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FUS PD

Randomized Trial of Focused Ultrasound Subthalamotomy for Parkinson's Disease

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Year of Publication: 2020

Authors: R. Martinez-Fernández, I.U. Máñez-Miró, R. Rodríguez-Rojas, ..., and J.A. Obeso

Journal: New England Journal of Medicine

Citation: N Engl J Med 2020;383:2501-13. DOI: 10.1056/NEJMoa2016311

Link: https://www.nejm.org

Clinical Question

Does focused ultrasound subthalamotomy performed in one hemisphere improve motor features of Parkinson's disease in selected patients with markedly asymmetric motor signs compared to sham procedure?

Bottom Line

Focused ultrasound subthalamotomy in one hemisphere improved motor features of Parkinson's disease at 4 months in selected patients with asymmetric signs, with an 8.1-point greater improvement in MDS-UPDRS III motor score for the more affected side compared to sham, but was associated with adverse events including dyskinesias, speech and gait disturbances, and weakness on the treated side.

Major Points

  • Randomized 2:1 ratio to focused ultrasound subthalamotomy (n=27) vs sham procedure (n=13) in patients with markedly asymmetric Parkinson's disease
  • Primary efficacy outcome: MDS-UPDRS III motor score for more affected side decreased 9.8 points in active treatment vs 1.7 points in control (between-group difference 8.1 points, 95% CI 6.0 to 10.3, P<0.001)
  • Procedure performed on hemisphere opposite main motor signs in off-medication state
  • Dyskinesia in off-medication state developed in 6 patients (22%) in active treatment group, persisting in 3 patients at 4 months
  • Speech disturbances occurred in 15 patients (56%) in active treatment group, persisting in 3 at 4 months
  • Weakness on treated side occurred in 5 patients (19%), persisting in 2 at 4 months
  • Gait disturbances occurred in 13 patients (48%), persisting in 2 at 4 months
  • Twelve of 13 control patients crossed over to receive active treatment in open-label phase
  • Trial funded by Insightec and others; ClinicalTrials.gov NCT03454425

Design

Study Type: Randomized, double-blind, sham-controlled trial

Randomization: 1

Blinding: Double-blind (patients and evaluating neurologists unaware of treatment assignment)

Enrollment Period: March 2018 through May 2019

Follow-up Duration: 4 months for primary outcome; 12 months for crossover patients

Centers: 2

Countries: Spain, United States

Sample Size: 40

Analysis: Intention-to-treat for efficacy outcomes; mixed model with repeated measures for primary outcome

Inclusion Criteria

  • Diagnosis of Parkinson's disease according to UK Brain Bank Clinical Criteria
  • Highly asymmetric parkinsonism with asymmetry index ≥1.5 at screening visit
  • Asymmetry index ≥1 indicating symmetry on the less affected side
  • Motor signs not well controlled on the more affected side despite use of dopaminergic medication

Exclusion Criteria

  • Axial motor manifestations of Parkinson's disease or motor signs on both sides of the body that were too severe (score ≥2.5 on modified Hoehn and Yahr scale while in off-medication state)
  • Severe levodopa-induced dyskinesia
  • History of stereotactic surgery or brain hemorrhage
  • Presence of cognitive impairment or any other serious neuropsychiatric or medical condition
  • Claustrophobia that prevented undergoing MRI
  • Skull density ratio of less than 0.35

Arms

FieldControlFocused Ultrasound Subthalamotomy
InterventionSham delivery of ultrasound acoustic energy; patients placed in MRI equipment and coupled to ultrasound transducer through stereotactic head frame, underwent identical preparation procedures, but power was disengagedFocused ultrasound subthalamotomy performed on the hemisphere opposite the main motor signs using acoustic energy delivery; ultrasound beams targeted dorsolateral subthalamic nucleus and pallidothalamic tract
DurationSingle procedureSingle procedure

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Between-group difference in the change from baseline to 4 months in the MDS-UPDRS III motor score (range 0 to 44) for the more affected side of the body in the off-medication statePrimary18.7 at baseline to 17.1 at 4 months (mean change 1.7 points)19.9 at baseline to 9.9 at 4 months (mean change 9.8 points)<0.001
MDS-UPDRS III score for more affected side - on-medication state at Month 4SecondaryChange from baseline 1.7 pointsChange from baseline 6.4 pointsNot specified
Dyskinesia on more affected side in off-medication stateAdverse06 (22%) total; 3 (11%) at 4 months
Weakness on more affected sideAdverse05 (19%) total; 2 (7%) at 4 months
Speech disturbanceAdverse015 (56%) total; 3 (11%) at 4 months
Gait disturbanceAdverse013 (48%) total; 2 (7%) at 4 months

Criticisms

  • Small sample size (40 patients total) limits generalizability
  • Trial approximates a single-center study (36 patients at one site, 4 at the other)
  • No prespecified plan for adjustment of 95% confidence intervals for multiple comparisons of secondary outcomes
  • Short follow-up period (4 months) for primary outcome
  • Selected patient population with markedly asymmetric parkinsonism limits applicability to broader PD population
  • High rate of adverse events including dyskinesias and neurologic complications
  • Patients and assessors correctly guessed trial-group assignments in many cases

Funding

Supported by Insightec, the Focused Ultrasound Foundation, Fundacion MAPFRE, Fundación Hospitales de Madrid, and the University of Virginia Center of Excellence

Based on: FUS PD (New England Journal of Medicine, 2020)

Authors: R. Martinez-Fernández, I.U. Máñez-Miró, R. Rodríguez-Rojas, ..., and J.A. Obeso

Citation: N Engl J Med 2020;383:2501-13. DOI: 10.1056/NEJMoa2016311

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