Investigating the Use of Complex Pulse Shapes for DBS in Movement Disorders (INSHAPE_DBS)

• ClinicalTrials.gov Identifier: NCT04725045
• Recruitment Status: Completed
• First Posted: January 26, 2021
• Last Update Posted: April 29, 2022
• Sponsor: KU Leuven
• Information provided by (Responsible Party): Myles Mc Laughlin, KU Leuven

Study Description

Brief Summary:

Parkinson's disease and essential tremor are chronic movement disorders for which there is no cure. When medication is no longer effective, deep brain stimulation (DBS) is recommended. Standard DBS is a neuromodulation method that uses a simple monophasic pulse, delivered from an electrode to stimulate neurons in a target brain area. This monophasic pulse spreads out from the electrode creating a broad, electric field that stimulates a large neural population. This can often effectively reduce motor symptoms. However, many DBS patients experience side effects - caused by stimulation of non-target neurons - and suboptimal symptom control - caused by inadequate stimulation of the correct neural target. The ability to carefully manipulate the stimulating electric field to target specific neural subpopulations could solve these problems and improve patient outcomes. The use of complex pulse shapes, specifically biphasic pulses and asymmetric pre-pulses, can control the temporal properties of the stimulation field. Evidence suggests that temporal manipulations of the stimulation field can exploit biophysical differences in neurons to target specific subpopulations. Therefore, our aim is to evaluate the effectiveness of complex pulse shapes to reduce side effects and improve symptom control in DBS movement patients.

Condition or disease	Intervention/treatment	Phase
Parkinson Disease; Essential Tremor	Device: Boston Scientific: Study tool computer	Not Applicable

Detailed Description:

The study had three stages. In the first stage, a wide range of investigatory pulse shapes in a small number of patients. The effect of the pulses on the therapeutic window will be assessed.

Stage 2 will perform a short-term chronic evaluation in a larger number of patients of the complex pulse shape selected as most interesting from stage 1.

• ET patients will first be assessed after 3 hours of the cathodic or complex pulse (double-blind design).
• PD patients will only be assessed after 1 week of each pulse.

Stage 3 will then focus on long-term evaluation (upto 2 years). Outcomes: see stage 2.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Randomized, crossover, double-blinded design
• Masking: Double (Participant, Outcomes Assessor)
• Masking Description: Double-blinded design
• Primary Purpose: Supportive Care
• Official Title: Investigating the Use of Complex Pulse Shapes for DBS in Movement Disorders
• Actual Study Start Date: February 12, 2019
• Actual Primary Completion Date: April 14, 2022
• Actual Study Completion Date: April 14, 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Standard clinical pulse shape; Standard clinical pulse shape as used in clinical practice (cathodic stimulation).	Device: Boston Scientific: Study tool computer; compare clinical outcome measurements of complex pulse shapes to standard clinical pulse shape
Experimental: Complex pulse shape; Complex pulse shape (i.e. biphasic pulse shape anode first, biphasic pulse shape cathode first, hyperpolarizing pre-pulse or depolarizing pre-pulse)	Device: Boston Scientific: Study tool computer; compare clinical outcome measurements of complex pulse shapes to standard clinical pulse shape

Outcome Measures

Primary Outcome Measures :

1. Stage 1: Therapeutic window = Amplitude at which therapeutic benefit is obtained versus amplitude at which side-effects occur, both expressed in mA (milliamperes). [ Time Frame: Immediately after testing ]
   Amplitude at which therapeutic benefit is obtained versus amplitude at which side-effects occur, both expressed in mA (milliamperes).
2. Stage 2 ET (3 hours): tremor scores [ Time Frame: Measured after 3 hours of stimulation ]
   FTM (Fahn-Tolosa-Marin) total score. Max 116 (higher score for more tremor).
3. Stage 2 ET (3 hours): ataxia scores [ Time Frame: Measured after 3 hours of stimulation ]
   ICARS (International cooperative ataxia rating scale): total score. Max 100 (higher score for more ataxia).
4. Stage 2 ET (1 week): number of treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: During 1 week of stimulation ]
   Follow-up of (S)AE related to the study during that week
5. Stage 2 PD (1 week): number of treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: During 1 week of stimulation ]
   Follow-up of (S)AE related to the study during that week
6. Stage 3 ET (2 years): number of treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: During 2 years of stimulation ]
   Follow-up of (S)AE related to the study during those 2 years

Secondary Outcome Measures :

1. Stage 1: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Upto one week after the study visit of stage 1 ]
   Follow-up of (S)AE related to the study upto 1 week after the experiment
2. Stage 2 ET (3 hours): Therapeutic window: Amplitude to elicit tremor arrest, amplitude to elicit ataxia, amplitude to elicit stim-induced side-effects [ Time Frame: Immediately after testing ]
   Amplitude to elicit tremor arrest, amplitude to elicit ataxia, amplitude to elicit stimulation-induced side-effects (all expressed in mA)
3. Stage 2 ET (3 hours): tremor subscores [ Time Frame: Measured at 1 hours, 2 hours and 3 hours after start of stimulation ]
   FTM (Fahn-Tolosa-Marin) subscores: items 5, 6, 11, 12 and 13 (max 48, higher score for more tremor)
4. Stage 2 ET (3 hours): ataxia subscores [ Time Frame: Measured at 1 hours, 2 hours and 3 hours after start of stimulation ]
   ICARS (international cooperative ataxia rating scale): item 10 (max 8, higher score for more ataxia)
5. Stage 2 ET (3 hours): speech assessment (least dysarthria) [ Time Frame: Measured at 1 hours, 2 hours and 3 hours after start of stimulation ]
   Tests: sustained phonation /a/, diadochokinesis /tatata/, text reading and spontaneous speech Outcome: which of both pulses has less dysarthria per test (either cathodic pulse, either experimental pulse)
6. Stage 2 ET (1 week): tremor scores and subscores [ Time Frame: Measured after 1 week of stimulation ]

   FTM (Fahn-Tolosa-Marin) tremor rating scale:

   • total score (max 116, higher score for more tremor)
   • subscores: items 5, 6, 11, 12 and 13 (max 48, higher score for more tremor)
7. Stage 2 ET (1 week): ataxia subscores and total score [ Time Frame: Measured after 1 week of stimulation ]

   ICARS (international cooperative ataxia rating scale):

   • total score: max 100, higher score for more ataxia
   • subscore: item 10 (max 8, higher score for more ataxia)
8. Stage 2 ET (1 week): tremor measured with Kinesia One wearable [ Time Frame: Measured after 1 week of stimulation ]
   Amount of postural tremor and kinetic tremor in both hands (max 4 per side, higher score for more tremor)
9. Stage 2 ET (1 week): tremor time measured with Kinesia 360 [ Time Frame: Measured during 1 week of stimulation ]
   Amount of tremor time measured with Kinesia 360 wearable (%, higher score for more tremor time)
10. Stage 2 ET (1 week): speech assessment (least dysarthria) [ Time Frame: Measured after 1 week of stimulation ]
    Tests: sustained phonation /a/, diadochokinesis /tatata/, text reading and spontaneous speech Outcome: which of both pulses has less dysarthria per test (either cathodic pulse, either experimental pulse)
11. Stage 2 ET (1 week): cognition [ Time Frame: Measured after 1 week of stimulation ]
    MoCA (Montreal Cognitive Assessment). Max 30, higher score for better cognition.
12. Stage 2 ET (1 week): quality-of-life [ Time Frame: Measured after 1 week of stimulation ]
    QUEST (Quality-of-life in essential tremor questionnaire). Max 100%, higher score for worse quality-of-life.
13. Stage 2 ET (1 week): quality-of-life [ Time Frame: Measured once daily during 1 week of stimulation ]

    VAS (visual analogue scale) for:

    • amount of tremor
    • discomfort due to tremor Max 10, higher scores for worse outcome.
14. Stage 2 PD (1 week): therapeutic window (amplitude at loss of rigidity and amplitude at stim-induced side-effects) [ Time Frame: Immediately after testing ]
    Amplitude at loss of rigidity and amplitude at stimulation-induced side-effects
15. Stage 2 PD (1 week): assessment motor symptoms in Parkinson's [ Time Frame: Measured after 1 week of stimulation ]
    MDS-UPDRS-III (Movement Disorders Society Unified Parkinson's Disease Rating Scale, part III). Max 132, higher score for more parkinsonian symptoms.
16. Stage 2 PD (1 week): assessment non-motor symptoms in Parkinson's [ Time Frame: Measured after 1 week of stimulation ]
    NMSS (non-motor symptoms scale). Max 30, higher scores for more symptoms.
17. Stage 2 PD (1 week): assessment of motor symptoms in Parkinson's with Kinesia One wearable [ Time Frame: Measured after 1 week of stimulation ]
    Wearable scores finger tapping and hand opening. Max 4 per item, higher scores for more symptoms.
18. Stage 2 PD (1 week): assessment motor symptoms in Parkinson's with Kinesia 360 wearable [ Time Frame: Measured after 1 week of stimulation ]
    Wearable score amount of time that patient was bradykinetic and dyskinetic. Expressed as %, higher scores for more symptoms
19. Stage 2 PD (1 week): assessment of speech (least dysarthria) [ Time Frame: Measured after 1 week of stimulation ]
    Tests: sustained phonation /a/, diadochokinesis /tatata/, text reading and spontaneous speech Outcome: which of both pulses has less dysarthria per test (either cathodic pulse, either experimental pulse)
20. Stage 2 PD (1 week): cognition [ Time Frame: Measured after 1 week of stimulation ]
    MoCA (Montreal Cognitive Assessment). Max 30, higher score for better cognition.
21. Stage 2 PD (1 week): quality-of-life [ Time Frame: Measured after 1 week of stimulation ]

    PDQ-39 (Parkinson's disease Questionnaire): 39-item questionnaire on quality-of-life.

    Expressed in %, higher score for more symptoms.

22. Stage 2 PD (1 week): quality-of-life [ Time Frame: Measured once daily during 1 week of stimulation ]

    VAS (visual analogue scale) for:

    • amount of parkinsonian symptoms
    • discomfort due to parkinsonian symptoms Max 10, higher scores for worse outcome.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria for PD:

• Diagnosis of idiopathic Parkinson's disease where the diagnosis was made by a Movement Disorder Specialist according to the MDS criteria of 2015, with a Hoehn and Yahr scale (H&Y) of at least 2 (bilateral involvement).
• Onset of the symptoms more than five years ago.
• MDS-UPDRS-III score of ≥30 without medication or DBS.
• Electrodes are implanted in target area STN.

Inclusion Criteria for ET:

• Patient is diagnosed with essential tremor by a Movement Disorder Specialist.
• Diagnosis since more than 3 years.
• Patient has a disabling medical-refractory upper extremity tremor without medication or DBS.
• Patient has a postural or kinetic tremor severity score of at least 3 out of 4 in the extremity intended for treatment on the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor without medication or DBS.
• Electrodes are implanted in target area VIM.

General Inclusion Criteria:

• Post-op the implanted electrodes pass an integrity check, i.e. no open or shorted electrodes.
• Stable medications
• Lack of dementia or depression.
• Patient is willing and able to comply with all visits and study related procedures
• Patient understands the study requirements and the treatment procedures and provides written informed consent before any study-specific tests or procedures are performed.
• Patient can tolerate at least 12 hours OFF medication and per clinical judgement be able to perform all study related procedures

Exclusion Criteria:

• Any significant psychiatric problems, including unrelated clinically significant depression.
• Any current drug or alcohol abuse.
• Any history of recurrent or unprovoked seizures.
• Have any significant medical condition that is likely to interfere with study procedures or likely to confound evaluation of study endpoints, including any terminal illness with survival <12 months.

Contacts and Locations

Locations

Belgium

KU Leuven

Leuven, Belgium, 3000

Sponsors and Collaborators

KU Leuven

Investigators

• Principal Investigator: Myles Mc Laughlin, Prof. Dr.; KU Leuven

More Information

• Responsible Party: Myles Mc Laughlin, Clinical Professor, KU Leuven
• ClinicalTrials.gov Identifier: NCT04725045
• Other Study ID Numbers: S61020
• First Posted: January 26, 2021
• Last Update Posted: April 29, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Parkinson Disease; Essential Tremor; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Synucleinopathies; Neurodegenerative Diseases