Asymmetric Subthalamic Deep Brain Stimulation for Axial Motor Dysfunction in Parkinson's Disease

A Single-center, Randomized, Double-blinded, Double-crossover Trial of Asymmetric Subthalamic Deep Brain Stimulation for Axial Motor Dysfunction in Parkinson's Disease

This single-center, randomized, quadruple-blinded, double-crossover comparative efficacy trial will study the effects of unilateral 50% voltage reduction in axial motor dysfunction for patients with Parkinson's disease that develop treatment-resistant postural stability gait dysfunction after bilateral subthalamic nucleus deep brain stimulation surgery.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease
• Intervention / Treatment: Other: Asymmetric STN-DBS

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 2S8
      • Movement disorders Centre, Toronto Western Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients with Parkinson's disease (PD) (previously diagnosed according to the UK brain bank criteria) who develop treatment-resistant postural instability gait dysfunction (PIGD) more than 6 months but less than 5 years after bilateral subthalamic nucleus deep brain stimulation (STN-DBS).
• Treatment-resistant PIGD will be defined as freezing of gait and UPDRS or MDS-UPDRS PIGD subscales of more than 6 points despite optimization of medications and bilateral STN-DBS programming.

Exclusion Criteria:

• Treatment-resistant PIGD less than 6 months or more than 5 years after STN-DBS surgery.
• PIGD responsive to optimization of medications and/or bilateral STN-DBS programming.
• Cognitive impairment or psychiatric comorbidities (including substance abuse) that would interfere with the informed consent process, study adherence or outcome assessments.
• Advanced PD or any other neurological, cardiovascular or musculoskeletal co-morbidities that would preclude or require assistance to complete the 10-meter walking test.
• Patients not able to comply with 4-week interval evaluations following their potential enrollment due to personal reasons.
• Serious illness (requiring systemic treatment and/or hospitalization) until subject either completes therapy or is clinically-stable on therapy, in the opinion of the site investigator, for at least 30 days prior to study entry.
• Inability or unwillingness of subject or legal guardian/representative to give written informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Baseline STN-DBS; Maintenance of baseline bilateral STN-DBS settings.
Experimental: Asymmetric STN-DBS 1; Unilateral 50% reduction of voltage (e.g. right side)	Other: Asymmetric STN-DBS; Asymmetric deep brain stimulation
Experimental: Asymmetric STN-DBS 2; Unilateral 50% reduction of voltage (e.g. left side)	Other: Asymmetric STN-DBS; Asymmetric deep brain stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Gait Velocity	As measured during the 10-meter walk test. In this test, participants walk at their usual, regular pace over a total distance of 10 meters. The middle 6-meters (between the 2-meter and 8-meter marks) are timed to measure gait velocity during steady-state gait.	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Motor Function	As measured by the MDS-UPDRS (Movement Disorders Society Unified Parkinson's Disease Rating Scale), which is a clinical and research tool to measure symptoms and signs of Parkinson's disease. It has 4 parts: I (non-motor experiences of daily living), II (motor experiences of daily living), III (motor exam) and IV (motor complications). The MDS-UPDRS has 60 items, scored from 0-4 each. The minimum score is 0 and the maximum score is 240. The MDS-UPDRS (motor) is Part III and measures motor signs. It has 28 items, scored from 0-4 each, so the minimum score is 0 and the maximum score is 112. The MDS-UPDRS (axial motor) is composed of items 3.1 to 3.3a and 3.9 to 3.13 of Part III of the MDS-UPDRS and measures axial motor signs. It has 8 items, scored from 0-4 each, so the minimum score is 0 and the maximum score is 32. In the MDS-UPDRS total, motor and axial motor sub-scales, lower scores indicate better symptoms/signs and higher scores indicate worse symptoms/signs, respectively.	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)
Change in Axial Motor Function (1)	As measured by the Mini-BESTest. The Mini-BESTest is a shorter version of the BESTest (Balance Evaluation Systems Test). It is a clinical and research tool to measure balance control. The Mini-BESTest has 14 items, scored from 0-2 each, so the minimum score is 0 and the maximum score is 28. Lower scores indicate worse balance control and higher scores indicate better balance control.	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)
Change in Axial Motor Function (2)	As measured by the UPDRS-PIGD sub-scale. The UPDRS-PIGD is the Postural Instability Gait Dysfunction (PIGD) sub-scale of the Unified Parkinson's Disease Rating Scale (UPDRS). It is a clinical and research tool to measure PIGD. The UPDRS-PIGD has 5 items, scored from 0-4 each, so the minimum score is 0 and the maximum score is 20. Lower scores indicate better PIGD and higher scores indicate worse PIGD.	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)
Change in Axial Motor Function (3)	As measured by the Freezing of Gait Questionnaire. The Freezing of Gait Questionnaire is a clinical and research tool to measure freezing of gait. It has 6 items, scored from 0-4 each, so the minimum score is 0 and the maximum score is 24. Lower scores indicate better and higher scores indicate worse freezing of gait, respectively.	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)
Change in Quantitative Gait Analysis (1)	Changes in gait velocity in m/s as measured by a quantitative gait analysis system (Zeno walkway).	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)
Change in Quantitative Gait Analysis (2)	Changes in step length in cm (mean, right, left) as measured by a quantitative gait analysis system (Zeno walkway). Step length difference = [right - left step length]	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)
Change in Quantitative Gait Analysis (3)	Step length ratio = [right step length] / [left step length] Step length symmetry = ([right - left step length] / [right + left step length])	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)
Change in Quantitative Speech Analysis (1)	Changes in pitch in Hertz (Hz) as measured by the Praat software.	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)
Change in Quantitative Speech Analysis (2)	Changes in loudness in decibels (dB) as measured by the Praat software.	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)
Change in Quantitative Speech Analysis (3)	Changes in jitter measured in percentage by the Praat software. In this case, jitter is the percentage change in the stability of the frequency of speech tone (i.e. speech cycle-to-cycle frequency variation)	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)
Change in Quantitative Speech Analysis (4)	Changes in shimmer measured in percentage by the Praat software. In this case, shimmer is the percentage change in the stability of the amplitude of speech tone (i.e. speech cycle-to-cycle amplitude variation)	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)
Change in Quality of Life	As measured by the Total Score of the 39-item Parkinson's Disease Quality of Life Questionnaire (PDQ-39). The PDQ-39 is a clinical and research tool to measure quality of life in Parkinson's disease. It has 39 questions, which patients score as never (0% of the time), occasionally (25% of the time), sometimes (50% of the time), often (75% of the time) or always (100% of the time). The PDQ-39 Total Score or Summary Index is the average of the 39 questions, expressed. The minimum score is 0% (never) and the maximum score is 100% (always). Lower scores indicate better quality of life and higher scores indicate worse quality of life.	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)
Change in Select Cognitive Tasks	Left brain cognitive function: Hopkins Verbal Learning Test-Revised: Total recall trials 1-3 (0-36), delayed recall (0-12); Phonemic Verbal Fluency (0-no max); Semantic Verbal Fluency (Animal cue) (0-no max); Letter 1-back and 2-back working memory tasks (0-100%). Right brain cognitive function: Brief Visual Memory Test-Revised: Total recall trials 1-3 (0-36), delayed recall (0-12); Computerized landmark line bisection (-10 to 10); Spatial 1-back and 2-back working memory tasks (0-100%). Ranges in parentheses. Line bisection: closer to 0 is more accurate. For the rest: higher values are better	Baseline and 3 to 4 weeks after switching to each of the DBS conditions (Bilateral, Asymmetric 1, Asymmetric 2)

Collaborators and Investigators

• Sponsor: University of Toronto
• Investigators: Principal Investigator: Alfonso Fasano, MD, PhD, University of Toronto

Publications and helpful links

General Publications

• Fasano A, Herzog J, Seifert E, Stolze H, Falk D, Reese R, Volkmann J, Deuschl G. Modulation of gait coordination by subthalamic stimulation improves freezing of gait. Mov Disord. 2011 Apr;26(5):844-51. doi: 10.1002/mds.23583. Epub 2011 Mar 2.
• Lizarraga KJ, Jagid JR, Luca CC. Comparative effects of unilateral and bilateral subthalamic nucleus deep brain stimulation on gait kinematics in Parkinson's disease: a randomized, blinded study. J Neurol. 2016 Aug;263(8):1652-6. doi: 10.1007/s00415-016-8191-3. Epub 2016 Jun 8.
• Lizarraga KJ, Luca CC, De Salles A, Gorgulho A, Lang AE, Fasano A. Asymmetric neuromodulation of motor circuits in Parkinson's disease: The role of subthalamic deep brain stimulation. Surg Neurol Int. 2017 Oct 24;8:261. doi: 10.4103/sni.sni_292_17. eCollection 2017.
• Lizarraga KJ, Gnanamanogaran B, Al-Ozzi TM, Cohn M, Tomlinson G, Boutet A, Elias GJB, Germann J, Soh D, Kalia SK, Hodaie M, Munhoz RP, Marras C, Hutchison WD, Lozano AM, Lang AE, Fasano A. Lateralized Subthalamic Stimulation for Axial Dysfunction in Parkinson's Disease: A Randomized Trial. Mov Disord. 2022 May;37(5):1079-1087. doi: 10.1002/mds.28953. Epub 2022 Feb 13.

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2018
• Primary Completion (Actual): April 15, 2019
• Study Completion (Actual): April 15, 2019

Study Registration Dates

• First Submitted: March 5, 2018
• First Submitted That Met QC Criteria: March 5, 2018
• First Posted (Actual): March 12, 2018

Study Record Updates

• Last Update Posted (Actual): January 5, 2021
• Last Update Submitted That Met QC Criteria: December 9, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Parkinson's disease; axial motor dysfunction; asymmetric neuromodulation; subthalamic nucleus deep brain stimulation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: 17-5785

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: To be shared as supplementary data upon publication of the results of the trial.
• IPD Sharing Time Frame: To be shared as supplementary data upon publication of the results of the trial.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

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