DBS Programming for Essential Tremor

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Alfonso Fasano

Must be taking: Anti-tremor medication

Disqualifiers: Psychiatric condition, Depression, Drug abuse, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

15 Participants Needed

Trial Summary

What is the purpose of this trial?

Population Size and Eligible Patients: The investigators aim to recruit 5 to 10 patients with tremors who have previously undergone Ventral Intermedius Deep Brain Stimulation (VIM-DBS) treatment but have experienced early or late loss of benefits. Additionally, the investigators will enroll ten patients with essential tremor who require VIM-DBS surgery. These individuals will undergo bilateral implantation of Boston Scientific Genus Implantable Pulse Generator (IPG) devices, connected to Boston Scientific Cartesia™ 8-contact Directional Leads. Study Design: This study comprises two distinct phases. Phase 1 is a cross-sectional investigation designed to identify the optimal algorithm for patterned stimulation in the VIM region . Phase 2 is a prospective clinical trial focusing on the assessment of safety and efficacy of bilateral VIM-DBS in patients with essential tremor. Objectives: The primary objective in Phase 2 is to evaluate the safety and effectiveness of bilateral VIM-DBS in individuals with essential tremor. In Phase 1, the investigators seek to explore the impact of the Chronos programming software on tremor patients who have experienced early or late loss of benefits.

Will I have to stop taking my current medications?

The trial requires that you stay on a stable dose of your anti-tremor medication for at least 4 weeks before screening. So, you should not stop taking your current medications.

What data supports the effectiveness of the treatment Directional Bilateral Thalamic Patterned Stimulation for Essential Tremor?

Research suggests that using directional current steering and short pulse stimulation in the thalamus can reduce side effects in essential tremor patients, indicating potential benefits of this approach. Additionally, symmetric biphasic pulses, which are part of the treatment, have been shown to enlarge the therapeutic window, potentially improving effectiveness. ^{1 2 3 4 5}

Is DBS programming for essential tremor generally safe in humans?

Deep brain stimulation (DBS) for essential tremor has been studied for long-term safety, showing that while it can be effective, there are risks such as mild side effects that can be managed with adjustments, and device-related complications that may require additional surgeries. Some patients experienced asymptomatic brain bleeds and seizures, but these were not common. ^{2 3 5 6 7}

How is the Directional Bilateral Thalamic Patterned Stimulation treatment different from other treatments for essential tremor?

This treatment is unique because it uses directional and short-pulse deep brain stimulation (DBS) in the thalamus to potentially improve tremor symptoms while reducing side effects, unlike traditional DBS which may not offer these specific benefits. ^{2 3 4 8 9}

Eligibility Criteria

This trial is for patients with tremors, specifically those who have had VIM-DBS treatment but lost its benefits and those needing new VIM-DBS surgery. Up to 20 people will be enrolled, all of whom must have essential tremor and agree to receive a specific device implant.

Inclusion Criteria

Written and signed Informed Consent

I am an Essential Tremor patient needing Deep Brain Stimulation surgery.

Soft signs (categorizing patients as ET-plus) will be allowed and noted in the patient's chart

Exclusion Criteria

Presence of significant psychiatric or cognitive condition likely to compromise the subject's ability to comply with requirements of the study protocol

Any current drug or alcohol abuse, as determined by the investigator

Unwilling or inability to follow the procedures specified by the protocol

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 - Cross-sectional Investigation

Identify the optimal algorithm for patterned stimulation in the VIM region for patients with early or late loss of benefits from previous VIM-DBS treatment.

6 months

Baseline measurement before IPG replacement

Phase 2 - Prospective Clinical Trial

Assessment of safety and efficacy of bilateral VIM-DBS in patients with essential tremor, with programming in four different settings over 8 months.

8 months

Baseline, Month 2, Month 4, Month 6, Month 8

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Directional Bilateral Thalamic Patterned Stimulation

Trial Overview The study tests a DBS programming method using the Chronos software in two phases: first, finding the best stimulation pattern for tremor control; second, evaluating safety and effectiveness of this approach in new patients requiring bilateral VIM deep brain stimulation.

Participant Groups

Group I: Phase 2 Experimental Treatment 1 Intervention

Ten patients with ET needing DBS-VIM surgery will be recruited and will receive Boston Scientific Genus IPG bilaterally connected to Boston Scientific Cartesia™ 8-contact Directional Leads. The programming will be done in four different settings/periods during the course of 8 months.

Group II: Phase 1 Experimental Treatment 1 Intervention

5 to 10 patients with tremor already treated with VIM-DBS but not doing well because of early or late loss of benefits will be recruited by the PI over a 6 months period. If interested, the potential participants will be screened, informed, and consented by a research coordinator. Before the replacement of their IPG (implantable pulse generator), a baseline measurement will be performed.

Directional Bilateral Thalamic Patterned Stimulation is already approved in United States, European Union, Canada for the following indications:

Approved in United States as VIM-DBS for:

• Essential Tremor
• Parkinsonian Tremor

Approved in European Union as VIM-DBS for:

• Essential Tremor
• Parkinsonian Tremor
• Dystonic Tremor

Approved in Canada as VIM-DBS for:

• Essential Tremor
• Parkinsonian Tremor

Who Is Running the Clinical Trial?

Alfonso Fasano

Lead Sponsor

Trials

1

Recruited

20+

Boston Scientific Corporation

Industry Sponsor

Trials

758

Recruited

867,000+

Michael F. Mahoney

Boston Scientific Corporation

Chief Executive Officer since 2016

MBA from Wake Forest University, BBA in Finance from the University of Iowa

Kenneth Stein

Boston Scientific Corporation

Chief Medical Officer since 2020

MD from Harvard Medical School, MMSc in Clinical Investigation from Harvard-MIT Division of Health Sciences and Technology

Findings from Research

In a study involving 9 patients with essential tremor, it was found that increasing the interphase gap in symmetric biphasic pulses during deep brain stimulation significantly lowered both the therapeutic threshold and side-effect threshold, indicating a reduced therapeutic window.

The results suggest that using zero interphase gaps in anode-first biphasic pulses provides the largest therapeutic window, which may enhance the effectiveness and safety of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interphase Gaps in Symmetric Biphasic Pulses Reduce the Therapeutic Window in Ventral Intermediate Nucleus of the Thalamus-Deep Brain Stimulation for Essential Tremor. Boogers, A., Peeters, J., Van Bogaert, T., et al.[2023]

Directional deep brain stimulation (DBS) showed higher side-effect thresholds compared to traditional circular DBS, indicating it may be safer for patients with tremors.

Bipolar DBS with directional anodes resulted in fewer side effects than both monopolar and bipolar circular stimulation, while all stimulation methods provided similar tremor suppression effects just below their side-effect thresholds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bipolar Directional Deep Brain Stimulation in Essential and Parkinsonian Tremor. Steffen, JK., Reker, P., Mennicken, FK., et al.[2022]

In a study involving 8 patients with essential tremor, short pulse stimulation in the ventral intermediate thalamic nucleus (VIM) effectively reduced stimulation-induced side effects like ataxia and paresthesia while still suppressing tremor severity.

Directional current steering did suppress tremor but did not reduce adverse effects compared to short pulse stimulation, indicating that short pulse stimulation may be a better option for minimizing side effects in deep brain stimulation for tremor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thalamic short pulse stimulation diminishes adverse effects in essential tremor patients. Choe, CU., Hidding, U., Schaper, M., et al.[2019]

In a study involving 38 patients with essential tremor, bilateral deep brain stimulation (DBS) of the VIM nucleus resulted in a significant 29.6% additional improvement in total motor tremor scores compared to unilateral DBS, indicating greater efficacy for bilateral treatment.

While bilateral DBS provided enhanced tremor control, it was associated with a slightly higher rate of adverse events, suggesting that while more effective, the risks should be carefully considered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefits and Risks of a Staged-Bilateral VIM Versus Unilateral VIM DBS for Essential Tremor. Prakash, P., Deuschl, G., Ozinga, S., et al.[2022]

In a study of 38 essential tremor patients using deep brain stimulation, over half were aware they could switch between predefined stimulation programs, with 55% actively doing so to manage side effects.

The findings suggest that all patients, regardless of age, should be educated about the option to switch stimulation settings, and training by specialized nurses could enhance their confidence in using patient controllers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utilization of predefined stimulation groups by essential tremor patients treated with VIM-DBS. Barbe, MT., Pochmann, J., Lewis, CJ., et al.[2022]

Unilateral deep brain stimulation (DBS) of the VIM nucleus in the thalamus shows long-term efficacy in reducing essential tremor symptoms, with significant improvements noted in tremor scores at an average follow-up of 40.2 months after surgery.

While the treatment is effective for some patients, it is associated with device-related complications and a risk of loss of efficacy over time, necessitating additional surgical interventions in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety and efficacy of unilateral deep brain stimulation of the thalamus in essential tremor. Koller, WC., Lyons, KE., Wilkinson, SB., et al.[2022]

Unilateral thalamic deep brain stimulation (DBS) significantly reduced tremors in patients with essential tremor (ET) by 83% and in those with Parkinson's disease (PD) by 82%, demonstrating its efficacy in treating severe tremors that are resistant to medication.

The treatment was generally safe, with mild adverse events more common in ET patients, which were often resolved by adjusting the device settings; however, DBS did not improve other motor symptoms in PD patients, indicating it should be used selectively for those with significant tremor-related disability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson's disease tremor. Ondo, W., Jankovic, J., Schwartz, K., et al.[2019]

In a study involving 11 patients with essential tremor, both directional and short-pulse deep brain stimulation (DBS) significantly reduced tremor severity, with the best results seen using directional stimulation at a pulse width of 60 μs.

The combination of directional stimulation and shorter pulse widths (30 μs) not only effectively reduced tremor but also minimized side effects like ataxia and paresthesia compared to conventional stimulation methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Short-Pulse and Directional Deep Brain Stimulation of the Thalamic Ventral Intermediate Area for Essential Tremor. Hidding, U., Lezius, S., Schaper, M., et al.[2023]

Direct targeting of the dentato-rubro-thalamic tract in deep brain stimulation (DBS) for essential tremor resulted in better tremor control compared to indirect targeting of the ventral intermediate nucleus, with lower tremor severity both before and after surgery.

Patients who underwent direct targeting required lower stimulation parameters (voltage, pulse width, and frequency) for effective tremor control, indicating a more efficient method that could potentially reduce battery depletion in DBS devices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of tractography-assisted to atlas-based targeting for deep brain stimulation in essential tremor. Fenoy, AJ., Schiess, MC.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Interphase Gaps in Symmetric Biphasic Pulses Reduce the Therapeutic Window in Ventral Intermediate Nucleus of the Thalamus-Deep Brain Stimulation for Essential Tremor. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Bipolar Directional Deep Brain Stimulation in Essential and Parkinsonian Tremor. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Thalamic short pulse stimulation diminishes adverse effects in essential tremor patients. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Benefits and Risks of a Staged-Bilateral VIM Versus Unilateral VIM DBS for Essential Tremor. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Utilization of predefined stimulation groups by essential tremor patients treated with VIM-DBS. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Long-term safety and efficacy of unilateral deep brain stimulation of the thalamus in essential tremor. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson's disease tremor. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Combined Short-Pulse and Directional Deep Brain Stimulation of the Thalamic Ventral Intermediate Area for Essential Tremor. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Comparison of tractography-assisted to atlas-based targeting for deep brain stimulation in essential tremor. [2019]