Focused Ultrasound Unilateral Pallidotomy for Medication-Refractory Limb Dystonia

Official title

Focused Ultrasound Pallidotomy for Medication-Refractory Limb Dystonia (FUTURE Study)

Overview

The goal of this clinical trial is to find out if a non-invasive procedure called focused ultrasound can safely and effectively treat limb dystonia in adults who have not improved with medications or botulinum toxin injections. The main questions it aims to answer are: * Does focused ultrasound reduce the severity of limb dystonia symptoms? * Is the procedure safe and well tolerated? Researchers will compare people who receive focused ultrasound treatment to those who receive a sham procedure (a look-alike procedure without active treatment) to see if the treatment works. Focused ultrasound works by producing a very small (millimeter-size) lesion in a deep brain region. In this study, the lesion is located in a region called globus pallidus, which helps control movement. Participants will: * Be randomly assigned to one of two groups: focused ultrasound or sham * Undergo a procedure using MRI and focused ultrasound to target a part of the brain called the globus pallidus * Be followed for 6 months after treatment to assess changes in symptoms, quality of life, and brain function * Participants in the sham group will be offered the real treatment after 3 months This study may offer a new non-surgical treatment option for people with dystonia affecting the arm or leg, whose pharmacological control is unsatisfactory.

Detailed description

The FUTURE study is a prospective, randomized, double-blind, sham-controlled, multicenter national clinical trial aimed at assessing the efficacy and safety of unilateral MR-guided focused ultrasound (MRgFUS) pallidotomy in patients with limb dystonia that is refractory to standard pharmacological treatments.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions, causing abnormal movements or postures. In many cases, focal or segmental dystonias affecting the limbs can be managed with oral medications and botulinum toxin (BoNT) injections. However, a subset of patients does not respond adequately to these treatments. For such individuals, surgical intervention may offer relief, yet it remains underutilized due to concerns about invasiveness and complications.

Recent advancements in non-invasive neurosurgical techniques have introduced MRgFUS pallidotomy, a procedure that uses focused ultrasound beams under real-time MRI guidance to precisely ablate small brain targets-in this case, the globus pallidus internus (GPi). The FUTURE study specifically explores this technique as a less invasive alternative to deep brain stimulation, especially for patients with focal or segmental limb dystonia who are ineligible or reluctant to undergo conventional surgery.

The trial will enroll 34 adult patients with idiopathic or genetic limb dystonia that has proven resistant to pharmacologic and BoNT treatment. These patients will be randomly assigned in a 1:1 ratio to either:

* an active treatment group, undergoing unilateral GPi lesioning via MRgFUS, * or a sham control group, receiving the same procedural setup but without therapeutic sonications.

At three months post-randomization, all patients in the sham group will cross over to receive the active MRgFUS treatment, allowing within-subject comparisons while ensuring ethical access to the therapeutic intervention. The follow-up period for each patient will last six months after active treatment, totaling a maximum of nine months of participation.

The primary endpoint is the change in motor severity as measured by the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) at three months post-treatment. Secondary endpoints include adverse event frequency, patient and clinician global impressions of change, disability assessments (e.g., QuickDASH), quality of life (SF-36), and neurocognitive testing.

Additionally, the study will incorporate neurophysiological (TMS) and neuroimaging (resting-state fMRI) techniques to investigate treatment-induced changes in cortical excitability, plasticity, and functional connectivity, providing insight into the neural mechanisms underlying clinical improvement.

The FUTURE study is coordinated by the Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy with participation from other three major Italian neurological institutes. It represents a pioneering effort to evaluate focused ultrasound as a non-invasive therapeutic option for patients with disabling and treatment-resistant forms of limb dystonia.

Interventions

• Device Exablate MR-guided Focused Ultrasound Pallidotomy
  Active Pallidotomy
• Device Sham Sham Exablate MRgFUS Pallidotomy
  Sham procedure. Identical setup without thermal lesioning. Participants cross over to Active Pallidotomy after 3 months.

Primary outcome measures

• Chenge in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) [Time frame: Baseline to Week 12]

Secondary outcome measures (12)

• Incidence of treatment-related adverse events [Time frame: Baseline to Week 24]
• Changes in the Quick Disabilities of Arm, Shoulder & Hand (Quick-DASH) score [Time frame: Baseline, Week 12 and Week 24]
• Changes in the Clinical Global Impression of Change (CGIC) score [Time frame: Baseline, week 12 and week 24]
• Patient Global Impression of Change (PGIC) [Time frame: Baseline, Week 12 and week 24]
• Change in the 36-Item Short Form Survey (SF-36) score [Time frame: Baseline, week 12 and week 24]
• Changes in the Short-Interval Cortical Inhibition (SICI) [Time frame: Baseline and Week 24]
• Changes in intracortical facilitation (ICF) [Time frame: Baseline and Week 24]
• Changes in Paired Associative Stimulation (PAS) [Time frame: Baseline and week 24]
• Changes in brain activity (using functional connectivity) using resting-state functional magnetic resonance imaging (rs-fMRI) [Time frame: Baseline and Week 24]
• Changes in pallidotomy lesion morphology via contrast MRI [Time frame: 24-hour after the procedure, week 12 and week 24]
• Changes in the Montreal Cognitive Assessment (MoCA) score [Time frame: Baseline, week 12 and week 24]
• Change in Digit Span test score [Time frame: Baseline, week 12 and week 24]]

Eligibility criteria

Inclusion criteria

• Age 18-80 years
• Able and willing to consent and attend visits
• Idiopathic or hereditary limb dystonia (focal, segmental, or multifocal; isolated or combined)
• Refractory to oral therapy and botulinum toxin
• Stable medication for ≥30 days and ≥90 days since last BoNT
• Capable of communicating during Exablate procedure

Exclusion criteria

• Acquired secondary dystonia
• Dementia or other neurodegenerative disorders
• Any clinically significant or unstable medical condition, which, in the opinion of the principal investigator or the clinician delegated by the principal investigator, may put the participant at risk when participating in the study (e.g., unstable heart disease or coagulopathy; uncontrolled psychiatric comorbidity)
• Prior deep brain stimulation or other brain surgery
• Any contraindication to MRI
• Skull Density Ratio (SDR) < 0.40
• Significant brain lesions (eg brain tumor, significant white matter lesions or globus pallidus interna lesions on baseline MRI)
• Pregnancy

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Italy · 4 centers

• Azienda ULSS3 Serenissima — Mestre
• IRCCS Centro Neurolesi "Bonino-Pulejo" — Messina
• Fondazione IRCCS Istituto Neurologico Carlo Besta — Milan
• Azienda Ospedaliera Ospedali Riuniti Villa Sofia — Palermo

Publications

• Rothwell JC, Hallett M, Berardelli A, Eisen A, Rossini P, Paulus W. Magnetic stimulation: motor evoked potentials. The International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl. 1999;52:97-103. No abstract available. PMID 10590980
• Sohn YH, Hallett M. Disturbed surround inhibition in focal hand dystonia. Ann Neurol. 2004 Oct;56(4):595-9. doi: 10.1002/ana.20270. PMID 15455393
• Burke RE, Fahn S, Marsden CD, Bressman SB, Moskowitz C, Friedman J. Validity and reliability of a rating scale for the primary torsion dystonias. Neurology. 1985 Jan;35(1):73-7. doi: 10.1212/wnl.35.1.73. PMID 3966004
• Horisawa S, Yamaguchi T, Abe K, Hori H, Fukui A, Iijima M, Sumi M, Hodotsuka K, Konishi Y, Kawamata T, Taira T. Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Focal Hand Dystonia: A Pilot Study. Mov Disord. 2021 Aug;36(8):1955-1959. doi: 10.1002/mds.28613. Epub 2021 May 29. PMID 34050695
• Stieglitz LH, Mahendran S, Oertel MF, Baumann CR. Bilateral Focused Ultrasound Pallidotomy for Parkinson-Related Facial Dyskinesia-A Case Report. Mov Disord Clin Pract. 2022 May 9;9(5):647-651. doi: 10.1002/mdc3.13462. eCollection 2022 Jul. PMID 35844284
• Krishna V, Fishman PS, Eisenberg HM, Kaplitt M, Baltuch G, Chang JW, Chang WC, Martinez Fernandez R, Del Alamo M, Halpern CH, Ghanouni P, Eleopra R, Cosgrove R, Guridi J, Gwinn R, Khemani P, Lozano AM, McDannold N, Fasano A, Constantinescu M, Schlesinger I, Dalvi A, Elias WJ. Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease. N Engl J Med. 2023 Feb 23;388(8):683-693. doi: PMID 36812432
• Hariz M. Pros and Cons of Ablation for Functional Neurosurgery in the Neurostimulation Age. Neurosurg Clin N Am. 2023 Apr;34(2):291-299. doi: 10.1016/j.nec.2022.11.006. Epub 2023 Jan 30. PMID 36906335
• Horisawa S, Fukui A, Takeda N, Kawamata T, Taira T. Safety and efficacy of unilateral and bilateral pallidotomy for primary dystonia. Ann Clin Transl Neurol. 2021 Apr;8(4):857-865. doi: 10.1002/acn3.51333. Epub 2021 Mar 15. PMID 33720521

Identifiers

NCT: NCT07168850 · PNRR-MCNT2-2023-12378417

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗