A Continued Access 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

Version Date 
Amendment No. 
Protocol Number 
PAS Number 
Protocol Title 
Approvals: 
Site 
Principal Investigator 
Signature 
InSightec Confidential 
Version date: August 13, 2017 
InSightec 
Clinical Protocol - Appendix NCT02289560 
August 13, 2017 
2 
ET002-LTF 
P150038/S004 
A Long-term Observational Follow-up Study of Medication 
Refractory Essential Tremor Subjects Treated with ExAblate 
Neuro Thalamotomy under P150038 
Date 
Sponsor 
adir Alikacem, PhD, 
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 
  
  
 
InSightec 
4851 LBJ Freeway 
Suite 400 
Dallas, Texas  75244 

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Table Of Content 
1. 
1. BACKGROUND and SIGNIFICANCE ................................................................ 5 
 
Movement Disorder in Essential Disorders Patients .................................................... 5 
1.1
 
ExAblate Neuro System. ................................................................................................ 5 
1.2
2 
OBJECTIVES ............................................................................................................ 6 
 
Primary Endpoints ......................................................................................................... 6 
2.1
2.1.1 
Safety ....................................................................................................................................... 6 
2.1.2 
Effectiveness ........................................................................................................................... 6 
2.1.2.1 
Efficacy Assessments ..................................................................................................... 6 
 
Study Hypothesis............................................................................................................ 7 
2.2
 
Case Report Form Data ................................................................................................. 7 
2.3
3 
DESCRIPTION OF PATIENT POPULATION ...................................................... 7 
 
Patient Selection ............................................................................................................ 7 
3.1
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 
4.1
 
Exit from the study for reason of alternative treatment ............................................... 8 
4.2
 
Study Requirements and Visit Schedule ....................................................................... 8 
4.3
5 
DATA ANALYSIS PLAN ........................................................................................ 10 
 
Safety ............................................................................................................................ 10 
5.1
 
Efficacy ........................................................................................................................ 12 
5.2
 
Subject Health Status .................................................................................................. 12 
5.3
 
Statistical Considerations and Sample Size ................................................................ 12 
5.4
 
Missing Data ................................................................................................................ 12 
5.5
 
Statistical Analysis Plan. ............................................................................................. 13 
5.6
 
Subject Confidentiality ................................................................................................ 13 
5.7
6 
PMA P150038 Specific Questions ........................................................................... 13 
7 
RISK ANALYSIS ..................................................................................................... 14 
 
Criteria for Removal from the Study ........................................................................... 14 
7.1
 
Data Safety Monitoring Board .................................................................................... 14 
7.2
8 
POTENTIAL BENEFITS ....................................................................................... 15 
9 
MONITORING PLAN ............................................................................................. 17 
 
Electronic Data Capture (EDC) .................................................................................. 18 
9.1

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

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1. BACKGROUND and SIGNIFICANCE  
 
Movement Disorder in Essential Disorders Patients 
1.1
Essential tremor is the most common movement disorder with an estimated prevalence 
between 0.3% and 5.6%  [1-5].  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 
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).   
 
ExAblate Neuro System. 
1.2
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 
                                                 
1 http://www.medmerits.com/index.php/article/epidemiology_of_movement_disorders/P4 

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reduction of contralateral motor symptoms and potential medication side effects in ET 
subjects.  
2 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. 
 
Primary Endpoints 
2.1
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 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. 
2.1.2 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. 
2.1.2.1 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. 
 

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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 
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. 
 Study Hypothesis 
2.2
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. 
 
Case Report Form Data 
2.3
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    
 
Patient Selection   
3.1
3.1.1 Inclusion Criteria 
1. Subjects who have been treated with ExAblate thalamotomy for medication-
refractory ET under previous clinical trials.    
3.1.2 Exclusion Criteria 
1. Subjects who have had a subsequent intervention for ET on their treated side. 
4 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.   
 
LTF Follow Up Periods Years 2 – 5 Post Treatment 
4.1
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.   

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The following evaluations should be performed at Year 2, Year 3, Year 4 and Year 5: 
 Review of medications 
 Physical exam 
 CRST – Assessed by site evaluator 
 QUEST questionnaire should be completed by the subject 
 Adverse events 
 
Exit from the study for reason of alternative treatment 
4.2
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.  
 
  Study Requirements and Visit Schedule  
4.3
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 Error! No text of specified style in document.—1 
Summary of  Study Schedules and Measurements 
  
Screening 
Baseline 
Assessment* 
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.   
5 DATA ANALYSIS PLAN 
 
Safety 
5.1
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 

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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 
 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.  
 
Data Safety Monitoring Board 
5.2
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: 

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- 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? 
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.   
 
Efficacy 
5.3
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. 
 
Subject Health Status 
5.4
The results from the physical exams will be recorded in the CRFs and will be presented.  
 
Statistical Considerations and Sample Size 
5.5
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. 
 
Missing Data 
5.6
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. 

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Statistical Analysis Plan.   
5.7
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 
Supplement G120246/S06).  Please note, however, that for the PAS, all analyses will be 
performed using the site assessor data only. 
 
Subject Confidentiality  
5.8
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. 
6 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. 

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7 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 
(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. 
 Criteria for Removal from the Study 
7.1
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.    
 Data Safety Monitoring Board 
7.2
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. 

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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? 
- 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.   
8 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 
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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Moderate Numbness/Tingling of the thumb which interfered with the subject’s ability to 
hold a pen and write at work. 
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. 
9 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. 

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 Electronic Data Capture (EDC) 
9.1
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).   
10 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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