ExAblate Transcranial MR Guided Focused Ultrasound for the Treatment of Essential Tremors

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, local site's blinded assessor 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).

Study Overview

• Status: Completed
• Conditions: Essential Tremor
• Intervention / Treatment: Device: Transcranial ExAblate; Device: Sham Transcranial ExAblate

Detailed Description

This study is evaluating a new technique for performing Thalamotomy for tremor control. While current techniques have possible invasive or radiation effects, the use of ExAblate if totally non-invasive and without any radiation. After informed consent and screening, eligible subjects will be randomized to either an ExAblate treatment or an ExAblate Sham or "fake" procedure. The chance of randomization to Sham is one out of four. Subjects who are randomized to Sham Control will undergo the same procedure and follow-up visits through their Month 3 visit. After the Month 3 assessments are complete, all subjects will be unblinded and those in the Sham treated group will have the option for an actual ExAblate treatment in an unblinded fashion, as long as they still qualify for ExAblate treatment. All subjects will be followed at 6 and 12 months and for up to 5 years as directed by their doctor.

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • SunnyBrook Health Sciences Centre
• Japan
  • Tokyo, Japan, 162-8666
    • Tokyo Women's Medical University (TWMU)
• Korea, Republic of
  • Seoul, Korea, Republic of, 120-752
    • Yonsei University Medical Center
• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical System
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 22 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men and women, age 22 years and older
• Subjects who are able and willing to give informed consent and able to attend all study visits
• Subjects with a diagnosis of Essential Tremor as confirmed from clinical history and examination by a neurologist or neurosurgeon specialized in movement disorder
• Subject exhibits a significant disability from their ET despite medical treatment
• Subjects should be on a stable dose of all ET medications for 30 days prior to study entry
• Subject is able to communicate sensations during the ExAblate Transcranial procedure

Exclusion Criteria:

• Subjects with unstable cardiac status
• Severe hypertension
• Subjects with standard contraindications for MR imaging such as non-MRI compatible implanted metallic devices including cardiac pacemakers, size limitations, etc.
• Known intolerance or allergies to the MRI contrast agent including advanced kidney disease or severely impaired renal function
• Significant claustrophobia that cannot be managed with mild medication
• Current medical condition resulting in abnormal bleeding and/or coagulopathy
• 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
• History of intracranial hemorrhage
• History of multiple strokes, or a stroke within past 6 months
• Subjects who are not able or willing to tolerate the required prolonged stationary supine position during treatment
• Are participating or have participated in another clinical trial in the last 30 days
• Subjects unable to communicate with the investigator and staff
• Subjects with a history of seizures within the past year
• Subjects with brain tumors

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Transcranial ExAblate	Device: Transcranial ExAblate; Other Names: Thalamotomy; ExAblate; TcMRgFUS
Sham Comparator: Sham Transcranial ExAblate; Sham Treatment with Transcranial ExAblate	Device: Sham Transcranial ExAblate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tremor Motor Score - Clinical Rating Scale for Tremor (CRST Part A (Upper Extremity) + Part B) Percent Change From Baseline	The percent change from baseline to Month 3 follow-up in upper extremity Tremor-Motor scores for the treated side is a sub-scale of Clinical Rating Scale for Tremor (CRST) Part A and Part B sum that was used to measure treated-side upper extremity tremor changes over time. Tremor-motor scores range from 0-32 points. Individual subject's scores at Baseline and 3 Months were used to calculate percent change from baseline and averaged across subjects. High percent change from baseline is better (shows improvement).	Baseline, 3 Months post-treatment
Number of Device and Procedure Related Adverse Events	The cumulative sum of adverse events was followed through Year 5 of the study.	5 Years post treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tremor Motor Score - Clinical Rating Scale for Tremor (CRST) Part A (Upper Extremity) + Part B Percent Change From Baseline	The percent change from baseline to Month 3 follow-up in upper extremity Tremor-Motor scores for the treated side is a sub-scale of Clinical Rating Scale for Tremor (CRST) Part A and Part B sum that was used to measure treated-side upper extremity tremor changes over time. Tremor-motor scores range from 0-32 points. Individual subject's scores at Baseline and Follow Up were used to calculate percent change from baseline and averaged across subjects. High percent change from baseline is better (shows improvement).	Baseline, 3 Months, 6 Months, 12 Months, 2, 3, 4, 5 Years post treatment
Clinical Rating Scale (CRST) Part A - Posture Score, Percent Change From Baseline (Pre-treatment)	The Posture Score is a sub-Score of the Clinical Rating Scale for Tremor CRST Part A - Posture (Treated Side Upper Extremity Posture Score). The scores range 0-12 and higher scores indicate worse outcomes. For percent improvement compared to Baseline (pre-treatment visit) higher percents mean better outcomes.	Baseline, 3 Months, 6 Months, 12 Months, 2, 3, 4, 5 Years post treatment
Functional Disabilities - Clinical Rating Scale (CRST) for Tremor Part C Score Percent Change From Baseline	1. Subject daily functionalities: as measured by CRST Part-C (subscales) as percent change from Baseline. CRST Part-C is an 8-item score range 0-32. Higher percent change from Baseline means better outcomes.	Baseline, 3 Months, 6 Months, 12 Months, 2, 3, 4, 5 Years post treatment
Quality of Life in Essential Tremor Questionnaire (QUEST) Summary Total Percent Change From Baseline	The percent change from baseline to follow-up QUEST Summary Total was used to assess quality of life changes over time in tremor patients. The QUEST consists of five dimensions for each subject converted to a percent of the total (0-100%). The summary total is the average of the five dimensions. High percent change from baseline is better (shows improvement).	Baseline, 3 Months, 6 Months, 12 Months, 2, 3, 4, 5 Years post treatment

Collaborators and Investigators

• Sponsor: InSightec

Publications and helpful links

General Publications

• Yamamoto K, Sarica C, Elias GJB, Boutet A, Germann J, Loh A, Joel SE, Bigioni L, Gwun D, Gramer R, Li SX, Zemmar A, Vetkas A, Algarni M, Devenyi G, Chakravarty M, Hynynen K, Scantlebury N, Schwartz ML, Lozano AM, Fasano A. Ipsilateral and axial tremor response to focused ultrasound thalamotomy for essential tremor: clinical outcomes and probabilistic mapping. J Neurol Neurosurg Psychiatry. 2022 Aug 22:jnnp-2021-328459. doi: 10.1136/jnnp-2021-328459. Online ahead of print.
• Halpern CH, Santini V, Lipsman N, Lozano AM, Schwartz ML, Shah BB, Elias WJ, Cosgrove GR, Hayes MT, McDannold N, Aldrich C, Eisenberg HM, Gandhi D, Taira T, Gwinn R, Ro S, Witt J, Jung NY, Chang JW, Rosenberg J, Ghanouni P. Three-year follow-up of prospective trial of focused ultrasound thalamotomy for essential tremor. Neurology. 2019 Dec 10;93(24):e2284-e2293. doi: 10.1212/WNL.0000000000008561. Epub 2019 Nov 20.
• Elias WJ, Lipsman N, Ondo WG, Ghanouni P, Kim YG, Lee W, Schwartz M, Hynynen K, Lozano AM, Shah BB, Huss D, Dallapiazza RF, Gwinn R, Witt J, Ro S, Eisenberg HM, Fishman PS, Gandhi D, Halpern CH, Chuang R, Butts Pauly K, Tierney TS, Hayes MT, Cosgrove GR, Yamaguchi T, Abe K, Taira T, Chang JW. A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor. N Engl J Med. 2016 Aug 25;375(8):730-9. doi: 10.1056/NEJMoa1600159.
• Cosgrove GR, Lipsman N, Lozano AM, Chang JW, Halpern C, Ghanouni P, Eisenberg H, Fishman P, Taira T, Schwartz ML, McDannold N, Hayes M, Ro S, Shah B, Gwinn R, Santini VE, Hynynen K, Elias WJ. Magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor: 5-year follow-up results. J Neurosurg. 2022 Aug 5;138(4):1028-1033. doi: 10.3171/2022.6.JNS212483. Print 2023 Apr 1.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2013
• Primary Completion (Actual): February 24, 2021
• Study Completion (Actual): February 24, 2021

Study Registration Dates

• First Submitted: March 27, 2013
• First Submitted That Met QC Criteria: April 5, 2013
• First Posted (Estimated): April 10, 2013

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: ExAblate Transcranial MRgFUS
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Movement Disorders; Dyskinesias; Tremor; Essential Tremor
• Other Study ID Numbers: ET002

Plan for Individual participant data (IPD)

Study Data/Documents

1. Clinical Study Report