A Phase IV Post Approval Clinical Study of ExAblate Treatment of Metastatic Bone Tumors for the Palliation of Pain
Phase: NA
Conditions: Bone Metastasis
Sponsor: InSightec

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Clinical Protocol 
 
Version Date 
June 25, 2013 
Amendment No. 
A1 
Protocol Number 
BM-018 – NCT01833806 
PMA Number 
P110039/S2 
Protocol Title 
A Phase IV Post Approval Clinical Study of ExAblate Treatment 
of Metastatic Bone Tumors for the Palliation of Pain  
 
Approvals: 
Site 
Sponsor 
 
 ______________________________________  
Principal Investigator                                    Date 
Signature 
 
 ______________________________________  
Principal Investigator                                    Date 
Signature 
 
 
 
 
 Nadir Alikacem, PhD                  Date   
VP Global Regulatory Affairs 
InSightec 
 
 
 

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A Phase IV Post Approval Clinical Study of ExAblate Treatment of Metastatic Bone 
Tumors for the Palliation of Pain 
 
The goal of this study is to comply with FDA request to conduct a study to assess the 
device treatment under actual conditions of use part of PMA approval plan.   
 
The Indications for Use claim for this system is – per approved commercial labeling   
Palliation of Pain Associated with Metastatic Lesions in Bone for radiation 
failure patient who have received radiation without adequate relief from 
metastatic bone pain as determined by the patient and treating physician, for 
whom their treating physician would not prescribe radiation or additional 
radiation treatments, and those patients who refuse additional radiation therapy.   
 
 
Protocol Number: 
BM-018 
Date: 
June 25, 2013 
 
 
InSightec 
4851 LBJ Freeway 
Suite 400 
Dallas, Texas 

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Table Of Content 
1 
BACKGROUND and SIGNIFICANCE ..................................................................5 
1.1 
ExAblate delivery of MR guided Focused Ultrasound (MRgFUS) [1] ................... 5 
1.2 
Metastatic Bone Tumors .......................................................................................... 5 
1.3 
The ExAblate System ............................................................................................... 6 
1.4 
Clinical Experience with ExAblate .......................................................................... 7 
Uterine Fibroids (UF) – FDA Approved Indication........................................................................... 7 
Malignant and Benign Breast Studies – Investigational ..................................................................... 8 
ExAblate Transcranial Brain Studies – Investigational ...................................................................... 8 
Bone Feasibility Study IDE# G050177 ............................................................................................. 9 
2 
OBJECTIVES ....................................................................................................... 10 
2.1 
Background ............................................................................................................ 10 
2.2 
Safety ...................................................................................................................... 10 
2.3 
Effectiveness ........................................................................................................... 10 
Efficacy Assessments .................................................................................................................... 11 
2.4 
Study End Points .................................................................................................... 12 
Safety ............................................................................................................................................ 12 
Efficacy ......................................................................................................................................... 12 
Secondary Endpoints ..................................................................................................................... 12 
2.5 
Case Report Form Data ......................................................................................... 13 
3 
DESCRIPTION OF PATIENT POPULATION ................................................... 13 
3.1 
Patient Selection ..................................................................................................... 13 
3.2 
Subject Enrollment ................................................................................................ 13 
Inclusion Criteria ........................................................................................................................... 14 
Exclusion Criteria .......................................................................................................................... 16 
4 
INVESTIGATION PLAN ..................................................................................... 18 
4.1 
Study Design ........................................................................................................... 18 
Study Optimization Protocol: ......................................................................................................... 18 
4.2 
Pre-Treatment Procedures ..................................................................................... 20 
Pre-Treatment Procedure ............................................................................................................... 20 
4.3 
Treatment Procedures............................................................................................ 20 
4.4 
Follow-up ................................................................................................................ 23 
4.5 
Study Requirements and Visit Schedule ................................................................ 24 
5 
STATISTICAL ANALYSIS PLAN........................................................................ 25 
Safety ............................................................................................................................................ 26 
Efficacy ......................................................................................................................................... 26 
Secondary Endpoints ..................................................................................................................... 26 

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5.2 
Statistical Considerations and Sample Size ........................................................... 26 
Subject Confidentiality ....................................................................................................... 27 
5.3 
Missing Data ........................................................................................................... 27 
5.4 
Study Timeline ....................................................................................................... 27 
6 
RISK ANALYSIS .................................................................................................. 29 
6.1 
Potential risks – (ExAblate): .................................................................................. 29 
Risks associated with the ExAblate treatment ................................................................................. 30 
Risks associated with pathological fractures ................................................................................... 32 
6.2 
Anticipated Treatment Side Effects From ExAblate ............................................ 32 
6.3 
Adverse Effects and Precautions ........................................................................... 34 
6.4 
Criteria for Removal from the Study .................................................................... 34 
6.5 
Adverse Event Reporting ....................................................................................... 34 
7 
MONITORING PLAN .......................................................................................... 35 
7.1 
Electronic Data Capture (EDC) ............................................................................. 36 
7.2 
Investigator Responsibilities .................................................................................. 36 
7.3 
Definitions............................................................................................................... 36 
7.4 
Assessment of Fracture Risk .................................................................................. 37 
8 
APPENDICES ...................................................................................................... 38 
9 
REFERENCES ..................................................................................................... 39 
 

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1 BACKGROUND and SIGNIFICANCE  
1.1 
ExAblate delivery of MR guided Focused Ultrasound (MRgFUS) [1] 
MRgFUS is an attractive modality for non-invasive thermal ablation of soft tissue tumors 
[2-6].  Treatment begins by acquiring a series of MR images of the target organ. The 
physician then reviews the images on the ExAblate system workstation, identifies a target 
volume on the MR images, delineates the treatment contours on the images, and reviews 
the treatment plan. Therapy planning software calculates the parameters required to 
effectively treat the defined region. During the treatment, an ultrasound transducer 
generates a point of focused ultrasound energy, called a sonication (See Appendix-A for 
Glossary of Terms). The sonication raises the tissue temperature within a well-defined 
region, causing a thermal coagulation effect. MR images acquired during sonication 
provide a quantitative, real-time temperature map of the entire field-of-view around the 
target area to confirm the location of the sonication and the size of the coagulated region. 
The sonication process is repeated at multiple adjacent points to cover the entire 
prescribed treatment volume. 
1.2 
Metastatic Bone Tumors 
Bone is the third most common organ involved by metastatic disease behind lung and 
liver [7]. Breast and prostate cancer metastasize to bone most frequently, which reflects 
the high incidence of both these tumors, as well as their prolonged clinical courses.     
The increasing longevity of the population coupled with better therapeutic management 
of cancer patients contributes to the high incidence and prevalence of metastatic bone 
lesions.  Pain from bone metastases is the most common cause of cancer pain and as 
more patients are living with bone metastases, improving their quality of life becomes a 
major challenge.  In patients who die from breast, prostate, and lung cancer, autopsy 
studies have shown that up to 85% have evidence of bone metastases at the time of death 
[7-9].   
Current treatments for patients with bone metastases or multiple myeloma bone lesions 
are primarily palliative and include localized therapies [10], systemic therapies 
(chemotherapy, hormonal therapy, radiopharmaceutical, and bisphosphanates), and 
analgesics (opioids and non-steroidal anti-inflammatory drugs).  Recently, 
radiofrequency ablation has been tested as a treatment option for bone metastases [11].  
The main goals of these treatments are improvement of quality of life and functional 
level.  These goals can be further described:  
 
Pain relief 

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Preservation and restoration of function 
 
Local tumor control 
 
Skeletal stabilization  
Treatment with external beam radiation therapy (EBRT) is the standard of care for 
patients with localized bone pain, and results in the palliation of pain in the majority of 
these patients. More than 66% of patients with a limited number of well-localized bony 
metastases can be treated effectively by external-beam irradiation.  However, 
approximately 30% of patients treated with radiation therapy do not experience pain 
relief [8, 12-16].  Furthermore, there is an increased risk of pathologic fracture in the 
peri-irradiation period due to an induced hyperemic response at the periphery of the 
tumor. This weakens the adjacent bone and increases the risk of spontaneous fracture.  
Adding to this, patients who have recurrent pain at a site previously irradiated may not be 
eligible for further radiation therapy secondary to limitations in normal tissue tolerance. 
The speed of response to radiation therapy varies; most symptomatic bony metastases 
begin to respond over the course of 10 to 14 days, 70% of patients experience some pain 
relief within 2 weeks of starting therapy and, within 3 months 90% of the responding 
patients achieve pain relief.  
Patients, who had EBRT and failed to improve, may need to seek other therapies such as 
radio frequency ablation, surgical resection, etc., which are less efficient and have higher 
treatment related morbidity.  Because the ExAblate system is designed to non-invasively 
ablate tissue, ExAblate may meet the need of these EBRT failed patients.  The ExAblate 
system has the potential to achieve the first three of the four above mentioned goals, as 
well as changing the treatment limits and resulting morbidity in accordance with the 
above-mentioned goals [17]. The palliative effect of ExAblate is achieved by heating the 
bone periosteum, thus ablating the sensory origin of the pain and has the potential to 
achieve some tumor control.  
Based on the FDA approved phase-1 initial study (IDE # G050177 ) results and the 
results of the study that was performed outside the United States that the sponsor has 
done, palliation effects are significant in terms of mean improvement, the percent of 
treated patients who reported symptomatic improvement and in the treatment durability. 
1.3 
The ExAblate System 
The ExAblate system is a non-invasive thermal ablation device that has been used for the 
ablation of tissue.  This system combines a focused ultrasound surgery delivery system 
and a conventional diagnostic 1.5 T or 3T MRI scanner to implement MR guided focused 
ultrasound surgery (MRgFUS). The ExAblate system provides real-time therapy planning 
algorithm, thermal dosimetry, and closed-loop therapy control. The latter is achieved by 
utilizing the unique interactive MRI scan control features of the GE MRI system. The 

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ExAblate device is an integrated component of the MR table. The subject is placed on the 
MRI table and moved into the MRI scanner. 
The treatment process begins with the physician acquiring a set of MR images, 
identifying target volume(s), and drawing the treatment contours. The therapy planning 
software computes the type and number of sonications required to treat the defined region 
while minimizing total treatment time. MR images taken during the sonication provide a 
diagnostic quality image of the target tissue and a quantitative, real-time temperature map 
overlay to confirm the therapeutic effect of the treatment in real time. The transducer is 
then automatically moved to the succeeding treatment point and the process is repeated 
until the entire volume has been treated. Typically, ~30 individual sonications can be 
delivered over approximately 2 hours period to complete a metastatic bone tumor 
treatment.  
1.4 
Clinical Experience with ExAblate 
 
Uterine Fibroids (UF) – FDA Approved Indication 
The ExAblate 2000 system received FDA approval for the treatment of UF in November 
2004 (PMA #P040003).   The ExAblate 2000 had previously received CE Mark 
(European Authority approval and others) and AMAR authorization (Israel Ministry of 
Health) for the indication of treating UF. To date, approximately 8,000 treatments for 
uterine fibroids has been performed worldwide.  Since its approval, a number of other 
studies have been completed or are in process to assess changes in software and hardware 
or to provide additional information to support labeling changes.   
 
EXABLATE NEW SOFTWARE VALIDATION (IDE #G050221) 
This was an FDA-approved study to validate the new ExAblate application software as 
well as the use of the ExAblate system with 3T MR scanners for the treatment of UFs.  
This was only a safety study.  A total of 40 subjects were treated under this protocol IDE.  
The PMA-S was approved on February 27, 2007 under P040003/S002 
 
ENHANCED SONICATION PROTOCOL (IDE #G060017) 
This was an FDA-approved study to validate the new Enhanced Sonication feature of the 
ExAblate system, a detachable cradle, and several other modifications to the ExAblate 
2000 system.  This was a safety study only.  A total of 50 subjects were treated under this 
protocol IDE.  Following completion of this study, a full PMA supplement was submitted 
to FDA for review and approval [PMA# P040003].  Approval was granted on 12/22/2009 
under PMA Supp P040003/S006.  The system is marketed under the trade name 
ExAblate 2000/2100 and is indicated for use in treating symptomatic uterine fibroids. 
 
ENHANCED SONICATION POST MARKETING STUDY-P040003/S007 
InSightec is currently recruiting subjects for a post-market study using the FDA approved 
enhanced sonication feature to demonstrate the safety of the enhanced sonication feature 

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within current treatment guidelines of 100% individual fibroid ablation within established 
serosal and sacral treatment margins; this study will enroll 115 subjects and is nearing 
completion (P040003/S007). 
 
VALIDATION OF EXABLATE UF V2 – IDE G100127.  
InSightec is currently recruiting centers and initiating IRB review for study conduct in 
order to gain approval for the ExAblate Model 2100 Type 1.1 (also refer to as ExAblate 
UF V2).  This ExAblate system will be operated with a NEW Clinical Application SW 
utilizing the added 5th degree of freedom of the transducer (A/P movement) in its overall 
planning and treatment of the uterine fibroids.  This study will enroll 106 subjects under 
IDE # G 100127. 
 
Malignant and Benign Breast Studies – Investigational 
 
MRGFUS EXABLATE ABLATION OF BREAST CARCINOMA: CLINICAL STUDY WITH 
EXCISION 
InSightec conducted FDA approved clinical trials under IDE # G990184 and G990201 to 
evaluate the safety and efficacy of the ExAblate system in the ablation of breast 
carcinomas [1-3].  These are studies are closed.  Of all the patients treated, only three 
patients experienced non-significant adverse effects: one patient with mild event of 
redness at the ablation site, a second patient with mild event of firmness, and a third 
patient with a 3rd degree skin burn that was due to operator’s targeting error and not due 
to the device.   
 
MRGFUS EXABLATE ABLATION OF BREAST FIBROADENOMA 
InSightec conducted a feasibility FDA approved clinical trials under IDE # G930140 to 
evaluate the safety and efficacy of the ExAblate system in the ablation of breast 
fibroadenoma [4].  Following this feasibility study, InSightec initiated an FDA approved 
pivotal protocol to study ExAblate ablation of Breast Fibroadenoma (IDE # G010225). A 
total of 110 patients were approved for this trial, and only 27 patients were treated before 
the study was closed for enrollment due to lack of subjects enrollment.  No unanticipated 
adverse effects have been reported or detected by MRI.  Clinically, acute pain and 
discomfort were tolerable, and no long-term complications occurred.  
 
ExAblate Transcranial Brain Studies – Investigational 
 
EXABLATE MRGFUS TRANSCRANIAL TREATMENT OF BRAIN TUMORS: IDE # 
G020182 – EXABLATE TCMRGFUS LOW FREQUENCY SYSTEM 
In 2002, the FDA approved an IDE for a feasibility safety clinical study for the ExAblate 
Transcranial MRgFUS system in the treatment of brain tumors.  This study is currently 
enrolling.  A total of 10 patients will be treated under this IDE. 
 
EXABLATE TRANSCRANIAL MRGFUS THALAMOTOMY FOR MEDICATION 
REFRACTORY ESSENTIAL TREMOR PATIENTS  

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InSightec received FDA approval for a feasibility of ExAblate Transcranial MRgFUS for 
unilateral thalamotomy in the treatment of Essential Tremor under IDE # - G100169.  
Total of 15 patients were treated.  This study is currently on-going and 10 out of the 15 
patients have been treated to date.  Based on the investigator and the patient’s feedback, 
patients have shown a great level of acceptance of the procedure.  Furthermore, patients 
have shown a significant improvement in their Essential Tremor disease following their 
treatment with the ExAblate Transcranial MRgFUS device. Patients who completed the 
study requirements have shown stability of the tremor suppression all the way to the end 
of the study.   
 
Bone Feasibility Study IDE# G050177 
The objective of this trial was to evaluate the safety and effectiveness of using ExAblate 
as a treatment for pain palliation in patients with metastatic bone tumors.  This study was 
designed as a prospective, one arm, non-randomized study.  Ten subjects were enrolled at 
two sites.  Nine subjects completed the study; one subject could not complete treatment 
due to limited device accessibility to the lesion.  This study served as the basis for the 
Pivotal IDE study (IDE # G070022). 
 
EXABLATE CONFORMAL BONE SYSTEM (CBS) STUDY SUMMARY – FDA STUDY: 
IDE G 080206 
InSightec is currently conducting this study at three sites.  The study is enrolling and to 
date, seven subjects have been enrolled and treated with this conformal system.  The 
study was cleared for 50 subjects.  The study is still on-going. Although no data is 
available at this time, all the informal information from the participating investigators is 
that there is a very high level of patient acceptance of the ExAblate procedure.  To date, 
the safety profile continues to be favorable to the ExAblate procedure, and there were no 
new events that may be attributed to the device.   
 
BONE PIVOTAL STUDY IDE # G070022 – REVIEWED UNDER PMA P110039 
This study was designed as a prospective, randomized (3 ExAblate :1 Sham), single-blind 
multicenter sham-controlled clinical trial comparing ExAblate treatment against a Sham 
treatment with follow-up post-treatment to three months.  A total of 148 patients were 
enrolled and treated under this IDE.  This IDE study is under review under PMA # 
P110039.   

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2 OBJECTIVES 
2.1 
Background  
As part of the PMA # P110039 review process and approval, InSightec was requested to 
conduct a post-approval study.  Patients will be treated following the approved 
commercial treatment guidelines.   
For this study, participating sites will use the ExAblate device for the administration of 
the ExAblate treatment.  This study will be performed on either 1.5T or 3T MR scanners. 
For this study, a total of 70 patients meeting the approved commercial guidelines will be 
enrolled and treated with the ExAblate system at from 7 to 10 sites.  The proportion of 
responders is expected to be at least 30% greater than the proportion of subjects 
experiencing pain progression (i.e., 60% vs. 30%).  Additionally, at the 3 month visit, an 
analysis of both the safety and efficacy profiles will be compared to the original PMA 
pivotal study group.  This comparison will be descriptive with no statistical endpoints.   
2.2 
Safety 
Safety of ExAblate will be determined by an evaluation of the incidence and severity of 
device related complications from the first treatment day visit through the 3-Months 
post–treatment time point.   
2.3 
Effectiveness   
This study will follow the gold standard end points as stated by the “International 
consensus on palliative radiotherapy endpoints for future clinical trials in bone 
metastases”  [11, 24, 25].  For this purpose, this study will: 
• Capture patient based pain assessment using a 0-10 pain Numerical Rating Scale 
(NRS) with anchored points in conjunction with a body diagram.  
o Define “pain relief” complete response as a pain score of zero ( 0 ) at the 
treated site without increase in analgesic consumption. 

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o Define “pain relief” partial response as a reduction of 2 points on a 0–10 
scale at the treated site without increase in the analgesic consumption1. 
• Capture the dosage and frequency of analgesics/opiate consumption from baseline 
through the 3-Months post-treatment follow-up visit for each patient.  
• Capture the Quality of Life of each treated patient using the standard Brief Pain 
Inventory Questions 9A-G (BPI-QoL). 
• Following ExAblate treatment have 1-week, and 1, 2, and 3 months follow-up 
time points. 
• Response will be analyzed at 3 months.   
 
Efficacy Assessments 
Efficacy assessments used in this study are based on The International Bone Metastases 
Consensus Working Party on endpoint measurements [11, 24, 25] which recommends a 
0-10 point scale such as the NRS or BPI and to include a body diagram.   
 
NUMERICAL RATING SCALE (NRS) 
The Numerical Rating Scale is a validated standard instrument widely used for the 
assessment of cancer pain and have been used to investigate the effectiveness of radiation 
therapy to relieve pain resulting from bone metastases [26, 27].   
We propose to use the NRS to capture pain change at the treatment site during the course 
of the study and to use a human figure for patients to mark the location of pain [24, 25].  
The worst pain NRS will be used to assess pain in the present study and will include a 
body diagram for marking areas of pain.  Additionally, the average pain NRS scores will 
be collected.  Quality of life (BPI-QoL) and medications use will also be captured.  
Narcotic medications will be converted to morphine equivalents (Appendix D) 
 
BPI_QUALITY OF LIFE (BPI_QOL) 
To assess the impact of bone pain following targeted/localized treatment on health-
related quality of life, the pain interference scale from the BPI-QoL will be included 
[Appendix E].  Pain interference refers to the extent to which pain interferes with day-to-
day functioning and is more likely to be sensitive to anticipated changes in the health-
related quality of life among the study population.  The most common measure of cancer 
pain interference is the BPI -QoL[30].  This is a validated scale consisting of 7 items that 
ask respondents to indicate the extent to which pain interferes with general activity, 
 
1 Meds increase is defined as a change of 25% 1or more in MEU; per Chow, E., et al., International 
consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases. Radiother 
Oncol, 2002. 64(3): p. 275-80 

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mood, walking ability, normal work, relations with other people, sleep, and enjoyment of 
life”.   
2.4 
Study End Points 
 
Safety 
A full safety profile will be developed for the ExAblate treatment of bone metastases.  
All adverse events will be captured and summarized as defined in Section-6.2.  Adverse 
events (type, frequency, severity) are expected to be similar to those captured for the 
original PMA study (PMA # P110039).  
For his study, the Safety comparison with the data of the Pivotal (IDE Study G070022) 
study will be descriptive with no statistical endpoints.   
 
Efficacy 
A full efficacy profile will be developed for the ExAblate treatment of bone metastases.  
For this study efficacy will be determined by comparing outcomes at the 3 month visit to 
baseline within subjects.  Additionally the safety and efficacy of treatment Responders 
and Non-Responders will be tabulated, and compared with that of the original PMA 
(P110039).   
The primary endpoint is the proportion of responders at the 3 month study visit. 
Definition of terms: 
• Patient Responders: these are all ExAblate treated patients who experience at least 
a 2 point improvement from baseline on NRS at the treated site without increase 
in medications 
• Patient Non-Responders: these are all ExAblate treated patients who experience 
less than 2 points improvement from baseline to 3 months on the NRS at the 
treated site without increase of medication or increased medications. 
• Patient Pain Progression:  these are all ExAblate treated patients who either 
experience 2 points worsening from baseline to 3 months on the NRS at the 
treated site or who increase morphine equivalence 25% or more.  Pain progression 
is a subset of non-responders. 
 
Secondary Endpoints  
This study has two secondary end points.  The goal of these secondary end points is to 
assess the impact of the ExAblate treatment of painful bone Mets on the overall quality of 
life and clinical benefits to ExAblate MRgFUS treated patients: 

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Quality of life outcomes of all treated patients will be captured during the course 
of the study.  A comparison between baseline and 3 months post-ExAblate 
treatment of the BPI-QoL will be performed. 
Pain Medications of all patients will be captured and summarized.   Changes in 
narcotic medications will be expressed in morphine equivalents. 
2.5 
Case Report Form Data 
The study data will be collected electronically versus the traditional paper CRF entry 
method.  This electronic data capture (EDC) complies with the current guidance of 21 
CFR Part 11, Electronic Records and Signatures.  
3 DESCRIPTION OF PATIENT POPULATION    
3.1 
Patient Selection   
Patients with bone lesion(s): 
• Who have failed radiation therapy.  Radiation failure patients are those who have 
received radiation without adequate relief from metastatic bone pain as 
determined by the patient and treating physician, those for whom their treating 
physician would not prescribe radiation or additional radiation treatments, and 
those patients who refuse additional radiation therapy.   
• That appears to be metastatic disease or multiple myeloma by clinical and or 
imaging techniques with known history of malignancy. 
• Who have persistent intractable pain from a well defined tumor site. 
• Who have a fracture risk score  7, will be eligible for this study 
3.2 
Subject Enrollment 
a)  
Information concerning eligibility for the study will initially be taken from the 
patient’s case history.  Patients who appear to be eligible will be asked if they would like 
to participate in this study.  
b) 
Written informed consent will be obtained from each participating patient prior to 
collecting a patient history, other testing. The patient will be counseled concerning the 
research nature of this study, and the risks and possible benefits to participation.  This 

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study will utilize a pre-treatment imaging exam to confirm the diagnosis, and to estimate 
tumor size, location, and access for treatment. Participation is fully voluntary.  
 
Inclusion Criteria 
1. Men and women age 18 and older 
2. Patients who are able and willing to give consent and able to attend all study visits 
3. Patients who are suffering from symptoms of bone metastases or multiple 
myeloma bone lesions: 
Patients who have received radiation without adequate relief from 
metastatic bone pain as determined by the patient and treating 
physician, those for whom their treating physician would not 
prescribe radiation or additional radiation treatments, and those 
patients who refuse additional radiation therapy.   
4. Patient with NRS (0-10 scale) pain score ≥ 4 irrespective of medication  
5. Targeted bone/tumor interface are ExAblate device accessible and are located in 
ribs, extremities (excluding joints), pelvis, shoulders and in the posterior aspects 
of the following spinal vertebra: Lumbar vertebra (L3 – L5), Sacral vertebra (S1 – 
S5)  
6. Targeted bone/tumor interface (most painful lesion) size up to 55 cm2 in surface 
area  
7. Patient whose targeted (treated) lesion is on bone and the interface between the 
bone and lesion is deeper than 10-mm from the skin. 
8. Targeted (treated) tumor clearly visible by non-contrast MRI, and ExAblate 
MRgFUS device accessible  
9. Able to communicate sensations during the ExAblate treatment 
10. Patients on ongoing chemotherapy regimen at the time of eligibility:   
1. 
with same chemotherapy regime (as documented from patient 
medical dossier),  
And 
2. 
Worst pain NRS still ≥ 4 
And  
3. 
do NOT plan to initiate a new chemotherapy for pain palliation 
should be eligible for the study.   

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Note: Planned multiple courses of chemotherapy are not considered New 
Chemotherapy.   
11. No radiation therapy to targeted (most painful) lesion in the past two weeks 
12. Bisphosphonate intake should remain stable throughout the study duration. 
13. Patients will have from 1 to 5 painful lesions and only the most painful lesion will 
be treated. 
14. Patients with persistent distinguishable pain associated with 1 site to be treated (if 
patient has pain from additional sites, the pain from the additional sites must be 
evaluated as being less intense by at least 2 points on the NRS compared to the 
site to be treated). 

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Exclusion Criteria 
1. Patients who either 
• Need surgical stabilization of the affected bony structure (>7 fracture risk 
score, see Section 7.4) 
OR 
• Targeted tumor is at an impending fracture site (>7 on fracture risk score, 
see Section 7.4). 
OR 
• Patients with surgical stabilization of tumor site with metallic hardware 
2. More than 5 painful lesions, or more than 1 requiring immediate localized 
treatment 
3. Targeted (treated) tumor is in the skull 
4. Patients on dialysis 
5. Patients with life expectancy < 3-Months 
6. Patients with an acute medical condition (e.g., pneumonia, sepsis) that is expected 
to hinder them from completing this study. 
7. Patients with unstable cardiac status including: 
• Unstable angina pectoris on medication 
• Patients with documented myocardial infarction within six months of 
protocol entry 
• Congestive heart failure requiring medication (other than diuretic) 
• Patients on anti-arrhythmic drugs 
8. Severe hypertension (diastolic BP > 100 on medication) 
9. Patients with standard contraindications for MR imaging such as non-MRI 
compatible implanted metallic devices including cardiac pacemakers, size 
limitations, etc.  

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10. Patients with an active infection or severe hematological, neurological, or other 
uncontrolled disease. 
11. Known intolerance or allergies to the MRI contrast agent (e.g. Gadolinium or 
Magnevist) including advanced kidney disease  
12. KPS Score < 60 (See “Definitions” below)  
13. Severe cerebrovascular disease (multiple CVA or CVA within 6 months) 
14. Individuals who are not able or willing to tolerate the required prolonged 
stationary position during treatment (approximately 2 hrs.)  
15. Target (treated) tumor is less than 1cm from nerve bundles, bowels or bladder. 
16. Patients initiating a new chemotherapy regime for pain purposes only, or radiation 
(for the targeted most painful lesion) within the last 2 weeks 
Note: Planned multiple courses of chemotherapy are not considered New 
Chemotherapy.   
17. Patients unable to communicate with the investigator and staff. 
18. Patients with persistent undistinguishable pain (pain source unidentifiable of the 
targeted lesion)  
19. Patient whose bone-lesion interface is < 10-mm from the skin 
20. Targeted (most painful) tumor NOT visible by non-contrast MRI,  
21. Targeted (most painful) tumor Not accessible to ExAblate 
22. The targeted tumor is less than 2 points more painful compared to other painful 
lesions on the site specific NRS. 
 
 
 
 
 

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4  INVESTIGATION PLAN 
4.1 
Study Design 
This is a prospective, multi-site, one-arm study for evaluating the safety and effectiveness 
of ExAblate treatment of metastatic bone tumors.  Prospective study patients will sign the 
informed consent, complete study questionnaires and be evaluated in terms of inclusion 
exclusion criteria.  Patients not meeting the study criteria will be exited from the study as 
screen failures and not included in analyses.  All qualifying patients will complete a 
baseline CT scan, and in the event the CT scan is already available, then it should not be 
more than 3-months old; should an MR exam be available, it should be also considered 
(baseline MRI is not requested).  Any patients not meeting study criteria at imaging will 
be exited as screen failures.   
 
Study Optimization Protocol: 
Because the standard of care requires physicians to address pain when present and 
this specific patient population is suffering from painful metastases, the vast 
majority of patients referred to this study may already be receiving various pain 
medication regimens.  The Inclusion/Exclusion criteria of the protocol require 
patients to have functionality at study entry of KPS  60.  In most instances, 
patients with a KPS = 60 at enrollment will be considered to be on an optimized 
pain medications regimen.  Patients not previously on opioids pain medications 
will be required to proceed to optimization option-1 OR optimization option-2 as 
described below:   
 
OPTION – 1: THIS OPTION COMBINES PAIN STABILIZATION WITH FUNCTIONALITY 
Patients will start on a regimen similar to the NCCN guidelines while 
maintaining the level of function defined in the protocol (KPS  60).  
NCCN guidelines require frequent assessment and re-evaluation of 
moderate to severe pain generally every 24-48 hours and with long-acting 
agents after 5 half lives.  Study specific forms have been developed to 
document interventions taken to optimize pain control and to document 
patient response in regard to impact on pain and function due to 
medication-related adverse events.  Once it has been determined that pain 
control has been optimized such that a further increase in narcotics:  
o is not expected to result in a significant reduction in pain, defined 
as a 2 point or greater decrease on the NRS,  
OR 
o that interventions for pain control have resulted in a 10 point or 
greater decline in KPS 

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OR 
o that commonly recognized opioid-related side effects achieve 
Grade 3 or greater opioids related AE 
The NRS scale will be used to assess changes in pain and the KPS will be 
used to assess function.  Opioid-related side effects will be collected using 
“Common Terminology Criteria for Adverse Events v4.0 (CTCAE)” 
(http://ctep.cancer.gov) as a guideline for AE terminology and grade 
(severity) assessment.   Patients meeting any one of the above 3 criteria, 
and still meeting the study Inclusion/Exclusion requirements, specifically 
NRS  4 and KPS  60, will proceed to the ExAblate. 
 
OPTION – 2: THIS OPTION DETERMINES PAIN STABILIZATION 
All Patients who choose to follow Option-2 will be followed for pain 
stability for at least 1-week.  Patients will be counseled to maintain their 
medication intake unchanged during this period.  Daily capture of NRS 
pain score and medication intake will be performed at the same time of 
each day.  At the end of this period, a patient will be declared on a stable 
NRS if the NRS Score remains stable during this period; i.e., no more than 
2 points change from baseline.  
All patients failing this stabilization routine will be followed for another 
week.  All patients failing two consecutive weeks of this routine will be 
exited from the study and declared as screen failures. 
The NRS scale will be used to assess changes in pain and the KPS will be 
used to assess function.  Opioid-related side effects will be collected using 
“Common Terminology Criteria for Adverse Events v4.0 (CTCAE)” 
(http://ctep.cancer.gov) as a guideline for AE terminology and grade 
(severity) assessment.    
Patients passing the above stabilization criteria, and still meeting the study 
Inclusion/Exclusion requirements, specifically NRS  4 and KPS  60, 
will proceed to the ExAblate treatment. 
 

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4.2 
Pre-Treatment Procedures  
Patients potentially qualifying for the study will be offered an Informed Consent to sign 
prior to further evaluation.  Those who accept will complete study forms.  Any patients 
not qualifying will be exited from the study as screening failures and will not be included 
in the efficacy and safety analyses.   
A complete medical history will be obtained to determine the patient’s general health 
status, current symptoms, frequency and dosage of their current analgesic intake etc.  
Kidney and Liver function tests and coagulation profile will be performed.  Baseline pain 
scores will be established.  CT examination (with and without contrast) will also be 
performed. 
All patients will complete a run-in period to optimize patient pain meds at baseline in 
relation to patient pain, functionality and pain meds side effects, during which time study 
questionnaires (NRS, BPI-QoL, KPS, medications) will be completed.  
 
Pre-Treatment Procedure 
1. At the end of the run-in period and in the event the CT imaging is not already 
available, then baseline CT examination will be performed to identify the tumor 
size, location and extent and device accessibility as well as to evaluate the 
patient’s ability to cooperate during the ExAblate procedure.   
2. If at this point it is determined that the patient does not meet all Inclusion and 
Exclusion criteria and cannot be treated, the patient will be exited from the study.  
These patients will be considered screening failures, and will not be included in 
any of the safety or efficacy endpoint analyses.   
3. If the patient meets all study criteria, the patient may have the ExAblate 
treatment.   
4. ExAblate-treated patients will complete follow-up visits at, 1 week, and 1, 2 and 3 
months.   
4.3 
Treatment Procedures  
1. At the ExAblate treatment visit the patient will complete NRS, BPI-QoL, and 
KPS questionnaires and mark the primary and other sites where the most pain is 
felt prior to receiving any pre-treatment medications or seeing the clinician.  A 
quiet, private location may be provided for the patient to complete the 
questionnaires.  

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2. An IV line will be positioned for the delivery of medications and will be 
maintained throughout the procedure. The patient may require a urinary catheter 
to keep the bladder empty during treatment. Monitoring of heart rate and pO2 will 
be maintained throughout the procedure using standard MR-compatible 
monitoring devices. 
3. The patients’ skin will be closely examined for hair in the treatment path.  If 
necessary, the hair will be shaved around the treatment area and the skin will be 
cleaned, for example with alcohol, from any oil based skin product.  
4. Degassed water and possibly an acoustic gel will be placed atop of the 
transducers' window to generate acoustic coupling. 
5. Patients will be positioned on the ExAblate therapy bed in a selected position 
according to the planned treatment area. The patient’s area of treatment may be 
placed in a special-purpose imaging coil and positioned in the magnet in the 
treatment position.  
6. An MRI scan will be performed with T2 weighted sequence in all three 
orientations to localize and measure the target tumor to be treated (other 
sequences are allowed should they be needed).  
7. The skeletal structure in the treatment area will be evaluated to identify any 
abnormal anatomy that could prevent safe treatment.  Adjacent organs will be 
evaluated to ensure that no bowel, lung or major nerves are in close proximity to 
the treatment area, or that other obstructions are present in the pathway of the 
ultrasound treatment beam. Any prior scar will be identified on the image and the 
ultrasound treatment plan will be planned to avoid sonicating through the scar 
whenever possible.  
8. If the bone metastasis to be treated is identifiable on the MR images, accessible 
by the device for treatment, and the patient meets all inclusion and exclusion 
criteria, treatment planning will begin. 
9. The physician will trace the contour of the bone cortex in the targeted area  
10. The physician will draw the treatment volume using MR images from one or 
more scan orientations  using the following guidelines: 
a) 
Only one well defined lesion can be treated.   
b) 
Three most painful lesions are to be evaluated separately at baseline and 
throughout the pre-treatment period. 

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c) 
The targeted lesion must be at least 2 points more painful on the NRS 
compared to other painful lesions. 
11. A central point on the soft tissue-bone interface of the targeted bone (depending 
on patient anatomy) will be sonicated with a low thermal dose, generating sub-
lethal sonication, to verify targeting accuracy in the patient. Target placement and 
transducer positioning will be adjusted as necessary. 
12. If at this point it is determined that the patient cannot be treated, he or she will be 
withdrawn from the magnet and the IV line, catheter if inserted and pulse 
oximeter will be removed. The patient will be taken to the recovery area for 
observation and release.  Follow-up will consist of a phone call at 1-week post 
treatment.  These patients will be considered screen failures, and will not be 
included in either the safety or efficacy analyses.  
13. As part of our treatment procedure Geometric Verification in soft tissue is 
performed to confirm that the thermal location of the planned sonication spot is 
accurate.  Geometric Verification is used to correct any residual geometric errors.  
According to the treatment guidelines the procedure will be terminated if no MR 
thermal signal is observed during this verification phase.  Termination of 
treatment at this phase is before the planned therapeutic dose is administered.   
These patients will be considered screen failures and will not be included in the 
efficacy analysis.    
14. Treatment will begin.  Sonications will be performed on successive points 
[sonication duration between 15 – 60 sec]. The effect of each sonication will be 
measured by MR using phase map imaging, reflecting the temperature-dependent 
change in the proton resonance frequency.  Energy will be adjusted throughout 
the treatment, to achieve temperature between 65C and 85C from MR thermal 
images at the bone-soft tissue interface.  
a) Prior to the delivery of any treatment sonications, all patients 
MUST be adequately sedated for the treatment.  Failure to 
adequately manage the patient may lead to unnecessary intra-
procedure sonication related pain events.  For this study, ALL 
patients must receive adequate level of local medication, for 
example, intercostal nerve block; failure to manage patients may 
also lead to under treatment. Note: equivalent methods of patient 
management may also be performed per local site standards. 
b) Monitoring of heart rate and pO2 saturation will be maintained 
throughout the procedure 
c) During treatment, the nominal setting of the average of energy 
density for all treatment is set for 9 J/mm2 ; While the treating 

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physician still has the ability to tailor the energy during the 
treatment, it should be noted that 1) lower energy densities may 
lead to under-treatment, 2) high energy levels requires appropriate 
anesthesia regimen selection to ensure patient comfort.   
15. Sonications will continue until the prescribed targeted area has been treated. The 
goal is that the total time from 1st to last therapeutic sonication will be limited to 
180-minutes, or to patient tolerance. 
16. If no more than 3 planned sonications can be performed using therapeutic 
energies, then these patients will be considered as screen failures, and will NOT 
be included in the intent-to-treat analysis.  However, they will be added to the 
Safety analyses 
17. Criteria to terminate treatment include patient intolerance to the treatment, 
targeting difficulties due to patient motion or a decision of the treating physician 
18. Immediately post-treatment, a series of MR scans will be performed.  The 
scanning will include T2 weighted sequences and T1 weighted contrast enhanced 
sequences to evaluate general anatomy and to assess treatment effect.   
19. The patient will be taken off the therapeutic table and escorted to a recovery area 
for observation period pending release from hospital.  
20. All imaging exams taken during the study will be archived for later analyses 
21.  If during the treatment session, the physician did not complete the planned 
treatment, and determines that it would be to the benefit of the patient to continue 
treatment at a second session, a second treatment session may be completed 
within two (2) weeks of the first treatment.  However, only one painful site can be 
treated under this protocol and the purpose of the second treatment is to complete 
the original treatment plan.  This protocol does not allow for a second treatment 
due to continued pain at the treated site or the treatment of additional painful 
lesions.  The preparation procedures for the second treatment will be the same as 
the first, beginning with Step 4.3.2 above.  No more than two treatments should 
be performed within a two (2) week period. 
4.4 
Follow-up  
The follow-up visits of all patients will be completed at 1 week and 1, 2 and 3 
months post-ExAblate treatment.  Patients will be evaluated for general 
health, efficacy measurements as well as for device/procedure related AEs 
that may have occurred during the follow-up period. Additional data regarding 
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metastatic bone tumor induced pain will also be collected. Following 
treatment the study staff will mark the treatment NRS form indicating the 
place where the treatment was performed. These marked questionnaires will 
be provided to the patient to complete by the study staff for each time point in 
the follow up. The patient will be instructed to indicate the change of pain at 
the place of treatment.  Although the 1-Week, 1-Month, 2-Month and 3-
Month visits are office visits, and in view of the patient population general 
health may change at any given time due to the underlying cancer disease, 
participating sites may use their discretion to make the visit(s) a phone visit to 
accommodate the patient best interest.   However, all attempts should be made 
to ensure an office visit. The visits will be used to evaluate the patient’s NRS, 
BPI-QoL, and KPS, pain medication intake, symptoms and their general 
health, including any safety related issues and any changes in symptoms 
following treatment.  For phone visits, study personnel will contact the 
patient, inquire about AEs and question the patient according to the pain 
questionnaire, and pain medication intake, and fill it out in parallel.  Because 
the KPS is a physician completed assessment it may not be required for visits 
completed by telephone.  The study personnel will then sign and date the 
completed forms.  
All pre-treatment and post treatment MR and CT images will be de-identified and 
archived, and then will be forwarded to the Sponsor    
4.5 
Study Requirements and Visit Schedule  
The tables below summarize the data that will be captured during the course of this study.   

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5 STATISTICAL ANALYSIS PLAN 
This study is a designed as a single arm within subjects comparison of outcomes at the 3 
month visit to baseline.  For this study, a total of 70 patients meeting approved 
Table 1: Study Visits 
 
Window 
Allowance 
Imaging 
Questionnaire
s 
Additional Data 
Enrollment  
N/A  
CT** 
PE, NRS, BPI, 
KPS 
Freq. and dosage of 
analgesics.  
Run-in Visits:  
 
 
NRS, BPI, 
KPS 
Freq. and dosage of 
analgesics.  
Visit #1 Baseline MR 
Imaging and 
ExAblate Treatment 
(2nd session 
permitted). 
On Run-in Visit 2 
or within 1-week ± 
3 days of Run-in 
MR 
NRS, BPI, 
KPS 
Freq. and dosage of 
analgesics.  
Visit #2 (office): 1-
Week Post-Tx 
± 3 days 
 
PE, NRS, BPI, 
KPS 
Freq. and dosage of 
analgesics.  
Visit #3 (phone): 1- 
Month Post-Tx 
± 1 Week 
 
NRS, BPI, 
KPS 
Freq. and dosage of 
analgesics.  
Visit #4 (phone) 2- 
Months Post-Tx 
± 2 Weeks 
 
NRS, BPI, 
KPS 
Freq. and dosage of 
analgesics.  
Visit #5(office) 3-
Months Post-Tx 
± 2 Weeks 
 
PE, NRS, BPI, 
KPS 
Freq. and dosage of 
analgesics.  
**May be completed at any visit before treatment. 

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commercial guidelines for bone metastases will be enrolled and treated with the ExAblate 
system at from 7 to 10 investigational sites.   
 
Safety 
A full safety profile will be developed for the ExAblate treatment of bone metastases.  
All adverse events will be captured and summarized as defined in Section-6.2.  Adverse 
events (type, frequency, severity) are expected to be similar to those captured for the 
original PMA study (PMA # P110039).  For his study, the Safety comparison will be 
descriptive with no statistical endpoints.   
 
Efficacy 
A full efficacy profile will be developed for the ExAblate treatment of bone metastases.  
For this study efficacy will be determined by comparing outcomes at the 3 month visit to 
baseline within subjects.  Also, the outcomes will be compared with the original efficacy 
data of the PMA (P110039), where the proportion of treatment Responders and Non-
Responders will be tabulated and compared.   
The statistical hypothesis is that the proportion of responders will be significantly greater 
than the proportion of subjects experiencing pain progression (worsened pain or 
increased pain medications usage) by at least 30% or an odds ratio of at least 2. 
 
Secondary Endpoints 
Medications use and quality of life will be analyzed as secondary endpoints.   
 
PATIENT GENERAL HEALTH STATUS  
Patient overall quality of life status will be assessed by the BPI-QoL Pain Interference 
scale which will be administered pre-treatment and post-treatment.  The trajectory of 
change may be analyzed descriptively by regression slopes.  
 
BASELINE DATA ANALYSES  
Baseline clinical, demographic and patient reported outcome characteristics will be 
tabulated and compared descriptively to the original PMA.   
 
HEALTH COST AND SERVICES UTILIZATION 
Summary tabulations and figures may be developed for reimbursement purposes only. 
5.2 
Statistical Considerations and Sample Size 
The primary goal of the study is to evaluate the safety and efficacy of the ExAblate 
palliative treatment of painful bone metastases.  This study will be conducted with both 
the 1.5T and 3T MR scanners.  Seventy (70) patients will be enrolled and treated; 
enrollment will continue at from 7-10 research sites.   

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A sample size analysis was performed using the McNemar Test Power Analysis from the 
PASS2 program using parameters from the pivotal PMA study (PMA # P110039).  The 
response rate in the USA was 18/30 = 60%.  The proportion of non-responders 
experiencing pain progression was 30%.  Thus, the proportion discordant was 90%.  
Given  = 0.025 for a one-sided hypothesis, 1 -  = 0.7 requires a sample size of 65 
subjects to detect an odds ratio of 2.0.  The odds ratio is equivalent to a difference 
between two paired proportions of 0.30 which occurs when the difference in the 
proportion of responders (60%) is 30% greater than the proportion of subjects 
experiencing pain progression (30%).  In order to account for potential dropouts 70 
subjects will be initially enrolled in the study. 
The hypothesis can be specified as follows: 
H0: P10 = P01.  H1: P10 > P01, where P10 is the proportion of subjects that respond 
(improve by 2 points without increasing medications) and P01 is the proportion of 
subjects that worsen. 
Subject Confidentiality 
Subject confidentiality will be maintained throughout this study, including all 
publications.  Data collected and entered into the CRFs are the property of the study 
sponsor.  Representatives from the study sponsor or authorized sponsor representatives, 
the Institutional Review Board (IRB), Ethics Committee or the FDA may receive copies 
of the study records and may review medical records related to the study. 
5.3 
Missing Data 
Analyses will be performed on both observed and data with missing values imputed per 
the method of last observation carried forward (LOCF) where data for missing visits is 
assigned the value of the previous visit.  Analyses will include the presentation of results 
calculated based on the intent-to-treat principle.   
5.4 
Study Timeline 
The US study sites that participated in the recently approved pivotal study will be offered 
this protocol.  New sites can only be added if ExAblate bone systems are installed.  
Because this entails a detailed review and approval process, new purchases and 
installations typically take a minimum of 12-20 months to complete.  Thus, the timing for 
completion outlined below is premised on the assumption that the sites participating in 
 
2 Hintze, J. (2011). PASS 11. NCSS, LLC. Kaysville, Utah, USA. www.ncss.com. 

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this post-approval study (PAS) will be started with those already participating in the IDE 
investigation; should these sites accept to take part in this study.  New sites will be added 
as needed and in compliance with the total number of sites approved for this study.   
 
The following projections are our best evidence based estimates.  These estimates will be 
updated in the progress reports to the FDA. 
 
Facility Recruitment Complete — All available U.S. sites in the IDE will be offered 
participation in the PAS.  All sites that accept will be included.  This process will be 
completed within 3-6 months following final approval of the study. 
 
Physician Recruitment Complete — As InSightec adds sites (i.e. sells more systems), 
we will offer them participation in the PAS.  We will update the FDA of this effort in our 
progress reports, or per the agency instructions. 
 
IRB Process Complete— The IRB process will be initiated within approximately 3 
months after site participation has been confirmed. 
 
Study Enrollment at 50% Complete— As it was communicated to the agency during 
the PMA process as well as during the actual IDE study, the enrollment rate in the pivotal 
IDE study at US sites was approximately 0.07 subjects per month per site.  The rate of 
enrollment was very slow partly because of the terminally ill patient population and their 
limited life expectancy, and partly because this particular patient population is heavily 
managed by their oncologists who tend to rely on pain medications and existing familiar 
technologies.  However, in the pivotal IDE study, patients had the opportunity to receive 
an experimental palliative treatment that was not otherwise available.  Now, since the 
PMA has been approved, patients can elect the ExAblate treatment without participating 
in the PAS; there may be less of an incentive to participate in the PAS than in the IDE 
study.  Regardless, InSightec will use its best efforts to maintain a similar rate of 
enrollment in the PAS study as in the IDE study.  Based on the pivotal study enrollment 
rate of 0.07, 1 site enrolled by 2 months, and adding 2 sites each 4 months to a total site 
enrollment of 10 sites (7 sites by the 6th month and 10 by the 14th month), the 70th subject 
would be enrolled by the 105th month of the study. 
 
InSightec will continuously consider the possibility of increasing the number of 
participating sites; however, because of the large capital equipment investment and long 
installation time, it is expected that the number of sites that could be added to the study 
each year will be very limited, and would not meaningfully contribute to the increased 
rate of enrollment.  Nonetheless, all newly installed sites will be offered an opportunity to 
participate in the PAS in an effort to maximize enrollment. 
 
Final Study Report--Study results will be reported within 6 months of completion.  
Based on the timeline above, this is expected to be approximately 8 years and 10 months 
after full approval of the study. 

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6 RISK ANALYSIS 
Worldwide, over 8500 treatments have been performed to date with the MR guided FUS 
ExAblate 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, 
G050221, G060017, G060023, G070022, G080009, G080206, G100127, G100169, and 
P040003 and P110039).  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.  
Additional risks, new and unique to this study are discussed below. 
The potential risks described below will be explained to the subject in the informed 
consent process. 
6.1 
Potential risks – (ExAblate): 
Risk of MR Imaging 
• The study subject may find the 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  (trade name: 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%. 
Risks incidental to the treatment 
 
There is a potential risk of conscious sedation, which includes reaction to the 
drugs or over-sedation.  

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There is a potential risk from the intravenous catheter used during the treatment. 
Subjects can expect a small amount of pain and/or bleeding/bruising at the IV site.  There 
is a small risk of infection.  This procedure will follow the ‘standard of care’ at the Study 
Sites. 
 
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 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.   
 
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.   
 
Risks associated with the ExAblate treatment 
• There is a potential risk of hemorrhage around the treated area during ExAblate 
treatment. In ExAblate thermal ablation, the high temperatures result in 
immediate protein denaturation and coagulative necrosis, with the result that any 
bleeding that might occur in the capillary bed and within small vessels would be 
rapidly sealed.  At the end of the ExAblate procedure a contrast (Gadolinium or 
other MRI contrast agent) enhanced MR imaging is performed to assess the blood 
flow within the treated area and neighboring tissue. In addition to the repeated 
MR imaging during every sonication of the treatment, this final step is an 
independent treatment outcome assessment tool that is giving information on 
blood flow in the treated surroundings and could serve as a final check of tissue 
status. In the treatments that have been completed to date in other organs, this 
complication has never been observed.   
• Focused ultrasound therapy involves precisely controlled pulses of acoustic 
energy resulting in tissue heating (typically to 65-85°C for 15 seconds), in small 
tissue volumes.   Discrete small volumes are consecutively treated at operator 
controlled time intervals without significant overall heat accumulation in the 
body.  Since the beam is localized in the treatment area, there is no significant 
heating effect on pain sensitive areas such as adjacent normal tissue or skin. The 
patient will be sedated but in constant verbal contact with the physician and 
appropriate action can be taken in the event that a patient does experience 
discomfort.  Remedies could involve increasing the time interval between 
consecutive treatment pulses or increasing the level of anesthesia and/or 
analgesia. The patient also has the ability to stop the procedure at any time by 
activating a handheld shutdown circuit switch. 
• There is a risk to the patient from improper targeting of the focal point, and 
ablation of an area of tissue outside the planned treatment volume.  At the start of 
treatment, the system includes a mandatory step that requires the operator to first 
check the alignment of the patient anatomy, the focal point of the transducer and 

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the MR imaging system.  This procedure is done while the patient is in position 
for treatment. It achieves alignment within + 2 mm in all 3 axes.  For each 
sonication delivered during treatment, the operator gets continuous feedback on 
the position of the intended treatment point superimposed on the thermal 
dosimetry image and can make corrections where required. The system also 
includes an independent safety-monitoring loop that continuously compares the 
physical position of the transducer to the current intended treatment point to 
monitor 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 treatment 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 arterial embolization, cryo-therapy 
or Radiofrequency ablation of other tumors but has not been observed to a 
significant level thus far in the clinical experience accumulated from over 8500 
treatments with ExAblate.  
• There is a risk to the patient that the skin can become heated to the point where a 
burn can occur.  This heating can be caused by direct heating of the skin 
(improper treatment targeting), irregularities on the skin surface, or treatment of a 
volume of tissue too close to the skin and the conduction of sufficient heat to 
cause a burn at the surface.  In the case of a 1o or 2o burn, the skin should heal 
without a scar.  In the case of a 3o burn, a scar or loss of sensation in the area of 
the burn could result.  Following several reports of skin burns in uterine fibroids 
treatment that occurred due to tiny air bubbles trapped in the pubic hair, 
investigators were instructed to shave any hair in the beam path which 
significantly reduced events of skin burns.  No additional burns have been 
reported in over 30 cases of bone treatments.   
• There is a risk from 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.  
• There is a risk of cavitation in the tissue at the focal point. However, we believe 
that through proper system design, there is a very minimal risk that cavitation 
could occur during a treatment, even in the event of user error.  We have taken 
extensive steps in the system design to address cavitation as a potential risk and 
provide two layers of protection. The first is in the design of the sonication 
treatment planner.  This automated process takes as its input tumor depth in 
tissue, focal volume and tissue absorption, and based on pre-set safe operating 
limits selects sonication parameters that remain well below the cavitation 
threshold at the focal point. The system also includes a real time cavitation 
detection monitor.  A graphic output of this system is displayed to the user during 

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the treatment.  If cavitation is observed the user is instructed to immediately 
terminate the sonication before any harm would come to the patient being treated. 
It is not believed that a transient event of even a few seconds of cavitation could 
pose any medical risk to the patient 
 
 
Risks associated with pathological fractures 
 
Localized structural damage to the bone following ExAblate treatment could 
occur immediately following the treatment or could be delayed, resulting from 
death of osteocytes at and near the target zone (from the elevated temperature). 
No such events have been reported in the bone cases treated to date. 
 
Although patients will be screened for possible impending fractures 
(section 3.2.2 Exclusion Criteria, #1 and Section 7.4), there is still a risk of 
fracture during the study associated with the bone metastases themselves.  
Thus, fractures could occur near the treated site or at the site of untreated 
lesions.  All fractures will be captured on the adverse events CRF.  
Physicians will report the location of any fractures and assess their 
relationship to the procedure and the ExAblate device. 
 
6.2 
Anticipated Treatment Side Effects From ExAblate 
Based on previous treatment experience, the following anticipated side effects have been 
identified as possible treatment related complications of ExAblate treatment.  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 treatment are those, 
which normally resolve without sequelae within 10-14 days of the treatment: 
• Transient fever  
• Oral temperature >100.4oF/38oC  
• Pain in the area of treatment.  
• Transient pain in the skin.  
• Swelling or firmness in the treated area 

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• Minor (1o or 2o) skin burns less than 2 cm in diameter 
• Bruising in the treatment area 
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: 
• Necrosis of tissue outside the targeted volume due to heat conduction from heated 
bone. 
• Nerve damage, or loss of sensation in the area other then the treatment area. 
• Hemorrhage in the treated area requiring emergency treatment. 
• Skin burns with ulceration of the skin.  
• Skin retraction, and scar formation.. 
• Complications of conscious sedation (Cardiac, Pulmonary, Drug reactions) 
The table below summarizes all the potential risks to a patient from ExAblate treatment 
and the time course when they would most likely be observed.  
Immediate 
(up to 48 hrs post treatment) 
Mid term 
(up to one month) 
Long term 
(more than one month) 
Pain in the treatment area.  
Pain in the area of treatment 
Pain in the area of 
treatment 
Skin burns  
Swelling or firmness in the 
treated area 
Nerve damage or loss of 
sensation in the treated or 
neighboring areas 
Necrosis of normal tissue 
resulting from incorrect 
targeting 
Nerve damage or loss of 
sensation in the treated or 
neighboring areas 
Scar formation from skin 
burn.  
Risks of conscious sedation 
including reaction to drugs and 
over sedation. 
Fever as reaction to treated 
tissue.  
 
Adverse reactions to 
Gadolinium DTPA 
 
 

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Transient pain in skin or back 
Ulceration of skin or scar 
formation from skin burn.  
 
Bleeding in the treatment area. 
 
 
Pathological fractures 
Pathological fractures 
Pathological fractures 
 
The anticipated significant treatment side effects of the ExAblate treatment have an 
estimated combined incidence of less than 5% based on prior clinical experience in other 
organs.  
6.3 
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-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).  
6.4 
Criteria for Removal from the Study 
Subjects can be exited from the study at any time if in the opinion of the principal 
investigator it is not in the best interest of the patient to carry on as planned.  In Addition, 
patient may also chose to exit the study to pursue other alternative treatment options. 
6.5 
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.   

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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 AE’s (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.  
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 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 ICH-GCP requirements;  
• The Investigational Plan is followed;  
• Complete, timely, and accurate data are submitted;  

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• 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.  
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. 
7.1 
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 
the Oracle Software system, and is designed, run and hosted by Sponsor (Haifa, 
Israel).   
7.2 
Investigator Responsibilities 
All principal investigators will be required to sign an Investigator Agreement (see 
Attachment-C of this submission) 
7.3 
Definitions  
Karnofsky Performance Status (KPS):  

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SCORE 
FUNCTION 
100 
Normal, no complaint or evidence of disease 
90 
Able to perform normal activity; minor signs and symptoms of disease 
80 
Able to perform normal activity with effort; some signs and symptoms 
of disease. 
70 
Cares for self, unable to perform normal activity or to do active work 
60 
Requires occasional assistance, but is able to care for most needs 
50 
Requires considerable assistance and frequent medical care 
40 
Requires special care and assistance; Disabled. 
30 
Hospitalization indicated, although death not imminent; Severely 
disabled 
20 
Hospitalization necessary; active supportive treatment required, Very 
sick. 
10 
Fatal processes progressing rapidly; Moribund 
0 
Dead 
7.4 
Assessment of Fracture Risk 
Several radiological features of bone metastases that may contribute to fracture have been 
identified [31].  Fractures are common through lytic lesions in weight-bearing bones.  
Features that may be predictive of immanent fracture include larger size, lesions that are 
primarily lytic, and those that erode the cortex.  (Mirels, 1989 #46) developed a scoring 
system based on 1) location (upper limb, lower limb, peritrochanter), 2) pain severity 
(mild, moderate, severe), 3) lesion type (lytic, blastic, mixed), and the size of the lesion 
(<1/3, 1/3-2/3, >1/3).  Each variable is scored 1, 2 or 3 and summed to provide a score 
ranging between 3 and 12.  Using this system, lesions scoring >7 generally require 
surgical intervention [31].   

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8 APPENDICES 
Appendix-A:  Glossary of Terms 
Appendix-B:  Informed Consent 
Appendix-C: Case Report Forms  
Appendix-D: Morphine Equivalence Conversion Table 
Appendix-E: BPI_QoL Questionnaire 
  
    
 
 
 
 

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