A Prospective, Randomized, Controlled Trial to Test Safety and Effectiveness of Unilateral Exablate MR-guided Focused Ultrasound Subthalamotomy in Patients With Early-Stage Parkinson's Disease

Early Focus II: A Prospective, Randomized, Controlled Trial to Test Safety and Effectiveness of Unilateral Exablate MR-guided Focused Ultrasound (MRgFUS) Subthalamotomy in Patients With Early-Stage Parkinson's Disease (ESPD)

This prospective, randomized, multicenter study aims to evaluate in Early-Stage Parkinson's Disease (ESPD) patients the safety and effectiveness of treatment with Exablate MRgFUS subthalamotomy vs best medical treatment.

Study Overview

• Status: Active, not recruiting
• Conditions: Parkinson Disease
• Intervention / Treatment: Procedure: Exablate MRgFUS subthalamotomy; Drug: Best Medical Treatment

Detailed Description

This is a prospective, randomized (ratio 2:1), multicenter study to evaluate in Early-Stage Parkinson's Disease (ESPD) patients the safety and effectiveness of treatment with Exablate MRgFUS subthalamotomy vs best medical treatment. Patients assigned to the treatment arm will receive unilateral Exablate MRgFUS subthalamotomy. Patients assigned to control group will receive best medical treatment.

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Chile
  • Santiago, Chile
    • Pontificia Universidad Católica de Chile
• Germany
  • Kiel, Germany, 24105
    • Universitätsklinikum Schleswig-Holstein, Campus Kiel (UKSH)
• Spain
  • Móstoles, Spain, 28938
    • HM CINAC- Hospital Universitario HM Puerta del Sur
  • Pamplona, Spain, 31008
    • Clinica Universidad de Navarra

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men and women; age 30 to 65 years old
• Subjects who are able and willing to give consent and able to attend all study visits. - Subjects with a diagnosis of PD according to the modified clinical criteria by the Movement Disorders Society, for less than 5 years and more than 12 months.
• Off-medication MDS-UPDRS part III of the most affected body side ≥ 10
• Motor signs predominantly present in one body side: Asymmetry index (MDS-UPDRS III of the most affected side/MDS-UPDRS III of the least effected side) ≥ 2.
• Patients should have a stable pharmacological regime for the last 4-weeks prior to baseline evaluation.
• Topographic coordinates of the subthalamic nucleus are localizable on MRI so that it can be targeted by the Exablate device.
• Skull density ratio (SDR) score of 0.40 or higher*. The SDR is a determinant factor for the suitability to MRgFUS ablation. SDR is a ratio of ultrasound energy penetration through the skull. The SDR threshold for using Exablate 4000 is established at 0.4 with patients having SDR below that value considered unsuitable candidates.
• Able to communicate sensations during the Exablate MRgFUS treatment.

Exclusion Criteria:

• MDS-UPDRS part III OFF medications > 32 in the off state and/or Hoehn and Yahr state ON medication greater than 2.
• Significative evidence (by clinical history) of having developed features indicative of PD motor onset 2 or more years prior to formal diagnosis.
• Presence of clinically relevant levodopa-induced dyskinesia and/or motor fluctuations as noted by a score > 1 on questions 4.2 or 4.4 of the MDS-UPDRS, that assess disability resulting from motor complications.
• Levodopa daily dose higher than 500mg or 750 levodopa-equivalents daily.
• Presence of any symptoms or signs suggesting other central neurodegenerative disease such as multisystem atrophy, progressive supranuclear palsy, cortico-basal syndrome, dementia with Lewy bodies, and Alzheimer's disease.
• Any suspicion that parkinsonian symptoms are a side effect attributable to intake of neuroleptic or other medications.
• Subjects who have had deep brain stimulation or a prior stereotactic ablation for the treatment of movement disorders.
• Presence of significant cognitive impairment measured by standard of care method at the center.
• Patients with clinically relevant co-morbidity such as severe hypertension, diabetes, cardiac, metabolic, and psychiatric conditions
• Other exclusion criteria for the Exablate system.
• Subjects with significant depression as determined following a comprehensive assessment by a neuropsychologist. Significant depression is being defined quantitatively as a score of greater than 14 on the Beck Depression Inventory.
• Legal incapacity or limited legal capacity as determined by the neuropsychologist.

• Subjects exhibiting any behavior(s) consistent with ethanol or substance abuse as defined by the criteria outlined in the DSM-IV as manifested by one (or more) of the following occurring within the preceding 12-month period:

  • Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home (such as repeated absences or poor work performance related to substance use; substance-related absences, suspensions, or expulsions from school; or neglect of children or household).
  • Recurrent substance use in situations in which it is physically hazardous (such as driving an automobile or operating a machine when impaired by substance use).
  • Recurrent substance-related legal problems (such as arrests for substance related disorderly conduct).
  • Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (for example, arguments with spouse about consequences of intoxication and physical fights).

• Subjects with unstable cardiac status including:

  • Unstable angina pectoris on medication
  • Subjects with documented myocardial infarction within six months of protocol entry
  • Significant congestive heart failure defined with ejection fraction <40.
  • Subjects with unstable ventricular arrhythmias
  • Subjects with atrial arrhythmias that are not rate controlled.
  • Severe hypertension (diastolic BP >100 on medication).
• History of or 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 (e.g., Avastin) within one month of focused ultrasound procedure.
• Subjects with risk factors for intraoperative or postoperative bleeding as indicated by: platelet count less than 100,000 per cubic millimeter, a documented clinical coagulopathy, or INR coagulation studies exceeding the institution's laboratory standard.
• Patient with severely impaired renal function with estimated glomerular filtration rate <30mL/min/1.73m2 (or per local standards should that be more restrictive) and/or who is on dialysis.
• Subjects with standard contraindications for MR imaging such as non-MRI compatible implanted metallic devices including cardiac pacemakers, size limitations, etc.
• Significant claustrophobia that cannot be managed with mild medication.
• Subject who weighs more than the upper weight limit of the MR table and who cannot fit into the MR scanner.
• Subjects who are not able or willing to tolerate the required prolonged stationary supine position during treatment.
• History of intracranial hemorrhage.
• History of multiple strokes, or a stroke within past 6 months.
• Subjects with a history of seizures within the past year.
• Subjects with malignant brain tumors.
• Subjects with intracranial aneurysms requiring treatment or arterial venous malformations (AVMs) requiring treatment.
• Any illness that in the investigator's opinion preclude participation in this study.
• Subjects unable to communicate with the investigator and staff.
• Pregnancy or lactation.
• Patients without clinically relevant parkinsonism in the off- state as evaluated by two examining neurologists (or MDS- UPDRS III in the most affected side <10).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exablate Arm; Subjects will receive Exablate MRgFUS subthalamotomy	Procedure: Exablate MRgFUS subthalamotomy; Exablate MRgFUS subthalamotomy for Parkinson's Disease
Active Comparator: Reference Arm; Patients fulfilling all inclusion/exclusion criteria except for the SDR requirements (and so anatomically not able to undergo MRgFUS subthalamotomy) will be offered the option to receive best medical treatment and will be formally followed as a reference comparator for up to 3 years.	Drug: Best Medical Treatment; Subjects will be managed according to conventional therapeutic guidelines (i.e., best medical treatment) for Parkinson's Disease
Active Comparator: Control Arm; Subjects will receive best medical treatment. If patients from the control arm undergo the unilateral Exablate MRgFUS subthalamotomy between month 12 to 36, they will be exiting the study.	Procedure: Exablate MRgFUS subthalamotomy; Exablate MRgFUS subthalamotomy for Parkinson's Disease; Drug: Best Medical Treatment; Subjects will be managed according to conventional therapeutic guidelines (i.e., best medical treatment) for Parkinson's Disease

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MDS-UPDRS Part III OFF Medication	Between-group difference (Exablate and control) in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III at 12 months in the off-medication state.	12 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PD-specific spatial covariance patterns (PDRP or PD related metabolic pattern) with brain 18F-fluorodeoxyglucose- Positron emission tomography	The metabolic pattern will be quantified to obtain a PDRP expression scores at baseline, 12-month and to compare disease evolution between groups.	12 Months
MDS-UPDRS III OFF-med video-based evaluation	Between group comparison (Exablate and control) through month 12 and within group comparison vs baseline month 12 in MDS-UPDRS III OFF-med video-based evaluation by a blinded movement disorders neurologist (only at baseline and 12 months).	12 Months
MDS-UPDRS I, II, III (ON and OFF meds) and UPDRS IV	Between group (Exablate and control) comparison through month 12 and within and between group (Exablate and comparator) comparison vs baseline, month 12 to 36 in MDS-UPDRS I, II, III (ON and OFF meds) and UPDRS IV.	12 Months, 24 Months, 36 Months
MDS Unified Dyskinesia Rating Scale	Between group (Exablate and control) comparison through month 12 and within and between group (Exablate and comparator) comparison vs baseline, month 12 to 36 in MDS Unified Dyskinesia Rating Scale.	12 Months, 24 Months, 36 Months
Quality of life assessment (PDQ39)	Between group (Exablate and control) comparison through month 12 and within and between group (Exablate and comparator) comparison vs baseline, month 12 to 36 in Quality-of-life assessment (PDQ39).	12 Months, 24 Months, 36 Months
Levodopa equivalent dose change usage (milligrams)	Between group (Exablate and control) comparison through month 12 and within and between group (Exablate and comparator) comparison vs baseline, month 12 to 36 in Levodopa equivalent dose usage (milligrams).	12 Months, 24 Months, 36 Months
MDS-Non motor rating scale	Between group (Exablate and control) comparison through month 12 and within and between group (Exablate and comparator) comparison vs baseline, month 12 to 36 in MDS-Non motor rating scale.	12 Months, 24 Months, 36 Months
Patient Global Impression of Change (PGIC)	Between group (Exablate and control) comparison through month 12 and within and between group (Exablate and comparator) comparison vs baseline, month 12 to 36 in Patient Global Impression of Change (PGIC).	12 Months, 24 Months, 36 Months
Clinician Global Impression of Change (CGIC)	Between group (Exablate and control) comparison through month 12 and within and between group (Exablate and comparator) comparison vs baseline, month 12 to 36 in Clinician Global Impression of Change (CGIC).	12 Months, 24 Months, 36 Months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Incidence and frequency of adverse events related to the treatment.	Incidence and frequency of adverse events related to the treatment. The investigator will capture any untoward events related to the treatment in the case report forms along with severity, duration, and resolution, and whether the event is considered serious. The severity of adverse events will be categorized according to the definition of adverse events from the International Organization for Standardization (ISO).	36 Months
Exploratory assessment: F- Dopa PET assessment	F- Dopa PET assessment will evaluate difference in the progression of striatal dopaminergic denervation.	12 Months, 36 Months
Exploratory assessment: Time to Parkinson's Disease Progression	PD progression will also be defined by comparing between-group Kaplan-Meier curves of subjects exceeding the worsening thresholds of specific clinical scales	12 Months, 24 Months, 36 Months

Collaborators and Investigators

• Sponsor: InSightec
• Investigators: Principal Investigator: José Obeso, MD, PhD, HM CINAC- Hospital Universitario HM Puerta del Sur; Principal Investigator: Raúl Martínez-Fernández, MD, PhD, HM CINAC- Hospital Universitario HM Puerta del Sur

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2024
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: August 30, 2024
• First Submitted That Met QC Criteria: August 30, 2024
• First Posted (Actual): September 4, 2024

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: MRgFUS; Exablate; Subthalamotomy
• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurodegenerative Diseases; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Parkinson Disease
• Other Study ID Numbers: PD017

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No