. Upon 
histopathological examination, the ureters, seminal vesicles, deferent ducts, bladder, urethra and 
sigmoid colon were intact in all dogs. No necrosis was found in these tissues. 
The first intentional treatment of BPH with PAE in humans was done by Carnevale and 
colleagues (Carnevale 2010). They performed PAE for 2 patients with acute urinary retention 
due to BPH who were refractory to treatment with selective α-blockers, were being managed 
with long term indwelling catheters, and were waiting for surgery. Prior to embolization patients 

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were assessed using digital rectal examination, urodynamic testing, prostate biopsy, transrectal 
ultrasound (TRUS) and MRI. Malignancy and non-BPH causes of urinary obstruction were ruled 
out. Post treatment with embolization the patients had repeat urodynamic testing, TRUS and 
MRI at 30, 90 and 180 day follow up visits. 
The 2 patients underwent angiography and embolization with Embosphere Microspheres under 
local anesthesia. The first patient, aged 67 with a history of hypertension, had a prostate 
estimated at 63gm by TRUS and 69gm by MRI with an intravesical prostate protrusion (IPP) of 
9mm. Bilateral PAE was performed successfully without complications. 
The patient experienced mild retropubic pain for 24 hours, which was treated with non-opioid 
analgesics. He had no fever or hematuria and was discharged 3 days after PAE. The patient was 
able to urinate spontaneously when his catheter was removed 15 days after embolization. One 
month later at follow up his prostate was reduced by 33.3% and 39.1% by TRUS and MRI 
respectively, IPP was reduced to 4mm, and post void residual urine (PVR) volume was 8ml. At 3 
months post treatment the patient was urinating normally. The IPP was the same, but PVR was 
reduced to 5ml and the prostate size reduction was 39.7% and 44.9% by TRUS and MRI 
respectively. During the 6 month evaluation PVR was absent and prostate size was similar to that 
at 3 months. 
The second patient was aged 68 years, with a history of atrial fibrillation and hypertension. 
TRUS showed a prostate of 51gm and asymmetric hypertrophy of the right lobe, with an IPP of 
16mm. Prostate size was 54gm by MRI, and showed a discrete 1.1 cm avascular cystic node on 
the right, protruding at the bladder neck. Unilateral PAE of the right prostate arteries only was 
done because the left arteries could not be visualized. 
The patient had no post PAE symptoms, was discharged 3 days after treatment, and was able to 
urinate spontaneously when the catheter was removed 10 days after embolization. At 1 month 
the patient reported some episodes of nocturia. PVR was 110ml and IPP had not changed from 
baseline at 16mm, but prostate size was reduced 16.9% and 24.1% by TRUS and MRI 
respectively. MRI showed that the avascular nodule had increased from 1.1cm at baseline to 
1.3cm. By the 3 month follow up visit the patient was voiding normally. IPP continued at 16mm, 
but PVR was reduced to 68ml and size reduction was 25.5% and 27.8% by TRUS and MRI. The 
avascular area on the right persisted. The patient’s condition was similar at 6 month follow up. 
For both patients urine stream increased with time, accompanied by reduction of PVR and 
prostate size shrinkage that was sustained at 6 months. Reduction was greater in the patient who 
received bilateral embolization. 
The same investigators published midterm follow up data for these 2 patients (Carnevale 2011). 
The prostate of the first patient, who had had bilateral PAE, continued to decrease in size over 

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time, with a reduction of 53.6% by MRI at 18 month follow up, compared with 47.8% at 6 
months. The patient was continuing to void normally 30 months post embolization. 
 The second patient, for whom it had only been possible to do unilateral PAE due to prostate 
arteries on the left not being visualized during angiography, demonstrated an increase in prostate 
size at 18 months compared to imaging done at the 6 month follow up visit. MRI showed a 
12.2% reduction from baseline at 18 months compared to 27.8% at 6 months. PVR had increased 
to 200 ml and IPP was 17mm compared to 85ml and 15mm respectively at 6 months, but at both 
the 18 and 30 month visits the patient was continuing to void normally. 
Most recently Carnevale presented outcomes of 40 embolizations (Carnevale GEST 2012). 
Eleven patients with acute urinary retention treated with indwelling catheters were enrolled in a 
Phase I/II study and treated with PAE. This group includes the first 2 feasibility cases (Phase I, 
discussed earlier) plus 9 other patients (Phase II). After completion of this study 28 additional 
patients were treated. Evaluations at baseline, 1, 3, 6, and 12 months were done by MRI, TRUS, 
urodynamic testing (baseline and every 12 months), PSA, IPSS and IIEF. Embolization was done 
with Embosphere Microspheres under local anesthesia. Clinical success was achieved in 10 of 
the 11 phase I/II patients (91%), with patients able to urinate spontaneously after catheter 
removal and no recurrence of LUTS symptoms during 16-45 months of follow up. The single 
clinical failure was a patient who was embolized twice, but still was not able to urinate 
spontaneously. He was referred to surgery and treated by TURP. Minor adverse events included 
diarrhea, light rectal bleeding (2-3 tsp), hematuria, anal burning sensation, retropubic pain and 
dysuria. Only non-opioid pain medications were needed for management. One case of bladder 
ischemia was recognized retrospectively. The patient experienced no pain or urinary retention 
but a defect was seen in the bladder wall by MRI during follow up at 30 days. This resolved 
spontaneously, and was not seen at future MRI surveillance. No treatment was required. 
Average PSA levels dropped from 10.1ng/ml at baseline to 3.5ng/ml at month 3 (p=0.003), 
average prostate size reduction was approximately 30% by MRI (p=0.002) and TRUS (p=0.004). 
It was not possible to obtain IPSS and IIEF scores at baseline because all these patients had 
indwelling catheters prior to PAE, but these scores improved from first measurement at 30 days 
post treatment throughout a year of follow up, with the IPSS being statistically significant 
(p=0.04). Average response from the quality of  life question of the IPSS went from 6 (terrible) 
at baseline to 1.1 (pleased) at the 30 day follow up, and continued at <1 (delighted) from 3-12 
months of follow up. Urodynamic test results also demonstrated marked improvement. Average 
changes from baseline to 12 months were as follows: urine flow (Qmax) improved from 
4.2ml/sec to 10.8ml/sec (p=0.009), detrusor muscle pressure (Pdet) reduced from 85.7 to 51.5 
(p=0.007) and PVR decreased from 160.6ml to 60.0ml (p=0.04).  
In the subsequent patients without acute urinary retention or indwelling catheters at time of 
treatment, average IPSS scores decreased from 20.3 at baseline (severe) to 1.7 at 90 days (mild), 

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and prostate size reduction averaged 26.4% by MRI in the same time period. Urodynamic test 
results were also notable in this group: Qmax increased from an average 8.0ml/sec at baseline to 
17.4ml/sec at 90 days. Overall clinical success for all 39 patients, defined as LUTS improvement 
and ability to urinate spontaneously was 97.5%. 
These encouraging clinical outcomes with low risk profile have led to the development of this 
comparative study. 
2 Study Objectives 
2.1 Primary Objective 
The primary study objective is to evaluate improvement of symptoms from benign prostatic 
hyperplasia (BPH) as assessed by  the International Prostate Symptom Score (IPSS) for prostatic 
artery embolization (PAE) with Embosphere® Microspheres compared with conventional 
transurethral resection of the prostate (TURP). 
2.2 Secondary Objectives 
The key secondary objectives are to assess the outcomes listed below and compare the findings 
for patients treated with PAE and TURP. 
• Duration of hospitalization post procedure 
• Duration of post procedure catheterization 
 
Additional secondary objectives are to assess the outcomes listed below and to compare the 
findings for patients treated with PAE and TURP. 
• 
Change from baseline in peak urine flow rate (Qmax) 
 
• 
Change from baseline in post-void residual urinary volume (PVR) 
 
 
• 
Change from baseline in erectile function using the International Index of Erectile Function 
(IIEF) 
 
• 
Change from baseline in mean prostate volume, as determined by MRI 
 
• 
Change from baseline in prostate specific antigen (PSA) 
 
• 
Overall adverse events 

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• 
Procedure related adverse events 
3 
Patient Population 
3.1 
Inclusion Criteria: 
Patients must meet all of the following inclusion criteria in order to be entered into the study: 
1. 
Patient is age 50 to 79, inclusive  
2. 
Patient has signed informed consent 
3. 
Patient has had lower urinary tract symptoms (LUTS) secondary to BPH for at least 6 
months prior to study treatment 
4. 
Patient has a baseline IPSS Score > 13 at baseline 
5. 
Patient has a prostate size of at least 50 grams and not more than 90 grams, measured by 
MRI 
6. 
Patient has BPH symptoms refractory to medical treatment or for whom medication is 
contraindicated, not tolerated or refused   
7. 
Patient must be a candidate for TURP 
8. 
Patient must meet ONE of the following criteria: 
• Baseline Prostate Specific Antigen (PSA) <2.5 ng/mL (no prostate 
biopsy required) 
• Baseline PSA >2.5 ng/mL and ≤10 ng/mL AND free PSA > 25% of 
total PSA (no prostate biopsy required) 
• Baseline PSA >2.5 ng/mL and ≤10 ng/mL AND free PSA < 25% of 
total PSA AND a negative prostate biopsy result (minimum 12 core 
biopsy) within the prior 12 months 
• Baseline PSA >10 ng/mL AND a negative prostate biopsy (minimum 
12 core biopsy) within the prior 12 months 
 
 
 

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3.2 Exclusion Criteria 
Patients meeting any of the following exclusion criteria may not be entered into the study: 
1. 
Active urinary tract infection 
2. 
Biopsy proven prostate or bladder cancer, or any cancer other than basal or squamous 
cell skin cancer 
• 
The following patients must have undergone prostate biopsy with a minimum 
of 12 cores and have  had a negative histopathology report within the prior 12 
months to be enrolled in the study:  
o Patients with DRE findings suspicious for prostate cancer 
o Patients with baseline PSA levels > 10 ng/mL 
o Patients with baseline PSA levels >2.5 ng/mL and < 10ng/mL AND 
free PSA < 25% of total PSA  
• 
Patients with cystoscopy findings suspicious for bladder cancer must undergo 
biopsy and have a negative histopathology report to be enrolled in the study 
3. 
Bladder atonia, neurogenic bladder disorder or other neurological disorder that is 
impacting bladder function (eg multiple sclerosis, Parkinson’s disease, spinal cord 
injuries, etc)  
4. 
Urethral stricture, bladder neck contracture, sphincter abnormalities, urinary obstruction 
due to causes other than BPH, or other potentially confounding bladder or urethral 
disease or condition 
5. 
Patient has taken beta blockers, antihistamines, anticonvulsants, or antispasmodics 
within 1 week of study treatment AND has not been on the same drug dosage for 6 
months with a stable voiding pattern 
• Dosage of these medications should not change during study participation unless 
medically necessary 
6. 
Patient has taken antidepressants, anticholinergics, androgens or gonadotropin-releasing 
hormonal analogues within 2 months of study treatment AND has not been on the same 
drug dosage for at least 3 months with a stable voiding pattern 
7. 
Patient has taken 5-alpha reductase inhibitors or alpha blockers within 1 month of study 
treatment AND has not been on the same drug dosage for at least 3 months with a stable 
voiding pattern 
8. 
Previous non-medical BPH treatment, including surgery, TURP, needle ablation, 
microwave or laser therapy, balloon dilation, stent implantation, or any other invasive 
treatment to the prostate 

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9. 
Any known condition that limits catheter-based intervention or is a contraindication to 
embolization, such as intolerance to a vessel occlusion procedure or severe 
atherosclerosis.  
10. 
Patient is unable to stop taking anticoagulant, NSAID or anti-platelet therapy for 7 days 
prior to study treatment 
11. 
Unable to have MRI imaging (eg metal implant including pacemaker, replacement joint, 
etc) 
12. 
Patient has an asymmetric prostate, with > 20% difference in size between lobes 
13. 
Cardiac condition  including congestive heart failure or arrhythmia, uncontrolled 
diabetes mellitus, significant respiratory disease or known immunosuppression which 
required hospitalization within the previous 6 months  
14. 
Baseline serum creatinine level > 1.8 mg/dl 
15. 
Known upper tract renal disease 
16. 
Cystolithiasis or chronic hematuria within 3 months prior to study treatment 
17. 
 Active prostatitis  
18. 
Previous rectal surgery other than hemorrhoidectomy, or history of rectal disease 
19. 
History of pelvic irradiation or radical pelvic surgery 
20. 
Patient is interested in future fertility 
21. 
Coagulation disturbances not normalized by medical treatment   
22. 
Acute urinary retention requiring an indwelling catheter 
23. 
Known major iliac arterial occlusive disease 
24. 
Allergy to iodinated contrast agents 
25. 
Hypersensitivity to gelatin products 
 
 

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4 Study Design 
 
This is a phase 3 multicenter, prospective study designed to evaluate the safety and effectiveness 
of treating patients with symptomatic BPH with PAE using Embosphere Microspheres compared 
to conventional TURP.  Approximately 186 patients with LUTS due to BPH will be enrolled 
using a 2:1 ratio, with approximately 124 receiving treatment with PAE and 62 receiving 
conventional TURP, in order to have 100 patients in the PAE and 50 patients in the TURP arm 
complete 12 month follow up. 
  
The study will consist of a screening period in which patient eligibility will be determined and 
baseline assessments performed.  Once eligibility is confirmed, patients will be enrolled within 4 
weeks of baseline imaging to receive either TURP or PAE with Embosphere Microspheres. After 
treatment, patients will return for follow-up visits at Months 1, 3, 6, and 12. At each of these 
visits patients will complete IPSS and IIEF questionnaires and have a physical exam, laboratory 
assessments (including PSA), a DRE, and a transrectal ultrasound of the prostate.  At each visit 
patients will have a cystoscopy and proctoscopy if medically indicated. Cystoscopy is necessary 
in all cases of hematuria (injury associated with bleeding).  Proctoscopy is necessary in all cases 
of bleeding per the rectum.  An MRI of the prostate will be conducted at the 3 and 12 month 
visits. Uroflowmetry testing will be performed at the 1 and 12 month visits, and at other visits if 
medically indicated. MRIs will be assessed by blinded Central Reviewers.   
 
The primary endpoint will be improvement of symptoms from BPH evaluated using the IPSS at 
12 months post treatment. Patients will continue to be followed annually for up to 4 additional 
years. At a minimum, patients will be requested to complete the IPSS and IIEF questionnaires by 
telephone, email or mail once per year during this long term follow up period. Patients who are 
willing to return to the clinic will have a physical exam, MRI of the prostate, digital rectal exam 
(DRE), transrectal  ultrasound of the prostate, PSA, and uroflowmetry  testing performed each 
year. Treatments for LUTS due to BPH after the study treatment and 12 month follow up are 
complete will be documented during the long term follow up period to the extent possible. This 
long term follow up data will be summarized and submitted separately from the data for the 
initial 12 months of this study. 
 
Safety will be evaluated throughout the initial 12 months of the study by assessing adverse 
events, as well as changes in laboratory values, and findings on physical examination. 
Concomitant medication usage will be assessed. A follow up ECG will be performed at the 12 
month visit. 
 

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Patient recruitment is anticipated to take approximately 2 years. Duration of each patient’s 
participation is expected to be 5 years, including a 4 year long term follow up period. The total 
duration of the study will be approximately 7 years, including long term follow up. 
5 Enrollment and Blinding 
Patients will be recruited separately to receive either PAE with Embosphere Microspheres or 
conventional TURP on a 2:1 basis, with more patients enrolled in the PAE group. Enrollment 
will occur after informed consent has been signed and it has been confirmed that the patient 
meets all study eligibility criteria.   
 
Patients will be recruited at each site in blocks of 15. The first 10 patients meeting all the 
inclusion criteria and none of the exclusion criteria will be enrolled in the PAE cohort. The next 
5 patients meeting all the inclusion criteria and none of the exclusion criteria will be enrolled in 
the TURP cohort. Patients will not be able to choose their treatment arm, only to accept or 
decline participation in the study cohort that is being enrolled. Patients in the TURP cohort will 
be offered a stipend of $75.00 per completed study visit in consideration of the additional visits 
and evaluations they will undergo as part of the study, and which would not be standard of care 
if they were treated by TURP outside the study. 
 
It is not possible to blind either the patient or the treating physician to treatment group because 
the two treatment methods are easily identifiable. Evaluation of size and location of prostate by 
MRI will be assessed by Central Reviewers who will not be given any treatment information. 
Patient MRIs will be identified by study ID number only. 
6 Treatment and Assessment 
After patients have been treated, follow up visits will take place at 1, 3, 6, and 12 months, + 2 
weeks for each visit, calculated from the day of treatment (Day 1) according to the Schedule of 
Events (Appendix A) and Study Flow Chart (Appendix B). Long term surveillance data for up to 
4 additional years will be collected.  
Patients who receive PAE with Embosphere Microspheres procedure will be treated with a single 
procedure.  The microspheres will be mixed with a contrast agent and will be delivered to the 
arteries supplying the prostate via microcatheter. The occlusion endpoint will be stasis.  
Patients who receive conventional TURP will be treated with a single procedure according to the 
standard of care for their institution. 
6.1 Visit -1: Screening/Baseline (within 4 weeks of enrollment unless stated otherwise) 
Prior to enrollment, each patient will have the following assessments performed: 

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• Obtain Informed Consent 
• Medical history, including demographics 
• Concurrent medical conditions 
• Physical exam, including vital signs, height (baseline only), weight, and genitourinary 
evaluation 
• Baseline serum blood tests 
o Complete Blood Count (CBC) including red blood count (RBC), white blood 
count (WBC), platelets, hemoglobin, hematocrit, neutrophils 
o Chemistry including albumin, alkaline phosphatase, blood urea nitrogen (BUN), 
serum creatinine, total bilirubin, prothrombin time (PT) 
• Urinalysis  
o Specific gravity, protein, glucose, blood, leukocytes, nitrites 
• Prostate Specific Antigen (PSA) and free PSA 
• Digital rectal exam (DRE) 
• Transrectal  ultrasound of the prostate 
• MRI of the prostate 
• Urodynamic testing including maximum flow rate (Qmax), average flow rate, detrusor 
muscle pressure (Pdet), voided volume (minimum voided volume must be >125 mL for 
a valid test), total time of voiding, and  post void residual volume (PVR) within 3 
months prior to enrollment 
• International Prostate Symptom Score (IPSS) 
• International Index of Erectile Function (IIEF) 
• Electrocardiogram (ECG) 
• Cystoscopy within 3 months prior to enrollment  
o Examination will include evaluation for bladder neck obstruction or contracture, 
urethral strictures, sphincter abnormalities, bladder cancer, or other disorders of 
the bladder, urethra or prostatic urethra and assessment of prostate size, lobar 
distribution and anatomy and length from the verumontanum to the bladder neck 
• Recording of concomitant medications 
• The following patients must have undergone prostate biopsy with a minimum of 12 
cores and have had a negative histopathology report within the prior 12 months to be 
enrolled in the study:  
o Patients with DRE findings suspicious for prostate cancer 
o Patients with baseline PSA levels > 10 ng/mL 
o Patients with baseline PSA levels >2.5 ng/mL and < 10ng/mL AND free PSA < 
25% of total PSA  
Patients meeting all the inclusion criteria and none of the exclusion criteria are eligible for 
participation in the study.    

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6.2  Visit 1: Study Treatment  
Patients will be enrolled within 4 weeks of baseline imaging. 
PAE with Embosphere Microspheres will be done following the procedure in Appendix C. 
Conventional TURP will be done following the institution’s standard of care. 
Treatment data recorded will include the following: 
• Date of procedure 
• Date and time of hospital admission and discharge 
• Medications received immediately prior to and during the procedure 
• Date and time of urinary catheter insertion and removal (if patient is discharged with 
catheter in place, catheter removal information will be collected at the first follow up 
visit) 
• Medications at time of discharge 
• Adverse events 
6.3 Visit 2: Month 1 (4 weeks ± 2 weeks from Visit 1) 
Patients will have the following assessments performed: 
• Physical exam including vital signs, weight, and genitourinary evaluation 
• Blood and urine laboratory evaluations, including the same parameters as at baseline 
• Prostate Specific Antigen (PSA) and free PSA 
• Digital rectal exam (DRE) 
• Transrectal  ultrasound of the prostate 
• Uroflowmetry  testing, including the same parameters as at baseline except Pdet 
• International Prostate Symptom Score (IPSS) 
• International Index of Erectile Function (IIEF) 
• Cystoscopy, if medically indicated, and necessary in all cases of hematuria.  
• Proctoscopy, if medically indicated, and necessary in all cases of bleeding per the 
rectum.  
• Adverse Events 
o Including clinically significant changes in laboratory values from baseline 
• Concomitant Medications 
Effort must be made to have patients complete the physical assessments of this visit.  If patient 
refuses to come in for a visit, at a minimum the patient should complete the IPSS and IIEF 
questionnaires and report any adverse events by telephone. 

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6.4 Visit 3:  Month 3 (12 weeks ± 2 weeks from Visit 1) 
Patients will have the following assessments performed: 
• Physical exam including vital signs, weight, and genitourinary evaluation 
• Blood and urine laboratory evaluations, including the same parameters as at baseline 
• Prostate Specific Antigen (PSA) and free PSA 
• Digital Rectal Exam (DRE) 
• Transrectal  ultrasound of the prostate 
• MRI of the prostate 
• International Prostate Symptom Score (IPSS) 
• International Index of Erectile Function (IIEF) 
• Adverse Events 
o Including clinically significant changes in laboratory values from baseline 
• Concomitant Medications 
• Cystoscopy and/or urodynamic or uroflowmetry testing if medically indicated.  
Cystoscopy will be necessary in all cases of hematuria. 
Effort must be made to have patients complete the physical assessments of this visit.  If patient 
refuses to come in for a visit, at a minimum the patient should complete the IPSS and IIEF 
questionnaires and report any adverse events by telephone. 
6.5 Visit 4:  Month 6 (24 weeks ± 2 weeks from Visit 1) 
Patients will have the following assessments performed: 
• Physical exam including vital signs, weight, and genitourinary evaluation 
• Blood and urine laboratory evaluations, including the same parameters as at baseline 
• Prostate Specific Antigen (PSA) and free PSA 
• Digital rectal exam (DRE) 
• Transrectal  ultrasound of the prostate 
• International Prostate Symptom Score (IPSS) 
• International Index of Erectile Function (IIEF) 
• Adverse Events 
o Including clinically significant changes in laboratory values from baseline 
• Concomitant Medications 
• Cystoscopy and/or urodynamic or uroflowmetry testing if medically indicated.  
Cystoscopy will be necessary in all cases of hematuria. 

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Effort must be made to have patients complete the physical assessments of this visit.  If patient 
refuses to come in for a visit, at a minimum the patient should complete the IPSS and IIEF 
questionnaires and report any adverse events by telephone. 
6.6 Visit 5:  Month 12 (52 weeks ± 2 weeks from Visit 1) 
Patients will have the following assessments performed: 
• Physical Exam, including vital signs, weight, and genitourinary evaluation 
• Blood and urine laboratory evaluations, including the same parameters as at baseline 
• Prostate Specific Antigen (PSA) and free PSA 
• Digital rectal exam (DRE) 
• Transrectal   ultrasound of the prostate 
• MRI of the prostate 
• Uroflowmetry  testing including the same parameters as at baseline, except Pdet 
• International Prostate Symptom Score (IPSS) 
• International Index of Erectile Function (IIEF) 
• Electrocardiogram (ECG) 
• Adverse Events 
o Including clinically significant changes in laboratory values from baseline 
• Concomitant Medications 
• Cystoscopy, if medically indicated, and necessary in all cases of hematuria. 
Effort must be made to have patients complete the physical assessments of this visit.  If patient 
refuses to come in for a visit, at a minimum the patient should complete the IPSS and IIEF 
questionnaires and report any adverse events by telephone. 
6.7 Annual Long Term Follow-up 
Patients will be followed for up to 4 additional years after the 12 month visit (Visit 5). Patients 
will be encouraged to come to the clinic on an annual basis for the following evaluations: 
• Physical Exam, including vital signs, weight, and genitourinary evaluation 
• Prostate Specific Antigen (PSA) and free PSA 
• Digital rectal exam (DRE) 
• Transrectal  ultrasound of the prostate 
• MRI of the prostate 
• Uroflowmetry  testing including the same parameters as at baseline, except Pdet 
• International Prostate Symptom Score (IPSS) 
• International Index of Erectile Function (IIEF) 
• Documentation of any new treatments for BPH and/or LUTS 

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Patients who are unwilling to come to the clinic will be asked to complete the IPSS and IIEF 
questionnaires and provide information of any new treatments for BPH and/or LUTS by 
telephone, email or mail. Information on medications and adverse events will not be captured 
during the long term follow up period following the 12 month visit. 
7 Withdrawal of Patients  
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. The Investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
 
• Adverse events 
• Refusal of treatment 
• Patient request 
• Inability to complete study procedures 
• Lost to follow up 
• Non compliance with study requirements 
If a patient is withdrawn or discontinued from the study, the reason for withdrawal from the 
study will be recorded in the source documents and on the Study Termination CRF. All patients 
withdrawn from the study will be encouraged to complete, if possible, all clinical evaluations 
scheduled for the 12 month visit. All adverse events should be followed as described in Section 
8.  Patients who are withdrawn from the study for any reason will not be replaced.   
The study may be terminated by the Sponsor at any time. 
8 Adverse Events 
8.1 Definitions 
 
Adverse Event (AE) 
 
An AE is any untoward medical occurrence in a patient or clinical investigation subject and does 
not necessarily have to have a causal relationship with the treatment.  An AE therefore can be 
any unfavorable or unintended sign (including a clinically significant abnormal laboratory 
finding, for example), symptom or disease temporally associated with the use of a medicinal 
product or procedure, whether or not considered related to the product or procedure.  A non-
serious AE is any untoward medical occurrence that does not meet any of the criteria for an SAE 
as defined below. 
 

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Laboratory data are to be collected as stipulated in this protocol.  Clinical syndromes associated 
with laboratory abnormalities are to be recorded as appropriate (eg, diabetes mellitus instead of 
hyperglycemia). 
 
Patients should be instructed to report any AE that they experience to the Investigator or Study 
Coordinator.  AEs will be assessed at each visit.  AEs occurring during the clinical trial and the 
protocol-defined 12 month follow-up period should be recorded on the appropriate AE CRF.   In 
order to capture the most potentially relevant safety information during this study, it is important 
that the Investigators record AE terms accurately and consistently throughout the study.     
Wherever possible, a specific disease or syndrome should be reported on the CRF rather than the 
associated individual signs and symptoms.   If observed or reported signs or symptoms are not 
considered a component of a specific disease or syndrome by the Investigator, they should be 
recorded as separate AEs on the CRF. 
 
All adverse events will be assessed for severity, relationship to study treatment, subsequent 
treatment required for the adverse event, and outcome/resolution. This information will be 
recorded on the Adverse Event CRF pages. 
 
Adverse events that might occur in this study include, but are not limited to: 
 
• For cystoscopy, PAE and TURP: 
o Burning in the urethra, urinary infection, hematuria, pain 
• For PAE and TURP: 
o Hematospermia, hemorrhage, injury to bladder, including bladder neck, ureteral 
orifice or trigone, impact on future fertility 
• For TURP: 
o Ejaculatory dysfunction, incontinence, erectile dysfunction 
• For PAE: 
o Vasospasm, rectorrhagia, inguinal hematoma, bladder/bladder neck ischemia and 
necrosis, bladder resection, allergic reaction to microspheres or contrast agent, 
radiation exposure, vascular perforation. 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that:  
• Results in death. 

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• Is life-threatening, where life-threatening means that the subject was at immediate risk 
of death from the reaction as it occurred (i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form).  
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered AEs if the illness or disease 
existed before the subject was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than planned).  
• Results in persistent or significant disability/incapacity, where disability is defined as 
a substantial disruption of a person’s ability to conduct normal life functions.  
• Is a congenital anomaly/birth defect. 
• Is an important medical event as defined by the Investigator. An important medical 
event is an event that may not result in death, be life-threatening, or require 
hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, it may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definitions for SAEs. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.  
Clarification should be made between the terms “serious” and “severe” since they are not 
interchangeable. The term “severe” is often used to describe the intensity (severity) of a 
specific event (as in mild, moderate, or severe myocardial infarction); the event itself, 
however, may be of relatively minor medical significance (such as a severe headache). 
This is not the same as “serious,” which is based on subject/event outcome or action 
criteria described above and are usually associated with events that pose a threat to a 
subject’s life or functioning. A severe adverse event does not need to be considered 
serious. For example, persistent nausea of several hours duration may be considered 
severe nausea but not constitute a SAE, unless the patient would be admitted to the 
hospital or the event would meet any other of the criteria for seriousness. On the other 
hand, a stroke resulting in only a minor degree of disability may be considered mild, but 
would be defined as an SAE based on the above noted criteria. Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations.  
Under this protocol, scheduled hospitalizations or elective surgical procedures will not be 
considered SAEs.  Prolongation of a scheduled hospitalization will be considered an SAE 
as defined above.  Complications associated with surgical procedures or study treatments 
resulting in one of the outcomes above are considered SAEs. 

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8.2 Adverse Event Reporting 
The Investigators are responsible for monitoring the safety of patients who have been enrolled in 
this study.   All AEs considered to be related to study treatment will be followed until the event 
resolves.    Adverse events will be evaluated for severity using NCI CTCAE (Common Toxicity 
Criteria for Adverse Events) where applicable. 
 
Investigators are required to document all AEs occurring during the study commencing with the 
date of treatment and including the protocol defined post-treatment follow-up period (21 CFR 
§312.64[b]), which is defined as 12 months post day of treatment, on the designated CRF pages.  
AEs that occur following the signature of informed consent but prior to treatment will not be 
captured.    
 
Serious adverse events (SAEs) must be reported to Merit Medical or its representative within 24 
hours of knowledge of their first occurrence.  SAEs that occur following the signature of the 
informed consent but prior to treatment will not be reported.   
8.3 Serious Adverse Event Reporting 
Any unanticipated adverse event or SAE, including death due to any cause, that occurs during 
the study treatment or initial 12 month follow up period, whether or not related to the study 
treatments, must be reported to the Sponsor immediately (not to exceed 24 hours within site 
notification of the event)  using the electronic SAE form provided by the Sponsor.  The SAE 
must be completely described on the AE CRF as well as the provided safety report form. 
 
Safety Contact Information: Melodie R Domurad PhD 
Email:    mdomurad@merit.com 
Phone:   +781 681 7912 
 
9 Symptom Assessments 
9.1 International Prostate Symptom Score (IPSS) 
The IPSS is a validated 8 question tool that is self-administered by the patient, and evaluates 
symptoms (7 questions) and quality of life (1 question). A copy of the IPSS questionnaire can be 
found in Appendix D. 

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9.2 International Index of Erectile Function (IIEF) 
The IIEF is a validated 15 question tool that is self-administered by the patient, and evaluates 
male sexual function, sexual desire, and intercourse satisfaction. A copy of the IIEF 
questionnaire can be found in Appendix E. 
10 Statistical Analysis 
10.1  General Considerations 
In general, continuous variables will be summarized as n, mean, standard deviation, median, 
minimum, and maximum. Categorical variables will be summarized as the number and 
percentage of patients in each category.   
Data from all investigational sites will be pooled in the analyses. Summary tables will present 
data for both treatment groups and overall, where appropriate. Data listings will include all data 
collected on the case report forms (CRFs), as well as any derived variables (study day, age, etc.). 
Data collected on patients who are screen failures will not be included in any summary tables, 
listings, or analyses. 
For each parameter, baseline is defined as the value reported prior to the study procedure.  If 
multiple values were collected prior to the procedure, the value closest to the date/time of the 
initiation of the procedure will be used as baseline. This may include values collected earlier in 
the day on the date of procedure. 
Unscheduled data, such as information from unscheduled visits, repeat laboratory tests, or 
Investigator comments, will be included in the data listings. In general, these data will be 
excluded from the summary tables unless otherwise specified. 
Any outliers detected during the review of the data will be investigated.  If needed the data will 
be queried and corrected in the database prior to database lock and the generation of the final 
tables and listings. 
All primary and secondary analyses will be performed on a locked database after all patients 
have completed the 12 month follow up of the investigation or been lost to follow up.  Data from 
the long term follow up period will be analyzed separately. 
 Analyses will be performed using SAS® (Statistical Analysis System), version 9.1 or higher.   
10.2 
Sample Size Calculations 
Assuming 95% of patients in both groups improve by at least 3 points on the IPSS total score 
from baseline to 12 months, with 150 patients enrolled in a 2:1 ratio in favor of PAE with 
Embosphere Microspheres (ie, 100 treated with PAE and 50 treated with TURP), the lower limit 

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of the 1 sided-95% confidence interval for the difference in proportions for the two treatments 
(PAE-TURP) will be expected to exceed -10% with 88% power. 
It is anticipated that 20% of patients will not complete the 12 month IPSS assessment; therefore a 
total of 186 patients will be enrolled at 12 sites in order to have 100 patients in the PAE group 
and 50 patients in the TURP group with 12 month IPSS data. 
10.3 
Analysis Populations 
10.3.1 Safety Population (SAF) 
All patients who have a PAE with Embosphere Microspheres or TURP will be included in the 
Safety Population. 
 
 

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10.3.2 Intent-to-Treat Population (ITT) 
The Intent- to-Treat (ITT) Population is defined as all patients enrolled in the study, regardless of 
treatment status. This will be the primary population for the efficacy analyses. 
10.3.3 Evaluable Population (EVAL) 
All patients who have a PAE with Embosphere Microspheres or TURP and who have valid IPSS 
data for the 12 month time point and who do not have any major protocol violations will be 
included in the Evaluable Population.  
10.4 
Demographic and Baseline Characteristics 
Patient characteristics will include the following: 
• Patient demographics (age, gender;  race, ethnicity, if possible)   
 Note: Many EU countries do not allow collection of information about race or 
ethnicity. 
• Baseline BPH/LUTS characteristics (size of prostate by MRI, PSA, free PSA, maximum 
flow rate (Qmax), average flow rate, detrusor muscle pressure (Pdet), voided volume, 
total time of voiding, and post void residual volume (PVR)) 
• Clinically significant medical history 
• Concurrent medical conditions 
• Prior BPH/LUTS therapy 
• Concomitant medications and treatments (these will be recorded throughout the study) 
10.5  Efficacy Analysis 
10.5.1  International Prostate Symptom Score (IPSS) 
The primary efficacy outcome will be based on the IPSS.  The IPSS is a frequently used, 
validated 8 item (7 symptom questions and 1 quality of  life question) instrument which can be 
performed multiple times to compare the progression of symptoms and their severity over 
months and years. 
Patients are asked to assess how often they have experienced the following seven symptoms in 
the past month: incomplete emptying, frequency, intermittency, urgency, weak stream, straining 
and nocturia.  The response categories range from 0=not at all to 5=almost always.  The total 
IPSS score is calculated by summing the responses for the seven symptoms. The eighth item is 
an assessment of patient quality of life (QOL) due to urinary symptoms and does not contribute 
to the IPSS total score calculation.  
Patients will be classified into one of three symptom severity categories based on their total IPSS 
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• Mildly symptomatic: 0-7 
• Moderately symptomatic: 8-19 
• Severely symptomatic: 20-35 
The proportion of patients improving at least 3 points on the IPSS total score at the 1 month, 
3month, 6 month and 12 month time points will be summarized for both treatment groups and 
the corresponding 95% confidence intervals will be calculated. 
The primary efficacy analysis is the comparison of the proportion of patients in both treatment 
groups who have improved by at least three points on the IPSS total score from baseline to 12 
months for the ITT analysis population.  The 95% one-sided confidence interval will be 
calculated for the difference in proportions between the two treatment groups (PAE-TURP). 
Non-inferiority will be declared if the lower limit of the confidence interval is -10% or higher 
(ie, the difference is no more than 10%).   
A secondary analysis of the proportion of patients in both treatment groups who have improved 
by at least one IPSS symptom category (ie, severe to moderate, severe to mild, severe to 
moderate) from baseline to 12 months will be performed.  The 95% one-sided confidence 
interval will be calculated for the difference in proportions between the two treatment groups 
(PAE-TURP). 
Secondary analyses of the total IPSS score analyzed as a continuous outcome will be performed.  
The total IPSS score will summarized for both treatment groups for the baseline, 1 month, 3 
month, 6 month, and 12 month timepoints, including change from baseline.   The difference in 
treatment means will be calculated for each timepoint, including the corresponding 95% 
confidence interval. 
The single IPSS QOL item will be summarized separately. 
Similar IPSS analyses will also be performed for the Evaluable population. 
10.5.2  Duration of hospitalization 
The duration of hospitalization associated with the procedure will be calculated in hours.  This 
will be a key secondary analysis in support of the indication for use and performance of PAE.  
Summary statistics will be calculated for both groups.  The difference in treatment means will be 
calculated, including the corresponding 95% confidence interval, and treatment groups will be 
compared using Student’s t-test for the ITT and Evaluable populations. If the distribution of the 
data is found to differ substantially from normal, appropriate methods will be used to analyze the 
data, including a data transformation or time to event analysis.  It is expected that the PAE group 
will have a statistically significant improvement in duration of hospitalization compared to the 
TURP group. 

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10.5.3  Duration of post procedure catheterization  
The duration of post procedure catheterization will be calculated in hours. Summary statistics 
will be calculated for both groups.  This will be a key secondary analysis in support of the 
indication for use and performance of PAE. The difference in treatment means will be calculated, 
including the corresponding 95% confidence interval and treatment groups will be compared 
using Student’s t-test for the ITT and Evaluable populations. If the distribution of the data is 
found to differ substantially from normal, appropriate methods will be used to analyze the data, 
including a data transformation or time to event analysis.  It is expected that the PAE group will 
have a statistically significant improvement in duration of post-procedure catheterization 
compared to the TURP group. 
10.5.4  Peak urine flow rate (Qmax) 
The peak urine flow rate (Qmax) from the urodynamic and uroflowmetry assessments will be 
summarized for both treatment groups for the baseline and 12 month timepoints, including 
change from baseline.  The difference in treatment means will be calculated for each timepoint, 
including the corresponding 95% confidence interval for the ITT and Evaluable populations. 
10.5.5  Post void residual urine volume (PVR) 
The post void residual volume (PVR) from the urodynamic and uroflowmetry assessments will 
be summarized for both treatment groups for the baseline and 12 month timepoints, including 
change from baseline.   The difference in treatment means will be calculated for each timepoint, 
including the corresponding 95% confidence interval for the ITT and Evaluable populations. 
10.5.6  Detrusor muscle pressure (Pdet) 
The Detrusor muscle pressure (Pdet) from the urodynamic assessments at baseline will be 
summarized for both treatment groups.  
10.5.7  International Index of Erectile Function (IIEF) 
The IIEF is a commonly used, validated instrument which consists of 15 items.  Five subscales 
are calculated as follows: 
• Erectile Function (items 1, 2, 3, 4, 5, 15) 
• Orgasmic Function (items 9, 10) 
• Sexual Desire (items 11, 12) 
• Intercourse Satisfaction (items 6, 7, 8) 
• Overall Satisfaction (items 13, 14) 

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Each subscale will be summarized separately for both treatment groups for the baseline, 1 month, 
3 month, 6 month, and 12 month timepoints, including change from baseline.   The difference in 
treatment means will be calculated for each timepoint, including the corresponding 95% 
confidence interval for the ITT and Evaluable populations. 
10.5.8 Mean prostate volume 
The mean prostate volume as assessed by MRI will be summarized for both treatment groups for 
the baseline, 3 month and 12 month timepoints, including change from baseline.  The difference 
in treatment means will be calculated for each timepoint, including the corresponding 95% 
confidence interval for the ITT and Evaluable populations. 
10.5.9  Prostate specific antigen (PSA) 
Prostate specific antigen (PSA) will be summarized for both treatment groups for the baseline, 1 
month, 3 month, 6 month, and 12 month timepoints, including change from baseline.  The 
difference in treatment means will be calculated for each timepoint, including the corresponding 
95% confidence interval for the ITT and Evaluable populations. 
10.5.10 Additional Variables from Urodynamic and Uroflowmetry Testing 
The average flow rate, voided urine volume and total time of voiding from the urodynamic and 
uroflowmetry assessments will be summarized for the baseline and 12 month timepoints, 
including change from baseline.   
 10.5.11 Handling of Missing and Spurious Efficacy Data 
All available data for treated patients will be included in the by-patient data listings and 
summary tables.   
Obvious outliers for continuous data will be investigated prior to unblinding the data and data 
queries will be generated as appropriate.   If an outlier is determined to be a valid response, the 
summary analyses may be performed both including and excluding the outlier in order to 
evaluate the impact on the summary statistics.  All outliers impacting the summary analyses will 
be discussed in the study report. 
Multiple imputation (MI) methods will be used to assign values to those patients in the ITT 
population with missing data for the primary effectiveness analysis.  This approach assumes the 
data is missing at random (MAR).  MI introduces appropriate random error into the imputation 
process making it possible to obtain approximately unbiased estimates of all parameters. An 
appropriate MI model that incorporates random variation which will be run 3-5 times to generate 
several imputed “complete” datasets which will allow for good estimates of the standard errors.   

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In order to assess the robustness of the statistical inferences based on the primary imputation 
method (MI) for the primary effectiveness analysis, sensitivity analyses will be performed 
including but not limited to a “worst-case imputation,” and  a “tipping point analysis.”  
10.5.12  Adjustment for Multiplicity 
In addition to the primary analysis based on the IPSS total score, key secondary analyses will be 
performed comparing the treatment groups on the Duration of Post-Procedure Catheterization 
and Duration of Hospitalization post procedure for the ITT population.  These analyses will be 
used to support the indication for use and performance of PAE in the treatment of BPH.  The 
Bonferonni Correction will be used to adjust these secondary analyses in order to control the 
experimentwise (overall) Type I error rate at the 0.05 level.  No adjustment will be performed on 
the primary efficacy outcome analysis.   
Multiple inferences for key secondary outcomes will be conducted only if the primary 
effectiveness outcome is met.  
10.6 Safety Analysis 
All safety analyses will be performed for the Safety Population on the locked database after all 
patients have completed the 12 month follow up or are lost to follow up. 
10.6.1  Adverse Events 
Safety summaries will include the incidence of treatment-emergent adverse events (TEAEs).  
Treatment-emergent adverse events (TEAEs) are defined as any event that began on or after the 
date of treatment or worsened in severity or frequency after treatment was initiated.  Events 
worsening in severity should be considered new adverse events.  Adverse events recorded on the 
CRF which began prior to treatment will not be included in the summary tables but will be 
included in the AE data listings. 
All TEAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
summaries will present data for both treatment groups by System Organ Class (SOC) and 
Preferred Term.   TEAEs will be evaluated for severity using the CTCAE when available.       
A summary of the total number of reported TEAEs will be generated for both treatment groups.  
In addition, TEAEs will be summarized based on the number of patients experiencing an event, 
not the number of AEs experienced.  For example, if a patient reports the same AE on 3 separate 
occasions that patient will be counted only once for that preferred term. Patients reporting more 
than one AE in a SOC will be counted only once in the SOC total.  The denominator used for 
calculation of the percentages will be the number of patients in the Safety population in each 
treatment group. 
Separate summaries will be generated for the following types of TEAEs: 

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▪ 
Overall TEAEs 
▪ 
Severe TEAEs (grade 3 or higher) 
▪ 
TEAEs related to treatment 
▪ 
Serious adverse events (SAEs) 
▪ 
Serious adverse events related to treatment 
▪ 
TEAEs resulting in death 
Treatment groups will be compared on adverse event rates using Fisher’s Exact Test.  
10.6.2  Laboratory Evaluations 
Summary statistics for baseline and change from baseline will be summarized for both treatment 
groups for all hematology and chemistry parameters for the 1, 3, 6 and 12 month timepoints. 
Urinalysis data will be presented in the data listings only. 
10.6.3  Vital Signs 
Summary statistics for baseline and change from baseline will be summarized for the 1, 3, 6 and 
12 month timepoints for both treatment groups for the following vital sign parameters:  
• Blood pressure (mmHg) 
• Weight 
• Pulse (beats per minute) 
• Respiration rate (breaths per minute) 
• Temperature (oC) 
10.6.4  Physical Examinations 
Data from physical exams (scheduled and unscheduled) will be presented in the data listings.  All 
pre-treatment clinically significant findings, as determined by the Investigator, will be reported 
as concurrent medical conditions.  All clinically significant findings on exams performed after 
treatment will be reported as adverse events. 
10.6.5 Electrocardiogram (ECG) 
Data from the baseline and 12 month ECGs will be presented in the data listings.  All pre-
treatment clinically significant findings, as determined by the Investigator, will be reported as 
concurrent medical conditions.  All clinically significant findings on the 12 month ECG will be 
reported as adverse events. 
 
 

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10.6.6 Cystoscopy 
 
Cystoscopy results will be summarized by treatment group for baseline visits. Any clinically 
significant findings on the post-baseline cystoscopies will be reported as adverse events.   
 
10.6.7 Proctoscopy 
 
Any clinically significant findings on proctoscopies will be reported as adverse events.   
 
10.6.8 Concomitant Medications 
 
Medications will be coded using the World Health Organization (WHO) Drug Dictionary.  The 
number and percentage of patients taking concomitant medications will be presented by Drug 
Class and preferred term. Patients taking a medication multiple times during the study will be 
counted once for the Drug Class and preferred term in the summary tables. Concomitant 
medications will be summarized by treatment group. 
11 Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will be formed consisting of at least 3 individuals with 
expertise and experience in clinical trials and safety evaluations, but without direct involvement 
in the conduct of the study. The exact responsibilities, procedures, and guidelines used to 
manage the DSMB are described in a separate charter. 
12 Records and Confidentiality 
Each patient will be identified by study ID number only in the trial records. Study data will be 
recorded on electronic CRFs. Monitoring of study data recorded on the CRFs to source 
documents will be conducted for all patients to ensure accuracy and completeness.  
13 Quality Control and Assurance 
This study will be initiated and conducted under the sponsorship of Merit Medical Systems, Inc. 
through its wholly owned subsidiary BioSphere Medical. The sponsor will supply electronic 
CRFs to all sites. Representatives of BioSphere Medical will monitor the study to verify study 
data, medical records, and CRF data in accordance with current ICH, GCPs and other applicable 
regulations and guidelines. 

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14 Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonization 
(ICH) E6 for Good Clinical Practice (GCP): Consolidated Guidance and the appropriate 
regulatory requirement(s). The Investigators will be thoroughly familiar with the appropriate use 
of the treatment procedure as described in the protocol. Essential clinical documents will be 
maintained to demonstrate the validity of the study and the integrity of the data collected. 
Master files should be established at the beginning of the study, maintained for the duration of 
the trial and retained according to the appropriate regulations.  
15 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB/EC will review all appropriate study documentation in order to safeguard the 
rights, safety and well-being of the patients. The study will only be conducted at sites where the 
IRB/EC approval has been obtained. The protocol, informed consent, advertisements (if 
applicable), written information given to the patients, safety updates, annual progress reports, 
and any revisions to these documents will be provided to the IRB/EC by the Investigator.  
16 Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
patient prior to any study specific procedures being performed. The informed consent form used 
at each site will be approved by the IRB/EC prior to use.  The method of obtaining and 
documenting the informed consent and the contents of the consent will comply with ICH-GCP 
and all applicable regulatory requirement(s).  
17 Patient Confidentiality 
In order to maintain patient privacy, all CRFs, study reports and communications will identify 
the patient the assigned patient ID number only. The Investigator will grant monitor(s) and 
auditor(s) from BioSphere Medical, or its designee, and regulatory authority(ies) access to the 
patients’ original medical records for verification of data gathered on the CRFs and to audit the 
data collection process. The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.  
 
 

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18 Protocol Compliance 
The Investigators will conduct the trial in compliance with the protocol provided by BioSphere Medical, 
and given approval/favorable opinion by the IRB/EC and the appropriate regulatory authority(ies), if 
required. Modifications to the protocol should not be made without agreement of the Investigator and 
BioSphere Medical. Changes to the protocol potentially affecting safety or efficacy will require written 
IRB/EC approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to patients. The IRB/EC may provide, if applicable regulatory 
authorities permit, expedited review and approval/favorable opinion for minor change(s) in ongoing trials 
that have the approval/favorable opinion of the IRB/EC. BioSphere Medical will submit all protocol 
modifications to the regulatory authority(ies) in accordance with the governing regulations.  
A record of patients screened, but not entered into the study, will be maintained. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to the 
patient, the Investigator will contact BioSphere Medical or designee, if circumstances permit, to discuss 
the planned course of action and the action will be fully documented in the case report form and source 
documentation.  
19 Monitoring, Verification of Data, Audit and Inspection 
A BioSphere Medical monitor, or designee, will visit each center periodically to monitor the progress of 
the clinical trial and review CRFs and original source documents with the study personnel, to verify 
accuracy of data recording. Periodically some/all of the facilities used in the trial (e.g., laboratory) may be 
reviewed or inspected by the IRB/EC and/or regulatory authorities. 
 
The Investigator will ensure that the trial participants are aware of and consent that personal 
information may be reviewed during the data verification process as part of the monitoring/auditing 
by properly authorized agents of BioSphere Medical or subject to inspection by regulatory authorities.  
The audit or inspection may include, for example, a review of all source documents, drug records, original 
clinical medical notes, some or all of the facilities used in the trial. During monitoring or audit/inspection, 
participation and personal information is treated as strictly confidential to the extent the applicable law 
permits and is not made publicly available 
 
 

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20 Data Recording and Retention of Study Data 
In compliance with Good Clinical Practice (GCP), the medical records/medical notes, etc. should be 
clearly marked and permit easy identification of participation by an individual in the specified clinical 
trial. The Investigator must record all data with respect to protocol procedures, drug administration, 
laboratory data, safety data and efficacy ratings on the BioSphere Medical CRFs. 
 
If the Investigator relocates or retires, or otherwise withdraws his/her responsibility for 
maintenance and retention, BioSphere Medical must be notified (in writing) so that adequate provision 
can be made with regard to the trial documents. 
 
Trial documents must be retained until at least two years after the last approval of a marketing application 
in an ICH region and until there are no pending or planned marketing applications in an ICH region by 
BioSphere Medical.  Documents must be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with BioSphere Medical, who will inform the 
Investigator, in writing, as to when these documents no longer need to be retained. 
21 Confidentiality, Publication and Disclosure Policy 
The Investigators understand that BioSphere Medical will use the information developed in the clinical 
study in connection with the development of the study treatment. This information may be disclosed to 
other study Investigators, the FDA, and other government agencies.  All information disclosed to the 
Investigators by BioSphere Medical for the purpose of having the Investigators conduct the clinical trial 
described in this protocol or generated by the Investigators as results in the clinical trial shall be treated by 
the Investigators as strictly confidential. The Investigators shall not use such information other than for 
the purpose of conducting the clinical trial and may not disclose such information to others, except when 
such disclosure is to colleagues and/or employees who reasonably require the information to assist in 
carrying out the clinical trial and who are bound by like obligations of confidentiality. Notwithstanding, 
the Investigators may use or disclose to others any information which: (i) was known to the Investigators 
prior to the date of its disclosure, (ii) is now, or becomes in the future, publicly available; or (iii) is 
lawfully disclosed to the Investigators on a nonconfidential basis by a third party who is not obligated to 
BioSphere Medical or any other party to retain such information in confidence. 
 
Biosphere Medical acknowledges that the Investigators have certain professional responsibilities to report 
to the scientific community on findings in clinical investigations they conduct. The Investigators shall 
have the right to publish the results of research performed under this protocol, provided such publication 
does not disclose any confidential information or trade secrets of BioSphere Medical (other than the data). 
The study is a multi-center protocol, and as such the Investigators agree not to independently publish their 
findings except as part of an overall multi-center publication, unless specifically approved in writing by 
BioSphere Medical.  
 
 
 

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22 Bibliography 
 
Carnevale, FC, Antunes AA, da Motta Leal  Filho JM, et al. Prostatic artery embolization as a primary 
treatment for benign prostatic hyperplasia:  Preliminary results in two patients. Cardiovasc Intervent 
Radiol 2010; 33(2): 355-361. 
Carnevale, FC, da Motta Leal Filho JM, Antunes AA, et al. Midterm follow-up after prostate embolization in 
two patients with benign prostatic hyperplasia. Cardiovasc Intervent Radiol 2011; 34(6): 1330-1333. 
Carnevale FC, da Motta Leal Filho JM, Antunes AA, et al.  Quality of life and symptoms relief support 
prostatic artery embolization for patients with acute urinary retention due to benign prostatic hyperplasia. 
J Vasc Interv Radiol 2012; 23(3): S4. 
Carnevale FC, Antunes AA. Prostatic artery embolization for benign prostatic hyperplasia: results. Global 
Embolization Symposium and Technology, New York, NY, May 2012. 
da Motta Leal Filho JM, Antunes AA, Carnevale FC, et al. A Prospective analysis of prostatic artery 
embolization as a primary treatment for benign prostatic hyperplasia:  A pilot study.  J Urol 2011; 185 
(4S):e845. 
da Motta Leal Filho JM, Carnevale FC, Antunes AA, et al. Relevant angiographic findings during prostatic 
arterial embolization for the treatment of benign prostatic hyperplasia.  J Vasc Interv Radiol 2012; 23(3): 
S34. 
DeMeritt, JS, Elmasri FF, Esposito MP et al. Relief of benign prostatic hyperplasia-related bladder outlet 
obstruction after transurethral polyvinyl alcohol prostate embolization. J Vasc Interv Radiol 2000; 
11(6):767-770. 
Faintuch S, Mostafa EM, Carnevale FC, et al.  Prostatic artery embolization as a primary treatment for benign 
prostatic hyperplasia in a canine model.  J Vasc Interv Radiol 2008; 19(2): S7. 
Kacker R, Williams SB. Endourologic procedures for benign prostatic hyperplasia. Urol J 2011; 8(3):171-
176. 
McVary KT, Roehrborn CG, Avins AL, et al. Update on AUA Guideline on the management of benign 
prostatic hyperplasia. J Urol 2011; 185:1793-1803. 
http://kidney.niddk.nih.gov/kudiseases/pubs/prostateenlargement. Accessed June 12, 2012. 
Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A.  The International Index of Erectile 
Function (IIEF): A multidimentional scale for assessment of erectile function. Urology 1997; 49: 822-
830. 
Sun F, Sanchez FM, Crisostomo V, et al. Benign prostatic hyperplasia:  Transcatheter arterial embolization as 
potential treatment – Preliminary study in pigs. Radiology 2008; 246 (3):783-789. 

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Sun F, Sanchez FM, Crisostomo V, et al.  Transarterial prostatic embolization: Initial experience in a canine 
model. AJ R 2011; 197:495-501. 
Wei JT, Calhoun E, Jacobsen SJ. Urologic disease in America project: Benign prostatic hyperplasia. J Urol 
2005: 173(4):1256-1261. 
 

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verumontanum to the bladder neck; baseline cystoscopy must be performed within 3 months prior to enrollment.  Cystoscopy will be necessary in all 
cases of hematuria.  Proctoscopy will be necessary in all cases of bleeding per the rectum. 
4 Patients will be enrolled within 4 weeks of baseline MRI imaging  
5 Patients will be treated with PAE using Embosphere Microspheres or conventional TURP based on cohort enrollment 
6 Post treatment evaluations includes: duration of hospital stay, procedural medications and post treatment catheter duration 
APPENDIX B:  Study Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BASELINE (Visit -1) 
o ICF 
o Demographics Medical Hx, Concurrent 
Medical Conditions, Physical Exam  
o Labs (blood and urine), including PSA 
o Prostate Exam: DRE, US, MRI, 
o Urodynamic testing 
o IPSS and IIEF 
o ECG 
o Cystoscopy 
o Prostate Biopsy (if needed per protocol) 
o Concomitant medication assessment 
MONTH 1 FOLLOW-UP (Visit 2) 
(4 weeks +2 after Visit 1) 
o Physical Exam 
o Labs (blood and urine), including PSA 
o Prostate Exam: DRE, US 
o Uroflowmetry testing 
o IPSS and IIEF 
o Cystoscopy, if medically indicated 
o Proctoscopy, if medically indicated 
o AE & medication assessment 
MONTH 12 FOLLOW-UP (Visit 5) 
(52 weeks +2 after Visit 1) 
o Physical Exam 
o Labs (blood and urine), including PSA 
o Prostate Exam: DRE, US, MRI 
o Uroflowmetry testing 
o IPSS and IIEF 
o ECG 
o AE & medication assessment 
o Cystoscopy, if medically indicated 
o  
MONTH 3 FOLLOW-UP (Visit 3) 
(12 weeks +2 after Visit 1) 
o Physical Exam 
o Labs (blood and urine), including PSA 
o Prostate Exam: DRE, US, MRI 
o IPSS and IIEF 
o AE & medication assessment 
o Cystoscopy and/or Urodynamic 
testing, if medically indicated 
MONTH 6 FOLLOW-UP (Visit 4) 
(24 weeks +2 after Visit 1) 
o Physical Exam 
o Labs (blood and urine), including PSA 
o Prostate Exam: DRE, US 
o IPSS and IIEF 
o AE & medication assessment 
o Cystoscopy and/or urodynamic 
testing, if medically indicated 
STUDY TREATMENT (Visit 1) 
PAE or TURP 
ANNUAL LONG-TERM FOLLOW-UP 
(Annually for 4 years after Visit 5) 
o Physical Exam 
o PSA 
o Prostate Exam: DRE, US, MRI 
o Uroflowmetry testing 
o IPSS and IIEF 
o Documentation of any new treatments 
for BPH and/or LUTS 
ENROLLMENT 
 
PAE vs. TURP

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APPENDIX F 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

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