- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03354455
Investigating the Causal Role of preSMA in Levodopa-induced Dyskinesia in Parkinson's Disease
Targeting the Pre-supplementary Motor Area With Repetitive Transcranial Magnetic Stimulation to Alleviate Levodopa-induced Dyskinesia in Parkinson´s Disease
Using a within-subject cross-over design, we will include 20 patients with Parkinson disease (PD) and peak-of-dose dyskinesia.
Patients will be studied after withdrawal from their normal dopaminergic medication.
On two separate days, each patient will receive off-line, effective (high-intensity) or ineffective (low-intensity) 1 Hz repetitive transcranial magnetic stimulation (rTMS) of the presupplementary motor area (preSMA) before functional magnetic resonance (fMRI). Immediately after the patient will perform a Go/No-Go task during fMRI in the the OFF state for 9 minutes. Then the scan is paused and the patient will receive 200 mg fast-acting oral levodopa and undergo whole-brain task-related fMRI at 3 Tesla until peak-of-dose dyskinesia will emerge.
During task-related fMRI, patients has to click on a mouse with their right hand (Right-Go), left hand (Left-Go), or no action (No-Go) in response to arbitrary visual cues.
The patients will also be tested for different aspects of impulsivity using neuropsychological questionnaires and computerized tests.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
The most common form of levodopa-induced dyskinesias (LID) manifests when levodopa levels are highest and is referred to as peak-of-dose dyskinesia. 50% of patients experience LID after 4-6 years of treatment, reaching a frequency of 40% after 4-6 years. The main risk factors for developing LID are disease duration, levodopa dose and age-at-onset, but none of these factors alone can predict whether and when an individual patient with PD will develop LID. There is converging evidence that exogenously administered levodopa induces non-physiological release and reuptake of dopamine in the striatum. This non-physiological dopaminergic stimulation gives rise to aberrant plasticity in the striatum that causes a sensitization of the cortico-basal ganglia system to levodopa. Dyskinesia often severely affects patients' quality of life requiring advanced treatment.
Adopting a novel pharmacological fMRI (ph-fMRI) approach, our group recently identified a functional signature of LID in the human brain: To bypass any problems due to movement artefacts, fMRI was performed in the time-span between the administration of levodopa and the onset of dyskinesia. Ph-fMRI revealed that a single oral dose of levodopa caused an abnormal cortico-striatal activation and connectivity pattern in pre-SMA and putamen in LID patients relative to PD patients without LID. We predict that 1 Hz rTMS of pre-SMA will attenuate the levo-dopa-induced overactivity in the pre-SMA and putamen and normalise the pre-SMA-putamen connectivity pattern. This may possibly involve an altered interaction with the right inferior frontal gyrus (rIFG).On two separate days, each patient will receive effective (high-intensity) or ineffective (low-intensity) 1 Hz rTMS (i.e. control rTMS session) of the pre-SMA before fMRI (Off-line rTMS).
Pharmacological fMRI (ph-fMRI): Immediately after rTMS the patient will perform a Go/No-Go task during fMRI in the the OFF state for 9 minutes. Then the scan is paused and the patient will receive 200 mg fast-acting oral levodopa and undergo whole-brain task-related fMRI at 3 Tesla until peak-of-dose dyskinesia will emerge. During task-related fMRI, patients press a computer mouse with the right hand (Right-Go), left hand (Left-Go), or no action (No-Go) in response to arbitrary visual cues.
We want to include 20 patients in the final analysis of the study. In a previous comparable study we experienced a drop-out rate around a third. We therefore aim to enrol 30 patients.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Capital Region
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Hvidovre, Capital Region, Denmark, 2650
- Danish Research Centre for Magnetic Resonance
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Clinical diagnosis of Parkinson's Disease (Hoehn & Yahr 1-3)
- Peak-of-dose levodopa-induced dyskinesia
Exclusion Criteria:
- Insufficient Danish language skills
- Neurological disease other than Parkinson's Disease
- Major psychiatric illness
- Sedatives or serotonergic medication in their current treatment.
- Severe tremor
- Montreal Cognitive Assessment score < 26
Contraindication for transcranial magnetic stimulation:
- Epilepsy or epilepsy in 1st degree relatives
- Contraindications for MRI-scanning:
- Pacemaker
- Pregnancy
- Metallic foreign objects inside the body
- Severe claustrophobia
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: REAL TMS
30 minutes of repetitive transcranial magnetic stimulation with 100% of the patients' individual resting motor threshold.
|
Frequency: 1 Hz., Pulse shape: biphasic, Duration: 30 minutes (1800 pulses). Neuronavigation: MRI-guided and robot-assisted neuronavigation using Localite software and an Axilum robot. |
Sham Comparator: SHAM TMS
30 minutes of repetitive transcranial magnetic stimulation with 30% of the patients' individual resting motor threshold.
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Frequency: 1 Hz., Pulse shape: biphasic, Duration: 30 minutes (1800 pulses). Neuronavigation: MRI-guided and robot-assisted neuronavigation using Localite software and an Axilum robot. |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Levodopa-induced change in task-related regional neural activity as indexed by the blood oxygen level dependent (BOLD) signal
Time Frame: Within the first 60 minutes after levodopa intake
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A single priming session of REAL rTMS over the preSMA will attenuate the abnormal pharmacodynamic BOLD response (which is an index of regional neural activity) in the cortico-basal ganglia loop after levodopa challenge compared with SHAM rTMS.
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Within the first 60 minutes after levodopa intake
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Onset of LID
Time Frame: Within the first 60 minutes after levodopa intake
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A single priming session of REAL rTMS over the SMA will prolong the time to onset of LID compared with SHAM.
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Within the first 60 minutes after levodopa intake
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Severity of LID
Time Frame: Within the first 60 minutes after levodopa intake
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A single priming session of REAL rTMS over the SMA will lower the the severity of LID measured on the Unified Dyskinesia Rating Scale (UDysRS) compared with SHAM.
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Within the first 60 minutes after levodopa intake
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Hartwig R Siebner, MD, DMSci, Danish Research Centre for Magnetic Resonance
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Chemically-Induced Disorders
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Neurologic Manifestations
- Parkinsonian Disorders
- Basal Ganglia Diseases
- Movement Disorders
- Synucleinopathies
- Neurodegenerative Diseases
- Drug-Related Side Effects and Adverse Reactions
- Poisoning
- Neurotoxicity Syndromes
- Parkinson Disease
- Dyskinesias
- Dyskinesia, Drug-Induced
Other Study ID Numbers
- H-15017863
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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