Focal MR-Guided Focused Ultrasound Treatment of Localized Intermediate Risk Prostate Lesions
Phase: NA
Conditions: Localized Intermediate Risk Prostate Lesions
Sponsor: InSightec



 
 
InSightec 
 
Page 2 of 37 
PCa003 
 
 
A Pivotal Study to Evaluate the Safety and Preliminary Effectiveness of Focal MR-Guided 
Focused Ultrasound Treatment of Locally Confined Intermediate Risk Prostate Lesions 
 
The goal of this study is to develop data to evaluate the safety and effectiveness of focal 
MRgFUS treatment of intermediate risk prostate lesions. 
 
 
Protocol Number:  PCa003 
 
 
InSightec  
4851 LBJ Freeway, Suite 400 
Dallas, TX 75244 
 
 
 
 
 
 
 

 
 
InSightec 
 
Page 3 of 37 
PCa003 
 
 
1 
BACKGROUND and SIGNIFICANCE ................................................. 5 
1.1 
MR Guided Focused Ultrasound Treatment of Prostate Lesions ............................ 5 
1.2 
Prostate Cancer ............................................................................................................. 6 
1.3 
Rationale for Focal Therapy ........................................................................................ 8 
1.4 
The ExAblate System .................................................................................................... 9 
1.5 
Prior Studies ................................................................................................................ 10 
2 
OBJECTIVES .................................................................................... 10 
2.1 
Background ................................................................................................................. 10 
2.2 
Safety ............................................................................................................................ 12 
2.3 
Effectiveness ................................................................................................................ 12 
2.4 
Study Hypothesis ......................................................................................................... 13 
3 
DESCRIPTION OF PATIENT POPULATION .................................... 13 
3.1 
Subject Enrollment ..................................................................................................... 13 
3.2 
Inclusion Criteria ........................................................................................................ 13 
3.3 
Exclusion Criteria ....................................................................................................... 14 
4 
INVESTIGATION PLAN .................................................................... 15 
4.1 
Study Design ................................................................................................................ 15 
4.2 
Pre-Treatment Procedures ......................................................................................... 16 
4.3 
Treatment Procedures ................................................................................................ 16 
4.4 
Follow-up ..................................................................................................................... 20 
5 
Study Visit Schedule ........................................................................ 21 
6 
STATISTICAL CONSIDERATIONS................................................... 24 
6.1 
Sample Size .................................................................................................................. 24 
6.2 
Data Analysis ............................................................................................................... 24 
7 
RISK ANALYSIS ............................................................................... 25 
7.1 
Potential risks .............................................................................................................. 25 
7.2 
Adverse Effects and Precautions ............................................................................... 32 
7.3 
Criteria for Removal from the Study ........................................................................ 32 

 
 
InSightec 
 
Page 4 of 37 
PCa003 
7.4 
Adverse Event Reporting ........................................................................................... 32 
7.5 
Adverse Events Analysis – Data Safety Monitoring Board .................................... 33 
7.6 
Monitoring Plan .......................................................................................................... 33 
7.7 
Electronic Data Capture (EDC) ................................................................................ 35 
7.8 
Investigator Responsibilities ...................................................................................... 35 
8 
REFERENCES .................................................................................. 36 
9 
APPENDICES.................................................................................... 37 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 5 of 37 
PCa003 
  
1 BACKGROUND and SIGNIFICANCE 
1.1 MR Guided Focused Ultrasound Treatment of Prostate Lesions 
“ExAblate” by InSightec is a device for MR Guided Focused Ultrasound Surgery (MRgFUS). It 
is a non-invasive thermal ablation device that is integrated with an MR Imaging system to allow 
real time controlled ablation of tissue (1, 5). Physician acquires a set of MR images, identifies one 
or more target volume(s) of tissue to be treated, and draws the treatment contours. Therapy 
planning software calculates type and number of sonications (a sonication is an acoustic 
transmission burst of 5sec to 50sec) required to completely treat defined region while minimizing 
total treatment time. During treatment, a small ‘bean’ shaped volume of focused ultrasound energy 
is directed into the target for 5-50 seconds and heats the tissue to temperatures around 65o-85oC to 
induce thermal coagulation. MR images taken during sonication provide visualization of the target 
tissue and a quantitative, real-time temperature map overlay to confirm therapeutic effect of the 
treatment (2). The transducer is then automatically moved to a succeeding treatment point and the 
process is repeated until the entire target volume has been treated. Typically, ~15 - 200 individual 
sonications can be delivered over a 2 to 3 hours period to complete a treatment.  
In recent studies, the ExAblate MR guided Focused Ultrasound Surgery (MRgFUS) has been 
evaluated as a source of controlled thermal energy for coagulation of benign and malignant tumors.  
Specifically, InSightec has completed pivotal study for the use of MRgFUS to treat uterine fibroids 
and gained FDA-PMA approval for this application at October 2004 (3) under PMA number 
P040003. In addition, feasibility studies at several sites are done to evaluate the use of MRgFUS 
for treatment of benign and malignant tumors such as breast cancer and brain tumors, and a pivotal 
study for treatment of bone metastatic tumors (4).  
Furthermore, this system gained both AMAR authorization (Israel Ministry of Health) and CE 
(European and others) approval for the indication of treating Uterine Fibroids for Bone Mets 
Palliation. 
 
 
 
 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 6 of 37 
PCa003 
  
1.2 Prostate Cancer 
In 2009, the American Cancer Society (ACS) estimated that 194,032 new cases of prostate cancer 
were diagnosed in the United States.  This 2009 census of the American Cancer Society reported 
cancers of the prostate were the most frequently diagnosed cancers in men followed by lung and 
colorectal cancers.1  Approximately 1 in 6 men will be diagnosed with prostate cancer during his 
lifetime, but only 1 in 34 will die of this disease. Over 1.8 million men in the United States are 
survivors of prostate cancer.  
Prostate cancer is the second leading cause of cancer death in American men, exceeded only by 
lung cancer. The American Cancer Society estimates that 26,328 men in the United States will die 
of prostate cancer during 2009. Prostate cancer accounts for about 9% of cancer-related deaths in 
men. 
Most prostate cancers grow slowly. Autopsy studies show that many older men who died of other 
diseases also had a prostate cancer that never affected them and that neither they nor their doctor 
were aware of. Over 60% of men between ages 60 and 70 will have prostate cancer detected at 
autopsy. That number climbs to 80% for men in their 80’s.  Some prostate cancers, however, can 
grow and spread quickly. Among men diagnosed with prostate cancer, about 99% survive at least 
5 years, 92% survive at least 10 years, and 61% survive at least 15 years. These figures include all 
stages and grades of prostate cancer but do not account for men who die from other causes.   
Ninety percent of all prostate cancers are found in the local and regional stages (local means it is 
still confined to the prostate; regional means it has spread from the prostate to local nodes nearby 
areas, but not to distant sites such as bone).  Of the men whose prostate cancers have already spread 
to distant parts of the body at the time of diagnosis, about 34% will survive at least 5 years.   
Today’s prostate cancer screening methods often result in the detection of prostate cancer that is 
not clinically significant in many patients (i.e., if left untreated, prostate cancer would not threaten 
health). Traditionally, men diagnosed with localized low risk prostate cancer are required choosing 
between two therapeutic options, either radical surgery with almost certain impairment in quality 
of life (i.e., genitourinary dysfunction), or active surveillance, with the risk of disease progression 
involving significant burden to the patient and health care systems, as well as long-term 
psychological pressure. It has been shown that about 90% of the patients under active surveillance 
will eventually undergo some kind of radical treatment. The aim of focal treatment is combining 
adequate tumor control while avoiding unnecessary treatment related complications. This patients’ 
population will be monitored over time with reasonable criteria for intervention, which will 
identify more aggressive disease in a timely fashion while avoiding excessive treatment when not 
required. (14, 15).  
Current treatment options and their post treatment concerns are listed below in Table 1. 
                                                 
1 American Cancer Society – 2009.  www.cancer.org  

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 7 of 37 
PCa003 
  
Table 1   Current treatment options for prostate cancer 
Procedure 
Description 
Concerns 
Active 
Surveillance 
(AS) 
Monitoring PCa without administering any 
treatment until disease progression 
Quality of life, risk of cancer 
progression and metastases 
without detection. 
Radical 
Prostatectomy 
Surgical procedure to remove prostate, 
surrounding tissue and nearby lymph nodes 
Major surgical procedure with 
early and possibly lasting side 
effects of impotence and 
incontinence 
Radiation 
Therapy 
External beam radiation (EBRT) therapy 
uses a radiation source outside the body to 
irradiate the cancer. Internal radiation 
therapy uses a radiation sources sealed in 
needles, seeds, wires, or catheters that are 
placed directly into or near the cancer. 
Delayed onset impotence and 
rarely incontinence, questions 
about long term toxicity. 
Post radiation colitis 
Hormone 
Therapy 
Suppression or blockage of male hormones 
(androgen) effects, to stop cancer cells 
from growing. 
Hot flashes, night sweats, 
impaired sexual function, loss 
of desire for sex, osteoporosis. 
One of the most active areas of prostate cancer treatment research is in the field of high intensity 
focused ultrasound (HIFU), utilizing trans-rectal ultrasound imaging to image the prostate gland 
and plan the treatment (6, 7). However, since ultrasound imaging is generally unable to visualize 
cancerous foci, treatment strategy used with ultrasound (US) guided HIFU is to ablate the entire 
prostate, or roughly base the treatment volume on pre-diagnosed cancer (by mapping biopsy and 
multi-parametric MRI).  Unfortunately, this often results in inadequate tumor control or over-
ablation of unnecessary normal tissue with subsequent genitourinary toxicity.  
First reported use of US guided HIFU in human prostate cancer was by Mandersbacher et al in 
1995 (8), it showed feasibility of the procedure in ten patients.  In a study performed by Gelet et 
al, 50 patients were treated and followed up for 24 months duration.  These patients also received 
subsequent radiation treatment (9). Among these patients, 56% were cancer free at the time of 
follow-up. Treatment device used in this study underwent two iterations – first had a 50% 
complication rate, the second had a 17% complication rate. In another paper by Gelet et al, 
incontinence and impotency rates were recorded as 14% and 61% respectively at 19 months post-
treatment. In both studies, total procedure time was long due to the number of sonications required 
to cover entire prostate and inability to monitor temperatures. MR thermal monitoring and 
localization of lesions/zones within prostate should allow optimization of treatment rate while 
monitoring and improving safety. 
In a study by Uchida et al (10), transrectal probes utilized for ultrasound guided HIFU have been 
used to treat large areas of the prostate – however, lack of urethral or rectal cooling methods and 
lack of real time thermometry resulted in overheating of normal tissues. This resulted in urethral 
strictures, urinary retention and rectal fistula. Part of this was later addressed by addition of rectal 
cooling however; real time thermometry is currently impossible with ultrasound imaging.   

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 8 of 37 
PCa003 
  
These previous studies have shown effectiveness of focused ultrasound for use in treating lesions 
despite significant adverse events. InSightec has reason to believe that MRI as an imaging modality 
can be used to (a) identify localized prostate lesions in some of the patients (b) identify nerve 
bundles (c) using MR thermometry to prevent overheating of non-targeted tissues and verify 
treatment of targeted tissue. Therefore, MRgFUS has the potential of treating localized prostate 
lesions (instead of the entire prostate), while preventing/reducing the risk of incontinence and 
impotence.  
1.3 Rationale for Focal Therapy 
Historically, definitive treatment of solid lesions included whole-gland extirpation with radical 
surgery. For many organ systems, outcome data have supported more selective, organ-sparing, or 
even ablative therapies, such as breast-conservation surgery and less extensive surgery for 
melanoma. 2,3 
Similar trends have been witnessed in urologic oncology. Historically, standard treatment for all 
solid renal masses was radical nephrectomy. Within the past decade, cancer control following 
partial nephrectomy has been shown to be equivalent for lesions<4 cm, with the benefit of 
preserving renal function. 4,5  
Once established as an accepted treatment for smaller lesions, investigators have subsequently 
shown similar outcomes following partial and radical nephrectomy in patients with masses ≤7 cm.6 
Likewise, partial cystectomy has proven effective for the treatment of bladder cancer in 
appropriately selected patients. Prostate lesion ablation may be amenable to organ-sparing, focal 
treatment. Prostate is a small, easily accessible organ, and many urologists are familiar with 
performing image-guided procedures in the gland through the rectum, perineum, or urethra. 
Intuitively, treatment would be required solely at the area of lesion with lesion free margins, 
limiting collateral damage to normal tissue. While the potential of such therapies makes them 
attractive, the ramifications of treatment failure bear considerable forethought in the development 
of focal treatment trials. The issues of patient selection, appropriate targeting of lesions, and impact 
of focal treatments on outcome with salvage surgical or radiation treatment all deserve 
consideration. Criteria for follow-up and patient evaluation, as well as indications for repeat 
treatment, also remain to be standardized. 
                                                 
2 Morris AD, Morris RD, Wilson JF, White J, Steinberg S, Okunieff P, Arriagada R, Le MG, Blichert- 
Toft M, van Dongen JA. Breast-conserving therapy vs mastectomy in early-stage breast cancer: a 
meta-analysis of 10-year survival. Cancer J Sci Am 1997;3:6–12. 
3 de Braud F, Khayat D, Kroon BB, Valdagni R, Bruzzi P, Cascinelli N. Malignant melanoma. Crit 
Rev Oncol Hematol 2003;47:35–63. 
4 Fergany AF, Hafez KS, Novick AC. Long-term results of nephron sparing surgery for localized renal 
cell carcinoma: 10-year followup. J Urol 2000;163:442–445. 
5 Lee CT, Katz J, Shi W, Thaler HT, Reuter VE, Russo P. Surgical management of renal tumors 4 cm. 
or less in a contemporary cohort. J Urol 2000;163:730–736. 
6 Leibovich BC, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. Nephron sparing surgery 
for appropriately selected renal cell carcinoma between 4 and 7 cm results in outcome similar to 
radical nephrectomy. J Urol 2004;171:1066–1070 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 9 of 37 
PCa003 
  
The role for focal therapy in the treatment of prostate lesions may be most applicable to patients 
with lesions that pose little risk of progression, as long as the treatment has minimal effect on 
quality of life and does not adversely impact survival. Focal ablation of the index lesion, or of the 
sector of the prostate that harbors that lesion, could be very attractive for patients with 
intermediate-risk lesions who are uncomfortable with the risks associated with active surveillance 
and the side effects of radical therapy. The unanswered questions are whether appropriate 
candidates can be identified, whether the index lesion can be reliably identified and characterized 
while excluding higher-grade lesions, and whether focal ablation can reliably target and destroy 
the index lesion with few complications and side effects. Even with effective treatment, such 
patients will have to be followed closely after focal therapy, since they may be at high risk for 
developing another lesion in the prostate. Ultimately, benefits of focal therapy will need to be 
proven with a randomized clinical trial comparing focal ablation to active surveillance or radical 
therapy. With these considerations in mind, a patient best suited for focal therapy would have a 
well localized, targetable lesion of relatively small volume with a low-to-intermediate risk of 
spread and compliant with follow-up including repeat prostate biopsy procedures.  
One option for focal treatment that appears to meet several of these criteria is MRgFUS therapy, 
which involves a thermal treatment with relative sparing of tissue outside of the treatment field. 
The advantages of MRgFUS are the ability to specifically target identified lesions due to the energy 
delivering mode that spares the structures on the way between the energy source and the target, 
and due to the good anatomical visualization of the target and its surroundings. The real-time MR 
thermometry allows closed loop monitoring and controlling the treatment to ensure selective and 
adequate lesion ablation.  
1.4 The ExAblate System 
The ExAblate system is a non-invasive thermal ablation device that has been used for ablation of 
tissue. This system combines a focused ultrasound surgery (FUS) delivery system and a 
conventional diagnostic 1.5T or 3T MRI scanner. ExAblate system provides real-time therapy 
planning algorithm, thermal dosimetry, and closed-loop therapy control. Later is achieved by 
utilizing the unique interactive MRI scan control features of 1.5/3T MRI system manufactured by 
General Electric. FUS device is fully integrated into the MR system and cradle. Subject is placed 
on the MRI table/cradle and moved into the MRI scanner. 
The treatment process begins with physician acquiring a set of MR images, identifying target 
volume(s) of tissue to be treated, and drawing treatment contours. The therapy planning software 
computes the type and number of sonications required to treat defined region while minimizing 
total treatment time. MR images taken during the actual sonications provide quality diagnostic 
image of target tissue and a quantitative, real-time temperature map overlay, to confirm therapeutic 
effect of the treatment. The focus is then automatically moved electronically or mechanically to 
succeeding treatment point and the process is repeated until entire volume has been treated. 
Typically, 15 to 200 individual sonications can be delivered over a 2-3 hours period to complete a 
treatment.  
 
 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 10 of 37 
PCa003 
  
The ExAblate 2000 system received FDA approval for the treatment of Uterine Fibroids in 
October 2004 (PMA # P040003). Furthermore, this system gained both Israeli (AMAR) 
authorization and European (CE) approval for the indication of treating uterine fibroids.  In 
December 2009, FDA approved the ExAblate 2100 System for treatment of women with uterine 
fibroids.  ExAblate 2100 is a multi-application MRgFUS (Magnetic Resonance guided Focused 
Ultrasound) system platform, designed to work with GE’s 1.5T and 3.0T MR line of scanners.  
The designation of “2100” is to differentiate the system that has a fixed cradle (ExAblate 2000) 
from the system with a detachable cradle (ExAblate 2100).  All the features (system HW and 
SW) that were part of the 2000 system are still part of the 2100 system.  This cradle change 
became necessary to accommodate the new clinical applications such as the one for prostate 
cancer.    A full description of the ExAblate 2100 Prostate System is provided in the Investigator 
Brochure, along with relevant preclinical and clinical testing to provide reasonable assurance of 
potential benefit and safe use in patients with localized, and intermediate- risk prostate lesion. 
1.5 
 Prior Studies  
1.5.1 Focal Treatment for Low-Risk Locally Confined Prostate Cancer - Pilot Study 
InSightec conducted pilot studies at the NN Petrov Institute of Oncology, St. Petersburg, Russia, 
and National Cancer Center in Singapore General Hospital, Singapore to evaluate the safety and 
preliminary effectiveness of the ExAblate Prostate System for focal treatment of locally 
confined, low-risk prostate cancer. The actual study protocols are similar to the proposed study 
protocol.  To date, 14 treatments were performed in these two centers and recruitment is 
ongoing.  Additional details are summarized in the Investigator Brochure.    
In Sapienza University of Rome, Italy an investigator initiated and sponsored study comprising 
of focal treatment with subsequent prostatectomy and pathology evaluation is conducted – results 
are not available for Company’s analysis. 
In Jaslok Hospital, Mumbai, India - a near-total gland MRgFUS ablation clinical trial is 
performed.  To date only 3 patients were treated. 
2 OBJECTIVES 
2.1 Background  
Objective of this trial is to assess safety and effectiveness of ExAblate MRgFUS in the treatment 
of intermediate risk, localized (organ confined) prostate lesions.  Investigators selected for the 
study will be trained on proper use of the ExAblate system (Appendix B). 
ExAblate treatment will be implemented as a focal lesion-selective therapy, directed at pre-defined 
volume(s)/sector(s) in the prostate, identified abnormal by mapping biopsy and multi-parametric 
MRI), rather than a whole gland or hemi-ablation treatment.  
Safety: evaluate incidence and severity of adverse events associated with ExAblate’s 
MRgFUS focal treatment of intermediate risk organ confined prostate lesions. The risk of 
ExAblate treatment–related incontinence and impotence will also be assessed in this study. 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 11 of 37 
PCa003 
  
Effectiveness: determine the lesion control effect of ExAblate’s MRgFUS focal treatment 
of intermediate risk organ-confined prostate lesion (confirmed by IMAGE-guided mapping 
biopsy results).  
The proposed study is to evaluate the preliminary effectiveness and safety of the ExAblate 2100 
Prostate System for focal treatment of patients with intermediate risk, localized prostate lesions.  
Study results will be submitted to FDA as previous discussions with the Agency in a 510k for 
commercial clearance.   
Per FDA requirement, the full 510K submission will be performed following the last treated 
subject completing their 12-Months visit. Assessments of primary efficacy endpoints will compare 
the 6-months after ExAblate treatment to Baseline measurements. Safety of ExAblate Prostate 
treatment will be collected for one year after ExAblate.  
It should be noted that all patients will be consented and followed up all the way to 24-Months 
post treatment. 
This study will allow any IMAGE-guided biopsy methodologies (transrectal or transperineal) of 
14 cores or more to be used for baseline lesion localization and characterization and for follow-
up, but the methodology used should be consistent at all time points for each subject.  Successful 
lesion ablation by ExAblate would result in no residual and/or recurrent lesion at the 6 or 24 month 
follow-ups. Additional biopsies may be performed between 6- month follow-up visits if judged to 
be clinically indicated by the investigator.    
Post-therapy changes from Baseline to 24 months will be assessed for PSA levels along with 
results of the patient completed FACT-P (Version 4), ICIQ-SF, IPSS, IIEF-15 and SF12 
questionnaire. See Section 5 for the full schedule of events. 
Biopsy mapping must be performed to localize the region of interest for the focal ExAblate 
treatment.  The standards of performing biopsy will follow site specific mapping procedures, but 
the procedure must meet the minimum study guidelines for a 14 core mapping biopsy where 2 of 
these biopsies are directed anteriorly on the right and left hemi-gland as discussed in Appendix 
C.   
2.1.1 Prostate glands should be delineated into at least 14 sectors.  
Pathology results will be performed by the center’s pathology group according to their standard 
protocol, but cores must be individually labeled by anatomical location for mapping purposes. 
An ExAblate treatment’s target volume/ROT (Region of Treatment) will be defined as an intra-
prostatic volume containing a lesion that was identified by positive 14 core IMAGE-guided 
mapping biopsy where 2 of these biopsies are directed anteriorly on the right and left hemi-gland. 
The goal of the ExAblate MRgFUS treatment is to completely ablate the lesion, while sparing 
crucial structures; i.e., rectal wall, external sphincter, bladder wall, and optionally the urethra and 
one or both neurovascular bundles. 
Biopsy-confirmed lesions that are visible on T2w MRI will be treated based on MR visualized 
lesion margins with surrounding 5 mm lesion-free margins, wherever clinically applicable (i.e., 
treatment will not include 5 mm lesion free margins if these extend into structures to be spared 
(e.g.,  rectal wall, external urethral sphincter, bladder wall, etc.) 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 12 of 37 
PCa003 
  
When a single lesion extends into an adjacent sector, both sectors will be treated.  
Overall treatment volume should be up to 50% of the prostate gland for prostate volume <60cc, 
and up to 30cc should the entire prostate volume be larger than 60cc and avoid as much as 
possible vulnerable structures.   
Consented and enrolled patients will be assessed for eligibility by undergoing 14 core or more 
mapping biopsy will use a standard template (such as described in Appendix C, as an example) by 
either transperineal or transrectal access where 2 of these biopsies are directed anteriorly on the 
right and left hemigland.  Biopsy tissue specimens at screening and post-treatment will be 
processed and analyzed locally at each clinical site, for determining study eligibility and individual 
patient care throughout the study.  Patients with positive pre-treatment biopsies and correlating 
multi-parametric MR findings meeting all other inclusion and exclusion criteria may be enrolled 
into the study.  
This proposed study will be a prospective, single arm study of a minimum of 100 and a maximum 
of 103 patients treated at up to 15 sites.  
Study will be performed utilizing either 1.5T or 3T MR scanners with a torso P/A or cardiac P/A 
coil. MR imaging at screening may include an endorectal coil.  
Follow-up will focus on device- or procedure-related adverse events for primary safety analysis.   
Efficacy will be based on outcomes of mapping biopsy outcome at the 6 month follow-up period 
or sooner per future discussion(s) with the FDA for the 510K submission. 
2.1.2 Regulatory history of the IDE (IDE # G100108) study 
The current IDE has had 4 amendments to date. The 4th Amendment aim was to define 
the patient population that will be part of the 510K submission (IDE G100108/S011). To 
ensure a cohesive patient population for the 510K FDA review, only those patients 
treated after site IRB approval of Amendment 4 will be counted toward the primary 
analysis population. Other safety and efficacy analyses that include data from subjects 
enrolled prior to the approval of G100108/S011 may be reported as supplementary 
information. 
To date (Sept-20-2018), 81 patients have been treated under protocol Amendment-4.  
2.2 Safety 
Safety of ExAblate MRgFUS for focal treatment of intermediate risk organ-confined prostate 
lesion will be determined by evaluation of incidence and severity of device/treatment related 
complications from treatment day visit through the 24-month follow-up.   
2.3 Effectiveness 
Results of prostate mapping biopsies will be used to assess lesion control achieved by the 
treatment. 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 13 of 37 
PCa003 
  
Post-treatment PSA, non-perfused volume (NPV), FACT-P (Version 4), ICIQ-SF, IPSS, IIEF-15 
and SF12 questionnaire results through Month 24 visit will be summarized as secondary measures 
of effectiveness.   
2.3.1 Central Pathology Assessment 
To assist in evaluating effects of ExAblate focal therapy for prostate lesion, this study is utilizing 
a central pathology lab to standardize interpretation of post-treatment effects.  If Gleason graded 
tumor is identified in the 6 month biopsy in the treatment zone of the specimen, then it will be 
sent to a central pathology lab for confirmation and grading.  If a discrepancy is reported 
between the site and the lab, then the judgment of the central pathology lab will take precedence.  
Decisions about patient eligibility and post-treatment care will be determined by the local site 
principal investigator, based upon results of the site pathological findings and clinical 
examination.         
2.4 Study Hypothesis 
The hypothesis of this study is that focal treatment with ExAblate MRgFUS has the potential to 
be an effective non-invasive treatment for intermediate risk, organ-confined prostate lesions, with 
a low incidence of morbidity. The study hypothesis will be tested by measuring treatment-related 
safety and effectiveness parameters in the ExAblate MRgFUS treated patients, as described 
above. 
3 DESCRIPTION OF PATIENT POPULATION    
This study involves patients with organ-confined, intermediate risk prostate lesions for treatment 
with the ExAblate 2100 Prostate System.    
3.1 Subject Enrollment 
Patients will be counseled concerning the research nature of this study, including potential risks 
and benefits associated with participation in the study. Patients providing written informed 
consent will be screened for study eligibility.    
3.2 Inclusion Criteria 
1. Male subjects age 50 and older. 
2. Biopsy proven adenocarcinoma of the prostate (using a IMAGE-guided 14+ core 
mapping biopsy), and targeted cores as needed obtained up to 6 months prior to 
scheduled treatment. 
3. Patient with intermediate risk, early-stage organ-confined prostate cancer (T1a up to T2b, 
N0, M0) and voluntarily chooses ExAblate thermal ablation as the non-invasive 
treatment, who may currently be on watchful waiting or active surveillance and not in 
need of imminent radical therapy.   

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 14 of 37 
PCa003 
  
4. Patient with PSA less than or equal to 20 ng/mL 
5. Gleason score r 7 (4 + 3 or 3 + 4), based on mapping prostate biopsy, with no more than 
15mm cancer in maximal linear dimension in any single core. 
6. Single hemilateral index Gleason 7 lesion, identified in the prostate based on biopsy 
mapping with supporting MRI; may have secondary Gleason 6 lesion on ipsilateral or 
contralateral side confirmed with biopsy and/or MRI. 
7. Gleason 7 tumors must be MRI visible: 
a. In the event that a tumor is in contact with the capsule, the length of the contact 
should be ≤ 5 mm, on axial images. 
b. Largest imaging dimension of cancerous finding < 20-mm  
8. No definite evidence of extracapsular extension or seminal invasion by MRI 
9. Patient should be eligible for both spinal/epidural anesthesia (planned procedure), and 
general anesthesia (in case of complication, requiring intervention).  
10. Patient is willing and able to give consent attend all study visits and complete all 
questionnaires as defined in the protocol 
11. Tumor distance, including tumor free margins, should not be more than 40mm from the 
rectal wall.  
3.3 Exclusion Criteria 
1 
ASA status > 2 
2 
Contraindications to MRI 
2.1 Claustrophobia 
2.2 Implanted ferromagnetic materials or foreign objects 
2.3 Known intolerance to the MRI contrast agent 
3 
Severely abnormal coagulation (INR>1.5) 
4 
Patients with unstable cardiac status including: 
4.1 
Unstable angina pectoris on medication 
4.2 
Patients with documented myocardial infarction within 40 days prior to enrolment 
4.3 
Congestive heart failure NYHA class IV 
4.4 
Patients with unstable arrhythmia status, already on anti-arrhythmic drugs 
5 
Severe hypertension (diastolic BP > 100 on medication) 
6 
Severe cerebrovascular disease (multiple CVA or CVA within 6 months) 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 15 of 37 
PCa003 
  
7 
History of bilateral orchiectomy, PCa-specific chemotherapy, brachytherapy, cryotherapy, 
Photodynamic therapy or radical prostatectomy for treatment of prostate cancer; any prior 
radiation therapy to the pelvis for prostate cancer or any other malignancy. 
8 
Patient under medications that can affect PSA for the last 3 months prior to MRgFUS 
treatment (Androgen Deprivation Treatment; alpha reductase inhibitors)  
9 
Patients with lesions of Gleason 7 or greater outside the planned treatment area. 
10 Individuals who are not able or willing to tolerate the required prolonged stationary supine 
position during treatment (approximately 3 hrs. sonication time) 
11 Any rectal pathology, anomaly or previous treatment, which could change acoustic 
properties of rectal wall or prevent safe probe insertion (e.g., fistula, stenosis, fibrosis, 
inflammatory bowel disease, etc). 
12 Any spinal pathology which can prevent safe administration of epidural/spinal anesthesia 
13 Identified calcification of 2 mm or more in largest diameter neighboring the rectal wall (in a 
distance of less than 5 mm) and interfering with the acoustic beam path.  
14 Lower limb musculoskeletal fixed deformities preventing probe insertion or patient 
positioning during procedure. 
15 Prostate with multiple cystic lesions. 
16 Evidence of distant prostate cancer, i.e., including lymph nodes and/or metastasis of cancer 
on imaging  
17 Bladder cancer 
18 Urethral stricture/bladder neck contracture 
19 Active UTI 
20 Prostatitis NIH categories I, II and III. 
21 Compromised renal function  
22 Implant near (<1 cm) the prostate  
23 Interest in future fertility 
24 Current participation in another clinical investigation of a medical device or a drug or has 
participated in such a study within 30 days prior to study enrollment. 
4 INVESTIGATION PLAN 
4.1  Study Design 
This is a multi-center, prospective, single arm study to evaluate MRgFUS treatment of 
intermediate risk, organ-confined prostate lesions. All subjects will be treated and then 
followed up clinically for up to 24 months to evaluate any procedure or device related 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 16 of 37 
PCa003 
  
adverse events as well as to assess efficacy endpoints of the study. Additional data related 
to quality of life of treated subjects will also be collected.  
4.2 Pre-Treatment Procedures 
1. 
Patients will be screened for eligibility for the study. Those meeting the criteria will 
be offered to participate and sign an informed consent form.  
2. 
Complete medical history, physical exam with DRE and concomitant medications 
will be obtained to determine patients’ general health status, and presence of 
symptoms. The following questionnaires will be completed by participating 
subjects:  FACT-P, ICIQ-SF, IPSS, IIEF-15, and SF-12.   
3. 
Blood tests (PSA, CBC, serum chemistries), urinalysis and CT will be performed to 
verify compliance with eligibility criteria.  
a. Urinalysis will include Specific gravity, pH, Glucose, Protein, RBC, Casts, WBC, 
Bacteria, culture, if indicated 
4. 
IMAGE-guided mapping prostate biopsy (TPBx or TRBx per Appendix C) 
followed by pathology examination and analysis will be performed to evaluate 
oncology staging of disease and subject’s eligibility for the study. 
5. 
Pre-treatment multi-parametric (1.5/3T) MRI scans (E-coil may be used) will be 
performed not less than 6 weeks after a prostate biopsy. CT will also be performed. 
6. 
Subject will have assessment for anesthesia (general and epidural) by an attending 
Anesthesiologist. 
7. 
For subjects who met all eligibility criteria and had formally agreed to participate in 
the study, ExAblate MRgFUS treatment will be scheduled. 
8. 
Treatment will be performed after a minimum of 30 days from IMAGE-guided 
prostate mapping biopsy. 
9. 
Subject will be instructed to adhere to low residue diet without milk ingredients 48 
hours pre-treatment, with no oral intake during the last 12 hours before treatment.  
On the evening prior to the procedure and on the morning of the treatment, the 
subject will undergo colon preparation (using laxatives) similar to colonoscopy 
preparation.   To avoid existence of any fecal residue in the rectum during the 
procedure, two (2) hours prior to anesthesia, a cleansing enema will be performed.  
4.3 Treatment Procedures  
On day of treatment before any procedures, patient should complete the NRS, ICIQ-SF, 
FACT-P, IPSS, IIEF-15, and SF-12 questionnaires before prepping for treatment.   
1. 
IV line will be inserted. 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 17 of 37 
PCa003 
  
2. 
The recommended anesthesia for the treatment is either epidural or general. 
Anesthesia should allow continuous pelvic muscle relaxation without any 
movement throughout the procedure. Analgesics may be administered prior to and 
during the procedure. 
3. 
Bladder drainage: The procedure requires continuous bladder drainage during 
treatment including planning and post-treatment imaging scans. A Foley catheter 
would usually be adequate for continuous bladder drainage unless the urethra is 
included in treatment area; where a suprapubic catheter will be used for urine 
drainage, per site standards. 
4. 
Prophylactic antibiotics will be administered prior to procedure, in accordance with 
local standard of care. 
5. 
The system will be prepared for the treatment according to instructions provided in 
the Operator Manual. Specifically, the endorectal balloon covering the FUS 
transducer will be prepared by partial filling it with degassed water prior to the 
patient’s arrival; lack of air bubbles in the balloon will be confirmed by the 
operator. Degassed water temperature inside the rectal balloon during its insertion 
should be not under ~34°C to avoid anal spasm while inserting the endorectal 
probe. 
6. 
At this stage subject will be inserted into the MRI-ExAblate suite.  
7. 
Subject will be placed on the treatment table in Head First, supine position with 
bent knees and slightly elevated legs on the MRgFUS treatment table.  
8. 
Vital signs (i.e., peripheral oxygen saturation, heart rate, and preferably blood 
pressure) will be monitored throughout entire procedure using MR compatible 
equipment. Other measurements for applied anesthesia will be based on the 
decision of the attending Anesthesiologist.  
9. 
Attending physician will perform a rectal examination. 
10. 
After lubricating the probe with non-viscous water-based ultrasound-transparent-gel 
and carefully filling the patient’s rectum with about 10cc of gel (using a large 
opening syringe to avoid air bubbles formation) the endorectal probe will be 
inserted through the patient’s anus while the patient is in supine position with his 
knees bent. (Screening imaging may provide some general information regarding 
expected probe’s location, based on specific anatomy).  
11. 
Once inserted and reasonably positioned, the probe will be locked to the positioner 
system. Additional water will be pumped into the balloon.  
The balloon should be inflated to achieve tight contact with the entire 
circumference of the rectal wall; thus, achieving adequate coupling and avoiding air 
bubbles to enter between the endorectal balloon and the rectal wall. 
12. 
An MRI localizer will be performed to verify positioning of the probe with relation 
to the prostate and the treatment area. If positioning corrections will be required, 
they will be done with repeated localizer imaging. 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 18 of 37 
PCa003 
  
13. 
High quality T2w images, and other MR protocols, if clinically beneficial, will be 
acquired for planning.  
14. 
T1w Axial images will be acquired in order to verify acoustic coupling between the 
rectum and the cooling balloon. 
15. 
Water temperature in the rectal cooling balloon would be set to 37°C to produce 
baseline reference for thermometry. Following acquisition of this baseline 
thermometry, ExAblate system would start circulation of cold degassed water in the 
balloon, providing sufficient protection of the rectal wall. 
16. 
Meanwhile, treating physician will draw the prostate capsule; the capsule will be 
further used for motion detection and for treatment planning by the WS. 
17. 
The treating physician will identify the focus/foci or positive sector(s) to be targeted 
on the current scan and draw the desired ROT (Region of Treatment) using MR 
images on one scan orientation (preferably, axial view), and verify the ROT(s) on 
the two other orientations (sagittal and coronal views).  In case of clearly visible 
lesion boundaries on T2w-MRI, the ROT will be drawn to include the entire focus 
with surrounding 5mm of lesion free tissue margins where applicable (lesion free 
margins will not be kept if they include the rectal wall or the sphincter, for 
example). Whenever biopsy confirmed lesion boundaries are not clearly visible on 
T2-w MRI, the physician will draw the selected sector(s) based on positive core(s) 
coordinates.  In patients with a single biopsy proven focus, when an additional 
(second) focus which, based on multi-functional MRI, is also in need of treatment 
based on multi-functional MRI is found, but has not been confirmed by biopsy, the 
investigator may treat both the biopsy proven focus and the MRI suspicious focus, 
providing total ablated volume does not exceed 15mm plus 5mm lesion free 
margins for each lesion. Overall treatment volume should be up to 50% of the 
prostate gland for prostate volume <60cc, and up to 30cc should the entire prostate 
volume be larger than 60cc. (Please note: in case an MRI suspicious focus is found 
in addition to two biopsy confirmed foci – the patient will be excluded from the 
study). 
18. 
Treating physician will also mark the following safety regions that should be spared 
(i.e., rectal wall, urethral sphincters and bladder wall; urethra and NVB’s 
preservation will be per clinical decision)  
19. 
A central location of the ROT will be sonicated using low thermal dose, generating 
sub-lethal sonication, to reconfirm targeting geometrical accuracy in the patient.  
20. 
Continuing with treatment process, acoustic energy transmission at therapeutic 
power level, accompanied with thermometry, will be performed to verify that 
thermal dose correlates well with the system’s predicted dose. Energy levels will be 
adjusted as necessary to achieve sufficient level of heating to allow tissue 
coagulation. 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 19 of 37 
PCa003 
  
21. 
Actual treatment will begin. Per each slice, planning software will compute the 
treatment plan with the bean path delineated.  Treating physician will review/edit 
the sonications and make modifications as needed. Sonications will be performed 
according to plan.  
22. 
Effect of each sonication will be measured by MR thermometry. Acoustic power 
will be adjusted throughout the treatment, to achieve temperatures between 65C 
and 85C at focal point.  
23. 
Sonications will continue until entire target volume has been treated. The goal is a 
total procedure (i.e. ablation or sonication) time of up to 180 minutes.  If the doctor 
determines the planned treatment is not possible after the first 3 therapeutic 
sonications, and another treatment session is not planned, the patient will be 
considered a screen failure and exited from the study.   The reason for early exit 
will be documented on the CRF.  The patient will be taken to recovery area for 
observation and release. The patient will undergo a 1-week follow-up visit for 
safety purposes, prior to study exit.    
24. 
After completion of the treatment, a final MR scan will be done. This scan will 
include T2 weighted and T1 contrast enhanced sequences including subtraction to 
evaluate tissue ablation.  
25. 
Transrectal device will be removed by physician and then patient will be transferred 
from the magnet/ ExAblate Suite to a recovery room for an observation period, 
according to clinical considerations.  
26. 
Treatment exports and all MR images taken during the study will be archived by the 
Sponsor.  
27. 
In the event of an incomplete treatment due to device failure, patient request, 
physician’s decision, or unforeseen circumstance, a second treatment will be 
offered to the patient, provided no medical contraindications exist.   Second 
treatment will be scheduled within 12 weeks from the original treatment.   Patient 
follow-up visits will be based on the date of the second treatment. 
28. 
Patient should complete a post-treatment NRS.     

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 20 of 37 
PCa003 
  
4.4 Follow-up  
1. 
Immediate post treatment follow-up and monitoring will start in the recovery room. 
This time period will be used to evaluate the patient’s health post-treatment, and any 
safety related issues. 
2. 
The Foley catheter will be removed at the end of the procedure and the patient will 
be re-catheterized in case of urinary retention, unless the investigator decides to keep 
the catheter for a longer period (e.g., due to known pre-existing urinary obstructive 
symptoms). In case where the urethra was included in the treatment volume, and a 
suprapubic catheter (SPC) is used, it may remain in the bladder until the patient is 
able to spontaneously urinate, with a residual post-voiding urine volume of 50 ml or 
less (per ultrasound imaging). Oral antibiotics will be administered as long as the 
SPC remains in situ.  
3. 
Antibiotics may be administered based on physician’s clinical judgment. 
Administration and cause will be captured in the CRF. 
4. 
For this study, it is recommended that patient will be released after spontaneous 
urination (in case of using a Foley catheter), or according to physician’s clinical 
decision.  When using an SPC, patients should be instructed regarding handling of 
the catheter prior to their discharge.  Catheter may be required for up to 6 weeks post-
treatment. 
5. 
Post treatment NSAID’s, analgesics or alpha blockers will be administered after 
procedure per clinical decision and will be captured in the CRF record.  
6. 
Follow up visits will be completed at 1-week, and 1, 3, 6, 9, 12, 18, and 24 months 
post-ExAblate treatment to assess adverse events and concomitant medications, as 
well as specific procedures outlined below:  
a) 
At 1 week visit patients will be evaluated for general health (physical exam), 
ICIQ-SF, and NRS, concomitant medications, and AEs.   
b) 
At the 1 month follow-up, patient will be evaluated by a physical exam with 
a DRE, concomitant medications, and AEs.  Patient will be asked to 
complete the NRS, ICIQ-SF, and IPSS questionnaires.  Proctoscopy and/or 
uroflowmetry will be performed in the presence of clinical symptoms, based 
on individual investigator judgment. 
c) 
At 3 months follow-up patients will be evaluated for physical exam with a 
DRE, concomitant medications, AEs and completion of the ICIQ-SF, FACT-
P (v4), IPSS, IIEF-15, and SF-12 questionnaires. 
d) 
At 6-month follow visit patients will be evaluated for physical exam with DRE 
and urinalysis (culture, if indicated), Multi-parametric MRI, PSA test, 
concomitant medications, adverse events, and completion of the ICIQ-SF. 
FACT-P (v4), IPSS, IIEF-15, and SF-12 questionnaires. In addition, all 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 21 of 37 
PCa003 
  
patients will undergo a mapping biopsy using the same technique as for 
screening.  
e) 
At 9-month follow-up visit, patients will be evaluated for physical exam, with 
DRE, concomitant medications, AEs and completion of the ICIQ-SF. FACT-
P (v4), IPSS, IIEF-15, and SF-12 questionnaires. 
f) 
At 12-month follow-up visit, patients will be evaluated for physical exam, with 
a DRE, PSA test, clinical labs for CBC, serum chemistries, urinalysis (with 
culture if indicated), post-void residual and uroflowmetry if medically 
indicated based upon the physician’s decision, concomitant medications, AEs; 
and completion of the ICIQ-SF. FACT-P (v4), IPSS, IIEF-15, and SF-12 
questionnaires. 
g) 
At 18-month follow-up visit, patients will be evaluated for physical exam, with 
a DRE, urinalysis (with culture, if indicated) and PSA, concomitant 
medications, and AEs and completion of the ICIQ-SF. FACT-P (v4), IPSS, 
IIEF-15, and SF-12 questionnaires. 
h) 
At 24-month follow visit, patients will be evaluated for physical exam, with a 
DRE, PSA test, clinical labs for CBC, serum chemistries, urinalysis (with 
culture if indicated); post-void residual and uroflowmetry if medically 
indicated based upon the physician’s decision, concomitant medications, AEs; 
completion of the ICIQ-SF. FACT-P (v4), IPSS, IIEF1-5, and SF-12 
questionnaires In addition, all patients will undergo a mapping biopsy using 
the same technique as used at Baseline and 6-month follow-up.  
i) 
IMAGE-guided mapping biopsy between the 6-month and the 24-month visits 
will be done if clinically indicated, based on individual investigator medical 
opinion. 
 
4.4.1 Early discontinuation of the study may occur for reasons including patient decision, 
investigator decision, Sponsor decision, decision to pursue alternative treatments for 
their tumor.   Attempts should be made to complete the final visit study procedures 
prior to exiting the study.   The reason for early discontinuation will be captured on 
the study Case Report Forms.  
 
4.4.2 Wherever possible, in cases of potential surgical resection of the gland MRgFUS-
treated patients, pathology results will be evaluated and compared to the treatment 
and post treatment data. 
5 Study Visit Schedule 
See visit schedule on next pages.

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 22 of 37 
PCa003 
  
 
 
 
PCa003 Study Schedule 
Visit 
Window 
Allowance 
Clinical Office and Lab Tests 
Imaging ** 
Questionnaires 
Screening  
 
––––– 
DRE; PSA 
IMAGE-guided TPBx or TRBx; Clinical 
labs for CBC, serum chemistries and 
urinalysis (cultures, if indicated);  
Physical Exam 
Concomitant medications 
CT, Multi-parametric MRI (E-
coil may be used) 
FACT-P (v4); 
 ICIQ-SF;  
IIEF-15 (SHIM);  
IPSS 
SF-12 
Treatment *** 
––––– 
DRE; peripheral oxygen saturation, 
heart rate, and blood pressure;  AEs 
MR for planning, treatment 
and post Tx 
Pre-Txt: NRS, FACT-P (v4); ICIQ-
SF;  IIEF-15 (SHIM); IPSS; SF-12 
 
Post-Txt - NRS 
1 week 
±3 days 
AEs;  Physical exam; Concomitant 
medications 
 
NRS; ICIQ-SF 
1 month 
± 7 days 
AEs;  Physical exam with DRE; 
Proctoscopy and/or post-void residual 
and Uroflowmetry if indicated;  
Concomitant medications 
 
ICIQ-SF;  
IPSS 
NRS 
3 months  
± 1 week 
AEs;  Physical exam; DRE; Concomitant 
médications  
 
FACT-P (v4); ICIQ-SF;  
IIEF-15 (SHIM); IPSS; SF-12; 
6 months 
± 1 month 
AEs;  Physical exam; DRE; urinalysis 
(culture, if indicated), PSA; TRBx or 
TPBx;  Concomitant medications 
Multi-parametric MRI 
FACT-P (v4); ICIQ-SF;  
IIEF-15 (SHIM); IPSS; SF-12 
9 months 
±1 month 
AEs;  Physical exam; DRE;  
Concomitant medications 
 
FACT-P (v4); ICIQ-SF;  
IIEF-15 (SHIM);  
IPSS ; SF-12 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 23 of 37 
PCa003 
  
12 months 
± 2 month 
AEs;  Physical exam; DRE; PSA 
Clinical labs for CBC, serum chemistries 
and urinalysis (cultures, if indicated); 
post-void residual and Uroflowmetry if 
indicated; 
Concomitant medications 
 
FACT-P (v4); ICIQ-SF;  
IIEF-15 (SHIM); IPSS; SF-12 
18 months 
± 2 months 
AEs;  Physical exam; DRE, urinalysis 
(Culture, if indicated); PSA 
Concomitant medications 
 
FACT-P (v4); ICIQ-SF;  
IIEF-15 (SHIM); IPSS; SF-12 
24 months 
± 2 months 
AEs;  Physical exam; DRE; PSA 
Clinical labs for CBC, serum chemistries 
and urinalysis (cultures, if indicated);  
post-void residual and Uroflowmetry if 
indicated; 
IMAGE-guided TRBx or TPBx;  
Concomitant medications 
 
FACT-P (v4); ICIQ-SF;  
IIEF-15 (SHIM); IPSS ; SF-12 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 24 of 37 
PCa003 
  
6 STATISTICAL CONSIDERATIONS 
This study will evaluate the effectiveness and safety of the ExAblate 2100 Prostate System for the 
treatment of patients with intermediate-risk, localized prostate lesions.  All patients will be 
consented and followed as it would be defined by 510k submission/approval requirements.  Data 
will be analyzed for efficacy based on data collected per FDA agreement for a 510(k) commercial 
clearance as previously discussed with FDA.  Patients will continue to be followed post treatment 
for long-term outcomes. 
6.1 Sample Size 
The current IDE has had 4 amendments to date. The 4th Amendment aim was to define 
the patient population that will be part of the 510K submission (IDE G100108/S011). To 
ensure a cohesive patient population for the 510K FDA review, only those patients 
treated after site IRB approval of Amendment 4 will be counted toward the primary 
analysis population. Other safety and efficacy analyses that include data from subjects 
enrolled prior to the approval of G100108/S011 may be reported as supplementary 
information. 
 
To date (Sept-20-2018), 81 patients have been treated under protocol Amendment-4.  
Based on our accumulated experience when conducting studies for a new indication, there 
is a great level of experience and knowledge acquired from a study in which many sites 
participate in the study.  This has proven to be critical in the design and conduct of Pivotal 
studies.  The need for at least 15 sites in the proposed study is further supported by the 
discussion of the FDA panel meeting discussing prostate focal therapy, and also by the 
Pivotal study that is running for the Sonablate 500 ultrasound HIFU device for a 
population that is similar to the proposed study. 
6.2 Data Analysis 
6.2.1 510(k) Analysis 
This is a clinical study involving a minimum of 100 to a maximum of 103 subjects. Descriptive 
analyses of safety and effectiveness data will be used to summarize results for a 510(k) submission 
for commercial clearance.  Safety and effectiveness data will address both results of biopsy as well 
as functional analysis.  
Primary effectiveness analyses will be based on the 6-month biopsy results. Proportions of treated 
patients reporting a negative biopsy and/or MRI verification of index lesion ablation at 6-months.         
Descriptive summaries will be presented for: PSA testing, NRS, FACT-P (v4), IPSS, and SF-12 
questionnaires and percentage of non-perfused volume (NPV). 
Baseline assessment of erectile dysfunction and incontinence will be captured as per the 
incontinence/ED questionnaires and they will be followed also using the same questionnaires. Any 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 25 of 37 
PCa003 
  
worsening of the baseline condition to a worsened CTCAE grade will be captured as an adverse 
event and will be graded on CTCAE Version 4.0 published May 28, 2009 (v.4.03:June 14, 2010) 
and will be reviewed by the Data Safety Monitoring Board. 
6.2.2 Final Analysis 
Final safety and effectiveness analyses will be presented to the FDA per 510K submission 
requirements. 
7 RISK ANALYSIS 
Worldwide, over 5000 treatments have been performed to date with the MR guided FUS ExAblate 
2000 device.  Risk analysis for InSightec ExAblate systems/clinical investigations has been 
conducted as part of previously approved FDA IDE submissions (G930140, G990151, G990184, 
G990201, G000203, G010225, G020001, G020182, G050177, and G060023, G070022, G080009, 
G080206, G100127, G100169, G120017, G120246, G140018, G140082, P040003 and subsequent 
supplements, P110039, and P150038).  This data has been re-examined by the study sponsor and 
it has been concluded that this risk analysis is applicable to the proposed clinical investigation.  
The key consideration here is the fact that this proposed study has the same purpose as the previous 
ones, namely to coagulate soft tissue within the body by means of ExAblate.  The original risks 
and additional risks, new and unique to this study are discussed below. 
Potential risks described below will be explained to subject in the informed consent process. 
7.1 Potential risks  
7.1.1 Risk of Transperineal Mapping Biopsy 
Transperineal biopsy is associated with7,8: 
• ~10% risk of urinary retention after biopsy in patients with large prostates (>60 mL)  
• 20-42% of hematuria 
• 13-50% of hematospermia 
• 31% of pain (18% requiring analgesia after procedure) 
• 6:1000 -1.2% risk for sepsis 
                                                 
7 Webb JA, Shanmuganthan K, McLean A. Complications of ultrasound guided transperineal biopsy. A prospective 
study. Br J Urol. 1993; 72: 775-7 
8 Miller J, Perumalla C, Heap G. Complications of transrectal versus transperineal prostate biopsy. ANZ J Surg. 
2005; 75:48-50. 
 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 26 of 37 
PCa003 
  
7.1.2 Risk related with Transrectal Mapping Biopsy 
Transperineal biopsy is associated with 
• Urinary retention requiring catheterization for bladder drainage is seen in ~1% 
• Discomfort and pain in the rectal area  in > 80% of the patients 
• Hematuria occurs in about 66% of the patients and may persist for 3-7 days in about 
50% of the patients 
• Hematospermia is reported in about 1-2% of the patients 
• Rectal bleeding occurs roughly in 9%-27% of the patients 
• Infection (most frequently – UTI) requiring hospitalization occurs in about 0.7% of the 
patients undergoing prostate biopsy 
7.1.3 Risk of MR Imaging 
• Study subject may find MR unit claustrophobic and request to leave the study despite 
pre-procedure sedation. 
• MRI has no known deleterious biological effects in patients with no contraindications.  
The incidence of claustrophobia during MRI examinations is approximately 10-15%, 
although it is expected to be less frequent in the study population due to the use of 
sedation. 
• Gadolinium DTPA (Magnevist/Omniscan) is an intravenously injectable contrast 
medium for MRI. The package insert notes that there are no known contraindications.  
Precautions should be exercised for patients with a history of grand mal seizures, 
severely impaired renal function or hemolytic anemia.  The very unlikely possibility of 
a reaction, including anaphylactic or cardiovascular reactions, should be considered 
especially for patients with a known sensitivity to Gd or history of asthma.  Adverse 
reactions include: headache (incidence 8.7%), localized pain, vomiting, paresthesia, and 
dizziness and localized warmth (incidence less than 2%).  Additional adverse effects 
listed on the package insert occur with an incidence of less than 1%. 
• Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy (NFD), 
kidney disorders, may occur in patients with moderate to end-stage kidney disease after 
they have had a MRI scan with gadolinium-based contrast agent.  NSF causes fibrosis 
of the skin and connective tissues throughout the body. Patients develop skin thickening 
that may prevent bending and extending joints, resulting in decreased mobility of joints.  
NSF usually starts in the lower extremities. Fibrosis can also develop in the diaphragm, 
muscles in the thigh and lower abdomen, and lung vessels.   
7.1.4 Risks related to the use of a urinary catheter:  
• Local discomfort and/or pain that might last up 1 or 2 days after catheter removal 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 27 of 37 
PCa003 
  
• Partial or complete urinary retention is expected in all patients for the first post-
treatment 48 hours. It may last however longer or occur after successful voiding 
(in 1-9% of the patients).  
• Urinary retention requiring surgical intervention may occur in 2% of the cases. 
Occurrence, severity, duration and management will be recorded in the CRF and 
AE form 
• Urethral stricture requiring intermittent sound dilatation or bladder neck stricture 
requiring bladder neck incision is reported in 1-25%. (Usually rates are less with 
SPC than with Foley catheter.) The use of SPC and the ability to plan around 
structures, such as the bladder wall by using the editor function of the software 
(LEDR) expected to reduce the risk of bladder neck injury. 
• Dysuria – immediate dysuria due to prostatic urethral sloughing occurs in all 
patients for a week following treatment, but dysuria may last even 6 weeks. 
Dysuria may be associated with urinary tract infection. Measurement will be by 
NRS score during post-treatment visits; duration and treatment will be recorded in 
the CRF.  
• Perineal edema may occur in some patients and this usually resolves spontaneously 
and completely within 7 days. 
• Urinary tract infection (UTI) is frequent (reported in 5-48%) due to the prolonged 
catheterization and non-sterile handling. Patients and their supporting family 
members will be instructed to handle the catheter adequately, and patients will be 
under oral antibiotics until catheter extraction, but it should be expected that even 
then symptomatic UTI will occur. Occurrence of symptomatic UTI, symptoms, 
severity, duration and management will be recorded in the CRF and AE form. 
• Occasionally, infection persists and leads to such complications as prostatitis, 
epididymitis, cystitis, pyelonephritis.9 Prostatitis  (reported in less than 2%)  and/or 
epididymo-orchitis (manifested as pain, swelling and tenderness in the scrotum) is 
reported in 5-7.5% of the patients who were fitted with a SPC (as opposed to 8.5% 
in patients with urethral catheter. occurrence, duration and treatment will be 
recorded in the CRF and AE form. 
 
7.1.5 Risks Related to Anesthesia 
7.1.5.1 Epidural anesthesia may involve the following risks:  
• Low blood pressure, which is the reason the patient is routinely hydrated prior to the 
placement of either of these forms of anesthesia.  
                                                 
9 Kunin CM. Detection, prevention, and management of urinary tract infections. 3rd ed. Philadelphia: Lea and Febiger, 
1979. 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 28 of 37 
PCa003 
  
• Postdural puncture headache occurs infrequently with these techniques. The risk is 1% 
with Epidural. This is believed to be due to a leak of Cerebrospinal fluid from the 
needle hole in the dura.  
• Backache is an infrequent problem. It most likely is due to ligament strain due to 
profound muscle relaxation or surgical positioning.  
• Other complications that can occur include, but are not limited to, infection, nerve 
damage (including paralysis, loss of bladder and bowel function, loss of sexual 
function), allergic reactions, seizures, cardiac arrest and death. Although the result of 
these is severe they occur very rarely. 
7.1.5.2 General anesthesia may involve the following risks: 
• Serious side effects of general anesthesia (GA) are uncommon in people who are 
relatively healthy when conducted by a certified Anesthesiologist with required 
resuscitation skills (as required in this study). 
 
Estimated death rate 1:2,000,000-250,000 cases; and overall complication rate is 
<3%   
• Aspiration - GA suppresses the normal throat reflexes that prevent aspiration, such 
as swallowing, coughing, or gagging. To help prevent aspiration, an endotracheal 
(ET) tube is inserted during general anesthesia. When an ET tube is in place, the 
lungs are protected so stomach contents cannot enter the lungs. Aspiration during 
anesthesia and surgery is very uncommon. To reduce this risk, patients are instructed 
not to eat or drink anything for 12 hours before anesthesia so that the stomach is 
empty, per local site standards.  
• Changes in blood pressure or heart rate or rhythm 
• Cardiac event, or stroke 
• Damage to teeth and lips 
• Swelling in the larynx  
• Sore throat and/or hoarseness caused by injury or irritation of the larynx.  
• Allergic reactions to medications are rare – potential allergies will be evaluated by 
the anesthetist before anesthesia. 
• Nausea and vomiting after anesthesia – occur in less than 10% of the patients 
 
7.1.6 Risks incidental to the treatment 
• There is a potential risk to the patient of deep venous thrombosis from lying stationary 
for 3 to 4 hours. The risk to the patient from lying still for this treatment should be 
no greater that of lying still for any other reason.  For treatments under this protocol, 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 29 of 37 
PCa003 
  
it will be the surgeon discretion to provide patients with compression stockings or 
wraps for the period of the treatment.   
• There is a risk that the patient may experience a sore neck or discomfort from lying 
in the same position for a long time during the treatment. 
7.1.7 Risks associated with the ExAblate MRgFUS treatment and/or biopsy mapping 
• While the goal of the ExAblate treatment is to completely ablate the prostate tissue 
lesion(s), there is a risk that abnormal tissue may still exist for varying reasons 
including failed biopsy detection at screening and/or incomplete ablation of the entire 
lesion. 
• Pain or discomfort requiring oral analgesia is expected to occur in almost all patients 
after treatment.  
• Severe pain in the treatment areas (pelvis, rectum or scrotum area) for which patients 
return to the physician/hospital is reported in 1.4-3% of the treatments. Pain 
symptoms will be specified for location and recorded in the CRFs for occurrence and 
duration; severity will be measured by NRS score during post-treatment follow-up. 
• Incontinence rates following resolution of immediate dysuria are <2%. In patients 
undergoing primary HIFU treatment. In the treatment performed with the ExAblate 
MRgFUS device, the urethral sphincters are preserved by marking them as LEDR’s, 
thus avoiding therapeutic dose accumulation at these structures. The ability to 
customize the energy to the specific case and the real-time monitoring and control of 
the applied energy, associated with the MRI which provides high resolution 
visualization of the anatomical structures, significantly reduces the risk of urinary 
sphincters injury.  Thus, we expect even lower rates of incontinence after ExAblate 
treatments. 
• Erectile dysfunction in previously potent men is reported to range between 40 and 
50% in ultrasound-guided HIFU treatments. In ExAblate MRgFUS treatments, the 
NVB’s are clearly visualized and can be protected if needed by marking them as 
LEDR’s. We expect therefore, that in potent patients that have no evidence for cancer 
adjacent to the NVB’s – post-treatment impotence rate will not exceed 10%. 
• Retrograde ejaculation - since the treatment includes the orifices of the seminal 
vesicles in the urethra, retrograde ejaculation may be permanent in 3% of the patients; 
occurrence, duration and treatment will be recorded in the CRF’s. 
• Perineal hematoma development as a result of treatment is very low. The probe is 
inserted, manipulated extracted by authorized experienced Urologists. No sharp 
edges are in contact with the rectum At the end of the ExAblate procedure, a contrast 
(Gadolinium) enhanced MR imaging is performed to assess the blood flow within the 
treated area and neighboring tissue.  
• Unintended ablation of vulnerable structures outside the planned treatment volume 
due to improper targeting of the focal point At the start of treatment, the system 
includes a mandatory step that requires the operator to first check the alignment of 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 30 of 37 
PCa003 
  
the patient anatomy, the focal point of the transducer and the MR imaging system in 
all three axes.  This procedure is done while the patient is in position for treatment. 
Then the operator has to mark the prostate capsule (to detect potential movements of 
the organ during the treatment), the desired treatment boundaries and the structures 
that should be preserved (i.e., rectum, sphincters, bladder wall, urethra, NVB). For 
each sonication delivered during treatment, the operator gets continuous feedback on 
the position of the treatment point superimposed on the anatomical image and can 
make geometrical and dose corrections where required. The system also includes an 
independent safety-monitoring loop that continuously compares the physical position 
of the transducer for any un-commanded motion in the system from any source.  If 
such a move is detected, the system immediately stops the delivery of energy to the 
patient, and notifies the operator of the error. The rectal wall is especially protected 
by cooling the degassed water inside the balloon to 14°C.  
• The protocol results in the necrosed tissue being left in situ to be naturally removed 
by the body. There is a potential risk to the patient from a reaction to the volume of 
treated tissue (fever or infection).  This effect has been often observed in other 
technologies of tissue ablation such as Cryo-therapy or Radiofrequency ablation of 
other lesions but rarely seen in ExAblate MRgFUS ablation. Furthermore, since the 
treatment in this protocol is a focal treatment that will never exceed 35 cc this concern 
practically almost does not exist. Overall treatment volume should be up to 50% of 
the prostate gland for prostate volume <60cc, and up to 30cc should the entire prostate 
volume be larger than 60cc. 
• A risk of damage to the rectal wall from either targeting a prostate area that is too 
close to the rectal wall or from problems in acoustic coupling between the balloon 
and the rectal wall or from unexpected high acoustic absorption at the rectal wall. 
Fistulae were reported in about 0.5% of the Ultrasound-guided HIFU patients. The 
system includes water cooling of the interface, planning aimed to protect the rectal 
wall; automatic warning to the user if an edited spot is too close to the rectal wall, 
and use of acoustic gel as a coupler between the balloon and the rectum.  Based on 
animal trials and few initial feasibility studies, the rectal wall is adequately protected 
from thermal injury. 
• There is a risk of patient motion during a sonication, or between sonications.  This 
could cause a movement of the tumor relative to the planned treatment volume on the 
system, and in extreme cases could result in the treatment of a point outside the 
planned treatment volume. Motion tracking is being done by the operator using 
fiducials placed on the anatomic images and by integrated 3D tracker inside the 
transducer. The use of epidural anesthesia with muscle relaxants.  
• There is a risk of damage to the anal sphincter from the insertion, extraction or 
repositioning of the rectal probe. To reduce this risk the probe would be inserted by 
a trained physician and with care, after pelvic muscle relaxation by epidural 
anesthesia. 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 31 of 37 
PCa003 
  
• There may be a risk of damage to the bladder from targeting a prostate area that is 
too close to the bladder. To mitigate this risk, the treating physician may utilize the 
system treatment tools as part of treatment planning to delineate the bladder area in 
question so that no “sonication” is allowed when they are close to the bladder. In any 
event, should a bladder injury event occur, cystoscopy may potentially be used to 
evaluate injury. 
• Nerve damage, or loss of sensation in the area other than the treatment area. 
• Risk of mechanical damage to the rectal wall by the insertion, extraction or 
repositioning of the transducer. To reduce this risk the probe would be inserted by a 
trained physician and with care. 
• Hematuria – occurrence, duration and treatment will be recorded in the CRF and AE 
form 
• Proteinuria – measurement will be by urine values; occurrence and duration will be 
recorded in the CRFs 
• Hematospermia – occurrence, duration and treatment will be recorded in the CRF 
and AE form 
7.1.7.1 Other Treatment Related Risks  
• Deep Vein Thrombosis (DVT) - lying stationary for 3 to 4 hours, increases risk for 
DVT. The risk to the patient from lying still for this treatment should be no greater 
than that of lying still for any other reason.  For treatments under this protocol, it 
will be the surgeon discretion to provide patients with compression stockings or 
wraps for the period of the treatment.   
• Minor bruises redness and pain at the site of the intravenous catheter insertion – is 
common and usually subsides spontaneously within a few days. 
• Phlebitis (local hardening of the vein) or infection from the intravenous catheter 
may occur in ~5% of the patients. 
7.1.8 Anticipated MRgFUS Treatment Side Effects   
Based on previous treatment experience, the above listed side effects have been identified as 
possible treatment-related complications of ExAblate treatment and procedure.  These can 
be classified into Non-significant and Significant Anticipated Treatment Side Effects based 
on their medical severity, additional treatment required and long term consequences for the 
patient.  All Treatment Side Effects will be reported in the Case Report Forms for the study 
and included in the final study analysis. 
Non-significant Anticipated Treatment Side Effects of ExAblate treatments are those, which 
normally resolve without sequelae within 10-14 days of the treatment. 
Significant Anticipated Treatment Side Effects of ExAblate are those which may require 
medical treatment, may have sequelae, and for which time of resolution is not defined.  The 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 32 of 37 
PCa003 
  
rate of anticipated significant treatment side effects of the ExAblate treatment is unknown, 
but expected to be infrequent based on prior clinical experience in other organs. 
7.2 Adverse Effects and Precautions 
The subjects will be counseled concerning what to expect during the procedure and the importance 
of communicating any problems to the investigator. All device and procedure-related AEs 
occurring in this study will be recorded in the Case Report Forms.  Each AE will be assessed for 
its probable cause (unrelated to the treatment, device related, procedure related, etc).  
7.3 Criteria for Removal from the Study 
Early discontinuation from the study may occur for reasons including patient decision, investigator 
decision, Sponsor decision, protocol compliance and decision to pursue alternative treatments for 
their tumor.  Attempts should be made to complete the final visit study procedures prior to exiting 
the study.  The reason for early discontinuation will be captured on the study Case Report Forms.  
7.4 Adverse Event Reporting 
It is the responsibility of the investigator to document all treatment-related and device-related 
Adverse Events (AE’s), which occur during the course of the study.  At each visit, the investigator 
will evaluate AE’s. AE’s not previously documented in the study will be recorded on the Adverse 
Event Log within the subject’s CRF. The nature of each event, date and time (when appropriate) 
of onset, outcome, frequency, maximum intensity, action taken, and attribution will be recorded. 
AEs already documented in the CRF (i.e., at a previous assessment) and designated as ‘ongoing’, 
should be reviewed at subsequent visits as necessary. If these have resolved, the documentation in 
the CRF should be completed including an end date for the event. If an AE increases in frequency 
or severity during a study period, a new record of the event will be started. 
Standard Code of Federal Regulation (CFR) definitions for Serious Adverse Events (SAEs) will 
be used for evaluation of adverse events.   
SAE [§803.3(aa)(1)] is an injury or illness that:  
• causes death 
• is life threatening, even if temporary in nature;  
• results in permanent impairment of a body function or permanent damage to a body 
structure; or  
• necessitates medical or surgical intervention to preclude permanent impairment of a body 
function or permanent damage to a body structure. 
All AEs (related or unrelated) meeting the criteria for an SAE require notification of the sponsor 
and the reviewing IRB as soon as possible, with subsequent completion of additional paperwork 
provided by the sponsor fully documenting the course of the event, all treatments, and final 
outcome.  Initial reporting of an SAE should be made to the sponsor no later than two (2) working 
days after the PI learns of the incident.  

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 33 of 37 
PCa003 
  
Standard Code of Federal Regulation (CFR) definitions for Unanticipated Adverse Device 
Effects (UADEs) will be used for evaluation of this type of adverse event. 
UADE [§812.3(s)] means any serious adverse event on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. 
Any UADEs will be reported to the Sponsor and to the reviewing IRB as soon as possible. 
However, in no event must this report be made later than two (2) working days after the PI learns 
of the incident.  
Other common non-study or non-device related, minor health complaints will not be collected as 
AE’s (for example: colds, sprains, headaches).  Patients who have a progression of their primary 
disease or symptoms that lead to an alternative treatment will not be reported as an AE.  
7.5 Adverse Events Analysis – Data Safety Monitoring Board  
Data safety monitoring will review all AE’s that occur throughout the study and determine if 
they are in fact related to the ExAblate, or some other cause.  
- Was the adverse event serious? 
Life-threatening, caused a disability, required or prolonged hospitalization, caused death. 
- Was the adverse event device related? 
- Was the adverse event unexpected? 
- Is there an unreasonable risk in continuing the trial? 
If in fact it is determined that an ExAblate-treated patient experienced an AE that met all of the 
above criteria, we would stop the trial pending further investigation.  If deemed appropriate, the 
protocol would be amended and submitted to FDA for approval to assure patient safety.  Any such 
amendment would be reported to the IRB and other regulatory body, as required by local applicable 
regulations. 
All adverse events will be assessed for their relationship to the study device or procedure.  Standard 
Code of Federal Regulation (CFR) definitions for SAEs and UADEs will be used in assessment of 
adverse events.  
7.6 Monitoring Plan  
Clinical Monitoring for this study will be managed by InSightec. The Clinical Monitor is qualified 
by training and experience to oversee the conduct of this study. The Clinical Monitor’s 
responsibilities include maintaining regular contact with each investigational site through 
telephone contact and on-site visits, to ensure that:  
• The trial is conducted according to FDA and local IRB requirements  

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 34 of 37 
PCa003 
  
• The Investigational Plan is followed  
• Complete, timely, and accurate data are submitted  
• Problems with inconsistent or incomplete data are addressed; 
• Complications and unanticipated adverse effects are reported to the Sponsor and the IRB  
• The site facilities will be monitored to stay adequate to meet the requirements of the study.  
 
 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 35 of 37 
PCa003 
  
The Clinical Monitor will initiate the Study during an on-site visit and will continue to perform 
on-site monitoring visits as frequently as deemed necessary. The first monitoring visit will usually 
be made as soon as possible after enrollment has been initiated. At this visit and all monitoring 
visits, the Clinical Monitor will compare the data entered onto the CRFs with the hospital or 
clinical records (source documents). Source documentation must be available to substantiate 
proper informed consent procedures, adherence to protocol procedures, adequate reporting and 
follow-up of AEs, and device procedure information. Findings from the review of CRFs and source 
documents during a monitoring visit will be discussed with the PI. Completed paper or electronic 
CRFs will be reviewed prior to data closure at each visit. The dates of the monitoring visits will 
be recorded in a Log to be kept at the clinical site. During monitoring visits, the Sponsor expects 
that the study coordinator and the PI will be available, the source documentation will be available, 
and a suitable environment will be provided for review of Study related documents.   
Sites should make every effort to contact all subjects for study follow-up to encourage visit 
compliance.  Sites should keep a log of dates of attempted contact and results. After 3 unsuccessful 
attempts at contact (e.g., by telephone or email) and sending 1 certified letter to solicit their visit 
compliance a subject may be considered lost to follow-up.    
Monitoring procedures will follow the Sponsor SOPs. 
7.7 Electronic Data Capture (EDC) 
Electronic CRFs (eCRFs) will be to capture protocol-specific information during the conduct of 
this study. This electronic data capture of the eCRFs is based on Oracle Software system, and is 
designed, run and hosted by the Sponsor (Haifa, Israel).   
7.8 Investigator Responsibilities 
Principal investigator will be required to sign an Investigator Agreement that defines their 
responsibilities. 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 36 of 37 
PCa003 
  
8 REFERENCES 
1. Cline, H. E. et al. (1995). “Focused US system for MR imaging-guided tumor ablation.” 
Radiology 194: 731-737 
2. Lewa, C. J. and Z. Majewska (1990). “Temperature relationships of proton spin-lattice 
relaxation time T1 in biological tissues.” Bulletin of Cancer (Paris) 67: 525-532. 
3. MRI Guidance of Focused Ultrasound Therapy of Uterine Fibroids: Early Results Jonathan 
Hindley1, et al.. AJR 2004; 183:1713-1719 
4. Feasibility of magnetic resonance imaging-guided focused ultrasound surgery as an adjunct to 
tamoxifen therapy in high-risk surgical patients with breast carcinoma, Gianfelice D. et al., J 
Vasc Interv Radiology 2003 Oct;14(10):1275 
5.  DeVita V.T. Jr., Hellman S., Rosenberg S.A. Cancer. Principles & Practice of Oncology. 7th 
Edition. Lippincott Williams & Wilkins 2001. Section 4, Chapter 64: 2883-2890. 
6. High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year 
experience, Balana A. et al., Urology 2004 Feb;63(2):297-300. 
7. High-intensity focused ultrasound and localized prostate cancer: efficacy results from the 
European multicentric study, Thuroff S. et al., J Endourol. 2003 Oct;17(8):673-7. 
8. Madersbacher, S., M. Pedevilla, et al. (1995). “Effect of high-intensity focused ultrasound on 
human prostate cancer in vivo.” Cancer Res 55(15): 3346-51. 
9. Gelet, A., J. Y. Chapelon, et al. (2000). “Transrectal high-intensity focused ultrasound: 
minimally invasive therapy of localized prostate cancer.” J Endourol 14(6): 519-28. 
10. Uchida, T., N. T. Sanghvi, et al. (2002). “Transrectal high-intensity focused ultrasound for 
treatment of patients with stage T1b-2n0m0 localized prostate cancer: a preliminary report.” 
Urology 59(3): 394-8; discussion 398-9. 
11. An analysis of men with clinically localized prostate cancer who deferred definitive 
treatment, Manish I. Patel et al., Journal of Urology, Vol. 171, 1520-1524, April 2004. 
12. Feasibility study: watchful waiting for localized low to intermediate grade prostate 
carcinoma with selective delayed intervention based on PSA, histological and/or clinical 
progression, Richard Choo et al., Journal of Urology, Vol. 167, 1664-1669, April 2002 
13. Expectant management of nonpalpable prostate cancer with curative intent: preliminary 
results, H. Ballentine Carter et al., the journal of Urology, Vol. 167, 1231-1234, March 2002 
14. Active Surveillance for Favorable Risk Prostate Cancer, Laurence Klotz, MD, FRCSC, J Natl 
Compr Canc Netw.  2007;5(7):693-698.  ©2007 Journal of the National Comprehensive 
Cancer Network. 
15. Will focal therapy become a standard of care for men with localized prostate cancer?, 
Hashim Uddin Ahmed*, Doug Pendse, Rowland Illing, Clare Allen, Jan HP van der Meulen 
and Mark Emberton, Nature Clinical Practice Oncology, November 2007  
 

 
 
                                            InSightec  
Focal MR-Guided Focused Ultrasound Surgery  
of Intermediate risk, Localized Prostate Lesions 
Page 37 of 37 
PCa003 
  
9 APPENDICES 
 
Appendix A:  Sample Informed Consent  
Appendix B:  Training Manual 
Appendix C: Examples of 14 core:  Mapping TransPerineal and Trans Rectal Biopsy 
Procedure