Prostate Artery Embolization (PAE) for Lower Urinary Tract Symptoms (LUTS) Due to Benign Prostatic Hyperplasia (BPH)
Phase: NA
Conditions: Benign Prostatic Hyperplasia
Sponsor: University of Minnesota

NCT02930889 
 
 
 
 
 
 
Title: Prostate Artery Embolization (PAE) for Lower Urinary Tracts 
Symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH) 
 
 
 
 
 
Protocol revision date 
24 May 2017 
 
 
 
 
 
Jafar Golzarian M.D. 
Professor and Head, Interventional Radiology 
University of Minnesota 
Department of Radiology 
golzarian@umn.edu 

 
 
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GENERAL INFORMATION 
 
Name and address of the person authorized to sign the protocol and amendments  
 
Jafar Golzarian, MD  
MMC 292 
420 Delaware St. SE 
Minneapolis MN  55455 
golzarian@umn.edu 
612-626-5388 
 
Name and address of study monitor 
 
Vu Huyhn  
717 Delaware St 
2nd Floor 
Minneapolis MN  55455 
huyn0089@umn.edu 
 
Name, title, address and telephone number(s) of the medical expert for the trial 
 
Jafar Golzarian, MD  
MMC 292 
420 Delaware St. SE 
Minneapolis MN  55455 
golzarian@umn.edu 
612-626-5388 
 
Name and title of the investigator(s) and sub-investigators responsible for the trial 
with address and phone number(s)   
 
Dr. Shamar Young, Department of Radiology, University of Minnesota 
Dr. Michael Rosenberg, Assistant Professor of Radiology, University of Minnesota 
Dr. Prashant Shrestha, Assistant Professor of Radiology, University of Minnesota 
 
Name and addresses of the clinical laboratories and/or other institutions involved 
in the trial 
 
University of Minnesota Academic Health 
Center 
Department of Radiology 
MMC 292 
420 Delaware St. SE  
Minneapolis, MN, 55455 
 
 
Fairview-University Medical Center 
500 Harvard Street SE 

 
 
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Minneapolis, MN  55455 
 
Table of Contents 
 
1 Introduction .................................................................................................................. 1 
2 BPH ................................................................................................................................ 1 
2.1 
Introduction .................................................................................................................................................................... 1 
2.2 
Signs and symptoms of Prostate Gland Enlargement ............................................................................. 1 
2.3 
Traditional management ......................................................................................................................................... 1 
2.3.1 
Medical ............................................................................................................................................................................. 1 
2.3.2 
Surgical ............................................................................................................................................................................ 2 
3 Report of Prior Transarterial Pelvic Embolization .................................................. 3 
3.1 
Pelvic Embolization ................................................................................................................................................... 3 
3.2 
Animal Studies of Prostate Embolization ....................................................................................................... 3 
3.3 
Prostate embolization as a therapy for BPH in humans ......................................................................... 4 
3.4 
Risk/Benefits ................................................................................................................................................................. 8 
3.5 
Rationale ......................................................................................................................................................................... 8 
3.6 
Trial Conduct ................................................................................................................................................................ 8 
3.7 
Population ...................................................................................................................................................................... 8 
4 Trial Objectives .......................................................................................................... 10 
5 Trial Design ................................................................................................................ 10 
5.1 
Primary Study Endpoints/Secondary Endpoints ....................................................................................... 10 
5.2 
Study Design/Type .................................................................................................................................................. 10 
5.3 
Inclusion Criteria ....................................................................................................................................................... 10 
5.4 
Exclusion Criteria ..................................................................................................................................................... 11 
5.5 
Pre-procedure Patient Evaluation .................................................................................................................... 11 
5.6 
Description of the Device ..................................................................................................................................... 13 
5.7 
Principle of operation of the devices............................................................................................................... 13 
5.8 
Anticipated changes in the devices ................................................................................................................. 13 
5.9 
Pre-procedure Patient Evaluation .................................................................................................................... 13 
5.10  Procedure ..................................................................................................................................................................... 13 
6 Assessment of Efficacy ............................................................................................ 14 
6.1 
Efficacy Parameters ................................................................................................................................................ 14 
6.2 
Method and Timing .................................................................................................................................................. 14 
7 Assessment of Safety ............................................................................................... 16 
7.1 
Definitions .................................................................................................................................................................... 16 
7.2 
Adverse Event Follow-up ..................................................................................................................................... 21 
8 Ethical Considerations ............................................................................................. 21 
9 References .................................................................................................................. 21 
 
 
 
 
 
 

 
 
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List of Abbreviations 
 
BPH=Benign Prostatic Hyperplasia 
CFR=Code of Federal Regulations 
CRF=Case Report Form 
FDA=Food and Drug Administration 
GCP=Good Clinical Practice 
ICH=International Conference on Harmonization 
IRB=Institutional Review Board 
PAE=Prostatic Arterial Embolization 
TRUS=Trans Rectal Ultrasonography 
PVR=Post Void Residual 
IPSS=International Prostate symptom score 
QoL=Quality of Life 
Qmax=Peak urinary flow rate 
PSA=Prostate Specific Antigen 
 

 
 
1 
Introduction 
This is an investigator-initiated application to evaluate a new prostate therapy that is 
intended to relieve the symptoms of Benign Prostatic Hyperplasia (BPH). There is no 
monetary support from commercial entities. The intent of the study is to evaluate the 
outcome of prostate artery embolization for treating benign prostatic hyperplasia. This 
procedure was originally reported from two separate groups, one in Lisbon, Portugal and 
one in Sao Paulo, Brazil. After their initially promising data several different groups in the 
United States, Asia, and Europe have added there data to the literature. The study will 
use commercially available embolic materials, which represents a new application for 
these devices, which have been cleared for sale for other indications. 
 
2 
BPH 
2.1 Introduction 
BPH is a highly prevalent condition in which there is nodular growth of prostatic tissue, 
enlarging the prostate and narrowing the urethra. BPH contributes to symptoms of 
frequency and urgency of urination in men as they age.  It is estimated that close to 80% 
of men will develop BPH.  Most men will be treatable for this condition with alpha-blockers 
or 5-alpha reductase inhibitors, but close to 10% of men who develop an enlarged 
prostate will need surgery to correct symptoms from this disorder.  The symptoms include 
frequent urinary traction infections, bladder stones, inability to urinate, and urinary 
incontinence. 
 
2.2 Signs and symptoms of Prostate Gland Enlargement 
 Weak urine stream, difficulty in starting urination 
 Stopping and starting while urinating, dribbling at the end of urination 
 Straining while urinating, frequent need to urinate 
 Prolonged urination 
 Urge incontinence – involuntary leakage followed by urgency 
 Increased frequency of urination at night (nocturia) 
 Urgent need to urinate and not being able to completely empty the bladder 
 Blood in the urine (hematuria) 
 Urinary tract infection 
 
2.3 Traditional management  
2.3.1 Medical  
Current medical management of BPH includes two class of medications that target the 
dynamic and stable aspects of prostatic obstruction; α-adrenergic blockers and 5α-
reductase inhibitors respectively. The α-adrenergic blockers directly inhibit sympathetic 
tone, which relaxes the smooth muscle of the prostate.  The 5α-reductase inhibitors 
(including Finasteride) prevent conversion of testosterone to dihydrotestosterone, which 

 
 
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is the chief hormone promoting stromal and epithelial proliferation in the prostate.  Over 
the course of a year, this can decrease peri-urethral prostate size and relieve obstruction. 
 
Anti-cholinergics are another class of medications used to ameliorate lower urinary 
obstructive symptoms. The urinary bladder contracts when muscarinic receptors on 
smooth muscle are stimulated by acetylcholine.  While these drugs do not benefit patients 
with symptoms secondary to BPH, some of these patients may in fact have co-incident 
bladder dysfunction and anticholinergic medications may prove beneficial [1]. 
2.3.2 Surgical 
Surgical therapy is reserved for patients exhibiting moderate to severe symptoms not 
controlled by medical therapy or in patients who refuse or do not tolerate medical 
treatment.  Traditionally open prostatectomy was the surgical option of choice, but with 
onset of new surgical techniques and technologies open prostatectomy is typically 
reserved for larger (usually >80-100g) prostates. Open prostatectomy may also be 
recommended when there is a concomitant bladder diverticulum or bladder stone. 
The current gold standard of medical refractory BPH is transurethral resection of the 
prostate (TURP). This procedure focuses on resecting peri-urethral prostatic tissue, which 
is most contributory to static obstruction.  Complications of TURP include significant 
bleeding (often requiring transfusions), TUR syndrome (hyponatremia secondary to 
absorption of hypotonic irrigation), retrograde ejaculation, impotence, and urinary 
incontinence.  Given these potentially serious adverse events, several new techniques 
have been developed and investigated.  However, a recent systematic review noted that 
there is little evidence that any of these are more efficacious than TURP and as such it 
remains the gold standard [2]. Some of these newer approaches include transurethral 
incision of the prostate, which is reserved for men with obstruction and a small prostate. 
This procedure is more rapid than TURP and outcomes in well-selected patients are 
equivalent to that of TURP with less morbidity from bleeding, TUR syndrome, and rate of 
retrograde ejaculation [3]. Several different protocols using laser surgery for the prostate 
have been described, the two main energy sources are Nd:YAG and holmium: YAG. 
These procedures can be performed under direct visualization or with transrectal 
ultrasound guidance.  Laser ablation is particularly useful in patients on anticoagulation 
as the risk of bleeding is minimal.  Similar to other coagulative techniques, the prostatic 
urethra is not immediately excised/resected; instead it is sloughed off over the course of 
a few weeks. Studies suggest that patients undergoing Holmium laser enucleation require 
shorter hospitalization, experience decreased blood loss, and have similar outcomes to 
TURP at the expense of increased procedure time [4]. Yet, despite these considerable 
attempts at innovation in the field, none of these technologies has been sufficiently 
effective to displace TURP. 

 
 
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3 
Report of Prior Transarterial Pelvic Embolization 
3.1 Pelvic Embolization 
Non-selective hypogastric artery embolization was originally described as a management 
option for refractory hematuria in 1974 [5] and was subsequently reported in case reports 
as an emergency treatment for refractory hematuria secondary to BPH, adenocarcinoma 
of the prostate, and post-operative/post-biopsy bleeding [6,7]. 
Over the past 3 decades there have been a number of case reports and small case series 
that have been published regarding embolization of pelvic tumors, including prostate and 
bladder cancer, and for bleeding after transurethral resection of the prostate. In total, 
there are 130 patients reported in the case reports and studies [5-17]. All were pelvic 
embolizations, with a wide range of pathologies. If one leaves out the study by Liguori 
[16], which included a variety of malignancies in the pelvis, all the other above cases, 86 
in total, were for treatment of bleeding from the urinary tract due either to malignancy of 
the bladder or prostate or from bleeding after transurethral resection of the prostate. The 
use of a variety of embolics in these reports, in the setting of emergency treatment, 
without reported injury to the bladder or other pelvic organs suggests that there may be 
a margin of safety in the embolization of the prostate and bladder 
3.2 Animal Studies of Prostate Embolization 
Several studies have since been performed to assess the safety and feasibility of prostatic 
embolization in animal models.  
 
Darewicz in 1980 [19] published the first investigation on transarterial prostatic 
embolization. Five dogs were catheterized and each internal iliac artery embolized with 
n-butyl-2-cyanoacrylate. This liquid embolic material results in complete occlusion of the 
vessels into which it is injected. After animal sacrifice, pathologic examination of the 
prostate tissue showed no macroscopic changes. Microscopic examination revealed 
infiltration of lymphocytes, histiocytes, and fibroblasts in the interstitial tissue. No injuries 
to other pelvic organs were noted. 
 
Sun et al [20] used pigs to evaluate transcatheter arterial embolization (TAE) as a 
potential treatment for BPH. Sixteen healthy large white male pigs were used in this study. 
Eight animals were randomly assigned to the TAE group, and eight were randomly 
assigned to the control group. Each pig in the TAE group underwent bilateral super 
selective catheterization of the prostatic branch of the inferior vesical artery and 
subsequent embolization with 500–700 µm microsphere particles (Embosphere; 
Biosphere Medical, Louvres, France). Three months after the procedure, both the pigs in 
the TAE group and those in the control group underwent testing of their sexual function 
with female pigs in estrus. The pigs were then sacrificed, and necropsy and pathologic 
analysis were immediately performed with particular attention paid to the prostate. There 
was no significant difference in sexual function between the two groups. The urinary 
bladder, ureters, deferent ducts, urethra, sigmoid colon, and rectum appeared to be 
normal in all animals. The prostate volume was significantly smaller (P<.001) in the TAE 
group than in the control group. In the TAE group pigs, microsphere particles were 
identified within occluded arterioles and there was fibrotic tissue formation and glandular 

 
 
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atrophy. 
 
In a study of prostate embolization in canines, benign prostatic hyperplasia was induced 
using hormones in 9 beagle dogs [21]. The dogs underwent hormonal stimulation for 
either 12 or 24 weeks. Five of the 9 beagles were embolized, in all cases with 255-355 
µm polyvinyl alcohol (PVA) particles, (Contour®, Boston Scientific, Natick, MA). Half the 
dogs were hormonally stimulated for 12 weeks and half for 24 weeks. All animals that 
were embolized (5 of the 9) were treated 12 weeks after the initiation of the hormones 
and were sacrificed 12 weeks after embolization (24 weeks after baseline). In the group 
stimulated for 24 weeks that were not embolized, there was evidence histologically of 
diffuse glandular hyperplasia with micro-cystic change. Those stimulated for 24 weeks 
who were embolized showed gross evidence of cystic change and microscopically 
atrophied glands intermixed with islands of normal glandular hyperplasia. The embolic 
material was found in the periphery of the gland with inflammatory cell infiltration. 
Pathologic examination of the bladders showed one specimen with focal hemorrhage in 
the bladder wall, but not involving the entire thickness of the bladder. No other bladder 
injuries were reported. 
 
The most recent study reported in 2011, again using hormonal stimulation in 10 beagles 
for 4 months [22].  Seven of the ten were randomly selected for embolization with 300-
500 µm tris-acryl gelatin microspheres (TAGM). The pathologic findings were similar to 
the study reported above. The embolized prostate glands showed gross cystic change 
and microscopic cysts lined with atrophied glands, compatible with major areas of 
glandular necrosis. There were no bladder injuries, but two animals were found to have 
a slight adhesion between the posterior surface of the prostate and the anterior wall of 
the rectum.  No mural or mucosal injuries to the rectum were reported. 
 
Animal studies in this setting have limitations. The beagle model does not replicate human 
BPH, symptom change cannot be assessed in animals, and objective improvement of 
urinary flow also cannot be measured, as the BPH model in canines does not induce 
bladder outlet obstruction. Also, most men who would be treated with this treatment are 
over 60 and many will have atherosclerosis. It is unclear if atherosclerosis limits collateral 
flow to the pelvic organs and what role this might play in bladder or rectal injuries. 
Therefore, while the animal studies provide useful data regarding tissue response and 
safety of embolization, human studies are needed to further clarify safety and 
effectiveness. 
 
3.3 Prostate embolization as a therapy for BPH in humans 
In 2000 DeMeritt reported a case describing selective prostatic embolization utilizing 150-
200 µm PVA particles in a 76-year-old patient with refractory hematuria and severe lower 
urinary tract symptoms (LUTS) secondary to BPH [23].  The gross hematuria resolved 
immediately after the procedure and follow-up at 12 months demonstrated a significant 
reduction in his LUTS as measured by the international prostate symptom score (IPSS) 
(24 to 13).  Further, there was a 40% reduction in prostate volume and a decrease in 

 
 
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prostate specific antigen (PSA) from 40 ng/ml to 4 ng/mL. Aside from a transient post-
operative fever, there were no complications in that patient.  
 
In the last five years there have been several small clinical trials on patients with BPH 
refractory to medical management. In Brazil, Carnevale et al. performed PAE with 300-
500 µm TAGM on two patients with acute urinary retention secondary to BPH who were 
initially managed on α-blocker therapy and urethral catheterization [24].  One patient was 
treated with bilateral embolization while the other was unilaterally embolized.  Preliminary 
results with 6-month follow-up demonstrated a 39.7% reduction on US and 47.8% 
reduction on MRI in prostate volume from baseline in the bilaterally treated patient and 
25.5% and 27.8% respectively in the unilaterally treated patient with no evidence of 
complications in either patient. Further follow-up at 18 months demonstrated interval 
increase in prostate size as measured by US and MRI in the unilaterally treated patient 
(19.6% and 12.2% reduction from baseline) while the bilaterally treated patient’s prostate 
volume remained stable (39.7% and 53.6% reduction from baseline) relative to 6-month 
follow-up.  Both patients reported significant improvement in their IPSS and quality of life 
(QoL) score at 18 months with the bilaterally treated patient reporting a score that 
decreased from 8 at 1 month follow-up to 1 while the unilaterally treated patient reported 
a decrease from 17 to 7 [25].  
 
This group presented results in a total of 12 patients, including the two discussed above, 
at the March 2012 Annual Meeting of the Society of Interventional Radiology [26]. All of 
these patients had catheter dependent urinary retention. The procedure was clinically 
successful in 10 patients. Patients had spontaneous urination after catheter removal a 
mean of 12 days post-treatment. While no major complications were noted, 3 of 12 had 
minimal rectal bleeding, 2 of 12 had diarrhea, and focal bladder ischemia in 1 of 12. Mean 
prostate volume reduction was 30% and most had significant improvement in IPSS and 
QoL scores.  
  
Finally, this group recently published results from a prospectively collected group of 35 
patients who had very large prostates (>90 g) which ranged in size from 90-252 g [27].  
This is a subset of patients that would typically require total prostatectomy.  They achieved 
technical success, defined as bilateral prostatic artery embolization, in 33 of 35 patients.  
In their report of 3 month follow up the mean prostate size decreased significantly (p < 
0.001), QoL scores improved significantly (p < 0.001), peak flow rate (Qmax) increased 
significantly (p < 0.001), and IPSS improved significantly (p < 0.001).  They also 
demonstrated a significant decrease in the PSA (p = 0.002).  They did have minor 
complications in a few patients which included two cases of rectal bleeding, two cases of 
hematosperima, one case of diarrhea, and one case of ureteral trauma secondary to 
Foley insertion.   
 
Pisco et al. published a clinical study with 15 patients performed in Portugal in early 2011 
utilizing 200 µm non-spherical PVA particles (Cook Inc., Bloomington IN) [28].  Technical 
success, defined as selective prostatic arterial embolization of at least one pelvic side, 
was achieved in 14 of 15 patients. Bilateral embolization was achieved in 13 patients, 
unilateral in 1 and embolization failed technically in one patient on both sides due to 

 
 
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vessel tortuosity.  With a mean follow-up of 7.9 months Pisco et al. reported a decrease 
of IPSS by a mean of 6.5 points (p=.005), improved QoL score by 1.14 (p=.065), an 
increase in erectile function score by 1.7 points (p=0.63), a mean decrease in PSA by 
2.27 ng/mL (p=.072), and a mean prostate volume reduction by 26.5 mL (p=.0001).  The 
authors reported a major complication in one patient that experienced severe 
intraoperative pain during embolization and was subsequently found to have a 1.5 cm2 
area of necrosis in the inferior bladder wall requiring surgical repair.  Of the 14 patients 
that were technically successfully treated, only 10 achieved clinical success (defined as 
an improvement of symptoms with an IPSS <20 and/or improvement of Qmax to greater 
than 7mL/sec). 
 
Pisco’s group also presented the results of 152 patients at the same SIR meeting in March 
2012 [29] with a subset of these patients being published in early 2013 [30].  However, 
later in 2013 the group published their largest patient series of 255 patients.  Of these 
patients the procedure was technically successful in 250 (98%) of patients.  The group 
presented data for follow up at 1, 3, 6, 12, 18, 24, 30, and 36 months for varying numbers 
of patients.  They found clinical improvement in 81.9% 80.7%, 77.9%, 75.2%, 72%, 72%, 
72%, and 72% respectively.  They also demonstrated statistically significant improvement 
of IPSS, QoL score, Qmax, PVR, prostate volume, and PSA at all time intervals.  The 
group reported only one major complication, the afore mentioned bladder wall ischemia.  
They reported urinary tract infections in 19 patients, transient hematuria in 14 patients, 
rectorrhagia in 6 patients, and balanitis in 4 patients.   
 
Recently, a report of early ﬁndings from a prospective United States clinical trial to 
evaluate the efﬁcacy and safety of PAE for BPH has been published [32]. 72 patients 
were screened and 20 patients underwent treatment. Embolization was technically 
successful in 18 of 20 patients (90%); bilateral PAE was successful in 18 of 19 (95%). 
Unsuccessful embolization were secondary to atherosclerotic occlusion of prostatic 
arteries. Clinical success was seen in 95% of patients (19 of 20) at 1 month, with average 
AUA symptom score improvements of 10.8 points at 1 month (P= .0001), 12.1 points at 
3 months (P = .0003), and 9.8 points at 6 months (P = .06). QoL scores improved at 1 
month (1.9 points; P = .0002), 3 months (1.9 points; P = .003), and 6 months (2.6 points; 
P = .007). Sexual function improved by 34% at 1 month (P = .11), 5% at 3 months (P = 
.72), and 16% at 6 months. (P= .19). Prostate volume at 6 months had decreased 18% 
(n = 5; P = .05). No minor or major complications were reported.   
 
Kubatov et al [33] also reported similarly good mid-term outcomes of 88 patients treated 
in Italy.  They too showed a significant improvement in mean IPSS (p < 0.05), mean Qmax 
(p < 0.05), post void residual (PVR) (p < 0.05), prostate volume (p < 0.05), and QoL score 
(p < 0.05) at 12 months.  They experienced no complication rates either minor or major 
as defined by the society of interventional radiology reporting standards  
 
A randomized prospective study has evaluated the effect of different particle size (100-
µm vs 200-µm) on the outcome of PAE on BPH.  No significant differences were found in 
pain scores and adverse events between two groups. Whereas PSA level and PV showed 

 
 
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greater reductions after PAE with 100-µm PVA particles, clinical outcome was better with 
200-µm particles. [34] 
 
Recently Wang et al published a study of 117 patients with prostrates >80 mL in Chinese 
patients.  They used 50 µm and 100 µm PVA [35].  They were technically successful, 
defined as unilateral or bilateral prostatic artery embolization, in 109 of 117 patients.  This 
group reported outcomes at 24 months in 84 patients which demonstrated significantly 
decreased IPSS (p < 0.001), QoL scores (p < 0.01), Qmax (p < 0.01), PVR (p < 0.01), 
and decreased prostatic volume (p < 0.01).  Some of these patients were followed for 
longer than 24 months after which there clinical improvement remained. This group 
reported no major complications with a small number of minor complications noted.  The 
most common minor complication was urethral burning.     
 
In early 2014 a prospective trial comparing TURP to PAE was conducted and published 
which demonstrated that while initially the TURP cohort showed significantly better 
improvement in IPSS, QoL scores, Qmax, and PVR at 1 and 3 months [36].  These 
differences disappear and the treatments become equivalent at 6 months and they 
remained equivalent at 12 and 24 months.  This is consistent with the expected course 
as time for the prostatic tissue to become necrotic and retract is required. This study 
demonstrated significantly more adverse events in the PAE group than the TURP cohort.  
However, this group seemed to miss classify post embolic syndrome as an AE instead of 
an expected outcome and did not report any incontinence, impotence, or retrograde 
ejaculation in the TURP cohort.  The lack of expected AEs in the TURP cohort, which is 
inconsistent with all other published data sets, have lead several authors to question the 
validity of the study.    
 
Finally, we retrospectively reviewed the outcomes of our first 15 patients with 
symptomatic BPH treated at University of Minnesota. Our initial experience showed a 
technical success and clinical improvement based on IPSS of 90% and 75% respectively. 
Following PAE, 2 out of 15 patients had hematuria; however, post-embolization 
cystoscopy showed no bladder ulceration or abnormalities. These patients had a good 
clinical outcome in the follow up. Using Cone-Beam CT (CBCT) has allowed to identify 
all the collateral and dangerous anastomosis and prevented from non-target 
embolization.  
 
These initial reports suggest that prostate embolization is safe. The results suggest that 
improvement in symptoms occurs in the majority of the patients and that shrinkage in 
prostate volume is likely. Only 1 major complication has been reported at this early stage. 
Even though it is unclear the incident of minor injuries to the bladder and rectal mucosa, 
based on the previous published data and our own personal experience, with the addition 
of CBCT, the incidence of clinically relevant complications are extremely rare. The 
materials used in these procedures have FDA clearance for other indications and are 
readily available for interventionalists to use in this treatment. The relevant clinical articles 
are included in Appendix G. The animal studies and the clinical studies related to prostate 
embolization as a treatment for BPH are provided. The studies and case reports related 
to the treatment of bladder or prostate hemorrhage can be provided if needed. 

 
 
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3.4 Risk/Benefits 
With the proposed procedure there are the general theoretical risks associated with all 
angiographic procedures, which include pain, post procedure groin hematoma, bruising 
or bleeding at the puncture site, pseudoaneurysm, transient or permanent renal injury, 
arterial dissection or thrombosis (very rarely necessitating amputation), infection, fever, 
and a potential for an allergic reaction to intra-arterial contrast administration.  Some of 
these complications can lead to the need for surgical intervention, new endovascular 
procedure, or even potentially death.   
 
Specific risks to PAE are limited and include migration or non-selective delivery of the 
embolic agent leading to a non-targeted distribution. The most severe result of this could 
include focal necrosis of a segment of the bladder wall.  They may have persistent urinary 
retention or incontinence.  The patient may also have abdominal pain and although never 
reported may theoretically develop sensory abnormalities.  
  
3.5 Rationale  
Current “gold standards” for treatment of BPH include reducing prostate mass through 
either an open or robotic simple prostatectomy or transurethral resection of prostate 
(TURP).  These are not without their own set of complications and risks. Known 
complications include erectile dysfunction, incontinence, bladder neck contractures, 
hematuria, retrograde ejaculation, etc. Estimates are as high as 1 in 5 (20%) will have a 
surgically related complication.  
 
It is anticipated that PAE, if successful, will offer at least equivalent results with a markedly 
decreased risk profile and fewer complications, enhancing patients’ lives and health. 
 
3.6 Trial 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 as soon as possible. 
3.7 Population 
 Male patients > 45 years old 
 Diagnosis of BPH with moderate to severe lower urinary tract symptoms refractory 
to medical treatment for at least 6 months  
 Currently has or willing to accept the risk of sexual dysfunction 
 PSA which meets one of the following criteria: 
o Baseline PSA ≤ 2.5ng/mL 
o Baseline PSA > 2.5 ng/mL and ≤ 10 ng/mL AND free PSA ≥ 25% of total 
PSA (no biopsy required); 

 
 
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o Baseline PSA > 2.5 ng/mL and ≤ 10 ng/mL AND free PSA < 25% of total 
PSA AND negative prostate biopsy result (minimum of 12 core biopsy) 
within 12 months; 
o Baseline PSA >10 ng/mL AND negative prostate biopsy result (minimum 
of 12 core biopsy) within 12 months; 
o Negative prostate biopsy (minimum 12 cores within 12 months) if 
abnormal digital rectal examination. 
 Prostate measured volume >40 mL 
 And one of the following 
o IPSS > 12 
o QoL >= 3 and up 
o Qmax, <15 mL/S  
 Acute urinary retention 
 Patients without prostate or urethral cancer 
 Patients without New York Heart Association Class III (moderate), or higher 
cardiac dysfunction 
 Patients without a history of recurrent urinary tract infections (>2/year), prostatitis, 
or interstitial cystitis.   
 Patients without medically refractive hypersensitivity to contrast material 
 Patients who are not willing to stop narcotic analgesia, androgen therapy, or GNRH 
(gonadotropin-releasing hormone) analogue therapy for 2 months prior to therapy.   
 Patients with glomerular filtration rates less than 40mL/min/1.73 m2 who are not 
already on dialysis 
 Patients who haved used anithistamines, anti-convulsants, and antispasmodics 
within one week of treatment unless they have been treated with the same drug 
(at the same dosage) for at least 6 months and has an associated stable voiding 
pattern.   
 Patients with a life expectancy greater than 1 year 
 Patients where embolization is possible distal to collateral vessels feeding non-
prostatic tissue 
 Patients who have not had a prostatectomy 
 Patients who do not have bilateral internal iliac artery occlusion 
 Patients who do not have major neurologic illnesses which could have symptoms 
that may be similar to or confused for BPH (eg Parkinson’s disease, multiple 
sclerosis, Shy-Drager syndrome, spinal cord injury, etc.). 
 Patients who have not started or changed their dosage of alpha blockers or 5-
alpha reductase inhibitors in the month prior to PAE 
 Patients who are willing to maintain the same dosage of (or not begin if not 
currently taking) alpha blockers or 5-alpha reductase inhibitors throughout the 
study period unless absolutely medically necessary to change it.    
 Patients who do not have urethral stents 
 
 

 
 
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4 
Trial Objectives 
The purpose of the trial is to determine the clinical outcome of Prostate Artery 
Embolization in the treatment of symptomatic BPH.   
 
5 
Trial Design 
5.1 Primary Study Endpoints/Secondary Endpoints 
The primary endpoints are adverse events, changes in symptom score as measured by 
IPSS, QoL score, and patient-reported change in medication use for prostate symptoms.  
Medical Therapy of Prostatic Symptoms (MTOPS) composite variable symptom score 
>30 and/or flow rate change of >15 ml/second.  
5.2 Study Design/Type 
This is a prospective cohort study without matched controls.  It is a preliminary pilot study 
for clinical outcome that will be used to develop a larger prospective randomized study.  
100 subjects will be enrolled, to reach a goal of 50 treated, and followed for one year after 
PAE.  The patients will complete an informed consent and be enrolled prior to any study 
related testing taking place, for this reason it is felt a significant number of patients will 
not ultimately meet inclusion/exclusion criteria and thus not proceed to PAE.   
 
5.3 Inclusion Criteria 
 Male, 45 years or older 
 Patients with a life expectancy greater than 1 year 
 Currently has or willing to accept the risk of sexual dysfunction 
 Diagnosis of Lower Urinary Tract Symptoms from Benign Prostatic Hyperplasia 
refractory to medical therapy for at least 6 months.  
 IPSS score at initial evaluation should be greater than 12, and uroflowmetry 
(Qmax) of <15mL/s (milliliters per second). 
 QoL >= 3 and up 
 All prostate volumes will be > 40mL 
 PSA which meets one of the following criteria: 
o Baseline PSA ≤ 2.5ng/mL 
o Baseline PSA > 2.5 ng/mL and ≤ 10 ng/mL AND free PSA ≥ 25% of total 
PSA (no biopsy required); 
o Baseline PSA > 2.5 ng/mL and ≤ 10 ng/mL AND free PSA < 25% of total 
PSA AND negative prostate biopsy result (minimum of 12 core biopsy) 
within 12 months; 
o Baseline PSA >10 ng/mL AND negative prostate biopsy result (minimum 
of 12 core biopsy) within 12 months; 
o Negative prostate biopsy (minimum 12 cores within 12 months) if 
abnormal digital rectal examination. 
  

 
 
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5.4 Exclusion Criteria 
 Patients with active urinary tract infections or recurrent urinary tract infections (> 
2/year), prostatitis, or interstitial cystitis. 
 Cases of biopsy proven prostate, bladder, or urethral cancer. 
 IPSS score at initial evaluation less than 12 
 QoL < 3  
 Patients on long-term narcotic analgesia, androgen therapy, or GNRH 
(gonadotropin-releasing hormone) analogue therapy who are unwilling to stop 
therapy for 2 months prior to the study. 
 Use of anithistamines, anti-convulsants, and antispasmodics within one week of 
treatment unless they have been treated with the same drug (at the same dosage) 
for at least 6 months and has an associated stable voiding pattern.   
 Patients who are classified as New York Heart Association Class III (Moderate), or 
higher, have cardiac arrhythmias, have uncontrolled diabetes, or are known to be 
immunosuppressed. 
 Hypersensitivity reactions to contrast material not manageable with prophylaxis. 
 Patients with glomerular filtration rates less than 40 who are not already on dialysis 
 Prostate volume <40 mL 
 Patients with bilateral internal iliac arterial occlusion 
 Patients with causes of bladder obstruction not due to BPH (eg urethral stricture, 
bladder neck contraction, etc) 
 Patients with neurogenic or bladder atonia 
 Prior prostatectomy  
 Cystolithiasis within the last 3 months 
 Patients interested in future fertility 
 Is not willing to accept the risk of sexual dysfunction 
 Patients with a life expectancy less than 1 year 
 Patients where embolization is not possible distal to collateral vessels feeding non-
prostatic tissue 
 Patients with major neurologic illnesses which could have symptoms that may be 
similar to or confused for BPH (eg Parkinson’s disease, multiple sclerosis, Shy-
Drager syndrome, spinal cord injury, etc.). 
 Patients with urethral stents 
 Patients who have undergone prior rectal surgery other than hemorrhoidectomy or 
pelvic irradiation.   
 Patients who have started or changed their dosage of alpha blockers or 5-alpha 
reductase inhibitors in the month prior to PAE 
 Patients who are unwilling to maintain the same dosage of (or not begin if not 
currently taking) alpha blockers or 5-alpha reductase inhibitors throughout the 
study period unless absolutely medically necessary to change it.    
 
5.5 Pre-procedure Patient Evaluation 
The pre-procedure evaluation will be billed to patients or their insurers.  Some of the 
tests are typical for benign prostatic hyperplasia work up while others are not.  The 

 
 
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patient will be informed of the possible cost not covered by insurance at the time of 
informed consent. 
 
Subjects will undergo pre- and post-embolization evaluation consisting of  
PSA test — if this is abnormal, subjects will be asked to have a prostate biopsy if one 
has not been obtained. PSA test is at 3 month follow up. This is a blood test requiring 
about 1 teaspoonful of blood.   
 
Comprehensive chemistry and CBC blood tests, and a urinalysis pre and at 3 month 
TRUS to measure prostate volume pre – and post-embolization 
 
Uroflowmetry measures the flow dynamics of urine released from the body, the speed 
with which it is released, and how long the release takes. The “post-void residual” is an 
ultrasound test to measures the amount of urine remaining in the bladder after urination. 
.  
Symptom scores, global quality of life, and IPSS questionnaires. 
  
MRI/MRA to evaluate the prostatic arteries, and assess the prostate gland perfusion. It 
also allows measurement of the size and the morphology of the prostate before 
embolization. If the patient is unable to have an MRI, then a CTA of the prostate should 
be performed. 
 
Cystoscopy — a test to look inside the bladder with a type of scope to see if there is 
abnormalities inside the bladder.  
 
Urine Culture: This will be performed prior to embolization to ensure the patient does 
not have a UTI.  It will be repeated as needed if signs or symptoms of UTI arise.   
 
5.5.5 Follow up evaluation 
At 1 month after PAE, subjects will be evaluated for adverse events and their medical 
history will be updated.  They will also have cystoscopy, uroflowmetry, and QoL/IPSS 
questionnaires.  The patients will also have pain evaluated by the revised faces pain 
scale.   
 
At 3 months after PAE subjects will be evaluated for adverse events and their medical 
history will be updated.  They will also have labs, TRUS*, uroflowmetry, IPSS/QoL, and 
CT or MR imaging.  The patients will also have pain evaluated by the revised faces pain 
scale. 
 
At 6 after PAE subjects will be evaluated for adverse events and their medical history 
will be updated.  They will also have IPSS/ QoL questionnaires performed. The patients 
will also have pain evaluated by the revised faces pain scale. 
 
At 12 months after PAE subjects will be evaluated for adverse events and their medical 
history updated. They will also have uroflowmetry, IPSS/QoL questionnaires performed. 
Additionally, they will have pain evaluated by the revised faces pain scale. 

 
 
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The International Index of Erectile Function (IIEF-5) Questionnaire is a validated, 
gender-specific measure of sexual function assessed at each follow-up visit 
 
*At time of TRUS the patients’ anus/rectum will also be evaluated. This will be done by 
using the ultrasound to evaluate the anus/rectal wall by adjusting the ultrasound depth 
and turning the ultrasound in a complete circle.    
5.6 Description of the Device 
We plan to use Three embolic materials, cleared for use by the FDA for other uses. It is 
listed below, along with the regulatory reference files. The letters confirming these 
reference files are provided in Appendix B. The embolics will be used to perform PAE. 
The materiasl we plan to use Embosphere® and Embozene™ particles that are 
commercially available and have been used for several years.  
1.            Embosphere Particles, Merit Medical (Rockland, MA). 
2.             Embozene Particles, Boston Scientific (Marlborough, MA). 
5.7 Principle of operation of the devices 
These materials are designed for intra-arterial injection and provide mechanical 
occlusion of the vessels distal to the injection site. The spheres or particles are carried 
by the arterial flow forward and wedge in the vessel once they reach a small enough 
diameter. The materials are permanent occlusive agents, in that they are not resorbed 
and are scarred into the vessel. The vessel occlusion causes ischemia in the tissue 
supplied by those vessels and in particularly sensitive tissue, such as fibroids, the 
ischemia results in infarction of the tissue. It appears that at least a portion of the 
hyperplastic tissue in the prostate also infarcts (based on non-perfusion on contrast-
enhanced MRI studies) and that results in volume reduction, presumed to be associated 
with an in improvement in lower urinary tract symptoms. 
5.8 Anticipated changes in the devices 
No changes will be made in these devices. 
5.9 Pre-procedure Patient Evaluation 
The pre-procedure evaluation is standard of care and will be billed to patients or their 
insurers. Laboratory analysis of PSA, hemogram and urinalysis; trans-rectal ultrasound 
(TRUS) for prostate volume at which time the anus and rectum will be evaluated, 
cystoscopy and uroflowmetry will be done in urology. A CT or MR perfusion imaging 
exam will be done in radiology.  This is the standard evaluation for benign prostatic 
hyperplasia.  Clinic visits with both an urologist and interventional radiologist will 
complete the pre-PAE evaluation.   
5.10 Procedure 
Subjects will be scheduled in Interventional Radiology for a PAE consult after they 
complete a urologic evaluation including TRUS, uroflowmetry, cystoscopy, and laboratory 
analyses.  The IR clinic consult will include screening for eligibility, informed consent, 
IPSS, QoL, and IIEF questionnaires as well as a consult appointment with the Principal 

 
 
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Investigator.  The PI’s coordinators and Urology coordinators will collaborate regarding 
the subject study calendar.   
Consented subjects will have prostate embolization.   
 The morning prior to the procedure the patient will be given ibuprofen and Omeprazol.  
The patient will be given ciprofloxacin just prior to the procedure.    
 Under US guidance right common femoral arterial access will be achieved using 
micropuncture technique and micropuncture needle ultimately exchanged for a 5 Fr 
introducer sheath. 
 The left internal iliac artery will be catheterized using an appropriate catheter.   A co-
axial microcatheter system will be advanced into the anterior branch of the internal 
iliac artery and angiograms obtained. 
 The catheter will then be selectively advanced into likely inferior vesical artery and 
microcatheter injections performed to identify and catheterize the prostatic artery. A 
CBCT may be performed at this stage.  CBCT is optional and will be used in cases 
where the provider feels that further spatial resolution is needed to avoid embolizing 
from a point that would cause non-target embolization.  This will be weighed against 
the increased radiation that comes with CBCT.   
 The microcatheter will then be positioned as distally as possible and CBCT study 
obtained to map the prostatic branches. 
 Once catheter position is confirmed embolization will be performed using Embosphere 
or Embozene particles of a size to be decided by the interventional radiologist at the 
time of procedure. 
 Recheck images will demonstrate good-coverage of the small prostatic branches. 
 At this point the right will be studied after catheterization of the left internal iliac artery 
using an appropriate catheter and angiograms obtained. 
 The microcatheter will be advanced into the prostatic branches and microcatheter 
injections performed. 
 Again a small fraction of microparticles will be injected with adequate coverage of 
vascular branch with preserving the bladder vascularity as much as possible. 
 The above process will be repeated on the contralateral side resulting in a bilateral 
embolization. 
 Hemostasis at the arterial puncture will be achieved using a closure device followed 
by gentle manual compression. 
6 
Assessment of Efficacy 
6.1 Efficacy Parameters 
The primary efficacy parameters are symptoms improvement as measured by IPSS and 
QoL scores and change in uroflowmetrics.  The primary clinical endpoint is Qmax at 3 
months. The primary endpoint will be reported after all subjects have completed 3 months 
of follow-up. 
 
6.2 Method and Timing 
Imaging, labs, uroflowmetry, and questionnaires will be completed prior to embolization 
but within 12 weeks of the procedure. Each follow up visit will be performed at the 

 
 
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specified time plus/minus 2 weeks (eg 1 month +/- 2 weeks).  This will help to determine 
the optimal follow-up timing for the larger randomized trial to follow.   
 
Table 1. Study-specific procedures 
 
Pre-
embolization 
PAE 
treatment 
1  
Month 
3  
Months 
6  
Months 
12  
Months 
Labs: 
PSA, 
CBC, UA 
Insurance 
IR clinic 
Insurance 
IR clinic 
TRUS  
prostate 
volume* 
Insurance 
Urology 
Insurance 
Urology 
 
 
**Cystoscopy Insurance 
Urology 
Research 
Urology 
Uroflowmetry 
-Qmax, PVR 
Insurance 
Urology 
Insurance
Urology 
Insurance 
Urology 
 
Insurance
Urology 
IPSS,QOL, 
IIEF-5 
Research 
IR clinic 
Research 
IR clinic 
Research 
IR clinic 
Research 
IR clinic 
Research 
IR clinic 
Prostate 
Artery 
Embolization 
 Research 
IR 
CTA/MR 
perfusion 
Insurance 
Radiology 
Insurance 
Radiology 
Adverse 
event 
assessment 
Research 
IR clinic 
Research 
IR 
Research 
IR clinic 
Research 
IR clinic 
Research 
IR clinic 
Research 
IR clinic 
Med HX 
Research 
IR clinic 
 
Research 
IR clinic 
Research 
IR clinic 
Research 
IR clinic 
Research 
IR clinic 
Pain Scale 
 
 
Research 
IR clinic 
Research 
IR clinic 
Research 
IR clinic 
Research 
IR clinic 
 
*The anus and rectum will also be evaluated at TRUS.  Anoscopy will be performed if 
abnormalities are seen at TRUS and/or if there is blood in the stools or concerning 
symptomatology.   
** Cystoscopy may be performed sooner or more frequently if there is hematuria and if 
the cystoscopy shows abnormalities after the procedure. 
 
The initial evaluations (new patient IR clinic visit, labs, urologic evaluations) are required 
for assessment of inclusion criteria and will be billed to the patient or their insurance in 
the usual manner.  After enrollment in the study, the evaluations will be billed to the study.  
Coordinators in Interventional Radiology and Urology will work together to keep subjects 
on calendar.  
  

 
 
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Prostate volume: We want to know if PAE can reduce prostatic volume. An increase in 
prostatic volume can also indicate the progression of BPH. TRUS can be used to measure 
both prostate length and weight. TRUS is the current standard imaging for the clinical 
assessment of the prostate gland [35] 
 
Uroflowmetry: Decreased peak urine flow rates are common in men with BPH.  
Uroflowmetry including peak and average flow rates, total void time, and total void volume 
at each follow-up visit.  
 
Post void residual (PVR) urine volume: PVR has generally been considered to reflect the 
severity of bladder outlet obstruction.   PVR will be measured at each follow-up visit to 
monitor impairment or improvement of bladder emptying due to the treatment or disease 
progression. 
 
CTA/MR perfusion: Will identify the prostatic vasculature and serve as a map for the 
embolization procedure.  
  
IPSS and Quality of life: BPH is associated with impairment of quality of life. A validated 
quality of life measure specific to BPH into the study includes the disease-specific quality 
of life question included with the AUA-SI (or IPSS) questionnaire. [38-39] 
 
Sexual function and dysfunction: Both BPH and many of its therapies adversely affect 
sexual function. The International Index of Erectile Function (IIEF-5) Questionnaire is a 
validated, gender-specific measure of sexual function assessed at each follow-up visit 
[40]. 
 
7 
Assessment of Safety 
7.1 Definitions 
To collect safety information reliably, all adverse events will be recorded.  The anticipated 
adverse events include:  
 
 Genitourinary events, i.e., events associated with the urinary tract and/or the 
surrounding genital region  
 Damage to the bladder floor, trigone, sphincters, and rectum 
 Infections  
 Secondary surgical interventions  
 All transient post-procedure events  
 Deaths  
 
Potential Complications of vascular embolization 
Vascular embolization is a high-risk procedure. Complications may occur at any time 
during or after the procedure, and may include, but are not limited to, the following: 
 
 Stroke or cerebral infarction 

 
 
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 Occlusion of vessels in healthy territories 
 Vascular rupture and hemorrhage 
 Neurological deficits 
 Infection or hematoma at the injection site 
 Allergic reaction, cutaneous irritations 
 Transient pain and fever 
 Vasospasm 
 Death 
 Ischemia at an undesirable location, including ischemic stroke, ischemic infarction 
(including myocardial infarction), and tissue necrosis 
 
Also, the Society of Interventional Radiology complications classes will be assessed 
following the PAE procedure.  These classes include vascular, device related, contrast 
related, neurologic, peripheral nervous system complications, respiratory/pulmonary, 
infectious/inflammatory, and death.   
Adverse events will be categorized according to their respective relatedness to the device 
or procedure, and their severity.  The onset, resolution and method of resolution will be 
documented.   
Adverse Events (AEs) encountered during treatment and post treatment periods will be 
recorded on the appropriate AE pages of the Case Report Form (CRF).   
For this protocol, an AE is any untoward medical occurrence (e.g., sign, symptom, 
disease, syndrome, intercurrent illness, abnormal laboratory finding) that begins or 
worsens (in severity or frequency) from baseline status during the treatment or post 
treatment periods. Note:  Unchanged, chronic medical conditions are NOT AEs and 
should not be recorded on AE pages of the CRF unless there is an exacerbation of a 
chronic condition. 
AEs will be classified according to NCI’s common terminology criteria for adverse events 
V 4.0 (CTCAE) and reported on the schedule below.  
A 
copy 
of 
the 
CTCAE 
can 
be 
downloaded 
from: 
http://ctep.cancer.gov/protocolDevelopment/electronicapplications/docs/ctcaev3.pdf 
AEs should be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE):  
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
 Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL).   
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 

 
 
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ADL.  
 Grade 4 Life-threatening consequences; urgent intervention indicated.  
 Grade 5 Death related to AE.  
Serious adverse events (SAEs) are adverse events occurring at any dose, which meet 
one or more of the following serious criteria: 
 
 AE resulted in death 
 
 Is life-threatening (i.e. The AE placed the subject at immediate risk of death; it 
does not apply to an AE which hypothetically might have caused the death if it 
were more severe.) 
 
 Requires or prolongs inpatient hospitalization (i.e. The AE required at least a 24-
hour inpatient hospitalization.)  Elective hospitalizations are not SAEs by this 
criterion. 
 
 Is disabling (i.e. temporary or permanent disruption in activities of daily living) 
 
 Is a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus 
of a subject exposed to the study drug prior to conception or during pregnancy) 
 
 It does not meet any of the above serious criteria but may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed above.  (This criterion should not be used for SAEs that meet any 
other seriousness criteria.) 
 
Unexpected Serious Adverse Events are those that have not been described in the: 
 
 Package insert or investigator's brochure (for FDA investigational agents); 
 
 Protocol; or 
 
 Informed consent document.  
 
Adverse Event - Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medical treatment 
or procedure regardless of whether it is considered related to the medical treatment or 
procedure. 
 
Attribution – The determination of whether an adverse event is related to a medical 
treatment or procedure. Attribution categories include Definite, Probable, Possible, 
Unlikely and Unrelated.  A clinical events committee will make this determination.  
 

 
 
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Unrelated:   
The adverse event is clearly not related to the investigational 
agent/procedure. -  i.e.  Another cause of the event is most plausible; 
and/or a clinically plausible temporal sequence is inconsistent with the 
onset of the event and the study medication administration; and/or a 
causal relationship is considered biologically implausible.   
 
Unlikely:    
The adverse event is doubtfully related to the investigational 
agent/procedure. 
 
Possibly: 
An event that follows a reasonable temporal sequence from 
administration of the study drug/procedure, follows a known or 
expected response pattern to the suspected drug, but that could readily 
have been produced by a number of other factors. 
 
Probably:   
The 
adverse 
event 
is 
likely 
related 
to 
the 
investigational 
agent/procedure. 
 
Definitely Related:  The adverse event is clearly related to the investigational 
agent/procedure – i.e. An event that follows a reasonable temporal 
sequence from administration of the study drug, follows a known or 
expected response pattern to the suspected drug, that is confirmed by 
improvement on stopping and reappearance of the event on repeated 
exposure and that could not be reasonably explained by the known 
characteristics of the patient’s clinical state. 
 
Figure: Summary of Expedited Reporting for Investigational Agents for Phase 1, Phase 
2, and Phase 3  

 
 
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Table 2. Adverse event expedited reporting system 
 
Attribution 
Adverse Event 
Grade 1 
Grade 2 
Grade 
3 
and/or 
hospitalization 
Grade 4 and/or 
hospitalization 
Grade 5 and/or 
hospitalization 
Unex
pecte
d 
Expec
ted 
Unexp
ected 
Expe
cted 
Unexpect
ed 
Expec
ted 
Unexpe
cted 
Expec
ted 
Unexpe
cted 
Exp
ecte
d 
Unrelated 
Unlikely 
Possible 
Probable 
Definite 
 
 
 
Reporting: All AEs should be coded using the CTCAE V4.0.  These AEs will then be 
reported to the FDA in a timely manner.  A Summary table will also be generated filling in 
the below variables: 
 
Variable 
Number of Patients 
Percentage of Patients 

 
 
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At least one AE 
 
 
At least one SAE 
 
 
At least one related AE 
 
 
At least one related SAE 
 
 
At least one AE leading to 
discontinuation 
 
 
At least one AE resulting in 
death 
 
 
 
7.2 Adverse Event Follow-up 
All patients with adverse events will be followed up by the PI until resolution or stabilization 
of chronic side effects related to their adverse events has been achieved.  The patients 
will also be referred to any applicable specialist for their expert opinion and assistance in 
managing/treating any adverse event.  Specifically patients who develop hematuria will 
be referred to Urology for cystoscopy and those who develop rectal bleeding will be 
referred for anoscopy.   
8 
Ethical Considerations 
This study will be conducted according to US and international standards of Good Clinical 
Practice (FDA regulations 21 CFR 312 for IND studies and FDA guidance E6) for all 
studies.  Applicable government regulations and University of Minnesota research 
policies and procedures will also be followed. 
 
This protocol and any amendments will be submitted to the University of Minnesota 
Institutional Review Board (IRB) for formal approval to conduct the study.  The decision 
of the IRB concerning the conduct of the study will be made in writing to the investigator.   
 
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.  The formal consent of a subject, using the IRB-approved 
consent form, will be obtained before that subject is submitted to any study procedure. 
The subject or legally acceptable surrogate must sign this consent form, and the 
investigator-designated research professional obtaining the consent.  
9 
References 
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tract symptoms suggestive of benign prostatic hyperplasia: a systematic review 
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2. Lourenco, T., et al., Alternative approaches to endoscopic ablation for benign 
enlargement of the prostate: systematic review of randomised controlled trials. 
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3. Yang, Q., et al., Transurethral incision compared with transurethral resection of the 
prostate for bladder outlet obstruction: a systematic review and meta-analysis of 
randomized controlled trials. J Urol, 2001. 165(5): p. 1526-32. 

 
 
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4. Tan, A., et al., Meta-analysis of holmium laser enucleation versus transurethral 
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9. Suzuki, Y., et al., Pelvic arteriovenous aneurysm caused by transurethral resection 
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11. Michel, F., et al., Arterial embolization for massive hematuria following 
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induced benign prostatic hyperplasia in dogs: a pilot study. J Vasc Interv Radiol, 
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