A Pivotal Study to Evaluate the Effectiveness and Safety of ExAblate Transcranial MRgFUS Thalamotomy Treatment of Medication Refractory Essential Tremor Subjects
Phase: NA
Conditions: Essential Tremor
Sponsor: InSightec

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Clinical Protocol  NCT01827904 
 
Version Date 
August 14 2014  
Amendment No. 
3 
Protocol Number 
ET-002 
IDE Number 
G120246 
Protocol Title 
A Pivotal Study to Evaluate the Effectiveness and Safety of 
ExAblate Transcranial MRgFUS Thalamotomy Treatment of 
Medication Refractory Essential Tremor Subjects 
 
Approvals: 
Site 
Sponsor 
 
 
 
 ______________________________________  
Principal Investigator                            Date 
 
  
Date 
Signature 
 
 
 
 
 __________________________________  
Nadir Alikacem, PhD,                Date 
VP Global Regulatory Affairs and CRO  
InSightec      
 
 
 

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A Pivotal Study to Evaluate the Effectiveness and Safety of ExAblate Transcranial 
MRgFUS Thalamotomy Treatment of Medication Refractory Essential Tremor 
Subjects  
 
The objective of this prospective, randomized, double-blind (to subjects and Tremor Core 
Lab assessor), crossover, multi site, two-arm study is to test the efficacy of treatment 
using the ExAblate Transcranial System against a sham control and to further 
demonstrate safety in medication-refractory tremor inpatients with essential tremor (ET).   
 
The Indications for Use claim for this system is as follows:  Treatment of medication-
refractory tremor in patients with essential tremor. 
 
 
  
Protocol Number: 
ET-002 
  
  
 
InSightec 
4851 LBJ Freeway 
Suite 400 
Dallas, Texas  75244 

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Table Of Content 
1 
BACKGROUND and SIGNIFICANCE ..................................................................6 
1.1 
ExAblate MR Guided Focused Ultrasound Treatments............................................. 6 
1.2 
Movement Disorders .................................................................................................. 6 
1.2.1 
Movement Disorder in Essential Disorders Patients ............................................................ 6 
1.3 
ExAblate MR Guided Focused Ultrasound Transcranial System .............................. 8 
1.3.1 
ExAblate Transcranial MRgFUS System. ........................................................................... 9 
1.3.2 
Rationale for ExAblate Transcranial MRgFUS Thalamotomy for the Treatment of the 
Essential Tremor............................................................................................................................ 10 
1.3.2.1 
Risks associated with the current standard of practice in stereotactic surgery. ........... 10 
1.3.2.2 
ExAblate Transcranial MR-guided Focused Ultrasound (TcMRgFUS) ..................... 12 
1.3.2.3 
Potential advantages of ExAblate TcMRgFUS Vim thalamotomy as a treatment for 
Essential tremor. ....................................................................................................................... 13 
1.3.2.4 
Potential risks of ExAblate TcMRgFUS Vim thalamotomy. ..................................... 13 
1.4 
Clinical Experience with the ExAblate MR Guided Focused Ultrasound 
Transcranial System ............................................................................................................ 15 
1.4.1 
Clinical ExAblate Body System ....................................................................................... 15 
1.4.1.1 
ExAblate Body System for the treatment of Uterine Fibroids ................................... 15 
1.4.1.2 
ExAblate New Software Validation (IDE #G050221) .............................................. 15 
1.4.1.3 
Enhanced Sonication Protocol (IDE #G060017) ...................................................... 15 
1.4.1.4 
Enhanced Sonication Post Marketing Study-P040003/S007 ..................................... 15 
1.4.1.5 
Validation of ExAblate UF V2 – IDE G100127. ...................................................... 15 
1.4.1.6 
ExAblate Body System for the treatment of Breast Cancer ....................................... 16 
1.4.1.7 
ExAblate Ablation of Breast Fibroadenoma ............................................................. 16 
1.4.1.8 
ExAblate Body System for the treatment of Prostate Studies – Investigational 
Feasibility Studies ..................................................................................................................... 16 
1.4.1.9 
ExAblate Body System for the Palliative treatment of Metastatic Bone Tumors ....... 17 
1.4.2 
ExAblate Transcranial System .......................................................................................... 18 
1.4.2.1 
ExAblate Transcranial Treatment of Brain ............................................................... 19 
2 
OBJECTIVES ....................................................................................................... 25 
2.1 
Primary Endpoints .................................................................................................. 25 
2.1.1 
Safety .............................................................................................................................. 25 
2.1.2 
Effectiveness.................................................................................................................... 26 
2.1.2.1 
Efficacy Assessments .............................................................................................. 26 
2.2 
Secondary Endpoints ............................................................................................... 26 
2.3 
Study Hypothesis ..................................................................................................... 27 
2.3.1 
The Hypotheses Tested .................................................................................................... 27 
2.4 
Case Report Form Data ........................................................................................... 27 
3 
DESCRIPTION OF PATIENT POPULATION ................................................... 27 
3.1 
Patient Selection ...................................................................................................... 27 
3.1.1 
Inclusion Criteria ............................................................................................................. 28 
3.1.2 
Exclusion Criteria ............................................................................................................ 28 
4 
INVESTIGATION PLAN ..................................................................................... 31 
4.1 
Study Design Points................................................................................................. 31 

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4.1.1 
Computer Algorithm for Randomization........................................................................... 31 
4.1.2 
ExAblate Test Arm Study Design ..................................................................................... 32 
4.1.3 
Sham Arm Study Design .................................................................................................. 32 
4.1.4 
Movement Disorders Central Lab Assessments ................................................................. 33 
4.1.5    Videotaping Procedure ....................................................................................................... 33 
4.1.5 
Data Safety Monitoring Board .......................................................................................... 33 
4.2 
Screening Procedures .............................................................................................. 34 
4.2.1 
Treatment Procedures....................................................................................................... 36 
4.2.1.1 
ExAblate Arm Treatment Procedures ...................................................................... 38 
4.2.1.2 
ExAblate Sham Arm Treatment Procedures ............................................................. 39 
4.2.1.3 
Patient Management during Treatment .................................................................... 39 
4.2.2 
Post-Treatment Follow-up – All procedures for follow-up are common between treatment 
groups.. 40 
4.2.2.1 
Day 1 Follow-up Procedures: .................................................................................. 40 
4.2.2.2 
Week 1 ................................................................................................................... 40 
4.2.2.3 
Month 1 and 3 ......................................................................................................... 41 
4.2.2.4 
Month 6 and 12 ....................................................................................................... 42 
4.3 
Study Requirements and Visit Schedule .................................................................. 43 
5 
DATA ANALYSIS PLAN ...................................................................................... 45 
5.1 
Safety ....................................................................................................................... 45 
5.2 
Efficacy ................................................................................................................... 45 
5.3 
Subject Health Status .............................................................................................. 45 
5.4 
Statistical Considerations and Sample Size ............................................................. 45 
5.5 
Randomization Plan ................................................................................................ 46 
5.6 
Analysis of Potential Confounders .......................................................................... 46 
5.7 
Missing Data ........................................................................................................... 46 
5.8 
Statistical Analysis Plan. ......................................................................................... 47 
5.9 
Subject Confidentiality ............................................................................................ 47 
6 
RISK ANALYSIS .................................................................................................. 47 
6.1 
General Procedure Related Risks ............................................................................ 47 
6.1.1 
Risk of Magnetic Resonance Scanners:............................................................................. 47 
6.1.2 
Risk of Intravenous (IV) Catheter: .................................................................................... 47 
6.1.3 
Risk of Urinary Catheter: ................................................................................................. 48 
6.1.4 
Risk of Stereotaxic Head Frame: ...................................................................................... 48 
6.1.5 
Risk of Contrast Agent ..................................................................................................... 48 
6.1.6 
Risks Incidental to the ExAblate Treatment ...................................................................... 48 
6.1.7 
Risks Associated with the ExAblate Treatment ................................................................. 49 
6.2 
Anticipated Treatment Side Effects from ExAblate ................................................. 55 
6.3 
Adverse Reactions and Precautions ......................................................................... 57 
6.4 
Criteria for Removal from the Study ....................................................................... 57 
6.5 
Rules for Stopping the Study ................................................................................... 58 

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6.6 
Adverse Event Reporting ......................................................................................... 58 
6.7 
Data Safety Monitoring Board ................................................................................ 59 
7 
POTENTIAL BENEFITS ..................................................................................... 60 
8 
MONITORING PLAN .......................................................................................... 60 
8.1 
Electronic Data Capture (EDC) .............................................................................. 61 
9 
INVESTIGATOR RESPONSIBILITIES .............................................................. 61 
10 APPENDICES ...................................................................................................... 61 
11 REFERENCES ..................................................................................................... 61 
 

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1 BACKGROUND and SIGNIFICANCE  
1.1 
ExAblate MR Guided Focused Ultrasound Treatments 
ExAblate MR Guided Focused Ultrasound is an attractive modality for non-invasive 
thermal ablation of soft tissue tumors [1-6].  Treatment begins by acquiring a series of 
MR images of the target tissue. 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.  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 
Movement Disorders 
Stereotactic radiofrequency lesioning and deep brain stimulation (DBS) have been used 
to treat a number of neurological and psychiatric diseases. Today, DBS is more 
commonly used to treat movement disorders, predominantly Parkinson's disease (PD), 
essential tremor (ET), and dystonia.  In this study, the investigation will be limited to 
treatment of movement disorders [7] as related to ET patients. 
1.2.1 Movement Disorder in Essential Disorders Patients 
Essential tremor is the most common movement disorder with an estimated prevalence 
between 0.3% and 5.55% [8-12].  Recent epidemiological reports1 indicate that prevalence 
across 19 countries (pooled) was 0.9%, but increased to 4.6% among those 65 years and as 
high as 21.7% in those aged 95 and older.  The condition is a genetically inherited disorder 
with a child of an ET person having a 50% chance of inheriting a gene causing the 
condition.  Approximately 50-70% of people diagnosed with ET have a positive family 
history for the condition.  Caucasians are 5 times more likely to report physician diagnoses 
of ET than are African Americans; Hispanics have a rate between them.  Gender 
predisposition as reported in various articles is variable depending upon the author’s 
population. 
ET is a slowly progressive neurological disorder characterized by a tremor of the arms or 
hands that occurs during voluntary movements (intention tremor), such as eating/drinking 
and writing.  The tremor may also present in the head (neck) and jaw and may affect 
voice.  The disease may present in the teens or in the 40-50 age range.  Generally, tremor 
 
1 http://www.medmerits.com/index.php/article/epidemiology_of_movement_disorders/P4 

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begins in the arms and then spreads to these other regions in selected patients.  Other 
types of tremor may also present, including postural tremor of the outstretched arms, and 
intentional tremor (below 5 Hz) and rest tremor of the arms.  The amplitude of an 
intention tremor increases as an extremity approaches the endpoint of deliberate and 
visually guided movement (hence the name intention tremor). An intention tremor is 
usually perpendicular to the direction of movement. An intention tremor causes the 
person to overshoots or undershoots their target, (dysmetria).   
ET is commonly viewed as a pure movement disorder with a relatively benign clinical 
course, but specialists familiar with movement disorders recognize its associated features 
and disabling aspects [13].  Gait abnormalities and ataxia may accompany severe ET [14, 
15], and patients may progress to develop head tremor [11] that results in more postural 
instability [16].  Cognitive deficits with verbal fluency, naming, and verbal memory have 
also been demonstrated during neuropsychological testing in patients with ET [17].  
While tremor is not medically dangerous, it is very disabling and affects mental status as 
well as functioning at home and in the work place [18].  In fact, Lorenz et. al. have 
demonstrated that patients with ET suffer more from the mental effects on quality of life 
measures than from the actual physical symptom [18].  Patients with ET may have lower 
perceived health status [19], and some suffer significantly from social phobias [20], and 
depression [21].   The degree of tremor does not always correlate with the severity of 
disability resulting from ET [22], and so it is not surprising that the number of ET 
patients who may benefit from treatment is likely underestimated [21].  
Up to 30% of tremor patients do not respond to first-line medical therapy, and thus may 
consider surgical treatment options [23].  It has long been known that stereotactic 
lesioning of the thalamus controls tremor, but the original targets were controversial [24].  
Improved imaging with MRI and refined electrophysiological localization over the past 
two decades have revealed that the Vim nucleus of the thalamus is the most effective 
target, integrating the inflow of cerebellothalamic projections with proprioceptive and 
kinesthetic sensory information.  Furthermore, an abundance of tremor cells which fire 
synchronously with the peripheral tremor can be recorded in this region [25].  With 
electrophysiological confirmation and identification of these cells, very small volumes of 
Vim (~40 mm3) can be targeted for effective treatment [26].  
Both stereotactic RF-thalamotomy and DBS targeted to the Vim have proven effective 
for the treatment of ET and other tremors [27].  Numerous studies of Vim ablation and 
stimulation have demonstrated dramatic improvements of appendicular tremors in ET, 
and prospective and retrospective comparisons of the two reports similar control rates of 
tremor with 69-90% improvement in appendicular symptoms [28, 29].  Qualitative and 
quantitative measures  have been used to depict the benefits of thalamic stimulation in the 
upper extremities [30].  Axial tremors also improve with Vim stimulation [31, 32] 
including those tremors that extend to the voice [33].  Most importantly, quality of life in 
ET improves with unilateral and bilateral therapies targeted to the Vim [34-36].    
A long term study of RF-thalamotomy, however, revealed that nearly 12% of treated 
patients experienced tremor recurrence when followed for a mean of 8.6 years [37].  DBS 
is now much more widely accepted because the therapy is reversible and adjustable.  

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Thalamic DBS is associated with long term tremor benefits [38], but tolerance to 
thalamic stimulation can occur in up to 30% of cases [38-41].  Furthermore, DBS has its 
own inherent hardware-related complications, infection, expense, maintenance demands 
and other risks mentioned above. 
The non-invasive high-intensity focused ultrasound has been coupled with high 
resolution MRI to provide precise, consistent treatments that can be monitored in real-
time.  The development of phased array transducers allows for tightly focused treatment 
volumes and for the ability to compensate for distortions by tissue heterogeneity [42-44].  
The landmark advance in the ExAblate TcMRgFUS for neurosurgeons occurred as the 
ability to sonicate through the intact cranium was achieved with phased array transducers 
and acoustic modeling using CT reconstructions of the skull [39, 42-45].  By coupling 
Focused ultrasound technology with MRI, the ExAblate system allows detailed treatment 
plans to be performed and real time intra-procedure monitoring [5].  Standard MR 
sequences have been shown to reliably predict tissue damage during thermal lesioning 
with ultrasound [5, 46].   The precision of the technology has already been demonstrated 
in animal models [47] and is currently being investigated in humans with brain tumors 
[48] and neuropathic pain syndromes [49].   Unlike stereotactic radiosurgery, the 
treatment can be monitored continuously in real time with MRI and MR-thermography 
[4, 50-55].  We anticipate that the ExAblate TcMRgFUS non-invasive thermal lesioning 
is similarly as safe as DBS (or other current procedure and will provide several years of 
benefit through reduction of contralateral motor symptoms and potential medication side 
effects in ET, while still permitting subsequent treatment with DBS should that become 
clinically desirable [56].   
1.3 
ExAblate MR Guided Focused Ultrasound Transcranial System 
Ultrasound energy was shown to propagate through intact skull. Transcranial ultrasound 
has been used in pediatric subjects to detect midline shift of the brain[57]. In adults, 
blood velocity in the basal arteries may be monitored through the intact temporal bone 
using the Doppler effect [58]. In fact, since the 1950's, the ability of focused ultrasound 
to produce focal thermal lesions deep in the brain has been shown in several studies. 
Animal studies and early clinical studies provided encouraging results, showing well-
defined tissue coagulation at the focal zone [59-62]. Fry et al. showed that a low 
frequency (around 0.5 MHz) beam could be focused through the skull [63, 64].  Their 
work produced thermal lesions in animal brains through a piece of skull immersed in 
water (bone temperature was not monitored).   
However, ultrasound is strongly attenuated by bone [65].  For this reason, a consensus 
was reached that therapeutic ultrasound cannot be delivered through an intact skull due to 
the deflecting effect of the bone; the variable thickness of the skull affects the wave 
propagation so much that the focal spot is lost [66].  
➢ high temperatures that are generated in the bone, due to energy absorption, could 
damage the scalp, bone and adjacent brain tissue.  

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For these reasons, previous focused ultrasound treatments of the brain have involved 
removal of the skull (i.e. craniotomy) for the sonication pathway [60, 67] resulting in an 
invasive procedure with additional risk and costs.  
The device used in this study, namely the ExAblate transcranial system (see below), 
addresses the above limitations by combining a large phased array, active water-cooling, 
acoustic aberration correction algorithm, and patient specific CT data of the skull 
thickness registration. 
Large Phased Array Transducer. The system utilizes a large phased array 
transducer that utilizes numerous transducer elements (current system has 1000 
elements).  InSightec numerous clinical studies has indeed shown that large 
hemispherical phased arrays can deliver adequate energy through human skulls to 
coagulate brain tissue in vivo without excessive temperature elevation on the skull 
surface [68, 69] (see Sections 1.4.2.1 for clinical experience with ExAblate 
transcranial system). 
Active water-cooling. The interface between the subject head and the transducer 
is filled with degassed water, which provides the acoustic coupling path. The 
system includes a chiller (refrigerating unit with degassing capabilities) that keeps 
the degassed water chilled at constant temperature so that the skull-bone 
temperature remains within safety limits.  
Acoustic aberration correction algorithm. Acoustic aberration is created mostly 
by the variations in the bony structure of the skull. The degree of compensation 
necessary for each transducer element is based on predicting the aberration along 
the acoustic path from that element to the target and calculating the relative phase 
and amplitude correction necessary for that element. The result of this 
compensation is that the acoustic energy contribution from each element will 
arrive at the focal point in phase.  
CT data analysis. The phase/amplitude correction algorithm, based on ray 
acoustics methods, relies on an input that provides the bone density profile along 
a ray cast between each acoustic element and the target point. This information is 
extracted from a three dimensional CT image of the skull [45].  This is done for 
each patient eligible for ExAblate treatment. 
InSightec has now conducted several clinical studies with the ExAblate Transcranial 
system both in the United States under Investigational Device Exemption (“IDE”) FDA 
approvals, and outside the United Sates under all applicable regulatory approvals.  To 
date, the clinical data shows a very favorable safety and effectiveness profiles of the 
ExAblate transcranial MRgFUS thalamotomy procedure as well as the initial safety and 
effectiveness in terms of ability to ablate a targeted brain tissue (see  Section-1.4.2.1). 
1.3.1 ExAblate Transcranial MRgFUS System. 
The ExAblate transcranial system combines a focused ultrasound surgery [70] delivery 
system and a conventional diagnostic 3T MRI scanner. This ExAblate transcranial system 
provides real-time therapy planning algorithm, thermal dosimetry, and closed-loop 

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therapy control. The latter is achieved by utilizing the unique interactive MRI scan 
control features of the GE MRI system.  
The treatment process concept of this ExAblate transcranial system is not different from 
the ExAblate body system which is currently in clinical use for some soft tissue 
applications (see Section 1.4).  The treatment begins with a series of standard diagnostic 
MR images to identify the location and shape of tumor/target to be treated. The ExAblate 
computer uses the physician's designation of the target volume to plan the best way to 
cover the target volume with small spots called "sonications." These treatment spots are 
cylinder shaped.  Their size depends on sonication power and duration.  During the 
treatment, a specific MR scan, which can be processed to identify changes in tissue 
temperature, provides a thermal map of the treatment volume to confirm the therapeutic 
effect [71]. The thermal map is used to monitor the treatment in progress, and confirm 
that the ablation is proceeding according to plan, thus closing the therapy loop. 
The ExAblate transcranial operates a helmet-shaped transducer (currently utilizing 1000-
element phased array transducer) positioned above the subject head. The ExAblate 
transcranial system also includes means to immobilize the subject head, cool the interface 
water, and software for CT analysis and phase correction computation. 
1.3.2 Rationale for ExAblate Transcranial MRgFUS Thalamotomy for the 
Treatment of the Essential Tremor 
Both stereotactic radiofrequency (RF) lesions and deep brain stimulation (DBS) targeted 
to the Vim have proven effective for the treatment of ET and other tremors [27].  
Ablation and stimulation have demonstrated equivalent dramatic improvements of 
tremors, with prospective and retrospective comparisons reporting 69-90% improvement 
in appendicular tremors [28, 29].  Stereotactic radiosurgery using the gamma knife (GK) 
is a third technique directed to the Vim thalamus to control tremor.  The GK 
thalamotomy does not require an incision or bur hole, and has been reported to have 
efficacy equal to other lesion methods.  Unlike the first two stereotactic techniques, the 
effects of the GK thalamotomy operation may require 6 months or more to develop.   
Niranjan et al. [72] compared results of 15 gamma knife thalamotomies, 13 RF 
thalamotomies, and 11 thalamic DBS implants.  They reported all three to be safe and 
effective, with each approach having advantages and disadvantages.   
1.3.2.1 Risks associated with the current standard of practice in stereotactic surgery.   
Hemorrhagic surgical complications 
Stereotaxy uses modern, computer-assisted, volumetric imaging techniques to identify 
targets deep in brain in order to advance an electrode to the target.  Both of these 
stereotactic procedures require a scalp incision, bur hole drilled through the skull, and 
then penetration of the brain with an electrode to reach the target location.  In any open 
stereotactic procedure, there is a risk of hemorrhage associated with insertion of the 
electrode.  The overall risk of hemorrhagic complications is about 2% per electrode 
insertion, with a risk of permanent neurologic deficit of about 1%.  Intraventricular 
hemorrhages occur in 5% of cases when the electrode traverses the lateral ventricular 

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system.  Typically in a stereotactic procedure, the majority of surgical complications are 
associated with traversal of overlying structures such as the cortex or cerebral ventricles 
[73].   
Placement error 
Target identification in stereotaxy is derived from preoperative CT or MR scans taken 
with the patient in a supine position [74].  The stereotactic surgery is often performed 
with the patient in a semi-recumbent position to minimize the loss of cerebrospinal fluid.  
Problems can arise under some circumstances [75] such that the brain moves relative to 
the preoperative scan and the calculated coordinates.  This represents a potential source 
of error in electrode placement.  Any deviation in the mechanical geometry of the 
electrode or the stereotactic apparatus will also contribute error which can have a 
considerable impact on the safety/efficacy of the treatment.   
Risk from RF ablation 
The electrode used for RF ablations has an RF heated tip.  The peak temperature and the 
time it is maintained define the ultimate size of the lesion.  Temperature drops off 
smoothly with distance from the heated tip, and there is a fairly wide zone of thermal 
injury that extends for several mm around the necrotic core of the lesion.  The damaged 
tissue will rapidly produce edema which can produce local mechanical stress.  The risk of 
perioperative hemorrhage after RF ablation is higher than after DBS implant [76].  This 
may be the result of damage to blood vessels within the perimeter of the lesion, in areas 
hot enough to damage the vessel but not hot enough to coagulate it.  Mechanical strains 
on the damaged vessel can develop as the necrotic tissue contracts and injured tissue 
swells, leading to a rupture and intracranial hemorrhage.  The ability to produce very 
sharp temperature gradients at the margins of the planned lesion would provide a more 
homogenous lesion and reduce the extent of potentially dangerous adjacent edematous 
regions. 
Risk from DBS 
DBS therapy has a lower risk of acute perioperative complications than does RF ablation 
[76].  It is also programmable and able to adapt to some degree to the typical progression 
of ET.  However, DBS requires the permanent implantation of at least one multi-contact 
electrode, a lead extension and an implanted pulse generator (IPG).  The DBS system will 
likely be in place for the life of the patient.  This means the patient will need to be seen in 
follow-up for device management several times per year, and undergo replacement of the 
IPG every 3 to 5 years.  Furthermore, DBS devices produce electromagnetic interference 
and are sensitive to high energy electrical fields which can switch them off or even cause 
a "factory reset" of the device.   
As an implantable device, the DBS hardware problems are not uncommon.  Some reports 
suggest that upwards of 10% of DBS patients experience some form of hardware failure, 
and this number is likely to rise as the existing implants age.  Hardware failures can lead 
to a precipitous, unexpected (and possibly dangerous) loss of efficacy and invariably 
require surgical intervention to replace one or more components.  Subjects receiving DBS 

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implants, either unilateral or bilateral, are still subject to the same safety events and 
complications that are typical of thalamotomy of the Vim of the nucleus such as 
paresthesia and pain, dysarthria, and balance [77].   
Implanted DBS hardware is associated with higher risks of infection and skin 
complications than lesioning procedures.  The rate of postoperative infection with DBS 
surgery has been estimated between 3-10%, and such infections typically lead to device 
explanation if the infection cannot be cleared with antibiotics.  Such a scenario leaves the 
patient without treatment.  Wound dehiscence can also occur over the implanted 
hardware leading to infection as well.  
Even though the DBS technology continues to gain acceptability, its technology remains 
very expensive.  A bilateral Vim implant will incur an institutional cost nearing $100,000 
for hardware and hospitalization.  Additionally, expensive pulse generator replacements 
are required every three to five years.   
An intervention to inactivate the Vim thalamus without requiring the use of implanted 
hardware would be much more economical and would avoid the considerable risks 
associated with chronic implants.  ExAblate TcMRgFUS lesioning can be repeated 
should symptoms progress or recur.  There is no reason why DBS could not be 
implemented should ExAblate lesioning be ineffective.   
Risk from gamma knife thalamotomy 
The GK uses ionizing radiation to denature cellular DNA and ultimately cause cell death 
within the area defined by the 50% isodose margins around the target.  It requires a long 
time (median several months) [72, 78, 79], for the lesion to develop.  This means that the 
procedure is performed without intraoperative testing to verify the target and confirm the 
absence of side effects.  In fact, it has been reported that the lesions eventually observed 
on MR after 3 months are variable in volume and distribution, although the clinical 
effects seem consistent [79].   
Because of a lack of intraoperative feedback and a small risk of radiation-induced 
neoplasia, GK thalamotomy remains very uncommon, restricted to patients with 
advanced age or medical conditions (e.g. anticoagulant therapy) perceived to be high risk 
for open stereotactic surgery such as DBS or RF lesioning.  Because "delayed 
complications have been reported, and clinical improvement may take weeks to months 
to occur," the American Academy of Neurology concluded in 2005 that "There is 
insufficient evidence to make recommendations regarding the use of gamma knife 
thalamotomy in the treatment of ET (Level U)" [23]. 
1.3.2.2 ExAblate Transcranial MR-guided Focused Ultrasound (TcMRgFUS)   
High-intensity focused ultrasound (HIFU) has been used to destroy soft tissue such as 
neoplasms for more than half a century [80].  Until very recently, lesioning brain by 
sonication has been difficult because the overlying skull absorbs most of the sound 
energy and distorts the transmitted acoustic waves.  The landmark advance in ExAblate 
TcMRgFUS technology for neuro-related clinical applications occurred with the ability 

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of the ExAblate to sonicate through the intact cranium [42-45].  By coupling CT-based 
phase tuning with ExAblate, precise and small (2x2x3mm) lesions have been produced in 
thalamus while real-time thermal monitoring is available to observe the heating caused 
with each sonication [5].  Standard MR sequences have been shown to reliably predict 
the precise locus of tissue damage during thermal lesioning with the ExAblate system [5, 
46]. The precision of the ExAblate technology has already been demonstrated in animal 
models [47] and in clinical trials for neuropathic pain syndromes [49], in treatment of 
essential tremor (IDE # G100169), and is currently being investigated in humans with 
brain tumors (IDE # G020182) as well as in humans with medication-refractory tremor 
dominant idiopathic Parkinson’s disease (IDE # G120017).    
1.3.2.3 Potential advantages of ExAblate TcMRgFUS Vim thalamotomy as a 
treatment for Essential tremor. 
As a non-invasive, non-ionized MR guided procedure with real time imaging and thermal 
feedback, ExAblate TcMRgFUS VIM thalamotomy has several advantages for the 
treatment of Essential tremor:  
➢ The treatment can be monitored in real-time with MRI and MR-thermography 
[56-62].  This allows for immediate confirmation of the targeting process.   
➢ Thermal lesioning can be performed discreetly and accurately, and can be 
evaluated immediately.   
➢ Unlike stereotactic radiosurgery, ExAblate TcMRgFUS does not use ionizing 
radiation and does not carry a risk of radiation-induced tumorigenesis.   
➢ Because the ExAblate TcMRgFUS procedure is non-invasive, there is no 
scalp incision, no bur hole, and no electrode penetrating the brain.  The risk of 
hemorrhagic complication should be reduced, and this noninvasive procedure 
should eliminate the risk of infectious complications.    
➢ Unlike DBS treatment, there is no implanted hardware, no concern of 
interference with external sources of electromagnetic noise, no need for 
extensive follow-up for programming, and no need for periodic battery 
replacement.  This represents a much simpler treatment plan for a patient 
suffering from ET.  There will be hours of clinic time that is saved from DBS 
device management and replacement.  Additionally, health care costs will be 
greatly reduced.   
➢ As with other surgical treatments, it will be possible to re-treat a patient who 
develops a recurrence of tremor if the disease progresses.   
1.3.2.4 Potential risks of ExAblate TcMRgFUS Vim thalamotomy. 
The full risks of the ExAblate TcMRgFUS thalamotomy in the treatment of Essential 
tremor are listed in this study protocol under Section -  6.1   For this study, a series of 

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risks mitigating factors have also been identified and implemented (see Attachment – B3 
of this submission) in similar fashion as in the feasibility study (IDE # G100169).   Here 
are two (2) potential risks, which are unique to the ExAblate system:   
A- Mis-registration of the CT skull model with the MR volume.   
If the CT and MR volumes are not well aligned the tuning of the ultrasonic 
elements will be suboptimal and distortion will make it difficult to achieve a crisp 
volume of heating   
Risk Mitigation- The software protocols for image fusion are well-established and 
will be visually confirmed by clinicians experienced in stereotactic targeting.  
Observation of the location, size and pattern of areas heated by the low-power 
sonication trials will provide direct confirmation of the accuracy of the ExAblate 
TcMRgFUS focus.   MR thermography allows for confirmation of accuracy 
before the process of therapeutic sonications begins. 
B- Skull heating may be sufficient to damage the bone and/or adjacent soft 
tissues.   
Risk Mitigation- The sonication times are calculated to keep skull temperatures 
below dangerous levels, and the minimum ten minutes allotted for skull cooling 
will provide time for the skull to return to normal temperature before any 
additional heating can take place.  The small target of Vim thalamus will not 
typically require serial coagulations to produce effective tremor control, so 
cumulative effects will be minimized.  Additionally, the patient will be awake, 
alert, and in constant communication with the investigators; so that any clinically 
significant heating of the scalp or skull can be immediately reported and the 
procedure suspended.  
The safety profile of the ET001 feasibility study that was conducted under the FDA IDE 
# G100169 for the ExAblate TcMRgFUS treatment of subjects with medication 
refractory essential tremor was very favorable (see Attachment-B2 of this submission) . 
Summary 
Based on published animal and human studies, InSightec animal study, as well as the 
various clinical studies performed with the ExAblate system, the ExAblate TcMRgFUS 
Vim thalamotomy safety and effectiveness are very favorable, and compare favorably to 
other surgical treatments within the currently accepted standard of care including RF 
lesioning and DBS.  A single ExAblate lesion targeted to the VIM nucleus should 
provide reduction of contralateral tremor symptoms in ET (as demonstrated during the 
pilot study (IDE # G100169), while still permitting subsequent treatment should that 
becomes clinically desirable.  The ExAblate technology has several potential advantages 
over current therapies including the fact that noninvasive lesioning can be performed in a 

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precise manner with continuous clinical and radiographic monitoring.  If the potential of 
the ExAblate TcMRgFUS thalamotomy can be realized, it may supplant other 
thalamotomy procedures (such as GK thalamotomy and RF thalamotomy), providing a 
viable alternative procedure for patients unable or unwilling to undergo an invasive and 
uncomfortable DBS procedure while still cost effective. 
1.4 Clinical Experience with the ExAblate MR Guided Focused 
Ultrasound Transcranial System 
1.4.1 Clinical ExAblate Body System  
1.4.1.1 ExAblate Body System for the treatment of Uterine Fibroids 
The ExAblate 2000 system received FDA approval for the treatment of Uterine Fibroids 
in October 2004 (PMA # P040003).  Furthermore, this system gained both AMAR 
authorization (Israel Ministry of Health) and CE (European and others) approval for the 
indication of treating Uterine Fibroids. Subsequent studies lead to a software upgrade and 
an enhanced sonication protocol.  A further upgrade to the system to allow the transducer 
arm 3-dimensional movement is currently under IDE investigation as IDE G100127 
1.4.1.2 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. 
1.4.1.3 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. 
1.4.1.4 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 
within current treatment guidelines of 100% individual fibroid ablation within established 
serosal and sacral treatment margins; this study has completed its enrollment.  Data 
analyses and final report are in progress, and due for submission to the FDA in March-
2013. 
1.4.1.5 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 

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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. 
1.4.1.6 ExAblate Body System for the treatment of Breast Cancer  
InSightec conducted FDA approved clinical trials under IDE # G990184 and G990201 to 
evaluate the safety and efficacy of the ExAblate system in the treatment of breast 
carcinomas [81-83].  Both of these studies are now closed.  Currently, InSightec has an 
FDA conditional approval for a new breast cancer phase-2 study (IDE # G060023).  
1.4.1.7 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 [2].  Under this study, a total of 11 subjects were treated.  The results of 
this study showed that 8 of the 11 subjects who had ablations were either partially 
(>50%) or completely (>90%) successful. No adverse effects were reported, except for 
one case of transient edema in the pectoralis muscle two days after therapy.  
Following this feasibility study, InSightec initiated an FDA approved pivotal protocol to 
study ExAblate ablation of Breast Fibroadenoma (IDE # G010225). A total of 110 
subjects were approved for this trial, and only 27 subjects 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. 
1.4.1.8 ExAblate Body System for the treatment of Prostate Studies – Investigational 
Feasibility Studies 
Prostate cancer is the second leading cause of cancer death in men in the United States.  
Most prostate cancers grow slowly with a high survival rate past 10 years if it is still 
confined to the prostate.  The current treatment methods (surgical, external beam 
radiation therapy and male hormone suppression therapy) have significant side effects, 
such as impotence, incontinence, post-radiation colitis, etc.  Because prostate cancer is 
usually slow growing, active surveillance at 6 month intervals using a prostate cancer 
marker (PSA – prostate-specific antigen) has been a primary treatment option.  A focal 
treatment that could destroy the cancerous cells without harming the neurovascular 
bundle could provide a more palatable treatment with fewer side effects and extend life 
expectancy from prostate cancer causes. 
Feasibility studies have been performed outside the United States to demonstrate the 
ability of the ExAblate to successfully target the prostate gland and ablate it (Total Gland 
Ablation – TGA).  Additionally studies are now underway using focal therapy to ablate 
only cancerous foci within the prostate and leave the remainder of the gland intact.  The 
difficulty here is in the methods available to identify the cancerous foci.  These cancerous 
foci are generally not visible on MRI or CT, so careful, methodical biopsy mapping with 
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performed in order to identify the portion of the gland with the cancer.  In pilot studies 
with 14 subjects treated to date, the outcomes generally have demonstrated a minimal 
degree of sexual and urinary side effects (except for transient obstructive urinary 
symptoms) unless the cancerous foci involve the neurovascular bundles and the 
conscious decision is made to include them in the treatment region-of-interest.  Subjects 
that are eligible for participation are those with slow cancer growth being followed with 
active surveillance or with Gleason score of 6 (3+3) and no more than 2 cancerous foci in 
two or fewer adjacent sectors that would be amenable to ExAblate treatment.  To date, 
feasibility studies are underway in Russia, India, Singapore, Italy, and will soon start in 
Canada.   
In the United States under FDA oversight, InSightec has received the full FDA approval 
under IDE # G100108) to initiate a feasibility study in the treatment of prostate cancer. 
1.4.1.9 ExAblate Body System for the Palliative treatment of Metastatic Bone 
Tumors 
First, InSightec performed FDA approved study for a feasibility study of ExAblate 
ablation of metastatic bone tumors under IDE # G050177.  A total of 10 subjects were 
enrolled and treated at two (2) study sites.  This study is now completed, and a final 
report was submitted to the FDA [84].  Most recently a PMA submission (PMA # 
P110039) with the pivotal study data was submitted to FDA on 5, DEC-2011. 
1.4.1.9.1   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 subjects 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.   
Only 3 mild AEs were reported in the study with no device-related deaths, life-
threatening injuries or permanent injuries, nor serious adverse events.  There were 2 
events of mild sonication-induced pain; both resolved the day that sonications ended.  In 
addition, there was 1 event of a mild shivering reaction to conscious sedation lasting only 
a few minutes during the procedure with subsequent resolution.  All of these events were 
anticipated side effects that were identified in the study protocol as possible treatment-
related complications. 
As noted above, effectiveness was measured by the level of pain relief (as measured by 
VAS), decrease in analgesics/opiate medication usage, and improved quality of life (as 
measured by SF-36).  Prior to ExAblate treatment, the mean pain score was 5.6 ± 1.2 
(N=10, score range: 4-7).  A very rapid and sustained relief response was observed in 
subjects’ pain relief.  At 3 months, the mean score had dropped to 0.4 ± 0.6 (a 93% 
decrease from baseline).  With respect to medication usage, all subjects maintained or 
decreased their medication usage.   
Overall, these results demonstrate the safety and effectiveness of using ExAblate as a 
treatment for pain palliation in subjects with metastatic bone tumors. 

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1.4.1.9.2   Pivotal Bone Metastasis Study (IDE# G070022) – Brief Overview 
InSightec received full approval for a phase-3 Pivotal study for the ExAblate treatment of 
bone metastases palliation (IDE # G070022).  A total of 148 subjects were to be enrolled 
and treated at up to 20 sites. The pivotal clinical trial was a prospective, randomized 
(3:1), single-blind, sham-controlled, multicenter, two-arm study with sham-crossover 
option.  Consistent with prior correspondence between the company and FDA, InSightec 
has conducted an interim analysis of study data, providing for a statistical penalty 
addressing the early look at the data, in order to initiate PMA approval for this indication.  
This interim analysis has been performed under the interim statistical analysis plan 
previously submitted to and approved by FDA (G070022/S54).  The study objective is to 
evaluate the safety and effectiveness of an ExAblate thermal ablation treatment as 
compared to a sham treatment (where no energy is delivered) to reduce/relieve the pain of 
metastatic or multiple Myeloma bone tumors in subjects who are not suitable candidates 
for radiation therapy. The submission is under review at the Agency (PMA # P110039). 
1.4.2 ExAblate Transcranial System  
InSightec has two ExAblate Transcranial systems: mid (650 KHz) and low frequency (200 
KHz).  These 2 systems (medium and low range frequency) have two different 
characteristics:  
1. Mid frequency: functional discrete lesioning for deep central locations; focal 
thermal lesions  
2. Low frequency: tumor ablation and has wide treatment envelope 
These differences are summarized in the following table:  

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Table 1:  Summary of main differences between the low and mid frequency 
ExAblate systems 
Low frequency ExAblate Transcranial 
System 
Mid frequency ExAblate Transcranial 
System 
Enables access to most of brain volume 
Deep brain targets 
Spot diameter: 4-12mm 
Spot diameter: 2-6mm 
Low frequency (~220kHz) 
Medium frequency (~650kHz) 
Support both standard and burst 
Sonication regimes 
Support standard sonications only 
Standard sonication delivers the required energy in a continuous fashion to the target 
Burst Sonication: delivers the energy in a series of burst (high amplitude short duration 
of each burst of energy).  The total accumulated energy is the same.  The only difference 
is the way it is delivered to the target. 
 
For the proposed study, the same mid-frequency ExAblate Transcranial system that was 
investigated for the treatment of Essential Tremor subjects (under IDE # G100169) will 
be used; it should be noted this same system is utilized for the FDA approved study for 
tremor in Parkinson’s disease subjects.  The system uses the same transducer, ALL 
clinical features and tools of this FDA ET IDE approved system version, subject interface 
and coupling, etc.  There is no change to the thermal modeling, energy delivery, beam 
forming, nor treatment parameters and guidelines, and mitigating steps.  Furthermore, the 
manufacturing process, device risk analysis, SW and HW verification and validation have 
also remained unchanged. 
1.4.2.1 ExAblate Transcranial Treatment of Brain 
1.4.2.1.1 Feasibility Study for Brain Tumor IDE # G020182 – ExAblate Transcranial 
Low Frequency System 
In 2002, the FDA approved an IDE for a feasibility clinical study for the ExAblate 
Transcranial system in the treatment of brain tumors[48]. The purpose of this study is to 
evaluate the safety of MRI-guided focused ultrasound thermal ablation of brain tumors 
performed through intact human skull using the ExAblate system.  Specifically, the 
objectives of this non-randomized study are: 
a) To evaluate the safety of FUS delivered through intact human skull to the brain, 
during the treatment, and during the follow-up period of 3 months. 
b) To evaluate the effect of thermal ablation in the target tumor with contrast MR 
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This study was limited to subjects with a newly diagnosed glioma, recurrent glioma, or 
metastatic cancer to the brain for whom surgery was felt to be not indicated by a physician 
not associated with the study.  
Per FDA order under IDE # G020182/S02, this study was approved for a total of 10 
subjects. Also, per same FDA order, a report was requested after enrollment and treatment 
of the first 3 subjects in order to gain the FDA approval for continuation.    
- 
During these 3 treatments, all safety subsystems and monitoring of the device 
provided the intended safety monitoring capabilities.  The adverse events that 
were captured were Non-Significant, Anticipated, Treatment Side Effects and 
incidental to the treatment. 
The treatment of the 4th subject was done with an upgraded system (approved under IDE 
G#020182/S04). The treatment day safety was no different than those previously 
reported.  The skull/dura temperature change was in the range of previous treatments.  
Utilizing the burst sonication regime, the designated tumor was completely ablated.  This 
was consistent with our overall plan to achieve the efficacy needed. 
Despite an apparently uneventful treatment, this tumor subject died of an intracerebral 
hemorrhage five days after ExAblate. The Study Safety Committee determined the cause 
of the hemorrhage to be unknown but possibly multi-factorial. It was related to the 
propensity of glioblastomas to bleed, exacerbated by radiotherapy, medications and an 
underlying coagulopathy.  The latter was suggested by the fact that this particular subject 
had a hemorrhage at the biopsy site long before ExAblate, skin bruising, and a peri-
orbital hematoma that worsened dramatically at the time of his demise. 
The neuropathologic findings raised the possibility that pre-existing changes in the 
vessels, such as mineralization and wall thickening, may have rendered those vessels 
more susceptible to damage by ultrasound at the doses or frequencies used.  The Study 
Safety Committee recommended protocol changes in the exclusion criteria (tumors with a 
known tendency to bleed, subjects with abnormal clotting studies or on drugs known to 
affect coagulation) and in clarification of the imaging criteria (target volume maximum 
size requirement < 2.5 cm diameter, or an 8 cc volume - the tumor volume may be larger, 
as long as true midline shift is < 5 mm and the subject is not clinically compromised; 
definition of midline shift > 5 mm – does not include tumor growth across midline).  
With these provisos, the Safety Committee recommended continuation of the study.  The 
FDA approved the recommendation of the Safety Committee under IDE # G020182/S15.  
The full FDA approval to restart this study was covered under IDE#G020182/S19. 
1.4.2.1.2  ExAblate Transcranial MRgFUS system and Thalamotomy Procedures  
The InSightec ExAblate TcMRgFUS system has been used in the thalamotomy treatment 
of neurological disorder such as neuropathic pain, essential tremor (“ET”), and 
Parkinson’s disease (“PD”) induced tremor.  These studies were conducted under FDA 
IDE approvals (ET under IDE # G100169; enrolling for PD under IDE G # 120017), 
Health Canada (ET under Application # 166556), Swissmedic (NP001 study included 
Neuropathic pain, ET and tremor in PD subjects – Reference: 2011-MD-0001), and 

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Korean FDA (ET under KFDA Application # 260) oversights.  Overall, more than fifty 
(50) subjects received the ExAblate TcMRgFUS thalamotomy procedure.   
1.4.2.1.2.1 Study for Neuropathic Pain Outside the United States   
The original study was an investigator initiated and sponsored study (Study number 
BZ001) in the treatment of neuropathic pain that was conducted at the University 
Hospital Zurich (Zurich Switzerland) using the InSightec ExAblate Transcranial (650 
KHz) system.  The study was approved by and performed according to the guidelines of 
the ethics committee of the University and the State of Zurich.  At the conclusion of this 
study, an InSightec sponsored study was conducted under Swissmedic (Reference #: 
2011-MD-0001) and local IRB approvals.  This study (NP001) included subjects with 
Neuropathic pain, Essential tremor, and those subjects with Parkinson’s disease induced 
tremor.   
To date, more than thirty-five (35) subjects underwent selective central lateral 
thalamotomy (CLT) using the ExAblate Transcranial treatment. For all subjects, the 
treatment was well tolerated and did not result in any side effects or neurological deficits.  
The safety profile of these procedures was no different from those known to occur in any 
thalamotomy procedure such as DBS or RF ablation.  To be specific, all the reported 
adverse events observed in these studies were all non-significant and anticipated events 
already identified as potential events in the study protocol.  These were headaches, 
nausea, and vomiting.  All resolved on the same day as treatment.  The only significant 
event reported to date from these two (2) studies an event of neurological deficit (Subject 
BZ001-12), i.e. “dysmetria (dyscoordination) of the right hand, dysarthria, motor neglect 
and gait disorder”.  This event, originally reported as part of IDE # G100169, was 
reported immediately following the last sonication.  All symptoms improved significantly 
1-hour post treatment.  By 24 hours, 70-80% of the motor symptoms had abated and with 
time all dysmetric symptoms cleared except when the subject tried to write or speak (see 
Jeanmonod et al paper2).   
As it was shown in the brain tumor study under IDE G020281, for these studies there was 
no clinically significant heating at the skull-brain interface.  The mean brain surface 
temperature was approximately 39° C.   
Other than a couple of subjects, all Neuropathic pain treated subjects (N=19) experienced 
some level of pain relief during the procedure, and at 48 hours after the treatment, 
subjects reported pain relief ranging from 32 to 100% (mean ≈ 65%).  Partial results of 
this study were published in the Annals of Neurology Journal 3   
 
2 Jeanmonod et al. “Transcranial magnetic resonance imaging-guided focused ultrasound:  noninvasive 
central lateral thalamotomy for chronic neuropathic pain”. Neurosurg Focus, 2012, Jan 32: E1 
3  
Martin, E., et al., High-intensity focused ultrasound for noninvasive functional neurosurgery. Ann 
Neurol, 2009. 66(6): p. 858-61. 

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1.4.2.1.2.2 Study for Tremor in Parkinson Disease subjects - Outside the United 
States   
As stated above, the Swissmedic NP001 included cohort of six subjects with Parkinson’s 
disease induced tremor.  Following the ExAblate treatment, the tremor suppression ranged 
from 20 to 50% at the 3-Months time point in 5 out of the 6 treated subjects.    
1.4.2.1.2.3  Study for Essential Tremor - Outside the United States   
In addition to the Swissmedic study that included cohort of 1 subject (study is still on-
going) with Essential tremor, InSightec conducted separate studies for the treatment of 
Essential tremor in both Canada and in Korea.  A total of 8 subjects were treated to date 
as follows: 3 subjects in Canada, and 5 subjects in Korea.  Both of these study protocol 
were similar to the FDA feasibility study (IDE G#100169).  Overall, the ExAblate 
treatment safety profile is no different from the FDA feasibility study ( for more details, 
see Section-1.4.2.1.2.4) nor from the safety profile of typical thalamotomy device 
procedures such as RF ablation and DBS.  In short, safety events such as Dizziness and 
vomiting were reported, and both resolved without sequelae.    
1.4.2.1.2.4 ExAblate Transcranial System Feasibility Study for Essential Tremor  
IDE - G100169  
InSightec received FDA approval for a feasibility study of ExAblate Transcranial System 
for unilateral thalamotomy in the treatment of Essential Tremor under IDE # G100169.  
Fifteen subjects were enrolled and treated at one site and the study report was recently 
completed.  Both the safety and effectiveness profiles showed a very favorable outcome 
of the ExAblate Transcranial MRgFUS treatment of patients with medication-refractory 
movement disorders, namely ET.  The clinical outcomes subscales as well as the quality 
of life measures showed a substantial improvement in subject disabilities and their quality 
of life.    
The incidence (number of patients experiencing an event) and severity of all device and 
procedure related AEs are summarized in Table 2.  This list of events includes the non-
significant and the significant anticipated treatment side effects as well as the events 
incidental to the treatment.   
Table 2  Overall Adverse Events and Severity:  ET-001 
 
Event 
Mild 
Moderate 
Severe 
Total # 
of Events 
Non-
Significant 
Anticipated 
Events 
Ache – pin site 
1 
0 
0 
1 
Balance 
7 
0 
0 
7 
Chest Pain 
1 
0 
0 
1 
Neural Deficit - speech 
2 
0 
0 
2 

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Table 2  Overall Adverse Events and Severity:  ET-001 
 
Event 
Mild 
Moderate 
Severe 
Total # 
of Events 
Neural Deficit – hand 
strength 
1 
0 
0 
1 
Emesis 
2 
0 
0 
2 
Fatigue 
3 
0 
0 
3 
Headache 1 Day 
4 
5 
0 
9 
Headache > 1 Day 
1 
2 
0 
3 
Numbness -- appendage 
1 
0 
0 
1 
Nausea 
2 
4 
0 
6 
Paresthesia - appendage 
3 
0 
0 
3 
Paresthesia - face 
4 
1 
0 
5 
light headedness  
7 
1 
0 
8 
Twitch 
1 
0 
0 
1 
Warm Sensation 
4 
0 
0 
4 
Edema 
1 
0 
0 
1 
Ataxia 
 
1 
0 
1 
Non-Significant Subtotal 
45 
14 
0 
59 
Significant Treatment Anticipated Events  
Balance 
2 
2 
0 
4 
Fatigue 
1 
0 
0 
1 
Infection – pin site 
1 
0 
0 
1 
Numbness – pin site 
1 
0 
0 
1 
Parasthesia - appendage 
1 
1 
0 
2 
Parasthesia - face 
4 
1 
0 
5 
Parasthesia - scalp 
4 
0 
0 
4 
Hypesthesia - scalp 
1 
0 
0 
1 
Burn – pin site 
1 
1 
0 
2 
Significant Subtotal 
16 
5 
0 
21 

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Table 2  Overall Adverse Events and Severity:  ET-001 
 
Event 
Mild 
Moderate 
Severe 
Total # 
of Events 
Incidental 
Events  
Sinusitus 
0 
1 
0 
1 
Bronchitus 
1 
0 
0 
1 
Incidental Subtotal 
1 
1 
0 
2 
 
Total 
62 
20 
0 
82 
The most significant results shown in Table 2 are that all these events are indeed anticipated 
events and were already identified as potential events in the study protocol.  Furthermore, 
NONE of the adverse events reported to date were severe in nature.  In fact, 76 % (62/82) 
were Mild events, and the remainder 24% (20/82) were Moderate.  Most of these events 
resolved either the same day (49% of the total events) or within 2 weeks of treatment (26% 
of the total events).  Hence, 61 events (i.e. 74%) resolved within 2 weeks of the procedure. 
Of all the events that did not resolve within the first 2 weeks post procedure, 14 out of 82 
events (17%) resolved in more than 2 weeks (not counting the incidental sinusitis (n=1)), 
and 7 events (9%) were reported as ongoing.   
1.4.2.1.3 Overall summary of ExAblate TcMRgFUS safety profile 
The safety events reported in all these studies present a favorable safety profile for brain 
surgery using the ExAblate TcMRgFUS for ablative therapy.  The majority of all events 
are mild and transient.  They generally fall into the pattern of other techniques indicating 
that these are generally the result of stereotactic device use (e.g., headache) and 
thalamotomy in general, regardless of the mechanism of therapy, due to brain tissue insult 
or due to heating of tissue locally surrounding the lesion target.  The overall effectiveness 
profile was also shown to be very favorable.   
 

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2 OBJECTIVES 
The objective of this prospective, randomized, double-blind (to subjects, local site and  
Tremor Core Lab assessors), crossover, multi-site, two-arm study (ExAblate treated arm 
Vs ExAblate Sham treated control arm) is to test the efficacy of treatment using the 
ExAblate Transcranial System and to further demonstrate safety in medication-refractory 
tremor in subjects with essential tremor (ET).   
Safety: To evaluate the incidence and severity of adverse events (AE/AEs) 
associated with ExAblate Transcranial MRgFUS treatment of medication-
refractory ET 
Effectiveness: To determine the effectiveness of the ExAblate Transcranial 
MRgFUS treatment of medication-refractory tremor (i.e. ET).  Efficacy will be 
determined utilizing the Clinical Rating Scale for Tremor (CRST) in ET from 
examinations at baseline and 3-Months post-ExAblate treatment.   
• This study is designed as a prospective, randomized, double-blind (to subjects 
and Tremor Core Lab assessor), crossover, multi-site, two-arm study (ExAblate 
treated arm Vs ExAblate Sham treated control arm). 
Assessments of primary efficacy endpoints will compare the three months after ExAblate 
treatment to Baseline measurements for clinical symptom relief.  Safety of ExAblate in 
the treatment of ET will be collected for one year after ExAblate Sham or active 
treatment.  Relative Safety will be evaluated using a common description of Significant 
Clinical Complications for patients treated in this study. This study will be performed on 
the 3T MR scanners. 
Note:  
It should be noted that the pre-market submission to the FDA will be performed 
following the completion of the 12 months follow up visit of the last Test Arm 
subject.  This pre-market submission will be performed in full consultation with 
and approval of the FDA.  However, per FDA order, all participating subjects 
will be consented for a total of 5 years.  
2.1 
Primary Endpoints 
2.1.1 Safety 
Safety of ExAblate will be determined by an evaluation of the incidence and 
severity of device / treatment related complications from the first treatment day 
visit through ALL study follow ups.  Adverse events (type, frequency, severity) are 
expected to be similar to those of previous studies using ExAblate TcMRgFUS for 
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All AEs will be reported and categorized by investigators as definitely, probably, possibly, 
or unrelated to the device or procedure and categorized by treatment group / treatment 
arm.  
2.1.2 Effectiveness   
Primary effectiveness will be evaluated using a validated, tremor rating scale: the Clinical 
Rating Scale for Tremors (CRST) for ET subjects, based upon subjects in whom 
unilateral ExAblate lesioning is attempted (i.e., Intent-to-Treat analysis).  The specific 
study hypothesis is as follows:   
At 3-months post-treatment, the treated (contralateral) upper limb CRST 
subscore (CRST Part-A & B applicable to upper limb) in the ExAblate-treated 
group will be statistically lower compared to that in the ExAblate sham-
treated control group. 
Clinical assessments will be made at the following time points:  screening, baseline with 
subjects on confirmed stable medication (at 1-months post screening), and post-treatment 
at 1 week, 1 month, 3 months, 6 months, and 12 months.   
2.1.2.1 Efficacy Assessments 
Tremor will be assessed for each treated ET patient using the CRST [85] at baseline 
following the medications observation period (i.e.: subjects on confirmed stable 
medication) but before treatment and at post-treatment intervals: 1 month, 3 months, 6 
months and 12 months.  The validated rating assessment of tremor will be administered 
by a movement disorder specialist (e.g.: neurosurgeon, or neurologist or physical therapy 
specialist in movement disorder).  The primary measure utilized in this protocol will be a 
reduction in the treated (contralateral) upper extremity CRST applicable subscores.  
Additionally, a total/overall tremor score (out of 160 points) will be obtained for each ET 
patient at each time interval by summing the appendicular and axial scores.   
Quality of life will be evaluated using the QUEST assessment.  The QUEST is an ET 
specific assessment of quality of life changes associated with ET.  Tröster et al., 2005, 
developed QUEST as a clinical tool for correlating changes in 30 aspects of tremor 
severity, social and personal disability, and perception of health.  An independent 
validation study of the QUEST performed by Martinez-Martin et al. concluded that most 
of the psychometric parameters were found to be satisfactory in their ability to assess the 
impact of ET on the patients’ quality of life. 
2.2 
Secondary Endpoints 
The secondary endpoints of the study are as follows: 
1. Quality life claims: Questionnaire for Essential Tremor (QUEST) outcome (upper 
extremity questions) at Months 3 change from Baseline.as compared between 
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2. Durability (as measured by QUEST upper arm extremity questions) of the 
procedure as reflected by the efficacy data through change from baseline 
measures through Month 12 follow up  
3. Subject daily functionalities: as measured by CRST Part-C (subscales) Month 12 
as compared to Baseline, and between treatment groups through Month 3. 
4. Crossover cohort treatment outcome (perform 1-3 as above for the Crossover 
cohort) 
2.3 
Study Hypothesis 
The purpose of this study is to determine the safety profile and to test the effectiveness of 
MRI-guided focused ultrasound thermal ablation of a designated area in the brain of 
patients suffering from medication-refractory ET, using the ExAblate transcranial system 
compared to a sham control. 
➢ For ET Patients: a unilateral  thermal lesion will be created in the ventralis 
intermedius nucleus of the thalamus [54] 
2.3.1 The Hypotheses Tested 
➢ At 3-months post-treatment, the treated (contralateral) upper limb CRST 
applicable subscores of Part-A & B in the ExAblate-treated group will be 
statistically lower compared to the ExAblate sham-treated limb in the sham-
treated group. 
Note: 
It should be noted that the pre-market submission to the FDA will be performed 
following the completion of the 12 months follow up visit of last Test Arm 
subject.  This pre-market submission will be performed in full consultation with 
and approval of the FDA. 
2.4 
Case Report Form Data 
The study data will be collected electronically.  This electronic data capture (EDC) 
system 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 confirmed medication-refractory ET as confirmed by screening will be 
eligible for this study; full copy of subject consent is provided as Appendix-A of this 
protocol.    

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3.1.1 Inclusion Criteria 
1. Men and women age 22 years or older  
2. Subjects who are able and willing to give consent and able to attend all study 
visits,  
3. A diagnosis of  ET  as confirmed from clinical history and examination by a 
neurologist or neurosurgeon specialized in movement disorder 
4. Tremor refractory to adequate trials of at least two medications, one of which 
should be a first line therapy of either propranolol or primidone.  An adequate 
medication trial is defined as a therapeutic dose of each medication or the 
development of side effects as the medication dose is titrated.  
5. Following the 1-month medication stability period, subject must be on stable 
medication for tremor 
a. The 1-Month stability period visit will be 1-month post consent date 
6. Vim nucleus of thalamus can be target by the ExAblate device.  The thalamic 
region must be apparent on MRI such that targeting can be performed by 
measurement from a line connecting the anterior and posterior commissures of 
the brain.  
7. Able to communicate sensations during the ExAblate TcMRgFUS treatment 
8. Postural or intention tremor severity score of greater than or equal to 2 in the 
dominant hand/arm as measured by the CRST rating scale while stable on 
medication.  
9. May have bilateral appendicular tremor  
10. Significant disability due to essential tremor despite medical treatment (CRST 
score of 2 or above in any one of the items 16-23 from the Disability 
subsection of the CRST: [speaking, feeding other than liquids, bringing 
liquids to mouth, hygiene, dressing, writing, working, and social activities])  
11. Inclusion and exclusion criteria have been agreed upon by two members of the 
medical team. 
12. Subjects on stable antidepressant medications for at least 3 months may be 
enrolled into this study (i.e., no change in medication drug or dosage for 3 
months). 
3.1.2 Exclusion Criteria 
1. Subjects with unstable cardiac status including: 
o Unstable angina pectoris on medication 
o Subjects with documented myocardial infarction within six months of 
protocol entry 
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o Subjects with unstable ventricular arrhythmias  
o Subjects with atrial arrhythmias that are not rate-controlled 
2. Subjects exhibiting any behavior(s) consistent with ethanol or substance abuse as 
defined by the criteria outlined in the DSM-IV as manifested by one (or more) of 
the following occurring within a 12 month period:   
➢ 
Recurrent substance use resulting in a failure to fulfill major role 
obligations at work, school, or home (such as repeated absences or poor 
work performance related to substance use; substance-related absences, 
suspensions, or expulsions from school; or neglect of children or 
household).  
➢ 
Recurrent substance use in situations in which it is physically 
hazardous (such as driving an automobile or operating a machine when 
impaired by substance use)  
➢ 
Recurrent substance-related legal problems (such as arrests for 
substance related disorderly conduct)  
➢ 
Continued substance use despite having persistent or recurrent 
social or interpersonal problems caused or exacerbated by the effects of 
the substance (for example, arguments with spouse about consequences 
of intoxication and physical fights).  
3. Severe hypertension (diastolic BP > 100 on medication)  
4. Subjects with standard contraindications for MR imaging such as non-MRI 
compatible implanted metallic devices including cardiac pacemakers, size 
limitations, etc.  
5. Known intolerance or allergies to the MRI contrast agent (e.g. Gadolinium or 
Magnevist) including advanced kidney disease 
6. Patient with severely impaired renal function with estimated glomerular filtration 
rate <30  mL/min/1.73m2 (or per local standards should that be more restrictive) 
and/or who is on dialysis; 
7. History of abnormal bleeding and/or coagulopathy 
8. Receiving anticoagulant (e.g. warfarin) or antiplatelet (e.g. aspirin) therapy within 
one week of focused ultrasound procedure or drugs known to increase risk or 
hemorrhage (e.g. Avastin) within one month of focused ultrasound procedure  
9. Active or suspected acute or chronic uncontrolled infection 
10. History of immunocompromise including those who are HIV positive. 
11. History of intracranial hemorrhage 
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13. Subjects with uncontrolled symptoms and signs of increased intracranial pressure 
(e.g., headache, nausea, vomiting, lethargy, papilledema).  
14. Individuals who are not able or willing to tolerate the required prolonged 
stationary supine position during treatment (can be up to 4 hrs of total table time.)  
15. Are participating or have participated in another clinical trial in the last 30 days 
16. Significant claustrophobia that cannot be managed with mild medication. 
17. Subjects unable to communicate with the investigator and staff. 
18. Presence of any other neurodegenerative disease such as Parkinson-plus 
syndromes suspected on neurological examination.  These include: multisystem 
atrophy, progressive supranuclear palsy, dementia with Lewy bodies, and 
Alzheimer’s disease.    
19. Anyone suspected to have the diagnosis of idiopathic Parkinson’s disease.  
Anyone with the presence of parkinsonian features including bradykinesia, 
rigidity, or postural instability will be excluded.  Subjects who exhibit only mild 
resting tremor but no other symptoms or signs of PD may be included.  
20. Presence of significant cognitive impairment as determined with a score ≤ 24 on 
the Mini Mental Status Examination (MMSE)  
21. Subjects with life-threatening systemic disease that include and not limited to the 
following will be excluded from the study participation: HIV, Liver Failure, blood 
dyscrasias, etc.  
22. Subjects with a history of seizures within the past year 
23.  Subjects with presence or history of psychosis will be excluded. Subjects with 
significant or active mood disorders including depression will be excluded. For 
the purpose of this study, we consider a significant mood disorder to include any 
subject who: 
➢ Scores ≥ 20 on the PHQ-9 questionnaire 
➢ Is currently  under the care of a psychiatrist  
➢ Is currently participating in cognitive-behavioral therapy 
➢ Has been hospitalized for the treatment of a psychiatric illness within 12 
months  
➢ Has ever received  transcranial magnetic stimulation 
➢ Has ever received electroconvulsive therapy 
 
 

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24. Subjects with risk factors for intraoperative or postoperative bleeding:  platelet 
count less than 100,000 per cubic millimeter, INR coagulation studies exceeding 
local institution laboratory standards, or a documented coagulopathy  
25. Subjects with brain tumors  
26. Any illness that in the investigator's opinion preclude participation in this study.  
27. Pregnancy or lactation.  
28. Legal incapacity or limited legal capacity.  
29. Subjects who have had deep brain stimulation or a prior stereotactic ablation of 
the basal ganglia 
30. Subjects who have been administered botulinum toxins into the arm, neck, or face 
for 5 months prior to Baseline. 
31. Subjects who have an Overall Skull Density Ratio of 0.45 (±0.05) or less as 
calculated from the screening CT. 
4 INVESTIGATION PLAN 
4.1 
Study Design Points 
4.1.1 Computer Algorithm for Randomization 
Randomization will be accomplished using a central computerized system (see also 
Section 5.5 below) with secure access from the study sites.  The investigator will be 
assigned a password to access the randomization and the site will be trained to 
maintain the blind.  For example, InSightec currently uses randomization routines 
provided by the Oracle database system which are accessible via the internet using 
Microsoft ISA (Internet Security and Acceleration).  These systems are maintained 
at InSightec’s main office in Haifa, Israel.   
It should be noted that: 
1 - The Core lab assessor and the participating sites will be blinded from each 
other’s databases.   
➢ Tremor Core Lab Assessor will review all videotaped assessments 
Baseline through Month 12 and will remain blinded to treatment 
assignment at all visits.  They will be asked if they can guess 
treatment group assignment at each recording they score in order to 
assess maintenance of blinding. 
➢ Additionally, the sites will have a designated individual qualified by 
training and expertise in movement disorders who will not be aware 
of the treatment arm assignment for each subject through Month 3 
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treatment group assignment at each recording through Month 3 in 
order to assess maintenance of blinding. 
➢ Subjects and site personnel (with the exception of the treating 
physician) will not be exposed to subject treatment assignment until 
al the Month 3 assessments are completed.  At Month 3, all subjects 
will be unblinded.  At each visit through Month 3, subjects will be 
asked if they can guess treatment group assignment in order to assess 
maintenance of blinding. 
2 - This randomization procedure and routines are similar to those used for 
the PMA P110039 that is currently under review (ExAblate body system for 
the palliation of painful bone metastases). 
4.1.2 ExAblate Test Arm Study Design 
The randomized ExAblate Test Arm subjects will proceed to the ExAblate treatment.  
These ExAblate Test Arm subjects will then be followed up for 3-months post-
ExAblate treatment to assess the study endpoints at study follow-up:  1day, 1week, 1 
and 3 month visits.  Subjects will be unblinded after the Month 3 assessments. 
All subjects will be followed for 12-months post-treatment to assess the treatment 
long term safety and durability with study visits at 6 and 12 months.  
4.1.3 Sham Arm Study Design 
The randomized, ExAblate Sham Arm subjects will proceed to the ExAblate sham 
treatment.  This ExAblate sham treatment procedure will be identical to that of 
ExAblate Test Arm except the energy output will be disabled.  These ExAblate 
Sham-treated subjects will then be followed up for 3-months post-ExAblate sham 
treatment to assess study endpoints; study follow-up:  1day, 1week, 1 and 3 month 
visits.   
At the 3-Months time point after all visit evaluation have been performed, 
all ExAblate Sham-treated subjects will be unblinded and offered cross over 
to the actual ExAblate treatment as long as they still meet all 
inclusion/exclusion protocol criteria.  They must exhibit a score of 2 or more 
on at least one of the Month 3 CRST questions 16-23 in order to continue 
to qualify.  All these Crossover Arm ExAblate-treated subjects will be 
followed according to the same schedule as the ExAblate-treated Arm 
through the Month 12 post treatment study visit.  Subjects may continue to 
be followed for an annual assessment through 5 years follow-up outside this 
protocol.  
 Note: at the time of the pre-Market submission, all available data of this 
cohort of crossed over subjects will be included in the submission. 
 

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4.1.4 Movement Disorders Central Lab Assessments 
For this study, the primary efficacy endpoint assessment from Baseline (i.e. immediately 
post medication observation/stability) through the Month 12 follow up visit will be 
performed by a central laboratory (Lab).  The PI of the central Lab will be a fully trained 
physician specializing in movement disorders. Core Lab will not be made aware of the 
study subject’s treatment assignment at any time during the course of the study. The 
purpose of the Tremor Core Lab review is to provide a uniform scoring across all sites. 
For this study, each subject’s tremor assessment (CRST) will be videotaped at Baseline as 
well as at each post treatment study visit so that they can be assessed by a blinded central 
Tremor Core Lab Assessor.  The videotapes/Memory cards (e.g.: SD Card) will be de-
identified and carefully labeled with the corresponding subject study ID number and sent 
to InSightec to catalogue and forward to the core lab for scoring.  The primary endpoint 
(mean change from Baseline) at Month 3 will utilize the Central Lab Blinded Assessor’s 
scoring.   
4.1.5    Videotaping Procedure  
The CRST assessments will be videotaped at all visits Baseline through Month 12; Routine 
Screening CRST video assessments may be obtained and used by core lab as a quality 
assurance check for videotaping techniques to provide feedback on best taping practices.  
Screening CRST assessments will not be used in determination of pivotal study endpoints.  
The goal of the videotaping procedure is to ensure a uniform format to enable the Core Lab 
assessor to score all subjects utilizing the same filming procedure.  This procedure is NOT 
meant to train assessors how to perform tremor assessment.  The CRST assessment will be 
done by qualified movement disorder specialists. 
The videotaping protocol is provided in Appendix B.  The videotaping protocol should be 
followed by all sites to provide a standardized format for core lab scoring as well as site 
scoring utilizing the same sequences.  The videotaping protocol provides a suggested 
sequence grouped by position to minimize discomfort of the subject and relocation of the 
camera.  Additionally, the items are grouped by body region and task for each position.   
4.1.5 Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will be used to review all AEs on the study. 
Their role is to evaluate all AE's that occur throughout the study and provide their 
assessment of the study safety profile as well as their recommendations for the study 
continuation.  The DSMB recommendations will be communicated to the FDA as part of 
the annual reporting for this proposed IDE study.   
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 (see Section-6.5). 

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4.2 
Screening Procedures 
The following steps are common to all subjects 
1. Subjects believed to have medication-refractory ET movement disorder will be 
offered an Informed Consent to sign prior to further evaluation.  Those who 
accept and sign the consent will be assigned a subject study identification number 
(ID#).  
2. The diagnosis of ET will be confirmed by a neurosurgeon or neurologist 
specializing in movement disorders, where a comprehensive neurologic 
examination will be performed, including the screening CRST  
3. Medication refractoriness will be defined when tremor persists despite adequate 
doses of at least trials of appropriate medical therapy.  At least one of the 
medications trialed should be a first line agent, namely propranolol or primidone.  
The other medication trialed should be a class B agent as defined by the AAN 
(2005 and 2011 references).  Adequate trial (daily) dosages are noted below or 
occur if dose-limiting side effects occur: 
First line (class A) tremor therapy:  
• Primidone 250 mg 
• Propranolol 240 mg 
• Propranolol LA 240 mg  
Second line (class B) tremor therapy: 
• Gabapentin 
• Topiramate 400 mg 
• Other Beta blockers: Atenolol or Sotalol 
Benzodiazepimes: Alprazolam or Clonazepam 
CT Imaging: 
For the purpose of this study, the CT exam should be an Axial scan with bone filter, an 
image resolution of 512x512, and image thickness of 1mm with zero (0) spacing.  This CT 
imaging will be utilized to compute the Skull Density ratio, and as part of the treatment 
planning should the subject qualifies for the study. 
During this one month “medication observation” phase, the current regimen of 
medications will be maintained to ensure tremor stability.  Screening laboratory and 
imaging studies will be obtained to complete the enrollment process.    
4. A complete medical history will be obtained to determine subject’s general health 
status; including blood analyses (for PT, PTT, CBC, platelets, and creatinine), and 
pregnancy urine test for women of childbearing age.  Positive test will exclude 
subjects from study.   In the event the pregnancy test is negative, she will be asked 
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5. PHQ-9 depression will be obtained.  All subjects who score ≥ 20 on the test will 
be excluded from the study.   
6. Medication stability and baseline measurements:  
In this study, all subjects will be tested again at the one month time point (±7days) post 
screening date.  At this visit, the following will be performed:  
• 
Medication stability: subjects will be asked to report any changes in 
medication taken for tremor consumed over the preceding month.   
o If the subjects do not show stability on mediations at 30 days, a 
second stabilization period may be initiated.   
• 
All those subjects on antidepressants must be on the same antidepressant 
medication at the same dose for the prior 3 months to be eligible. 
• 
Once the medication stability is confirmed, then all other baseline assessments  
will be performed;  
o CRST must be performed by a site blinded assessor (SBA) who is 
proficient in movement disorders.  The CRST evaluation must be 
videotaped for the Central Lab Assessment. 
o QUEST and imaging will also be performed after medication 
stability has been demonstrated.  
 
7. If at this point it is determined that the subjects does not meet all Inclusion and 
Exclusion criteria and cannot be treated, the subjects will be removed from the 
study.  These subjects will be considered screening failures, and will not be 
included in any of the safety or efficacy endpoint analyses.   
8. If the subject meets all the pre-imaging criteria, then the subjects will be 
scheduled for the MR .   
➢ MR Imaging:  For the purpose of this study, the following MR Exams will be 
performed.   
1. The pre-contrast MR Imaging should include the following: 
a) T2 Weighted imaging exam along these 2 axes: Axial and Sagittal 
8. A second physician specializing in movement disorders will review all the 
inclusion/exclusion criteria and verify that the subject meets the study screening 
criteria prior to randomization. 
9. Subjects who have been verified as meeting all study criteria may be scheduled 
for randomization to either the ExAblate Test Arm or ExAblate Sham Arm.  The 
Principal Investigator will log into the random database and obtain the treatment 
group assignment. 
 

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4.2.1 Treatment Procedures  
WARNING: 
In this study, subject participation is necessary during the course of the 
ablation procedures.  USE OF SEDATIVE MEDICATION MAY IMPAIR 
COGNITIVE FUNCTIONS OF THE SUBJECT. 
However, to alleviate subject anxiety that can develop during a lengthy 
procedure inside the MR scanner, low dose sedatives like benzodiazepines or 
dexmedetomidine or equivalent may be administered by slow titration so as 
to not impair the level of consciousness.  Subjects MUST always remain 
responsive to physician instructions. 
Any subject who is not appropriately responsive will not be allowed to 
continue on with any further treatment procedures until it is deemed 
clinically safe by the treatment team.  Sedation reversal with flumazenil or 
equivalent may be utilized if excessive sedation occurs.  If a subject cannot 
participate in the treatment after receiving sedation, the procedure will be 
aborted, and the subject will be considered as screen failure      
The following procedure steps would be common to all subjects.  Hence, the overall 
treatment procedure steps will be performed as follows: 
Subjects will present to the ExAblate TcMRgFUS treatment center on the morning 
of surgery “off” medication.   
1. An IV line of saline will be positioned for the delivery of fluids and any 
medications required during the procedure. Some of the subjects may require a 
urinary catheter to keep the bladder empty during treatment.  Noninvasive 
monitoring of heart rate, blood pressure, systemic oxygen saturation, 
electrocardiogram, and end-tidal CO2 will be maintained throughout the procedure 
using standard MR-compatible monitoring devices. 
o The anesthesiologist, or nurse anesthetist, or treating physician will be 
present to monitor subject’s overall well being.  Their major role is to 
monitor and control of blood pressure to prevent hypertension during the 
procedure.  Subjects must be able to communicate during the entire 
procedure, and must be able to operate the stop sonication button. 
o To address emergency situations should they occur, a standard ventilator 
should be available in close proximity to the MR scanning room; per local 
site clinical standards.   
2. The subject’s head will be carefully shaved and examined for pre-existing scalp 
scars or any other scalp lesions. 
3. Graduated compression stockings will be worn to prevent deep venous thrombosis 
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4. The subject’s head will be placed in the stereotactic head frame (similar to those 
used in stereotactic surgery and radiotherapy) for use during the actual ExAblate 
TcMRgFUS treatment. 
5. Subject will be positioned supine and headfirst on the MR/ExAblate therapy table.   
6. The half-spherical helmet containing the elements of ExAblate transducer will be 
positioned around the subject's head in the treatment position.  This should be 
done according to measurements taken from the pre-operative/imaging session(s).  
7. An elastic membrane will be attached to the Subject's head and to the transducer 
to create the acoustic coupling system between the ultrasound transducer and the 
scalp.  
8. The immobilization system will be secured over the subject head to maintain a 
constant relationship between the target and the transducer. 
9. A baseline assessment of symptoms of tremor will be obtained before the ablation 
procedure begins 
10. The interface between the scalp and the transducer (within the elastic membrane)  
will then be filled with degassed water.  This volume will be completely filled 
with care to avoid air bubbles between the face of the transducer and the scalp. 
Through active circulation and cooling system, the water will be maintained 
chilled throughout the procedure to avoid undesired heating of the scalp and skull. 
11. A 3D localizer MR scan will be obtained to allow further refinement of the 
position of the ExAblate transducer focal point with respect to the targeted zone.  
12. A series of MR images will be acquired to identify the target area, and plan the 
actual treatment   
o T2 Weighted imaging exam along at least 2 axes: Axial and Sagittal  
13. The pre-therapy MRI and CT image datasets will be registered to the T2 weighted 
MR images that were just acquired. This image fusion of pre-operative MR assists 
in the accurate delineation of the target area and determination of a safe 
sonication pathway 
o The fusion of the CT data is required for the computation of phase 
correction values to correct for skull aberration, and identification of 
intracranial calcifications 
o Scars of the scalp will be designated to ensure the ultrasound beam avoids 
these specific areas  
14. The treatment volume and plan will be defined by the neurosurgeon. The 
ExAblate TcMRgFUS system will automatically compute the number of 
sonications, and the (per sonication spot) phase and amplitude corrections 
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At this stage, all those subjects who do not meet the MR requirement will be 
considered screen failures. 
 
4.2.1.1 ExAblate Arm Treatment Procedures  
The following will be performed for all ExAblate Arm randomized subjects: 
1. A central point in the targeted area will be targeted with a low dose, sub-lethal 
energy level sonication to confirm the targeting accuracy on the MR images.  
Focal point position and/or transducer location will be adjusted as necessary. 
WARNING:  
The subject MUST be examined by the clinical team after each 
sonication for neurologic signs and symptoms and evidence of tremor 
suppression. 
2. To enhance the procedure safety and mitigate some of the inherent risks of thermal 
lesioning of brain tissue: 
a) 
The ExAblate Transcranial Thalamotomy will be performed as a series of 
sonications with increments in power within the designated target volume in 
the awake subject. 
b) The subject will be examined by the Subject Assessor during & after each 
sonication for neurologic signs and symptoms, and evidence of tremor 
suppression.  The subject assessor and subject are in direct communication 
with the neurosurgeon and treatment team at all times from within the MR 
suite. 
c) 
The series of sonications will start with low energy prior to permanent 
thermal ablation.  This is to ensure the planned sonication to be centered on 
the Vim nucleus of the Thalamus.  Low energy sonication will non-
destructively warm the target.  The warming will be captured by the MR 
thermometry and the MR thermal images will be displayed in real time to the 
treating physician.  The neurosurgeon will then verify that the warming is 
centered on the prescribed anatomic target.  This will allow the centering of 
the eventual permanent thermal lesion in the planned location. 
 
d) The titration of escalating focal sonications will continue up to full ablation 
of the targeted planned area for ablation.  This would be performed by 
utilizing the full feedback that is provided by the real time MR Thermometry.   
 
For this study, ONLY a unilateral lesioning/ablation will be performed using the 
ExAblate TcMRgFUS system in the absence of clinical side effect. 

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4.2.1.2 ExAblate Sham Arm Treatment Procedures  
The following will be performed for all ExAblate Sham Arm randomized subjects: 
To perform the sham treatment, the sonication will be performed with energy output 
disabled.   
For ethical reasons, the sham procedure should not exceed 45-min of sonication time 
and table time of no more than 1h 30min.  However, when possible the treating 
physician may determine a sonication (treatment) time for sham subjects to be similar 
to that which is occurring in the ExAblate Test Arm to maintain consistency between 
treatment arms.  It should be noted that all treatment times of both treatment arms will 
be captured in the study CRF. 
WARNING:  
The ExAblate Sham subject MUST be examined by the clinical team after each 
sonication for neurologic signs and symptoms in the same fashion as an 
ExAblate Test Arm subject. 
 
4.2.1.3 Patient Management during Treatment  
 The following treatment procedure instructions are applicable to all subjects in both 
treatment groups: 
• The ExAblate TcMRgFUS system is equipped with Stop Sonication Buttons:  
one for the subject to utilize, one for the nurse/anesthesiologist (subject 
monitor), and one for the treating physician to use.  Hence, in the event of 
discomfort or pain, the subject will have the ability to abort the sonication at 
any time by activating the Stop Sonication Button.  Once this button is 
activated, the system will instantly stop the energy delivery.  The same thing 
will happen in the event that the treating physician or the subject monitor 
activates their button.  After addressing the subject concerns or discomfort, the 
procedure may continue without further delay.  All adverse events that may be 
caused by these potential activation(s) of the Stop Sonication Button will be 
captured on the CRFs.  
• After the treatment, a series of MR images will be acquired to assess the 
treatment effects:   
a. T2 Weighted sequences to assess for peri-lesional edema, while the 
patient is still in treatment position 
Note: In the event new neurological deficits or seizures are observed, other 
imaging modalities (including CT) should be performed immediately per 
standard of care of local site for similar events.  These are in addition to 
neurological and physical examinations. 

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• Once the treatment is complete or otherwise terminated: 
a. Remove the subject from the ExAblate table and remove all 
monitoring equipment, elastic membrane, and stereotactic frame. 
b. Document neurological and physical examinations. 
• Following treatment subjects will complete a blinding form asking if they 
believe they received the test treatment or the sham treatment.  This will be 
used to evaluate the effectiveness of maintaining the blind.  
• Subject should be imaged again using the MR head Coil on the regular 
imaging scanner table.  This is to provide clinical quality imaging for analyses 
and comparison to baseline imaging: 
o T2 weighted sequence along the main axis.   
To make this additional imaging session more confortable to the subject, 
this may be performed within 24h of the completion of the treatment. 
• The subject will be transferred to the hospital for recovery and neurological 
observation until the next morning 
ALL imaging exams of this study must be forwarded to the Sponsor in a 
timely fashion immediately following their acquisition and properly 
anonymized from all subject identifiers. 
 
4.2.2 Post-Treatment Follow-up – All procedures for follow-up are common 
between treatment groups.. 
4.2.2.1 
Day 1 Follow-up Procedures:  
The neurosurgeon will perform the following exams and make a decision as to 
whether or not to discharge the subject.  Subjects who are found to be neurologically 
unstable will remain in the hospital until the neurosurgeon determines it is medically 
indicated to discharge.   
a) Review of medications 
b) physical exam 
c) neurological status 
Any adverse events will be recorded and followed.  The physician should treat the 
subject according to their best clinical judgment if adverse events are noted. 
4.2.2.2 
Week 1 
The following evaluations should be performed at Week 1: 
• Review of medications 
• Physical exam 

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• Neurological status 
• Adverse events 
• Blinding form asking if they believe they received the actual treatment or 
the placebo treatment.   
4.2.2.3 Month 1 and 3 
The following evaluations should be performed at 1 & 3 months: 
• Review of medications 
• Physical exam 
• Neurological Status 
• CRST by blinded site assessor with taping for Central Lab assessment 
• QUEST and PHQ-9-depression questionnaires should be completed by the 
subject 
o NOTE:   
At any follow up visit, any subject who scores ≥ 20 on the PHQ-9 
questionnaire, the subject should be referred out for psychiatric 
evaluation.  The Columbia Suicide Severity Rating Scale, or like, may 
be used.  Should there be a psychiatric treatment, then this psychiatric 
treatment should be recorded as an adverse event.  A Copy of the 
psychiatric evaluation should become part of the CRF information as 
part of the adverse event outcomes and description.  The investigator 
will evaluate whether the subject may continue participation in the 
study, or should be exited from the study for treatment 
 
• Adverse events 
• Blinding form asking if they believe they received the actual treatment or 
the placebo treatment.   
• At Month 3,  
1. 
All subjects may be un-blinded after completing all Month 3 
subject assessment measures. 
4.2.2.3.1 Sham Crossover 
At Month 3, Sham subjects may be crossed over to ExAblate treatment as long as they 
continue to meet all the inclusion/exclusion criteria in the protocol.  They must exhibit a 
score of 2 or more on at least one of the Month 3 CRST questions 16-23 and must score 
<20 on the PHQ-9 questionnaire in order to continue to qualify.  All crossover data and 
follow-up will be captured in the Crossover Arm database for this study.   

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4.2.2.3.2 Reasons for Study Exit 
In this study, subjects who opt for alternative treatments for Essential Tremor (not 
including medication change) at any point in the follow-up period will be exited from the 
study after completing required study examinations.  The last set of evaluations prior to 
alternative therapy is considered the last study visit.  The reason(s) for study exit will be 
noted on the Case Report Forms.  No analyses of post alternative treatment changes are 
planned.  
4.2.2.4 
Month 6 and 12 
To assess treatment long term safety and efficacy durability (i.e.: study secondary 
endpoint), follow up will also be completed at the 6 and 12 months post treatment.  At 
these visits, all the data will be collected in the same fashion with videotaped tremor 
assessments as during the other visits, except that subjects and site assessor may no 
longer be blinded.  These 6/12-Months videotapes must also be forwarded to the sponsor 
for storage. 
The following evaluations should be performed at Month 6 and 12: 
• Review of medications 
• Physical exam 
• Neurological status 
• CRST (SBA unblinded) with videotaping,  
• QUEST and PHQ-9-depression questionnaires should be completed by the 
subject 
o NOTE:   
At any follow up visit, any subject who scores ≥ 20 on the PHQ-9 
questionnaire, the subject should be referred out for psychiatric 
evaluation.  The Columbia Suicide Severity Rating Scale, or like, may 
be used.  Should there be a psychiatric treatment, then this psychiatric 
treatment should be recorded as an adverse event.  A Copy of the 
psychiatric evaluation should become part of the CRF information as 
part of the adverse event outcomes and description.  The investigator 
will evaluate whether the subject may continue participation in the 
study, or should be exited from the study for treatment 
• Adverse events 
• At Month 12 (ONLY), all subjects should undergo the following MR 
exams: 
• T2 weighted imaging  

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4.3 
  Study Requirements and Visit Schedule  
The table below summarizes the study visit schedule and procedures.   
 
The study visits are as follows: 
➢ Pre-treatment: 
Baseline: 1 Month ± 7 days post screening 
➢ Post-treatment: 
1 Week (i.e. 7 days) ± 3 days, 1 Month ± 7 days, 3 Month ± 14 days (or 2 weeks), 6 
Months ± 21 days (or 3 weeks), 12 Months ± 1 Month. 

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Table 4.2.2.3.2—1 
Summary of  Study Schedules and Measurements 
  
Screening 
Baseline 
A
t*
Treatment 
1 Day 
1 Week 
1 Month 
3 Month  
6 Month  
12 Month  
Consent 
X 
 
 
 
 
 
 
 
 
Eligibility Evaluation with labs 
X 
X 
 
 
 
 
 
 
 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
30 day meds stabilization 
 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
Neurological status 
X 
 
X 
X 
X 
X 
X 
X 
X 
CRST (unblinded) 
X 
 
 
 
 
 
 
X 
X 
Site Blinded Assessor CRST 
 
X 
 
 
 
X 
X 
 
 
Blinded Tremor Core Lab CRST 
 
X 
 
 
 
X 
X 
X 
X 
QOL (QUEST) 
X 
X 
 
 
 
X 
X 
X 
X 
PHQ-9 
X 
 
 
 
 
X 
X 
X 
X 
CT 
X 
 
 
 
 
 
 
 
 
MR 
 
X 
X 
 
 
 
 
 
X 
Treatment 
 
 
X 
 
 
 
 
 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
Exit Form 
 
 
 
 
 
 
 
 
X 

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5  DATA ANALYSIS PLAN 
5.1 
Safety 
Adverse events will be recorded and categorized according to severity, relationship to 
procedure and relationship to device.  All AEs will be assessed for their relationship to 
the study device or procedure. Standard Code of Federal Regulation definitions for 
Serious Adverse Events (SAEs) and Unanticipated Adverse Device Effects (UADEs) will 
be used in assessment of AEs. 
5.2 
Efficacy 
Primary effectiveness will be evaluated using validated scores; the Clinical Rating Scale 
for Tremors (CRST) for the ET patients, based upon patients where unilateral ExAblate 
thalamotomy was attempted (i.e., Intent-to-Treat analysis).   Efficacy is defined as a 
reduction in contralateral tremor of ET at 3-months post-treatment.    
5.3 
Subject Health Status 
The results from the physical and neurological exams will be recorded in the CRFs and 
will be analyzed.  
5.4 
Statistical Considerations and Sample Size 
The study will include a total of a minimum of 72 and a maximum of 80 randomized 
subjects in a 3:1 (treated:sham control) ratio at up to 8 sites. This sample size provides a 
20% increase due to potential subject dropout from the below rationale for 60 evaluable 
subjects. 
➢ The rational for this sample size is based upon the observation from the pilot study 
of a sample size of 15 of a 78% drop in Total CRST from a mean of 20.4 to 4.7 
while the untreated sample dropped 4%. Based upon these data, the power to detect 
a change in the treated vs sham control is greater than 99% with a sample size of 
60 subjects. In the crossover paired comparison, the power also is greater than 99%. 
➢ In order to detect the occurrence of side effects with at least a 5% frequency, the 
sample size was selected. With the proposed study design a total of 60 subjects will 
have safety data. With 45 subjects the probability of observing an event rate of 5% 
is 0.95 for the 60 subjects total, 0.90 for 45 subjects (treated vs control arm) and is 
0.52 for the 15 subjects in the crossover arm. The probability of observing an event 
rate of 0.01 is 45% with 60 subjects. 
➢ The additional 8 subjects above 72 is requested in order to accommodate treatment 
of subjects who have undergone the extensive screening and baseline evaluations 
from confirmation of eligibility to scheduling treatment within the center based 
upon availability of MR time. 

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5.5 
Randomization Plan  
The randomization of subjects, i.e., the actual treatment assignments, will be performed by 
the sponsor in advance of site enrollment using existing randomization routines in the 
Oracle software.  The randomization in a ratio of 3:1 (treated: sham control) will be 
performed.  The randomization plan will be known only to the Database Manager and the 
Clinical Project Manager in order to protect the blinding. 
5.6 
Analysis of Potential Confounders  
The effects of covariates will be assessed to determine the impact on the general 
applicability of the results obtained. Potential confounders assessed will include: 
• Study Center 
• Lesion location  
• Demographic characteristics such as Sex and Age 
• Baseline CRST Score 
A number of these potential confounders are categorical variables with a large number of 
categories (e.g., Study Center, Lesion Location). Keeping the number of categories as is 
will, in some cases yield small subgroups and substantially reduce power to evaluate 
potential confounders. To address this, categories will be combined by either grouping 
those with few observations into a single category (as is typically done for Study Center) 
or in a clinically meaningful manner. Grouping of categories will be specified and justified 
in the Statistical Analysis Plan (SAP) prior to data analysis. 
We will assess the effects of covariates (confounders) via logistic regression in which the 
dependent variable is Subject Success (Yes/No) and explanatory variables include 
Treatment and the covariate of interest. Each covariate will be tested separately. 
Assessing the effect of a potential confounder on treatment will be done by examining the 
degree to which the significance of the Treatment Effect changes with the inclusion of the 
covariate. Weakening or strengthening of the Treatment Effect in the presence of a 
covariate will be interpreted using both clinical and statistical considerations (e.g. 
examination of models that include interactions and including additional covariates in a 
single model). It is important to note that these interpretations must be done with care, as 
we can expect meaningful effects to occur by chance alone given the relatively large 
number of covariate analyses expected 
5.7 
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.  A sensitivity analysis of the baseline 
characteristics of subject drop-outs or withdrawals will also be performed to evaluate the 
presence of a drop-out bias.  

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5.8 
Statistical Analysis Plan.   
A comprehensive statistical analysis plan, including sensitivity analyses for example, will 
be completed in consultation with FDA prior to performing any data review or analysis for 
all data collected through Month 12.   
5.9 
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 [86], Ethics Committee or other regulatory bodies may 
receive copies of the study records and may review medical records related to the study. 
6 RISK ANALYSIS 
Worldwide, over 8000 treatments have been performed to date with the MR guided FUS 
ExAblate body system.  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, P040003 and 
subsequent supplements, and P110039).  This data has been re-examined by the study 
sponsor and it has been concluded that this risk analysis has limited applicability to the 
proposed clinical investigation.  The key consideration here is the fact that this proposed 
study is conducted with an ExAblate transcranial system that is completely different from 
the body system. This is system is referred to internally as the Brain system.  However, in 
principle, the body and brain systems have the same purpose namely to coagulate soft tissue 
within the body by means of MR guided high intensity focused ultrasound.  Additional 
risks, new and unique to this study are presented in Section-6.2. 
The potential risks described below will be explained to the subject in the informed consent 
process. 
6.1 
General Procedure Related Risks 
6.1.1 Risk of Magnetic Resonance Scanners: 
MRI has no known deleterious biological effects in subjects with no contraindications. The 
incidence of claustrophobia during MRI examinations is approximately 10-15%.  All 
subjects exhibiting claustrophobia will be exited from the study. 
6.1.2 Risk of Intravenous (IV) Catheter: 
There is a potential risk from the IV catheter used during the procedure. Participants 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 site. 

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6.1.3 Risk of Urinary Catheter:   
There is a potential risk if a urinary catheter is used during the treatment.  Participant may 
expect varying levels of Urinary Tract Infection due to the use of the urinary catheter.  In 
a different study for the ExAblate treatment of uterine fibroid (Pivotal study under IDE 
G020001 that lead to PMA approval under PMA # P040003), the incidence of this risk was 
found not to exceed 3.7%.  This procedure will follow the “standard of care” at the study 
site. 
6.1.4 Risk of Stereotaxic Head Frame:   
In this study, the Integra Radionics frame will be used for all treatments.  The main part 
of this frame is a metal based ring that serves as a base for the rest of the fixation 
components.  This frame comes with non-metallic posts mounts.  Into the non-metallic 
post mounts, accompanying nylon encapsulated screws with a metallic tip are fitted 
through the posts.  Only the metal tip of the screw is in contact with the patient.  The risk 
of any skin event at or in the vicinity of the metallic tips is mitigated by the fact that the 
screws outer shell are out of nylon, and therefore eliminates any electrical conductivity to 
the skin.  This is further mitigated by the fact that these screws are mounted on the non-
metallic posts that links them to the metallic ring.  Hence, the Integra frame is actually 
manufactured and sold with built in mitigating steps aimed at reducing / eliminating skin 
event risks. When the full set up is completed, the metallic ring is NOT in contact with 
the patient.  
6.1.5 Risk of Contrast Agent  
The MR contrast agent, Gadolinium-DTPA, is an intravenously injectable contrast medium 
for MRI.  The package insert notes that there are no known contraindications.   
Adverse reactions include: headache (incidence 8.7%), localized pain, vomiting, 
paresthesia, and dizziness and localized warmth (incidence less than 2%).  Additional AEs 
listed on the package insert occur with an incidence of less than 1%. 
Precautions should be exercised for subjects 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 
subjects with a known sensitivity to gadolinium or history of asthma.   
Nephrogenic Systemic Fibrosis or Nephrogenic Fibrosing Dermopathy (NFD), kidney 
disorders, may occur in subjects with moderate to end-stage kidney disease after they have 
had an MRI scan with gadolinium-based contrast agent.  NSF causes fibrosis of the skin 
and connective tissues throughout the body.  Subjects 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.   
6.1.6 Risks Incidental to the ExAblate Treatment 
There is a potential risk to the subject of deep venous thrombosis from lying in a supine 
position for 3 to 4 hours, but this risk is substantially mitigated by the avoidance of sedative 

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medications.   The risk to the subject from lying still for this treatment should be no greater 
than that of lying still for any other reason.  Subjects will be provided compression 
stockings, as described above (Section 4.3), for use during treatment and are able to move 
their lower extremities during the treatment.  DVT screening will be performed at the 
discretion of the primary treatment team for any subject deemed to be at a high risk for 
thrombosis.   
There is a risk that the subject may experience a sore neck or back, or discomfort / fatigue 
from lying in the same position for a long time during the treatment.   
6.1.7 Risks Associated with the ExAblate Treatment 
All efforts are undertaken to reduce risk related to the ExAblate treatment.  The following 
mitigations are in place for all procedures: 
1. The procedure is performed in the MR scanner. During the treatment MR images will 
be acquired. Using specific scanning sequences and a rapid post-processing program, 
changes in temperature can be detected, and a thermal map of the brain generated. 
This thermal map will reveal any potentially dangerous elevations in temperature. 
2. Study personnel can regularly assess cognitive and motor function throughout the 
procedure (i.e.: after each sonication) as well as general neurological function. This 
will help to reveal any indication that tissue damage may be occurring along the beam 
paths. 
3. Subjects are asked to relay all sensations (i.e., disorientation/dizziness, pain, 
numbness, etc) occurring during the procedure to the circulating staff so that 
adjustments can be made to accommodate modifications to the treatment plan or 
extend time between sonications. 
4. MR-compatible pulse oximeter, blood pressure cuff, and EKG monitor will be 
monitored throughout the procedure. This information will permit detection of tissue 
damage, edema, or bleeding, if brain or blood vessels along the beam paths are 
injured by heat. 
5. The subject, Subject Monitor and Assessor, and the neurosurgeon will each have a 
stop sonication button that can instantaneously interrupt the energy delivery at any 
time. The subject is given a stop sonication button in case aberrant tissue heating 
causes any compromise to speech, word finding, or other communication difficulties. 
The subject will be instructed prior to the proceeding that they should use the stop 
sonication button any time they feel excessive pain, discomfort, disorientation or any 
other unusual sensation. The neurosurgeon, Subject Monitor and Assessor, have stop 
sonication buttons so that if there is any sign of neurological change, the energy 
delivery can be immediately stopped and the subject carefully evaluated. Temporary 
interruption of energy delivery will in no way compromise the potential for 
therapeutic benefit to the subject. Following subject evaluation treatment can resume 
without delay   

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The following risks may be associated with the ExAblate Transcranial thermal ablation 
procedure: 
1. Pain and/or discomfort – There is a risk of discomfort to the subject caused by 
heating of tissue.  Focused ultrasound therapy involves precisely controlled pulses 
of thermal energy resulting in tissue coagulation (typically 55-65°C for several 
seconds) in small tissue volumes. This induces thermal coagulation of the targeted 
soft tissue.  The energy intensity at the level of the skin away from the pin sites is 
quite low and sonication through scar tissue should be avoided..  The subject may 
experience both a cold sensation from the active cooling circulation of water 
within the rubber diaphragm as well as a rise in temperature in the skull which 
should be kept to below pain level by the active cooling. Because the focal point 
of the beam will be > 2.5 cm from the dura and there are no pain receptors in the 
brain, there should be no pain associated with ablation, itself. 
The subject will be in constant verbal contact with the neurosurgeon and 
appropriate action can be taken in the event that a subject does experience pain 
discomfort. Remedies could involve lowering energy levels, or increasing the time 
interval between consecutive treatment pulses. The subject also has the ability to 
abort the sonication at any time by activating a handheld cut off circuit (i.e., stop 
sonication button). 
See also Risk 9c regarding heating of the dura mater and the meninges. 
2. Headache – The subject may experience a headache during or after the procedure 
which may be related to the pin site, slight swelling around the ablated brain 
tissue, or a reaction to the contrast media and should be transient. 
3. Disorientation, light-headedness, dizziness, unsteadiness, nausea/vomiting:  There 
is a potential risk that the subject will have sensations of light-headedness, 
dizziness, unsteadiness or even nausea/vomiting.  Based on the current data, these 
events should be transient and resolve within a day or so. 
4. Occurrences of transient numbness, tingling, eye twitch, hyperesthesia and/or 
paresthesia of the scalp, face and upper extremity have been reported in subjects 
undergoing Vim ablation for essential tremor.  These generally are transient are 
resolved within minutes to one day.  One paresthesia lasted for 4 days; one scalp 
numbness lasted 2.5 months.   
5. BBB disruption, edema, swelling, hemorrhage or stroke: There is a potential risk 
of hemorrhage during ExAblate procedure 
a. At the focal point or targeted area -  In ExAblate thermal ablation, the high 
temperature at the focal point results in immediate protein denaturation 
and coagulative necrosis. This should be expected to rapidly stop any 
bleeding that might occur in the capillary bed and within small vessels. 

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b. Outside and remote to the targeted area.. Alternatively, there could be a 
disruption of the Blood Brain Barrier (BBB) which would allow blood to 
seep out of the cranial blood vessels into the brain tissue.  These events 
may theoretically occur due to heating effects (i.e. secondary hot spots) 
and or to the pressure wave of the ultrasound beam.  To address the risks 
due to pressure waves of the ultrasound beam path, the system has been 
designed to be well below the “pressure wave threshold” that may trigger 
events of this nature.   
In all cases, thermal and regular imaging will be continuously assessed during the 
procedure.  Furthermore, at the end of the ExAblate procedure, a contrast (Gadolinium) 
enhanced MR scan is performed to assess the blood flow within the treated area and 
adjacent tissue.  This exam constitutes an independent treatment assessment tool that 
provides further information on blood flow and can serve as final check of the overall 
tissue status and alert the physician to any significant edema, hemorrhage, and any 
other significant BBB disruption effect(s).  Finally, the subject(s) is continuously 
monitored during the ablation procedure for any change in condition. 
6. Imprecise focal point and ablation of tissue outside of target. There is a risk of 
imprecise targeting of the focal point, and ablation of an area of tissue outside the 
planned treatment volume. If this occurred it is possible that serious neurological 
deficit or even death could result. To limit the risk of this occurring, the treatment 
process includes a mandatory verification step that requires the operator to first 
check the alignment of the subject anatomy, the focal point of the transducer and 
the MR imaging system.  This procedure, done while the subject is in position for 
treatment, uses a very low energy sonication to confirm of the alignment of the 
focal point and the targeted treatment point in all three 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.  
At any point in the treatment process this low-power verification of the localization 
may be repeated prior to full power sonication. 
7. Subject movement during the procedure that causes focal point to move/change 
location – There is a risk associated with subject motion during a sonication or 
between sonications. This could cause a movement of the tissue 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.  Also, because the 
skull functions as a defocusing lens, the phase correction map computed for the 
target spot will become ineffective if the subject moves.  To prevent or minimize 
this risk, there are several precautions taken to prevent motion, and to detect it, if 
it occurs:   
a. During subject positioning every effort will be made to make the subject 
comfortable and the subject will be educated as to the importance of 
maintaining their position during the treatment.  

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b. The subject will be placed in a head immobilization unit based on a 
stereotactic frame. This technology has been effective in preventing 
movement in stereotactic neurosurgery, and has been adapted and 
modified to the specification of the ExAblate.  The transducer and the 
immobilizer are locked together so that the transducer moves with the 
frame. 
c. The system is designed to detect motion and will abort a sonication if 
motion occurs during the sonication and will indicate that motion has been 
detected prior to the next sonication being performed. 
d. One or more members of the medical team will be in the room throughout 
the sonication to monitor the subjects' medical status and comfort.  Hence, 
subject motion will also be monitored. 
8. Risk of cavitation - There is a risk of cavitation in the tissue at the focal point. 
Cavitation is the collapse of rapidly developed gas bubbles at the focal point due 
an extreme intensity of ultrasound excitation. This rapid collapse could cause high 
pressure, shock waves, and high temperatures. However, we believe that through 
proper system design and careful selection of system operation envelope, there is 
a very minimal risk that cavitation could occur during a treatment, even in the 
event of user error. We have developed an automated treatment planner that takes 
as its input the targeted ablation area depth in tissue, focal volume and tissue 
absorption, and based on pre-set safe operating limits selects sonication 
parameters that will keep the intensity of ultrasound excitation well below the 
intensity levels that could cause cavitation. 
9. Risk related to sonication pathway - There is the risk that the tissue along the path 
to the target (scalp, skull, dura, brain, etc) could become heated to the point where 
tissue-damage might occur which could result in significant neurological damage 
or even death.  This heating could be caused by direct improper treatment 
targeting, irregularities on the skin surface (e.g.: scars), treatment of a volume of 
tissue too close to the skin or bone, energy absorption by the bone, or the 
conduction of sufficient heat to cause a burn. The heating in the energy pass zone 
is always monitored and an additional cooling time can be administered when 
elevated temperatures are detected.  Below are some possible risks related to the 
sonication pathway through different tissues in the head:. 
a. . Skin burn is a potential risk due to improper acoustic coupling. There 
have been no cases of skin burn in all ExAblate transcranial treatments to 
date.  The treatment set-up process includes filling the gap between the 
ultrasound transducer and the skull with a water-filled membrane to 
provide acoustic coupling. There is a possibility of small air bubbles 
remaining attached to the skin.  These could cause a small focal hot spot 
and cause local pain or a burn to the scalp. The active cooling mechanism 
unique to this system is designed to reduce the risk of skin burns and 

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improve subject comfort.  In previous studies, ExAblate treatments have 
caused burns of the skin using the ExAblate Body system. To minimize 
this risk, the scalp will be carefully shaved, and scars or other irregularities 
(e.g. eczema) will be kept outside the treatment pathway. Subjects with 
remarkable atrophy and poor healing capacity of the scalp (> 30% of the 
skull area traversed by the sonication pathway) will be excluded from this 
study 
The subject will be in constant verbal contact with the neurosurgeon and 
appropriate action can be taken in the event that a subject does experience 
pain discomfort. Remedies could involve lowering energy levels, or 
increasing the time interval between consecutive treatment pulses. The 
subject also has the ability to abort the sonication at any time by activating 
a handheld cut off circuit (i.e., stop sonication button). 
b. Skull and air-filled spaces: In the treatment planning, air-filled spaces 
(frontal, ethmoid, sphenoid sinus, mastoid) inside the skull are identified 
in bone window CT images and kept outside the pathway.  Should the 
operator not identify all air filled cavities on the treatment path, sonication 
through these areas could cause heating and result in burn of the tissue 
lining the cavity.  Operators are trained to avoid these sonication pathways 
by marking their existence on the CT scans. 
Other irregularities of the skull, which might scatter the acoustic energy, are 
compensated for in the system. Skull may become heated by absorbing 
more acoustic energy than normal soft tissue. The skull cannot sense pain 
but the overlying soft tissues may sense pain if the bone becomes heated. 
MRI thermometry at 1.5 T is able to detect changes of  ±3 Celsius in soft 
tissues [86]. Possible heat transfer from the skull bone to the brain by 
successive sonications is monitored by MRI thermometry of the cortex and 
white matter. The sonication duration and energy levels, and the cooling 
times between the sonications are adjusted so that the focus in the target 
tissue is heated while allowing other tissue to cool down between 
sonications. Local bone damage is unlikely because the active cooling 
mechanism system is designed to keep the bone temperature below a 
temperature that can damage it.  Based on the data acquired to date and 
reviewed by FDA under G020182/S04, the average temperature rise at the 
skull level ranges between 1° to 5° Celsius.  Hence, this active cooling 
strategy should continue to provide the safety needed.  
c. Dura, meningeal arteries and venous sinuses: The dura adjacent to the 
skull may absorb heat if the bone becomes heated. Dura itself may sense 
pain and the main branches of the arteries are sensitive to heat. The 
meningeal arteries can generally be avoided in the treatment planning as 
their grooves in the skull are visible in 3D-CT. Local necrosis of the dura 
is unlikely, and were it to happen, it would not cause cerebrospinal fluid 

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leakage. The venous sinuses between the two leaves of the dura, the 
sagittal sinus, the straight sinus and the transverse sinus may be in the 
sonication pathway. Their heating will be avoided by the active cooling 
sub system. The sigmoid sinus and the cavernous sinus will be kept 
outside the pathway due to their proximity to the skull base and cranial 
nerves, respectively.  
d. Subarachnoid space: Cerebrospinal fluid in the thin subarachnoid space 
between the dura and the cortex could possibly transfer heat from bone to 
the cortex.  There is no specific risk to the CSF itself becoming heated.   
Because it can flow within the subarachnoid space, this can serve as 
another mechanism to prevent local hot spots next to the skull.  
e. Cortex: In previous studies, ExAblate thermal ablation of deep foci in the 
rabbit brain there was no detectable heating of the cortex on MRI or 
evidence of opening of the blood-brain-barrier elsewhere than at the focus 
of the beam.  Elevated temperature in the eloquent cortical areas (motor, 
sensory, visual, auditory, speech) might cause neurological deficits or 
seizures Temperatures in the eloquent areas will be monitored by MRI 
throughout the procedure and the cooling time between sonications will be 
increased if unacceptable thermal buildup is detected. 
f. Brain, cranial nerves and cerebral arteries: In this study the treatment 
path will avoid cranial nerves and major cerebral arteries.  Operators are 
trained to mark them on the MR for the purpose of avoidance during 
sonication. 
g. Target ablation and the adjacent brain tissue:  Thermal lesioning for 
the treatment of tremor through thalamotomy may carry some risks in 
particular to the internal capsule, ventral posterolateral nucleus of the 
thalamus.  To mitigate these risks, the ExAblate treatment will be 
performed in small incremental sonications within the designated target 
volume in the un-anesthetized subject.. The subject will be examined by 
the Subject Assessor after each sonication for evidence of symptom 
suppression or clinical side effect.  The titration of escalating focal 
sonications will start from well before evidence of thermal heat is detect 
by MR thermometry and will continue until clinical symptom suppression. 
This procedure will allow re-adjusting the targeting based on real time 
feedback from intra-procedure examination.  This process is designed to 
enhance the procedure safety and minimize the potential adverse events 
that may be encountered in this study.  
h. Micro-calcification:  The subject population of this study may have some 
level of micro-calcification present in the brain tissue.  Given calcium’s 
higher absorption of ultrasound energy, its presence may create additional 
heating effect along the beam path.  This risk is mitigated by utilizing the 

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CT data (to localize the calcified areas) and the various tools of the 
ExAblate system to delineate these areas so that the beam is blocked from 
passing through these calcified areas.   
i. Secondary Hot Spots:  Theoretically speaking, there is a potential risk 
due to secondary hot spots that may occur along the beam path outside the 
focus.  This has been reported in the literature for different types of 
transducer configurations using similar frequencies.  The ExAblate 
system, with its unique, highly focused transducer configuration, was 
tested extensively using advanced simulations.  The results of this work 
showed no evidence of significant hot spots away from the focal area.  In 
any case, the real time thermal imaging feedback samples the entire field 
of view around the targeted tumor.  These thermal images are displayed 
during the course of the energy delivery and therefore if any evidence of a 
secondary hot spot is observed, the treating physician will be able to 
utilize the ExAblate system “real-time” stop sonication button that 
instantaneously halts energy delivery.  Importantly, the system is well 
equipped to handle it in real time and prior to incurring any tissue damage 
by shutting down the sonication prior to use of a Stop Sonication button 
being depressed.. 
10. Neurological risks Thermal “lesioning” in the brain may lead to heat transfer to 
immediately surrounding brain tissue or to hemorrhage. For a short period of time 
following the treatment, the surrounding tissue may be affected by inflammatory 
reaction. The length of the period cannot be predicted, but would be expected to 
resolve in 2-3 weeks based on our prior experience with sequential imaging in 
focused ultrasound thalamotomy for ET. These mechanisms may cause transient 
local neurological deficits or symptoms. These complications are not typically 
permanent. If these symptoms are detected, medical management with 
dexamethasone and/or mannitol might be effective.  In severe cases, a craniotomy 
can be performed to relieve increased intracranial pressure, and permanent 
neurological deficits or death could possibly result.  
No benefit – The subject may receive no benefit from this procedure.  While ablation of 
the Vim has generally been shown to be effective in tremor reduction, there is the chance 
that it will not be effective for the subject, or that the effect may not be permanent.   
6.2 
Anticipated Treatment Side Effects from ExAblate 
All adverse events will be reported in the Case Report Forms (CRFs) and analyzed for their 
relationship to the treatment device, the procedure, and disease progression. 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 
subject.  

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Non-significant Anticipated Treatment Side Effects of ExAblate treatment are those that 
normally resolve without sequelae within 1-14 days of the treatment: 
➢ minor pain from subject positioning or system interface (i.e. back pain, soreness 
in neck).  
➢ transient fever: oral temperature >100.4oF/38oC, lasting less than 24 hours 
➢ minor (1o or 2o) skin burns less than 2 cm in diameter 
➢ bruising of the skin along the treatment path 
➢ increase in edema surrounding the treatment area as shown on MRI.  
➢ Headache 
➢ Dizziness, nausea or vomiting 
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 
following side effects are thought to be improbable but their relative risk remains to be 
defined: 
Scalp in the sonication pathway: 
➢ skin burns (>2o) with ulceration of the skin 
➢ scar formation 
➢ Loss of sensation 
➢ atrophy 
Bone in the sonication pathway: 
➢ bone necrosis 
Dura, venous sinuses, and cortical veins 
➢ subdural bleeding 
➢ vein thrombosis 
➢ Cortex 
➢ seizures 
➢ symptoms from disturbances of eloquent cortical areas (motor, sensory, auditory, 
visual, speech) 
Other brain tissue 
➢ necrosis of normal tissue due to incorrect targeting 
➢ thermal damage to adjacent functional brain tissue (e.g.: optical tract) 
➢ bleeding in the treated area 
➢ cerebral infarction 
➢ neurological deficits 
➢ moderate or severe increase in cerebral edema as shown by MRI scans 

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➢ symptomatic increase of intracranial pressure 
➢ death 
Cerebral arteries 
➢ bleeding 
➢ coagulation thrombosis 
➢ vasospasm 
➢ death 
The experience of Significant Anticipated Treatment Side Effects in ExAblate treatment in 
the breast and uterus have been less than 5% as shown in prior clinical experience. In brain 
treatments there is limited prior experience with the ExAblate Transcranial system and the 
probability of an adverse effect is unknown.  It is the purpose of this study to gain 
experience that will allow us to evaluate the safety of ExAblate Transcranial system of 
TDPD (See also Section-6.1.7.d). 
6.3 
Adverse Reactions and Precautions 
The subjects will be educated as to what to expect during the procedure and the importance 
of immediately communicating any problems, unusual symptoms, or discomfort, to the 
investigator during the treatment and throughout the follow-up period. Subjects will also 
be educated as to what sensations or perceptions could indicate that neurological damage 
may be starting to occur. They will be told to use their handheld stop sonication button if 
they perceive anything unusual may be happening so that they can be neurologically 
assessed. All adverse reactions occurring in this study will be recorded in the Case Report 
Forms.  Each AE will be assessed for its cause (i.e., categorized as definitely, probably, 
possibly, or unrelated to the device, procedure or disease progression).  Alternative 
treatments resulting from post-surgical changes in neurological status will be captured and 
reported.   
6.4 
Criteria for Removal from the Study 
The investigator may withdraw subjects from the study as is deemed necessary or deemed 
to be in the best interests of the subject, such as, 
➢ continued noncompliance with the protocol or study visits,  
➢ severe illness or disability during the study for non-study issues, 
➢ pursuit of subsequent alternative treatment for the same condition, or 
➢ development of intolerable side effects where continued follow-up becomes too 
burdensome.   
In addition, a subject may also chose to exit the study at any time, but will be strongly 
encouraged to participate in the follow-up visits for safety reasons (continued monitoring 
of subject safety).   

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6.5 
Rules for Stopping the Study 
This study may be stopped, if, in the opinion of the DSMB, serious risks to the health and 
welfare of subjects are observed that are directly related to the use of the device.  The 
following scenarios would invoke this section of the protocol to stop the study while the 
cause of the safety concerns is being investigated and to determine relation of these safety 
events to the device, along with any possible mitigating steps s to protect patients from 
device harm.  Either of the following scenarios would create cause for stopping the study 
to evaluate patient safety: 
➢ Any death that is deemed to be caused by the ExAblate treatment 
➢ 2 or more events of intracranial hemorrhage deemed to be caused by the ExAblate 
device 
➢ Any other serious, related Unanticipated event that causes significant disability/ 
harm to the subject that is deemed to be the result of the ExAblate device. 
Investigator(s) shall promptly report the occurrence of any such events to the Sponsor (i.e. 
InSightec) and the Sponsor shall promptly initiate review by the DSMB as well as reporting 
such event(s) to the FDA.  Once the DSMB has had an initial assessment of an event of 
this type, it may recommend stopping the study in order to investigate fully the events and 
circumstances.  This will be communicated to FDA and all IRBs and sites.  With full 
cooperation of the treating investigator and the Sponsor, the DSMB will evaluate the 
circumstances of the event, determine relation of these events to the ExAblate, and whether 
any modifications to the protocol or the device must be made to improve safety.  The 
Sponsor will keep FDA informed of the results of the DSMB evaluation and of any 
potential actions taken by the Sponsor.  Once the review is completed and any mitigations 
are in place, and the DSMB recommends re-opening the study with concurrence by the 
FDA, then then InSightec will communicate this with all sites and their IRBs to begin to 
re-open and continue the study. 
6.6 
Adverse Event Reporting 
It is the responsibility of the investigator to document all AE’s occurring 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 CRF. The 
nature of each event, date and time (when appropriate) of onset, outcome, frequency, 
maximum intensity, action taken, expectedness, and causal relationship 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.  
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 

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• 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.  AE’s that do not 
affect the safety or overall well being of the subject, are mild/moderate in nature, are 
estimated to be temporary in duration even though the exact end date may not be 
determined a priori (e.g., eye twitch increased from baseline) may be presented and 
discussed with DSMB to determine their final classification status as a serious or non-
serious adverse event. 
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.  
6.7 
Data Safety Monitoring Board 
A Data Safety Monitoring Board will be used to review all AE’s on the study. Their role 
is to evaluate all AE's that occur throughout the study and determine if they are in fact 
related to the ExAblate, or some other cause. Investigators will monitor all treatments for 
any AE's, and consider the following questions for AEs in the Test Arm: 
- Was the adverse event serious? 
- Was the adverse event life-threatening, caused a disability, required or prolonged 
hospitalization, or caused death? 
- Was the adverse event device related? 
- Was the adverse event unexpected? 
- Is there an unreasonable risk in continuing the trial? 

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Adverse Events meeting all the above conditions would require reporting to the FDA, 
stopping the study pending the results of further investigation, and FDA approval to re-
start the study.  Following the DSMB review of the event, and if in the opinion of the 
DSMB, a modification of the study protocol were necessary to provide adequate protection 
to future study participants, the modification would be implemented prior to reinitiating 
the investigation.  Any such amendment would be reported to the IRB and FDA for their 
respective approvals to re-start the study as it is required by the 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 POTENTIAL BENEFITS 
There may or may not be any benefit to participating in this study.  This technique is still 
being investigated.  It may provide some therapeutic value for subjects with few or no other 
options due to the great risk that would be involved in open resection. The symptoms may 
decrease and/or the quality of life of the subject may improve due to relief of symptoms.  
However, there is no guarantee that this procedure will reduce, eliminate symptoms, or 
otherwise treat the underlying disorder.  Other subjects may benefit from this procedure in 
the future, if further trials prove it to be a safe and effective therapy.   
8 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 GCP requirements;  
➢ The trial is conducted according to InSightec internal SOPs 
➢ 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.  
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 

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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. 
8.1 
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).   
9 INVESTIGATOR RESPONSIBILITIES 
The Principal Investigator will be required to sign the Investigator Agreement.  All 
investigators will undergo extensive training on the protocol and operation of the ExAblate 
system, and provide documentation of their specialized training. 
10 
APPENDICES 
Appendix – A: Informed Consent 
Appendix – B: Videotaping Protocol 
 
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effective stimulation intensity. J Neurosurg, 2004. 101(2): p. 201-9. 
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Clement, G.T. and K. Hynynen, A non-invasive method for focusing ultrasound 
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array for trans-skull ultrasound surgery and therapy. Journal of Ultrasound in 
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Hynynen, K., et al., Pre-clinical testing of a phased array ultrasound system for 
MRI-guided noninvasive surgery of the brain--a primate study. European Journal 
of Radiology, 2006. 59(2): p. 149-56. 
45. 
Hynynen, K. and F.A. Jolesz, Demonstration of potential noninvasive ultrasound 
brain therapy through an intact skull. Ultrasound Med Biol, 1998. 24(2): p. 275-
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Cohen, Z.R., et al., Magnetic resonance imaging-guided focused ultrasound for 
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Ram, Z., et al., Magnetic resonance imaging-guided, high-intensity focused 
ultrasound for brain tumor therapy. Neurosurgery, 2006. 59(5): p. 949-55; 
discussion 955-6. 
49. 
Martin, E., et al., Focused Ultrasound for Non-invasive Neurosurgery. Annals of 
Neurology, 2009. In press. 
50. 
Jolesz, F.A., A.R. Bleier, and R.S. Lauter, Laser surgery benefits from guidance 
by MR. Diagn Imaging (San Franc), 1990. 12(9): p. 103-8. 
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imaging. Magn Reson Q, 1994. 10(2): p. 85-96. 
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Jolesz, F.A. and N. McDannold, Current status and future potential of MRI-
guided focused ultrasound surgery. Journal of Magnetic Resonance Imaging, 
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Moonen, C.T., et al., Thermal therapies in interventional MR imaging. Focused 
ultrasound. Neuroimaging Clinics of North America. 11(4): p. 737-47. 
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Salomir, R., et al., Image-based control of the magnetic resonance imaging-
guided focused ultrasound thermotherapy. Topics in Magnetic Resonance 
Imaging, 2006. 17(3): p. 139-51. 
56. 
Kleiner-Fisman, G., et al., Subthalamic nucleus deep brain stimulation for 
parkinson's disease after successful pallidotomy: clinical and electrophysiological 
observations. Mov Disord, 2004. 19(10): p. 1209-14. 
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White, D.N., Neurosonology pioneers. Ultrasound Med Biol, 1988. 14(7): p. 541-
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ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg, 
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59. 
Fry, W.J., et al., Production of focal destructive lesions in the central nervous 
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Lele, P.P., Production of deep focal lesions by focused ultrasound--current 
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5(2): p. 117-21. 
63. 
Fry, F.J. and J.E. Barger, Acoustical properties of the human skull. J Acoust Soc 
Am, 1978. 63(5): p. 1576-90. 
64. 
Fry, F.J., S.A. Goss, and J.T. Patrick, Transkull focal lesions in cat brain 
produced by ultrasound. Journal of Neurosurgery, 1981. 54(5): p. 659-63. 
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Lynn, J.G., et al., A new method for the generation and use of focused 
ultrasound in experimental biology. J. Gen. Physiol., 1942. 26: p. 179-193. 
66. 
Smith, S.W., et al., Some Advances in Acoustic imaging through Skull. 
Symposium on Biological Effects, 1997: p. 37-52. 
67. 
Guthkelch, A.N., et al., Treatment of malignant brain tumors with focused 
ultrasound hyperthermia and radiation: results of a phase I trial. J Neurooncol, 
1991. 10(3): p. 271-84. 
68. 
Clement, G.T., et al., A hemisphere array for non-invasive ultrasound brain 
therapy and surgery. Phys Med Biol, 2000. 45(12): p. 3707-19. 
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Clement, G.T., J. White, and K. Hynynen, Investigation of a large-area phased 
array for focused ultrasound surgery through the skull. Phys Med Biol, 2000. 
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patient with deep brain stimulation electrodes for the treatment of Parkinson 
disease. Case report. J Neurosurg, 2003. 99(4): p. 772-4. 
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Vykhodtseva, N., et al., MRI detection of the thermal effects of focused 
ultrasound on the brain. Ultrasound Med Biol, 2000. 26(5): p. 871-80. 
72. 
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Sansur, C.A., et al., Incidence of symptomatic hemorrhage after stereotactic 
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during stereotactic procedures. J Neurosurg, 2007. 107(5): p. 983-8. 
76. 
Xiaowu, H., et al., Risks of intracranial hemorrhage in patients with Parkinson's 
disease receiving deep brain stimulation and ablation. Parkinsonism Relat 
Disord. 16(2): p. 96-100. 
77. 
Pahwa, R., et al., Long-term evaluation of deep brain stimulation of the thalamus. 
J Neurosurg, 2006. 104(4): p. 506-12. 
78. 
Duma, C.M., et al., Gamma knife radiosurgery for thalamotomy in parkinsonian 
tremor: a five-year experience. J Neurosurg, 1998. 88(6): p. 1044-9. 
79. 
Ohye, C. and T. Shibazaki, Treatment of functional disorders with gamma knife 
thalamotomy. Prog Neurol Surg, 2009. 22: p. 170-81. 
80. 
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Part 1-a Historical Perspective with Modern Applications. Neurosurgery, 2009. 
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81. 
Gianfelice, D., et al., MR imaging-guided focused US ablation of breast cancer: 
histopathologic assessment of effectiveness-- initial experience. Radiology, 2003. 
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Gianfelice, D., et al., MR imaging-guided focused ultrasound surgery of breast 
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findings. Breast Cancer Res Treat, 2003. 82(2): p. 93-101. 
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Gianfelice, D., et al., Feasibility of magnetic resonance imaging-guided focused 
ultrasound surgery as an adjunct to tamoxifen therapy in high-risk surgical 
patients with breast carcinoma. J Vasc Interv Radiol, 2003. 14(10): p. 1275-82. 
84. 
Gianfelice, D., et al., Palliative treatment of painful bone metastases with MR 
imaging--guided focused ultrasound. Radiology, 2008. 249(1): p. 355-63. 
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Version date: August 13, 2017 
Clinical Protocol Appendix  NCT01827904 
 
Version Date 
August 13, 2017  
Amendment No. 
2 
Protocol Number 
ET002-LTF Appendix to ET002 
PAS Number 
P150038/S004 
Protocol Title 
A Long-term Observational Follow-up Study of Medication 
Refractory Essential Tremor Subjects Treated with ExAblate 
Neuro Thalamotomy under P150038 
 
Approvals: 
Site 
Sponsor 
 
 
 
 ______________________________________  
Principal Investigator                            Date 
 
  
Date 
Signature 
 
 
 
 
 __________________________________  
Nadir Alikacem, PhD,                        Date 
VP Global Regulatory Affairs and CRO  
InSightec      
 
 
 

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A Long-term Observational Follow-up Study of Medication Refractory Essential 
Tremor Subjects Treated with ExAblate Neuro Thalamotomy in Clinical Trials 
 
The Objective of this observational follow-up study is to collect long-term information 
regarding the Safety and Efficacy of medication-refractory Essential Tremor subjects 
treated with the ExAblate Neuro System under P150038 (original IDE# G120246).   
 
The Indications for Use claim for this system is as follows:   
The ExAblate Neuro is intended for use in the unilateral Thalamotomy 
treatment of idiopathic Essential Tremor patients with medication-
refractory tremor.  Patients must be at least age 22. The designated 
area in the brain responsible for the movement disorder symptoms 
(ventralis intermedius) must be identified and accessible for targeted 
thermal ablation by the ExAblate device. 
 
  
Protocol Number: 
ET002-LTF 
  
  
 
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Table Of Content 
1. 
1. BACKGROUND and SIGNIFICANCE ..............................................................5 
 
Movement Disorder in Essential Disorders Patients .................................................. 5 
 
ExAblate Neuro System. ............................................................................................ 5 
2 
OBJECTIVES .........................................................................................................6 
 
Primary Endpoints .................................................................................................... 6 
2.1.1 
Safety ................................................................................................................................ 6 
2.1.2 
Effectiveness...................................................................................................................... 6 
2.1.2.1 
Efficacy Assessments ................................................................................................ 6 
 
Study Hypothesis ....................................................................................................... 7 
 
Case Report Form Data ............................................................................................. 7 
3 
DESCRIPTION OF PATIENT POPULATION .....................................................7 
 
Patient Selection ........................................................................................................ 7 
3.1.1 
Inclusion Criteria ............................................................................................................... 7 
3.1.2 
Exclusion Criteria .............................................................................................................. 7 
4 
INVESTIGATIONAL PLAN ..................................................................................7 
 
LTF Follow Up Periods Years 2 – 5 Post Treatment ................................................. 7 
 
Exit from the study for reason of alternative treatment ............................................. 8 
 
Study Requirements and Visit Schedule .................................................................... 8 
5 
DATA ANALYSIS PLAN ...................................................................................... 10 
 
Safety ....................................................................................................................... 10 
 
Efficacy ................................................................................................................... 12 
 
Subject Health Status .............................................................................................. 12 
 
Statistical Considerations and Sample Size ............................................................. 12 
 
Missing Data ........................................................................................................... 12 
 
Statistical Analysis Plan. ......................................................................................... 12 
 
Subject Confidentiality ............................................................................................ 13 
6 
PMA P150038 Specific Questions ......................................................................... 13 
7 
RISK ANALYSIS .................................................................................................. 13 
 
Criteria for Removal from the Study ....................................................................... 14 
 
Data Safety Monitoring Board ................................................................................ 14 
8 
POTENTIAL BENEFITS ..................................................................................... 15 
9 
MONITORING PLAN .......................................................................................... 17 
 
Electronic Data Capture (EDC) .............................................................................. 17 

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10 INVESTIGATOR RESPONSIBILITIES .............................................................. 18 
11 REFERENCES ..................................................................................................... 19 
1. 

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1. BACKGROUND and SIGNIFICANCE  
11.1 Movement Disorder in Essential Disorders Patients 
Essential tremor is the most common movement disorder with an estimated prevalence 
between 0.3% and 5.6%  [1-5].  Recent epidemiological reports4 indicate that prevalence 
across 19 countries (pooled) was 0.9%, but increased to 4.6% among those 65 years and as 
high as 21.7% in those aged 95 and older.  The condition is a genetically inherited disorder 
with a child of an ET person having a 50% chance of inheriting a gene causing the 
condition.  Approximately 50-70% of people diagnosed with ET have a positive family 
history for the condition.  Caucasians are 5 times more likely to report physician diagnoses 
of ET than are African Americans; Hispanics have a rate between them.  Gender 
predisposition as reported in various articles is variable depending upon the author’s 
population. 
ET is a slowly progressive neurological disorder characterized by a tremor of the arms or 
hands that occurs during voluntary movements (intention tremor), such as eating/drinking 
and writing.  The tremor may also present in the head (neck) and jaw and may affect voice.  
The disease may present in the teens or in the 40-50 age range.  Generally, tremor begins 
in the arms and then spreads to these other regions in selected patients.  Other types of 
tremor may also present, including postural tremor of the outstretched arms, and intentional 
tremor (below 5 Hz) and rest tremor of the arms.  The amplitude of an intention tremor 
increases as an extremity approaches the endpoint of deliberate and visually guided 
movement (hence the name intention tremor). An intention tremor is usually perpendicular 
to the direction of movement. An intention tremor causes the person to overshoot or 
undershoot their target (dysmetria).   
11.2 ExAblate Neuro System. 
The non-invasive high-intensity focused ultrasound has been coupled with high resolution 
MRI to provide precise, consistent treatments that can be monitored in real-time.  The 
development of phased array transducers allows for tightly focused treatment volumes and 
for the ability to compensate for distortions by tissue heterogeneity [6-8].  The landmark 
advance in the ExAblate transcranial MR guided focused ultrasound for neurosurgeons 
occurred as the ability to sonicate through the intact cranium was achieved with phased 
array transducers and acoustic modeling using CT reconstructions of the skull [6-10].  By 
coupling focused ultrasound technology with MRI, the ExAblate system allows detailed 
treatment plans to be performed and real time intra-procedure monitoring [11].  Standard 
MR sequences have been shown to reliably predict tissue damage during thermal lesioning 
with ultrasound [11, 12].  We anticipate that the ExAblate Neuro non-invasive thermal 
lesioning is safe and will provide several years of benefit through reduction of contralateral 
motor symptoms and potential medication side effects in ET subjects.  
 
4 http://www.medmerits.com/index.php/article/epidemiology_of_movement_disorders/P4 

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12 OBJECTIVES 
The objective of this clinical trial is to follow, observationally, the medication-refractory 
Essential Tremor subjects who underwent ExAblate Neuro thalamotomy under IDE# 
G120246 to capture long-term safety and effectiveness out to Year 5.  
Safety: To evaluate long-term incidence and severity of adverse events (AE/AEs) 
associated with ExAblate Neuro treatment of medication-refractory ET 
Effectiveness: To collect long term effectiveness and quality of life of the 
ExAblate Neuro treatment of medication-refractory Essential Tremor (ET). 
This study is designed as a long-term prospective, observational clinical trial to follow 
device related safety, and long term effectiveness (CRST) and quality of life (QUEST) for 
subjects previously treated with ExAblate Neuro under IDE#120246. 
The purpose of this protocol is to set the follow-up schedule for all IDE #G120246 
subjects out to Year 5 in compliance with the post approval conditions. 
12.1 Primary Endpoints 
12.1.1 Safety 
Safety of ExAblate will be determined by an evaluation of the incidence and 
severity of device / treatment related complications from the treatment day visit 
through ALL study follow ups through Year 5.  Adverse events (type, frequency, 
severity) are expected to be similar to those of previous studies using ExAblate 
Neuro for Thalamotomy 
Recorded adverse events will be reported and categorized by investigators as definitely, 
probably, possibly, or unrelated to the device or procedure. Events which are not 
considered to be possibly or probably caused by the device are not required to be reported 
here. 
12.1.2 Effectiveness   
Primary effectiveness will be assessed using the CRST as scored by the site neurologist.   
Secondary effectiveness will be followed using the QUEST quality of life patient 
outcomes questionnaire. 
12.1.2.1 Efficacy Assessments 
Tremor symptom severity will be assessed using the CRST as scored by the site 
neurologist at each follow-up visit.  The CRST is a validated clinical instrument used to 
assess tremor symptom severity. 
 
Quality of life will be evaluated using the QUEST assessment to assess durability (as 
measured by QUEST upper arm extremity questions) of the procedure.  The QUEST is 
an ET specific assessment of quality of life changes associated with ET.  Tröster et al., 
2005, developed QUEST as a clinical tool for correlating changes in 30 aspects of tremor 

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severity, social and personal disability, and perception of health.  An independent 
validation study of the QUEST performed by Martinez-Martin et al. concluded that most 
of the psychometric parameters were found to be satisfactory in their ability to assess the 
impact of ET on the patients’ quality of life. 
12.2 Study Hypothesis 
The purpose of this study is to continue to follow the ExAblate-treated medication-
refractory ET subjects for long-term safety and effectiveness of MRI-guided focused 
ultrasound thalamatomy out through 5 years. 
12.3 Case Report Form Data 
The study data will be collected electronically.  This electronic data capture (EDC) 
system complies with the current guidance of 21 CFR Part 11, Electronic Records and 
Signatures.   
13 DESCRIPTION OF PATIENT POPULATION    
13.1 Patient Selection   
13.1.1 Inclusion Criteria 
13. Subjects who have been treated with ExAblate thalamotomy for medication-
refractory ET under previous clinical trials.    
13.1.2 Exclusion Criteria 
1. Subjects who have had a subsequent intervention for ET on their treated side. 
14 
INVESTIGATIONAL PLAN 
The IRBs will be notified of the Post-Approval condition to follow these subjects and the 
study will be converted from IDE#120046 to a Post-Approval Study status under P150038.  
The study data will be collected electronically.   
14.1 LTF Follow Up Periods Years 2 – 5 Post Treatment 
The treatment long term safety and effectiveness follow up will be completed annually 
from Year 2 through Year 5 post treatment under this protocol.  It should be noted that at 
these visits, the CRST assessments will be performed and scored by the site neurologist.   
The following evaluations should be performed at Year 2, Year 3, Year 4 and Year 5: 
• Review of medications 
• Physical exam 

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• CRST – Assessed by site evaluator 
• QUEST questionnaire should be completed by the subject 
• Adverse events 
14.2 Exit from the study for reason of alternative treatment 
In this study, subjects who opt for alternative treatments for Essential Tremor (not 
including medication change) at any point in the follow-up period will be exited from the 
study after completing the required study examinations.  The last set of evaluations prior 
to alternative therapy is considered the last study visit.  The reason(s) for study exit will 
be noted on the Case Report Forms.  No analyses of post alternative treatment changes 
are planned.  
14.3   Study Requirements and Visit Schedule  
All subjects who were part of the original IDE, IDE # G120246 in either the ET002 pivotal 
trial, or the ET002CA (Note: inclusive of all patients treated under the original Pivotal 
Study, those treated under the Continued Access approval, and those treated as part of the 
1.5T Coil cohort) will be rolled into this PAS study at whatever stage of follow-up is 
coming due.  Follow-up will be continuous from the time of treatment to the Year 5 visit. 
Subjects who have not attained Month 12 will continue their schedule of visits as 
(originally scheduled):   
1 Week ± 3 days 
1 Month ± 7 days,  
3 Month ± 14 days   
6 Months ± 21 days 
12 Months ± 4 month 
 
 

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Table 4.2.2.3.2—1 
Summary of  Study Schedules and Measurements 
  
Screening 
Baseline 
A
t*
Treatment 
1 Day 
1 Week 
1 Month 
3 Month  
6 Month  
12 Month  
Consent 
X 
 
 
 
 
 
 
 
 
Eligibility Evaluation with labs 
X 
X 
 
 
 
 
 
 
 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
30 day meds stabilization 
 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
Neurological status 
X 
 
X 
X 
X 
X 
X 
X 
X 
CRST  
X 
 
 
 
 
X 
X 
X 
X 
QOL (QUEST) 
X 
X 
 
 
 
X 
X 
X 
X 
PHQ-9 
X 
 
 
 
 
X 
X 
X 
X 
CT 
X 
 
 
 
 
 
 
 
 
MR 
 
X 
X 
 
 
 
 
 
X 
Treatment 
 
 
X 
 
 
 
 
 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
Forms “UB-04 (In Patient 
subjects) or CMS-1500 (Out 
Patient subjects) 
 
X 
X 
X 
X 
X 
X 
X 
X 
Exit Form 
 
 
 
 
 
 
 
 
X 
 
The table below summarizes the long-term study visit schedule and procedures.   
The study visits are as follows: 
Year 2 ± 4 Month;  
Year 3 ± 4 Month,  
Year 4 ± 4 Month,  
Year 5 ± 4 Month. 
 
 

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Table 4.2—2  Summary of  Study Schedules and Evaluations 
 
Year 2 4 
Month 
Year 3  ± 
4 Month  
Year 4  ± 
4 Month  
Year 5  ± 
4 Month 
Physical Exam 
X 
X 
X 
X 
CRST 
X 
X 
X 
X 
QOL (QUEST) 
X 
X 
X 
X 
ET medications 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
Exit Form 
X 
X 
X 
X 
 
Note:   
1.  To enable subject(s) retention in the Long Term Follow-up study as well as to 
ensure patient welfare and safety (in full compliance with all applicable patient 
consent regulation(s) and their corresponding IRB approvals), all participating 
sites  should make every effort to maintain frequent contact with subjects (at 
least 3 to 4 times a year)to encourage visit compliance and keep them engaged 
for patient retention.   
In the event a patient miss their scheduled visit to complete the study visit requirements, 
sites should at the very least inquire with subject to provide an overall assessment of their 
safety and of their tremor in full compliance with all applicable patient consent regulations 
and rights, and or schedule another clinical visit even if it is outside the visit window.   
15 
DATA ANALYSIS PLAN 
15.1 Safety 
Adverse events will be recorded and categorized according to severity, relationship to 
procedure and relationship to device.  All AEs will be assessed for their relationship to 
the study device or procedure. Standard Code of Federal Regulation definitions for 
Serious Adverse Events (SAEs) and Unanticipated Adverse Device Effects (UADEs) will 
be used in assessment of AEs. 
It is the responsibility of the investigator to document all AE’s occurring 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 CRF. The 
nature of each event, date and time (when appropriate) of onset, outcome, frequency, 
maximum intensity, action taken, expectedness, and causal relationship will be recorded. 
AEs already documented in the CRF (i.e., at a previous assessment) and designated as 

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‘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.  
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.  AE’s that do not 
affect the safety or overall well-being of the subject, are mild/moderate in nature, are 
estimated to be temporary in duration even though the exact end date may not be 
determined a priori (e.g., eye twitch increased from baseline) may be presented and 
discussed with DSMB to determine their final classification status as a serious or non-
serious adverse event. 
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.  
15.2 Data Safety Monitoring Board 
A Data Safety Monitoring Board will be used to review all AE’s on the study. Their role 
is to evaluate all AE's that occur throughout the study and determine if they are in fact 
related to the ExAblate, or some other cause. Investigators will monitor all treatments for 
any AE's, and consider the following questions for AEs in the Test Arm: 
- Was the adverse event serious? 

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- Was the adverse event life-threatening, caused a disability, required or prolonged 
hospitalization, or caused death? 
- Was the adverse event device related? 
- Was the adverse event unexpected? 
- Is there an unreasonable risk in continuing the trial? 
Adverse Events meeting all the above conditions would require reporting to the FDA, 
stopping the study pending the results of further investigation, and FDA approval to re-
start the study.   
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.   
15.3 Efficacy 
Primary effectiveness will be evaluated using the CRST scored by the site assessor based 
upon patients where unilateral ExAblate thalamotomy was performed.   Secondary 
efficacy will be collected using the QUEST. 
15.4 Subject Health Status 
The results from the physical exams will be recorded in the CRFs and will be presented.  
15.5 Statistical Considerations and Sample Size 
There is no statistical consideration or sample size for this study.  All ExAblate treated 
subjects who were treated under ET002 or ET002-CA will be included in this study, 
starting at the next scheduled study visit date; ET002-CA was FDA approved under IDE 
Supplement G120246/S07. 
15.6 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.    
NOTE:   
All Demographic, Screening, Baseline, Treatment and some amount of Follow-up 
data are collected under ET002 or ET002-CA and these data will be used in 
coordination with that collected under this protocol. 
15.7 Statistical Analysis Plan.   
The analysis will be performed based upon the Statistical Analysis Plan (“SAP”) 
procedures as defined for the pivotal study (FDA Approval of SAP under IDE 

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Supplement G120246/S06).  Please note, however, that for the PAS, all analyses will be 
performed using the site assessor data only. 
15.8 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, Data Safety Monitoring Board, Ethics Committee or 
other regulatory bodies may receive copies of the study records and may review medical 
records related to the study. 
16 PMA P150038 Specific Questions 
What serious or unexpected adverse events may occur in the long-term (up to 5 
years) after receiving treatment for the proposed indication? 
No known device-related SAEs/UADEs are expected over the follow-up of subjects 
through Year 5 based on historical literature on thalamotomies as published in the 
literature.  The ExAblate procedure is a one-time procedure.  However, per this study 
protocol, safety data will be collected through Year-5 as planned.  The full safety data 
will be reported to the Agency as required. 
 
In the long-term (5 years), will favorable Composite Tremor/Motor Function scores 
compared to the baseline be sustainable among the patients who have received the 
treatment? 
Based on historical outcomes as published in the literature, it is reasonable to believe that 
the Composite Tremor/Motor Function improvement will be maintained through follow-
up.  However, because this cohort of subjects is the first group of subjects to be treated 
using the ExAblate 4000 device and for many investigators, this was the first hands-on 
experience in using the device, it is reasonable to anticipate that there may be some 
patients who do not sustain their improvement over the duration of this study.  With the 
accumulation of user expertise in using the ExAblate 4000, it is expected that the 
composite Tremor/Motor score outcomes will be sustainable over long durations.  It is 
the purpose of this long-term follow-up protocol to capture the very long term data  of the 
composite Tremor/Motor scores for this cohort of subjects. 
17 RISK ANALYSIS 
Worldwide, over 12,7000 treatments have been performed to date with the MR guided FUS 
ExAblate body system.  Risk analysis for InSightec ExAblate systems/clinical 
investigations has been conducted as part of previously approved FDA IDE submissions 

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(G930140, G990151, G990184, G990201, G000203, G010225, G020001, G020182, 
G050177, and G060023, G070022, G080009, G080206, G100108, G100127, G100169, 
G120246, G120017, G140018, G140082, G160021, 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 has limited applicability to the proposed 
clinical investigation.  The key consideration here is the fact that this proposed study is 
conducted with an ExAblate Neuro system that is completely different from the body 
system. This is system is referred to internally as the Neuro system.  However, in principle, 
the body and neuro systems have the same purpose, namely to coagulate soft tissue within 
the body by means of MR guided high intensity focused ultrasound.   
There are no additional new risks anticipated under this study.  All the risks were described 
under the original treatment protocol and are still active for this protocol.  No new 
treatments are performed here as this is strictly a long-term observational study. 
17.1 Criteria for Removal from the Study 
The investigator may withdraw subjects from the study as is deemed necessary or deemed 
to be in the best interests of the subject, such as, 
➢ continued noncompliance with the protocol or study visits,  
➢ severe illness or disability during the study for non-study issues, 
➢ pursuit of subsequent alternative treatment for the same condition, or 
➢ development of intolerable side effects where continued follow-up becomes too 
burdensome.   
In addition, a subject may also chose to exit the study at any time, but will be strongly 
encouraged to participate in the follow-up visits for safety reasons (continued monitoring 
of subject safety).  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.    
17.2 Data Safety Monitoring Board 
A Data Safety Monitoring Board will be used to review all recorded AEs on the study. 
Note that only ET-disease, device and procedure-related adverse events will be recorded 
Their role is to evaluate all recorded AEs that occur throughout the study and determine 
if they are in fact related to the original ExAblate procedure, or some other cause. 
Investigators will capture all adverse events, and consider the following questions: 
- Was the adverse event serious? 
- Was the adverse event life-threatening, caused a disability, required or prolonged 
hospitalization, or caused death? 

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- Was the adverse event device related? 
- Was the adverse event unexpected? 
- Is there an unreasonable risk in continuing the trial? 
Adverse Events meeting all the above conditions would require reporting to the FDA, 
stopping the study pending the results of further investigation, and FDA approval to re-
start the study.  Following the DSMB review of the event, and if in the opinion of the 
DSMB, a modification of the study protocol were necessary to provide adequate protection 
to future study participants, the modification would be implemented prior to reinitiating 
the investigation.  Any such amendment would be reported to the IRB and FDA for their 
respective approvals to re-start the study as it is required by the applicable regulations. 
All recorded 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.   
18 POTENTIAL BENEFITS 
The pivotal trial cohort of subjects being followed in this study demonstrated a powerful, 
robust result at Month 3 with the ExAblate group experiencing a highly significant 
improvement in the PE and all secondary confirmatory endpoints (See table).  The 
outcomes were essentially unchanged and still favorable by Month 12. 

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The safety profile for the pivotal trial cohort demonstrated a rather benign and favorable 
profile in relation to benefit.  Many events were considered Transient and Unrelated and 
most resolved.  The remaining events were Procedure or Thalamotomy related events.  
All but one were Mild / Moderate in severity.  Only 1 serious, related event occurred of 
Moderate Numbness/Tingling of the thumb which interfered with the subject’s ability to 
hold a pen and write at work. 
Efficacy Analysis Summary  
 
% of Improvement 
At Month-3 – ITT 
% of Improvement At 
Month 12 – ITT 
ExAblate 
(N=56) 
Sham 
(N=20) 
Between 
Groups 
p-value 
ExAblate  
(N=56) 
P-value 
Vs 
Baseline 
Primary Endpoint – 
Composite 
Tremor/Motor 
Function 
46.9% 
- 0.1% 
p< 0.001 
39.6% 
p< 0.001 
..Lower 95% CI       
40.3% 
-9.6% 
34.0% 
  Upper 95% CI 
53.5% 
9.5% 
45.3% 
CRST, Part A-
Tremor “Posture” 
64.3% 
- 4.4% 
(n=17) 
P<0.001 
65.5 % 
p< 0.001 
..Lower 95% CI 
52.1% 
-26.9 
54.7 % 
  Upper 95% CI 
76.5% 
18.2 
76.3 % 
CRST, Part C 
63.8% 
1.8% 
p< 0.001 
64.0% 
p< 0.001 
..Lower 95% CI 
55.3% 
-6.7% 
55.2% 
  Upper 95% CI 
72.4% 
11.1% 
72.7% 
QUEST 
43.2% 
5.0% 
(n=19) 
p< 0.001 
47.1% 
p< 0.001 
..Lower 95% CI 
34.3% 
-14.9% 
36.5% 
  Upper 95% CI 
56.3% 
36.2% 
62.1% 
A negative sign “-“ indicates worsening 

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This PAS is simply an observational study to collect longer-term safety and durability of 
treatment effect in the IDE study population all the way out to 5 years. 
19 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 GCP requirements;  
➢ The trial is conducted according to InSightec internal SOPs 
➢ 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.  
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.    
The Clinical Monitor will continue to perform on-site monitoring visits as frequently as 
deemed necessary. 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 adherence to protocol procedures, 
adequate reporting and follow-up of AEs, and verification of all clinical data captured at 
the visit. 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. 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.   
Monitoring procedures will follow the Sponsor SOPs. 
19.1 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).   

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20 INVESTIGATOR RESPONSIBILITIES 
The Principal Investigator will be required to sign the Investigator Agreement.  All 
investigators will undergo extensive training on the protocol and operation of the ExAblate 
system, and provide documentation of their specialized training. 
 
 

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Hynynen, K. and F.A. Jolesz, Demonstration of potential noninvasive ultrasound 
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