Dyskinesia, Drug-InducedNCT03354455
Investigating the Causal Role of preSMA in Levodopa-induced Dyskinesia in Parkinson's Disease
A study testing Repetitive transcranial magnetic stimulation in people with Dyskinesia, Drug-Induced and Parkinson Disease, run by Danish Research Centre for Magnetic Resonance at 1 site in Denmark.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Dyskinesia, Drug-Induced, Parkinson Disease
- What is being tested?
- Repetitive transcranial magnetic stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteDenmark
- Study dates
- 1 Aug 2017to 16 Sep 2018
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Clinical diagnosis of Parkinson's Disease (Hoehn \& Yahr 1-3)
- Peak-of-dose levodopa-induced dyskinesia
Who cannot join
- 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
Show all 13Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Denmark1 site
Danish Research Centre for Magnetic Resonance
Hvidovre, Capital Region, 2650
About this study
Official title: 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.
Read more
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.
Read the 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.
- Conditions
- Dyskinesia, Drug-Induced, Parkinson Disease
- Being tested
- Repetitive transcranial magnetic stimulation
- Medical subject headings
- Dyskinesia, Drug-Induced, Parkinson Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Repetitive transcranial magnetic stimulationDevice
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.
| Study group | Role | What they receive |
|---|---|---|
| REAL TMS | Experimental | 30 minutes of repetitive transcranial magnetic stimulation with 100% of the patients' individual resting motor threshold. Receives: Device: Repetitive transcranial magnetic stimulation |
| SHAM TMS | Sham comparator | 30 minutes of repetitive transcranial magnetic stimulation with 30% of the patients' individual resting motor threshold. Receives: Device: Repetitive transcranial magnetic stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Levodopa-induced change in task-related regional neural activity as indexed by the blood oxygen level dependent (BOLD) signal
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.
Measured: Within the first 60 minutes after levodopa intake
Secondary outcomes (2)
Onset of LID
A single priming session of REAL rTMS over the SMA will prolong the time to onset of LID compared with SHAM.
Measured: Within the first 60 minutes after levodopa intake
Severity of LID
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.
Measured: Within the first 60 minutes after levodopa intake
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Nov 2017
- Study start1 Aug 2017
- Primary completion16 Sep 2018
- Study completion16 Sep 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Dyskinesia, Drug-InducedStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Danish Research Centre for Magnetic Resonance
- Sponsor type
- University, hospital or other
- Collaborators
- University Hospital Bispebjerg and Frederiksberg, Danish Movement Disorder Society (DANMODIS), Danish Parkinson Association
- Responsible party
- Sponsor
- Investigators
- Hartwig R Siebner, MD, DMSci, Principal investigator, Danish Research Centre for Magnetic Resonance
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03354455
- Sponsor's protocol ID
- H-15017863
- Status last verified
- Aug 2018
- First submitted
- 1 Jun 2017
- Last updated
- 6 Aug 2019
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 6 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Targeting the Pre-supplementary Motor Area With Repetitive Transcranial Magnetic Stimulation to Alleviate Levodopa-induced Dyskinesia in Parkinson´s Disease
- ClinicalTrials.gov ID
- NCT03354455
- Acronym / sponsor ID
- H-15017863
- Conditions
- Dyskinesia, Drug-Induced, Parkinson Disease
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Danish Research Centre for Magnetic ResonanceUniversity, hospital or other
- Collaborators
- University Hospital Bispebjerg and Frederiksberg, Danish Movement Disorder Society (DANMODIS), Danish Parkinson Association
- Study start
- 1 Aug 2017 (actual)
- Primary completion
- 16 Sep 2018 (actual)
- Study completion
- 16 Sep 2018 (actual)
- First posted
- 28 Nov 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| REAL TMS | Experimental | Device: Repetitive transcranial magnetic stimulation30 minutes of repetitive transcranial magnetic stimulation with 100% of the patients' individual resting motor threshold. |
| SHAM TMS | Sham comparator | Device: Repetitive transcranial magnetic stimulation30 minutes of repetitive transcranial magnetic stimulation with 30% of the patients' individual resting motor threshold. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Clinical diagnosis of Parkinson's Disease (Hoehn \& Yahr 1-3)
- Peak-of-dose levodopa-induced dyskinesia
Key exclusion criteria (13 listed)
- Insufficient Danish language skills
- Neurological disease other than Parkinson's Disease
- Major psychiatric illness
- Sedatives or serotonergic medication in their current treatment.
- Severe tremor
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Repetitive transcranial magnetic stimulationFrequency: 1 Hz., Pulse shape: biphasic, Duration: 30 minutes (1800 pulses). Neuronavigation: MRI-guided and robot-assisted neuronavigation using Localite software and an Axilum robot. | Device | REAL TMS, SHAM TMS |
Primary outcome
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
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.
2 secondary outcomes
Onset of LID
Time frame: Within the first 60 minutes after levodopa intake
Severity of LID
Time frame: Within the first 60 minutes after levodopa intake
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Aug 2019.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hartwig R Siebner, MD, DMSci principal investigator
Danish Research Centre for Magnetic Resonance
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Repetitive transcranial magnetic stimulation in people with Dyskinesia, Drug-Induced and Parkinson Disease, run by Danish Research Centre for Magnetic Resonance at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Aug 2019.