Deep Brain Stimulation (DBS) for the Suppression of Tremor

A Clinical Evaluation of the Advanced Neuromodulation System (ANS) Totally Implantable Deep Brain Stimulation System for the Suppression of Tremor in the Upper Extremities of Patients With Essential Tremor.

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02087046

Enrollment

127

Registered

2014-03-14

Start date

2005-10-31

Completion date

2017-12-31

Last updated

2023-04-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Action Tremor, Essential Tremor, Tremor, Tremor, Limb

Brief summary

The purpose of the proposed study is to demonstrate the safety and efficacy of the ANS Totally Implantable Deep Brain Stimulation System in the VIM nucleus of the thalamus implanted for the treatment of tremor due to essential tremor. This study will be included in the Pre-Market Approval Application to support the safety of this device in use.

Detailed description

This study is designed as a prospective, multi-centered study for 365 days in duration from device implantation. A maximum of 12 sites will enroll 160 patients. Each patient will be screened and then undergo a baseline evaluation followed by unilateral or bilateral implantation of the DBS system. During the implantation procedure, each patient will undergo a trial of stimulation in the operating room. The device may be internalized after a successful intra-operative trial or at a later surgery (no later than 4 weeks after initial lead placement). If the device is not activated immediately postsurgery, the patient may return to the clinic to determine optimum stimulation programming. Device programming will be optimized in as many visits as necessary following implantation. The day that the device is fully implanted will be classified as Day 0 for each patient. After Day 0 the patient will return to clinic for evaluations at, Day 90 (±14 days), and Day 180 (±14 days) and Day 365 (approximately 12 months ± 30 days after Day 0). These evaluations consist of the CRST, the QUEST, the SF36, Patient and caregiver Global Ratings and the Patient Satisfaction Rating. At Baseline and Day 180, the CRST evaluation session will be video recorded for analysis by an independent evaluator unaware of the functioning of the device. Additionally, at the Day 180 visit, the physician will have the option to provide the patient with amplitude control. A comparison of measures within the same person from pre-treatment to post-treatment will be performed. Also, pre-treatment and post-treatment group means and standard deviations will be determined. Patients completed follow-up visits as part of the original protocol (C-04-02) for one year (or in some cases longer if patient was bilaterally implanted) and continued to complete additional visits as part of the Long-Term Follow-up protocol (C-06-03) for up to 5 years post implant.

Interventions

DEVICEANS Totally Implantable Deep Brain Stimulation System

ANS Totally Implantable Deep Brain Stimulation System will be implanted in the VIM nucleus of the thalamus

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Patient or authorized representative has signed an informed consent. 2. Patient is over 18 years of age. 3. Patient is diagnosed with essential tremor for at least 3 years. 4. Patient has a disabling medical-refractory upper extremity tremor with no evidence of supraspinal central nervous system disease or injury (tremor not adequately controlled by medications for at least three (3) months before implant). 5. Patient has a postural or kinetic tremor severity score of at least 3 out of 4 in the extremity intended for treatment on the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor. 6. Patient will maintain a constant dose of anti-tremor medication indicated as best medical management for one (1) month prior to enrollment in study. 7. Patient is available for appropriate follow-up times for the length of the study.

Exclusion criteria

1. Patient is not surgical candidate; 2. Patient has other clinically or medically significant disease; 3. Patient has any neurological injury or disease other than essential tremor; 4. Patient has any condition requiring repeated MRI scans; 5. Patient has any condition requiring diathermy; 6. Patients on anticoagulant medications; 7. Patient has untreated clinically significant depression; 8. Patient has had an electrical or electromagnetic implant (cochlear prosthesis, pacemaker etc); 9. Patient has had a prior thalamotomy or surgical ablation procedure in either side of the brain; 10. Patient has dementia interfering with their ability to co-operate or comply with study requirements or comprehend the informed consent (mini-mental exam score \<24); 11. Patient abuses drugs or alcohol; 12. Patient has had botulinum toxin injections in the six (6) months prior to enrollment; 13. Patient has a history of cranial surgery; 14. Patient has a history of seizures; 15. Patient has any metallic implants that may interfere with the functioning of the device (e.g. aneurysm clips); 16. Patient has a history of stimulation intolerance in any area of the body; 17. Patient is a female of child bearing potential with a positive urine pregnancy test or not using adequate contraception.

Design outcomes

Primary

Measure	Time frame	Description
Primary Efficacy Endpoint: Difference in the Postural Tremor Score of the Target Limb Between Stimulation On and Stimulation Off, As Assessed by the Blind Reviewer	Day 180	The Fahn, Tolosa, Marin Tremor Rating Scale (referred to as the CRST), is a rating tool to assess the severity of postural, isometric, kinetic and task specific tremor in the dominant and non-dominant sides of the head, trunk and limbs of patients with ET. The CRST utilizes a 0 to 4 point scale where 0 indicates non-symptomatic (normal) and 4 indicates the most severe rating of the patient's tremor symptoms.
Primary Safety Endpoint: Percentage of Participants With Device-related or Procedure Related Adverse Events	Within 180 days following the initial implant	Percentage of device-related or procedure related adverse events will be assessed within 6 months following the initial unilateral implant. All such adverse events will be counted for 180 days following surgery or until the day of the second implant, which ever comes first.

Secondary

Measure	Time frame	Description
Clinical Rating Scale for Tremor (CRST) Evaluation- Mean Handwriting for Target Side Severity Score, As Assessed by the Site Physician	Baseline	The Fahn, Tolosa, Marin Tremor Rating Scale (referred to as the CRST), is a rating tool to assess the severity of postural, isometric, kinetic and task specific tremor in the dominant and non-dominant sides of the head, trunk and limbs of patients with ET. The CRST utilizes a 0 to 4 point scale where 0 indicates non-symptomatic (normal) and 4 indicates the most severe rating of the patient's tremor symptoms. The site physician will evaluate the patient's handwriting according to the CRST (scale 0-4).
Clinical Rating Scale for Tremor (CRST) Evaluation- Mean Handwriting for Target Side Severity Score, As Assessed by the Blind Reviewer	Day 180	The Fahn, Tolosa, Marin Tremor Rating Scale (referred to as the CRST), is a rating tool to assess the severity of postural, isometric, kinetic and task specific tremor in the dominant and non-dominant sides of the head, trunk and limbs of patients with ET. The CRST utilizes a 0 to 4 point scale where 0 indicates non-symptomatic (normal) and 4 indicates the most severe rating of the patient's tremor symptoms. The blind reviewer will evaluate the patient's handwriting according to the CRST (scale 0-4).
Clinical Rating Scale for Tremor (CRST) Evaluation- Mean Pouring From Target Side Severity Scores, As Assessed by the Site Physician	Baseline	The Fahn, Tolosa, Marin Tremor Rating Scale (referred to as the CRST), is a rating tool to assess the severity of postural, isometric, kinetic and task specific tremor in the dominant and non-dominant sides of the head, trunk and limbs of patients with ET. The CRST utilizes a 0 to 4 point scale where 0 indicates non-symptomatic (normal) and 4 indicates the most severe rating of the patient's tremor symptoms. The site physician will evaluate the patient's pouring ability according to the CRST
Clinical Rating Scale for Tremor (CRST) Evaluation-Mean Pouring From Target Side Severity Scores, As Assessed by the Site Physician	Day 90	The Fahn, Tolosa, Marin Tremor Rating Scale (referred to as the CRST), is a rating tool to assess the severity of postural, isometric, kinetic and task specific tremor in the dominant and non-dominant sides of the head, trunk and limbs of patients with ET. The CRST utilizes a 0 to 4 point scale where 0 indicates non-symptomatic (normal) and 4 indicates the most severe rating of the patient's tremor symptoms. The site physician will evaluate the patient's pouring ability according to the CRST
Clinical Rating Scale for Tremor (CRST) Evaluation- Pouring Ability From Target Side Severity Scores, As Assessed by the Blind Reviewer	Day 180	The Fahn, Tolosa, Marin Tremor Rating Scale (referred to as the CRST), is a rating tool to assess the severity of postural, isometric, kinetic and task specific tremor in the dominant and non-dominant sides of the head, trunk and limbs of patients with ET. The CRST utilizes a 0 to 4 point scale where 0 indicates non-symptomatic (normal) and 4 indicates the most severe rating of the patient's tremor symptoms. The blind reviewer will evaluate the patient's pouring ability according to the CRST
Clinical Rating Scale for Tremor (CRST) Evaluation- Mean Total Motor Score, As Assessed by the Site Physician	Baseline	The Fahn, Tolosa, Marin Tremor Rating Scale (referred to as the CRST), is a rating tool to assess the severity of postural, isometric, kinetic and task specific tremor in the dominant and non-dominant sides of the head, trunk and limbs of patients with ET. The CRST utilizes a 0 to 4 point scale where 0 indicates non-symptomatic (normal) and 4 indicates the most severe rating of the patient's tremor symptoms. The motor score adds together all responses to the tremor assessment for questions 1-9 of the CRST (whether or not the specific side is being treated).
Clinical Rating Scale for Tremor (CRST) Evaluation- Activity of Daily Living Score, As Assessed by the Site Physician	Baseline	The Fahn, Tolosa, Marin Tremor Rating Scale (referred to as the CRST), is a rating tool to assess the severity of postural, isometric, kinetic and task specific tremor in the dominant and non-dominant sides of the head, trunk and limbs of patients with ET. The CRST utilizes a 0 to 4 point scale where 0 indicates non-symptomatic (normal) and 4 indicates the most severe rating of the patient's tremor symptoms. The activity of daily living score adds together all responses to questions 15-21 of the CRST.
Clinical Rating Scale for Tremor (CRST) Evaluation-Bilateral Stimulation, As Assessed by the Site Physician	Baseline	The Fahn, Tolosa, Marin Tremor Rating Scale (referred to as the CRST), is a rating tool to assess the severity of postural, isometric, kinetic and task specific tremor in the dominant and non-dominant sides of the head, trunk and limbs of patients with ET. The CRST utilizes a 0 to 4 point scale where 0 indicates non-symptomatic (normal) and 4 indicates the most severe rating of the patient's tremor symptoms. For those patients that had bilateral stimulation, the site physician will evaluate the patient's non-target side after 180 days of bilateral stimulation.
Clinical Rating Scale for Tremor (CRST) Evaluation-Non-Target Limb Severity Scores, As Assessed by the Site Physician	Baseline	The Fahn, Tolosa, Marin Tremor Rating Scale (referred to as the CRST), is a rating tool to assess the severity of postural, isometric, kinetic and task specific tremor in the dominant and non-dominant sides of the head, trunk and limbs of patients with ET. The CRST utilizes a 0 to 4 point scale where 0 indicates non-symptomatic (normal) and 4 indicates the most severe rating of the patient's tremor symptoms. For those patients that had bilateral stimulation, the site physician will evaluate the patient's non-target side after 180 days with only the second side system On
Quality of Life in Essential Tremor (QUEST): Overall Summary Index	Baseline	The QUEST questionnaire consists of 30 items, which are rated from 0 to 4, corresponding to the frequency (from never to always). Those 30 items assess how tremor impacts a function or how it can be associated with feelings or attitudes. The 30 items contribute to five sub scales (number of items contributing to each scale in parentheses): Physical/ADL (9), Psychosocial (9), Communication (3), Hobbies/Leisure (3), and Work/Finances (6). The score on each sub scale is expressed as a percentage of the total score possible, with a higher score indicating greater dissatisfaction with that domain of QOL. As the scores were expressed as percentages, if a question was unanswered it was excluded and percentages were calculated based on the remaining answers. A total or quest summary index (QSI) was computed by calculating the mean of the five scales. Maximal score of 100 indicates worse quality of life, while minimal score 0 corresponds to best quality of life.
Change From Baseline for Quality of Life in Essential Tremor (QUEST): Overall Summary Index	Day 90	The QUEST questionnaire consists of 30 items, which are rated from 0 to 4, corresponding to the frequency (from never to always). Those 30 items assess how tremor impacts a function or how it can be associated with feelings or attitudes. The 30 items contribute to five sub scales (number of items contributing to each scale in parentheses): Physical/ADL (9), Psychosocial (9), Communication (3), Hobbies/Leisure (3), and Work/Finances (6). The score on each sub scale is expressed as a percentage of the total score possible, with a higher score indicating greater dissatisfaction with that domain of QOL. As the scores were expressed as percentages, if a question was unanswered it was excluded and percentages were calculated based on the remaining answers. A total or quest summary index (QSI) was computed by calculating the mean of the five scales. Maximal score of 100 indicates worse quality of life, while minimal score 0 corresponds to best quality of life.
Clinical Rating Scale for Tremor (CRST) Evaluation- Mean Target Limb Severity Score, As Assessed by the Site Physician	Baseline	The Fahn, Tolosa, Marin Tremor Rating Scale (referred to as the CRST), is a rating tool to assess the severity of postural, isometric, kinetic and task specific tremor in the dominant and non-dominant sides of the head, trunk and limbs of patients with ET. The CRST utilizes a 0 to 4 point scale where 0 indicates non-symptomatic (normal) and 4 indicates the most severe rating of the patient's tremor symptoms.
Global Assessment Scores by Examiner	Baseline	Global outcome measures are a self-rated questionnaire that measures a global assessment of the patient quality of life and the examiner's interpretation of the patient's quality of life.
Global Assessment by Caregiver	Baseline	Global outcome measures are a self-rated questionnaire that measures a global assessment of the patient quality of life and the caregiver's interpretation of the patient's quality of life
Global Assessment by Patient	Baseline	Global outcome measures are a self-rated questionnaire in which patients assess their own global outcome at each visit
Subjective Assessment by Patient Since Activation of System	Day 90	Subjective assessment includes changes in their ET symptoms since the last visit indicated as marked improvement, moderate improvement, mild improvement, worsening, or no change.
Number of Participants With Satisfaction With the DBS System's Functioning and Ability to Control Symptoms	Day 90	At each visit, patients will be asked about their satisfaction with the DBS system's functioning and ability to control symptoms
Number of Participants Who Would Choose to Receive the DBS System Again	Day 90	At each visit, patients will be asked if they would undergo the DBS procedure again
Number of Participants Who Would Recommend the DBS System	Day 90	At each visit, patients will be asked if they would recommend the DBS system to others
Beck Depression Inventory II (BDI - II) Score for Depression Symptoms	Baseline	The Beck Depression Inventory II is A clinical rating scale designed for detecting depression based on the Diagnostic and Statistical Manual of Mental Health Disorders-Fourth Edition (DSM-IV) criteria. This widely used instrument consists of 21 items to assess the intensity of depression in clinical and normal patients. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. The BDI II questionnaire contains 21 questions, each answer being scored on a scale value of 0 to 3. A score between 0-13 indicates minimal depression, 14-19 mild depression, 20-28 moderate depression and 29-63 severe depression. Total scores are obtained by computing the sum of each score. The scores range from 0 to 63, with higher score indicating greater severity of depressive symptoms.
Change From Baseline in Beck Depression Inventory II (BDI - II) Score for Depression Symptoms	Day 365	The Beck Depression Inventory II is A clinical rating scale designed for detecting depression based on the Diagnostic and Statistical Manual of Mental Health Disorders-Fourth Edition (DSM-IV) criteria. This widely used instrument consists of 21 items to assess the intensity of depression in clinical and normal patients. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. The BDI II questionnaire contains 21 questions, each answer being scored on a scale value of 0 to 3. A score between 0-13 indicates minimal depression, 14-19 mild depression, 20-28 moderate depression and 29-63 severe depression. Total scores are obtained by computing the sum of each score. The scores range from 0 to 63, with higher score indicating greater severity of depressive symptoms.
Mini Mental State Exam (MMSE) for Examination of Mental Status	Baseline	The Mini-Mental State Examination (MMSE) is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. It examines functions including registration (repeating named prompts), attention and calculation, recall, language, ability to follow simple commands and orientation. Any score of 24 or more (out of 30) indicates a normal cognition.
Change From Baseline in Mini Mental State Exam (MMSE) For Examination of Mental Status	Day 365	The Mini-Mental State Examination (MMSE) is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. It examines functions including registration (repeating named prompts), attention and calculation, recall, language, ability to follow simple commands and orientation. Any score of 24 or more (out of 30) indicates a normal cognition.
SF36 Components and Individual Domains	Baseline	The SF-36 questionnaire is a measure of health status with 36 items across 8 domains. The eight domains are separated into two summary scores of four domains, the physical component summary (PCS) and mental component summary (MCS). The SF-36 score is transformed into a scale of 0-100, with 100 indicating no disability. PCS and MCS are scaled in comparison to population norms to reflect a mean of 50 and standard deviation of 10 for the general population of the United States.
Clinical Rating Scale for Tremor (CRST) Evaluation- Target Limb Responder Analysis, As Assessed by the Site Physician	Day 90	The Fahn, Tolosa, Marin Tremor Rating Scale (referred to as the CRST), is a rating tool to assess the severity of postural, isometric, kinetic and task specific tremor in the dominant and non-dominant sides of the head, trunk and limbs of patients with ET. The CRST utilizes a 0 to 4 point scale where 0 indicates non-symptomatic (normal) and 4 indicates the most severe rating of the patient's tremor symptoms. During responder analysis, a 2-point reduction in kinetic tremor or postural tremor between stimulation Off and stimulation On show an improvement in activities of daily living was considered a response, was also performed using the site physician's ratings.

Countries

United States

Participant flow

Recruitment details

A total of 127 patients were enrolled from 12 investigational sites and implanted with the study device. The first patient was implanted with the SJM DBS Systems on 21 October, 2005. Of the 127 implanted subjects, 80 received unilateral implants and the remaining 47 patients received bilateral implants.

Pre-assignment details

Of the 150 subjects who were screened, 23 subjects were excluded from implantation due to inclusion or exclusion criteria, or the patient's decision to discontinue before surgery.

Participants by arm

Arm	Count
Stimulation ANS Totally Implantable Deep BrainStimulation System: ANS Totally Implantable Deep BrainStimulation System will be implanted in the VIM nucleus of the thalamus	127
Total	127

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	4
Overall Study	Death	1
Overall Study	Lost to Follow-up	3
Overall Study	Physician Decision	1
Overall Study	Withdrawal by Subject	2

Baseline characteristics

Characteristic	Stimulation
Age, Continuous	64.6 years STANDARD_DEVIATION 9.6
Race/Ethnicity, Customized African American	1 participants
Race/Ethnicity, Customized Caucasian	124 participants
Race/Ethnicity, Customized Hispanic	2 participants
Region of Enrollment United States	127 participants
Sex: Female, Male Female	58 Participants
Sex: Female, Male Male	69 Participants
Years since initial diagnosis of ET	14.8 years STANDARD_DEVIATION 11.8
Years since onset of tremor	29.1 years STANDARD_DEVIATION 17.4

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	3 / 127
other Total, other adverse events	91 / 127
serious Total, serious adverse events	28 / 127