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Feasibility Study to Evaluate the Safety and Effectiveness of Bilateral Magnetic Resonance-guided Focused Ultrasound (MRgFUS) Ablation of the Pallido-Thalamic Tract for the Treatment of Advanced Parkinson's Disease (PD005)

PD005 (PD005)

9

A total of nine patients diagnosed with advanced Parkinson's disease were included in the study. They were on average 58 years of age (three males and six females), and all were of Asian ethnicity.

A total of 11 patients with advanced PD were initially screened for this study, and 9 of them proceeded to receive the initial MRgFUS treatment. All nine patients completed the 12-month follow-up period as scheduled following unilateral treatment. The initial plan was to perform a second treatment (contralateral treatment) three months after the first. However, due to the significant improvement in bilateral symptoms and the decision by Insightec to discontinue the study, only two of the nine patients received a second treatment (contralateral treatment). Of the two patients, one completed the full 12-month follow-up period, while the other was followed for only three months due to death from renal failure. The study was designed to plan contralateral treatment three months after the initial treatment until the protocol was revised to version 6 on 17 December 2019. However, due to factors such as the marked improvement in symptoms on both sides, contralateral treatment was not performed in seven out of nine patients. Consequently, the prospective evaluation of efficacy was completed in numerous patients three months after unilateral treatment (the limited number of patients evaluated for efficacy does not constitute a protocol deviation). With regard to the assessment of safety, as the protocol required observation of the patients for a period of 12 months following contralateral treatment, the patients whose efficacy evaluation had already been conducted were also observed for 12 months (18 months in principle after the protocol was revised to the 6th edition on 17 December 2019).

With the exception of minor adverse effects such as headaches, one patient experienced permanent freezing after treatment on one side, and one patient experienced transient drowsiness and weakness of the lower limbs after treatment on one side. Although no causal relationship is believed to exist between this study and the incident, one patient died of accidental renal failure three months after evaluation and treatment on both sides.

Safety: Apart from mild adverse events such as headache, one patient experienced permanent freezing after unilateral treatment and one patient experienced transient drowsiness and lower limb weakness. One patient died of renal failure three months after bilateral treatment, but this was considered unrelated to the study. Efficacy: The MDS-UPDRS Part III score during the on period improved by 36.1% and 46.1% from a mean of 26.1 before surgery to 15.6 and 11.9 at 1 and 3 months, respectively. During the off period, the improvement rates were 45.8% and 48.7%, respectively, with 54.4 before surgery, 27 at 1 month, and 26.6 at 3 months. After additional contralateral treatment, there was a significant improvement from 30 before additional contralateral treatment to 19 after 3 months, and from 76 before additional contralateral treatment to 10 after 3 months, and the effect continued at 12 months. However, it should be noted that only one patient completed the 1-year follow-up after bilateral treatment. This study was designed to provide contralateral treatment 3 months after initial treatment until the protocol was revised to version 6 on December 17, 2019. However, contralateral treatment was not performed in 7 of the 9 patients due to significant improvement of symptoms on both sides. As a result, the efficacy evaluation of the prospective study was completed 3 months after unilateral treatment for many patients. Therefore, the primary endpoint is the evaluation at 3 months after unilateral treatment.

This study was an exploratory study to evaluate the feasibility of bilateral PTT-MRgFUS treatment for advanced PD, with the goal of evaluating its efficacy and safety. Significant improvement was also seen in the non-surgical side, and unilateral treatment alone was performed in 7 out of 9 cases. In terms of efficacy, unilateral treatment alone improved MDS-UPDRS part III by nearly 50% in both the on and off periods. In terms of safety, one case of permanent freezing was observed with unilateral treatment.

Jan. 31, 2025

No

No plans

https://jrct.mhlw.go.jp/latest-detail/jRCTs032180407

Ikezawa Jun

TOKYO METROPOLITAN NEUROLOGICAL HOSPITAL

2-6-1 Musashidai, Fuchu, Tokyo

jun_ikezawa@tmhp.jp

Taura Hisako

TOKYO METROPOLITAN NEUROLOGICAL HOSPITAL

2-6-1 Musashidai, Fuchu, Tokyo

+81-42-323-5110

hisako_taura@tmhp.jp

Complete

Dec. 28, 2017

Interventional

single arm study

open(masking not used)

no treatment control/standard of care control

single assignment

treatment purpose

1.Men and women age 30 years and older
2.Patients who are able and willing to give consent and able to attend all study visits
3.A diagnosis of idiopathic Parkinson's Disease by UK Brain Bank Criteria as confirmed from clinical history and examination by a neurologist specializing Parkinson's disease by the presence of tremor at rest, bradykinesia and rigidity
4.Levodopa responsive as defined by at least a 30% reduction in MDS-UPDRS motor subscale in the ON vs OFF medication state.
5.Symptoms have been resistant to optimal pharmacologic treatment including L-dopa and other antiparkinsonian drugs for at least 1 year.
6.Subjects on stable (i.e., no change in medication drug or dosage for 3 months) antidepressant medications for at least 3 months may be enrolled into this study.
7.Disabling motor complications of PD on optimum medical treatment (dyskinesia etc.) characterized by at least one of the two most clinically relevant symptoms (e.g. tremor at rest or dyskinesia - must have a score of >= 3 on the MDS-UPDRS, questions 3.17a-e or 4.2).
8. Strongly diminished quality of life.
9. The pallido-thalamic region can be targeted by the ExAblate device.
10. Able to communicate sensations during the ExAblate MRgFUS treatment.
11. Patients are on stable doses of all PD medications for 30 days prior to study entry.
12. Inclusion and exclusion criteria have been agreed upon by two members of the medical team.

1.Patients with unstable cardiac status including:
a)Unstable angina pectoris on medication
b)Patients with documented myocardial infarction within six months of protocol entry
c)Congestive heart failure requiring medication (other than diuretic)
d)Patients on anti-arrhythmic drugs
2.Criteria outlined in the DSM-IV as manifested by one (or more) of the following occurring within a 12 month period:
a)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).
b)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)
c)Recurrent substance-related legal problems (such as arrests for substance related disorderly conduct)
d)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).
3.Severe hypertension (diastolic BP > 100 on medication)
4.Patients with standard contraindications for MR imaging such as non-MRI compatible implanted metallic devices including cardiac pacemakers, size limitations, etc.
5.Severely impaired renal function (estimated glomerular filtration rate < 45ml/min/1.73 m2) or receiving dialysis
6.History of abnormal bleeding and/or coagulopathy
7.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
8.Active or suspected acute or chronic uncontrolled infection
9.History of intracranial hemorrhage
10.Cerebrovascular disease (multiple CVA or CVA within 6 months)
11.Individuals who are not able or willing to tolerate the required prolonged stationary supine position during treatment (can be up to 4 hrs of total table time.)
12.Symptoms and signs of increased intracranial pressure (e.g. headache, nausea, vomiting, lethargy, and papilledema)
13.Are participating or have participated in another clinical trial in the last 30 days
14.Patients unable to communicate with the investigator and staff.
15.Presence of any other neurodegenerative disease and/or dementia
16.Presence of significant cognitive impairment as determined with a score <= 24 on the Mini Mental Status Examination (MMSE)
17.History of immune-compromise, including patient who is HIV positive
18.Known life-threatening systemic disease
19.Patients with a history of seizures within the past year
20.Patients with current or prior history of psychiatric illness will be excluded, (e.g., presence or history of psychosis will be excluded; patients with mood disorders including unstable or uncontrolled depression will be excluded.) For the purpose of this study, we consider a significant mood disorder to include any patient who has:
a.been under the care of a psychiatrist for over 3 months for non-pharmaceutical therapy
b.has participated in cognitive-behavioral therapy
c.been hospitalized for the treatment of a psychiatric illness
d.received transcranial magnetic stimulation
e.received electroconvulsive therapy
21.Patients with risk factors for intraoperative or postoperative bleeding (platelet count less than 100,000 per cubic millimeter, a documented coagulopathy, INR coagulation studies exceeding the institutions laboratory standards.
22.Patients with brain tumors
23.Any illness that in the investigator's opinion preclude participation in this study.
24.Pregnancy or lactation.
25.Legal incapacity or limited legal capacity.
26.Patients who have had deep brain stimulation or a prior stereotactic ablation of the basal ganglia
27.Skull density ratio (SDR) < 0.30

Both

Parkinson's Disease

Staged, bilateral ExAblate Transcranial MRgFUS treatment

Parkinson's Disease

<Safety>
Frequency and severity of adverse events
<Efficacy>
Month 6 /12 ON (medicated) MDS-UPDRS motor subsection (part III) as compared to ON (medicated) MDS-UPDRS motor subsection (part III) at Screening.

Total MDS-UPDRS (parts I-IV),
OFF (medicated) MDS-UPDRS, part III motor subsection,
Unified Dyskinesia Rating scale,
Levodopa equivalent medication usage (mg),
Quality of life assessment with PDQ-39

+81-42-341-2712-7828

Feb. 08, 2019

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