rTMS for Motor and Mood Symptoms of Parkinson's Disease

Study Overview
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Brief Summary
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The purpose of this study is to determine if repetitive transcranial magnetic stimulation (rTMS), a method of noninvasive brain stimulation) is effective in the treatment of the motor (movement) and mood symptoms due to Parkinson's disease (PD).

Detailed Description
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Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive means of brain stimulation which can produce changes to brain excitability. Following a series of daily rTMS sessions, this modulation of neural circuits and other distant effects may help some of the motor and neuropsychiatric symptoms of PD for months at a time. Recently, the FDA approved daily rTMS over the prefrontal cortex as a treatment for medication-refractory depression after demonstration of efficacy in sham-controlled trials and its safety profile. Among several small and pilot studies of rTMS in PD patients, rTMS over either the motor cortex or prefrontal cortex has been reported to show beneficial effects on motor and mood (depression) symptoms with no serious adverse events. However, the relative effectiveness of rTMS over motor, prefrontal, or both regions on both mood and motor symptoms, has yet to be established in PD patients. We propose to conduct a four-center, blinded, sham-controlled, randomized, parallel-group study of fixed-dose, high-frequency rTMS in 160 PD patients who are experiencing depressive symptoms despite an adequate trial of at least one antidepressant. Subjects will be randomized to receive rTMS over either motor cortex, prefrontal cortex, both, or neither (sham-rTMS). Subjects will receive rTMS for 25 minutes over either the prefrontal cortex (the brain region associated with mood and depression), and/or primary motor cortex (associated with motor control), and/or sham-rTMS. After 10 days of rTMS (or sham) treatment over a 2-week period, all subjects will undergo a comprehensive assessment of motor, mood, cognition and quality of life on the first working day after the last rTMS treatment, and after 1, 3 and 6 months post-treatment. This study directly addresses the expansion of rTMS as an alternative treatment for depression in the PD population and will provide evidence as to whether motor cortex stimulation will provide additional and/or separate benefit to motor symptoms.

Official Title
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Repetitive Transcranial Magnetic Stimulation (rTMS) for Motor and Mood Symptoms of Parkinson's Disease (MASTER-PD), a Multicenter Clinical Trial

Conditions
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Parkinson's Disease, Depression

Intervention / Treatment
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* Device: Repetitive transcranial magnetic stimulation (rTMS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of PD according to the UK Brain Bank Criteria, confirmed by a neurologist with expertise in movement disorders. Minimum of 3 years since the formal diagnosis of PD, and requiring dopaminergic therapy (at a minimum, on levodopa and/or dopamine agonist therapy). Minimum baseline OFF score on the motor UPDRS of 15 points of more. Lack of features suggestive of atypical parkinsonism, such as early prominent cerebellar, pyramidal, or autonomic dysfunction; supranuclear gaze palsy; falls within the first year of symptoms; hallucinations prior to initiating a dopaminergic agent. No history of neuroleptics or other drugs that induce parkinsonism in the past 60 days. Currently optimally treated with medications and, in the view of the treating neurologist, will unlikely be requiring anti-PD medication adjustments in the next 6 months. On a stable dose of all medications for 30 days (except anti-depressants- which should be stable for at least 90 days). Lack of dementia such that, in the view of the enrolling investigator, the patient is able to give proper informed consent. In addition, all patients must score at least a 26 out of 30 on the screening MMSE. HAM-D score > 12 on the first 17 questions of the scale, despite the current use of antidepressant(s) for at least 90 days, or documentation of adequate trial of antidepressants (i.e. at least 6 weeks on an optimal dose), or documentation of intolerability to antidepressants. Untreated depression or on a stable dose of antidepressants for 90 days (untreated patients need to have tried at least one antidepressant in the past). Age 21 years or older. Patient meets the criteria for a depressive disorder based on either the MINI interview (major depression) or SCID (minor depression, or dysthymia). Exclusion Criteria: Intracranial metallic bodies (e.g. from prior neurosurgical procedure). Signs or symptoms of increased intracranial pressure. Implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, TENS unit or ventriculoperitoneal shunt. History of seizures or unexplained loss of consciousness. Possible pregnancy. Family history of medication refractory epilepsy. History of substance abuse within the last 6 months. History of known structural brain abnormality. History of exposure to repetitive TMS in the past (to minimizing risk of unblinding sham condition). History of exposure to ECT in the past. Patients with suicidal ideation deemed by the investigator to be significant enough to render the individual a suicidal risk. Patients with a history of hospitalization for suicidal ideation/attempts. Patients requiring hospitalization for their depression within the past six months will not be allowed in the study. If a participating subject's depression worsens during the study to a degree that hospitalization is deemed necessary, or if the subject develops significant suicidal ideation, he/she will be withdrawn from the study and referred to a psychiatrist for treatment. Patients with bipolar affective disorder and those whose depression is characterized by psychotic features. Patients with a history of spontaneous hallucinations or delusions as well as those with other underlying psychotic disorders (e.g., schizophrenia, schizoaffective disorder, delusional disorder). The presence of visual illusions or hallucinations deemed by the enrolling physician to be clearly related to antiparkinsonian medications will be allowed but only if the enrolling physician believes that they are stable and unlikely to require changes in medication (i.e., addition of an antipsychotic or reduction in antiparkinsonian drug dosage). Patients with delusions will be excluded. Subjects judged by the clinician investigator to have dementia (by DSM-IV and MMSE criteria) will be excluded. Subjects judged by the clinician investigator to have dementia (by MoCA criteria) will be excluded. Subjects with unstable medical condition such as diabetes, cardiac disease, and hypertension. Subjects with brittle or severe motor fluctuation that will cause severe discomfort during OFF medication testing at Baseline, immediately post-TMS, and at Months 1, 3, and 6. Excessive alcohol use or taking one of the following exclusionary medications: Imipramine, Amitriptyline, Doxepin, Nortriptyline, Maprotiline, Chlorpromazine, Clozapine, Foscarnet, Ganciclovir, Ritonavir, Amphetamines (MDMA, ecstasy), cocaine, phencyclidine (PCP, angel's dust), ketamine, gamma-hydroxybutyrate (GHB), theophylline, and haloperidol.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Double rTMS<br>High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). | Device: Repetitive transcranial magnetic stimulation (rTMS)<br>* DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.<br>* Other names: Magstim Corporation;|
| Active Comparator: M1 Active rTMS + DLPFC Sham rTMS<br>High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC). | Device: Repetitive transcranial magnetic stimulation (rTMS)<br>* DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.<br>* Other names: Magstim Corporation;|
| Active Comparator: DLPFC Active rTMS + M1 Sham rTMS<br>High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1). | Device: Repetitive transcranial magnetic stimulation (rTMS)<br>* DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.<br>* Other names: Magstim Corporation;|
| Sham Comparator: Double Sham rTMS<br>Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC). | Device: Repetitive transcranial magnetic stimulation (rTMS)<br>* DLPFC Active rTMS: Each treatment will consist of 2000 stimuli (50 X 4-second trains of 40 stimuli at 10 Hz, administered every 30 seconds for 25 minutes). Stimulus intensity for the first and second trains will be 80 and 90 percent of motor evoked potential (MEP), respectively. If no adverse effects are observed following each of the first two trains, then the subsequent trains will be given at MEP threshold. M1 Active rTMS: Stimulation will be applied one side at a time, to the motor cortex site at 90 percent of each subject's motor threshold intensity, and at a frequency of 10 Hz with 1000 stimuli per side (25 X 8-second trains of 40 stimuli). Sham rTMS: Patients from all four centers randomized to receive sham treatment will undergo the same procedures used in patients receiving active rTMS.<br>* Other names: Magstim Corporation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor Subscale of the Unified Parkinson's Disease Rating Scale (UPDRS Part III) | To evaluate the motor symptoms in Parkinson's Disease. The UPDRS-III mean scores were reported for each group at each time point. The UPDRS-III Score Range is 0 - 56, where higher the score indicates greater severity of the motor symptoms. | Pre-treatment; Post-treatment 0,1,3, and 6 months. | 
| Hamilton Depression Scale (HAM-D) | To evaluate the depressive mood symptoms in PD. The HAM-D mean scores were reported for each group at each time point. The HAM-D Score Range is 0 - 56, where higher the score indicates greater severity of depressive mood symptoms. | Pre-treatment; Post-treatment 0,1,3, and 6 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Anxiety Scale (CAS) | To evaluate anxiety in Parkinson's Disease. The CAS mean scores were reported for each group at each time point. The CAS Score Range is 0 - 100, where higher the score indicates greater severity of the anxiety symptoms. | Pre-treatment; Post-treatment 0,1,3, and 6 months. | 
| Apathy Evaluation Scale (AES) | To evaluate apathy in Parkinson's Disease. The AES mean scores were reported for each group at each time point. The AES Score Range is 0-42, where higher the score indicates greater severity of the apathy symptoms. | Pre-treatment; Post-treatment 0,1,3, and 6 months. | 
| Parkinson's Disease Questionnaire 39 (PDQ-39) | To assess the quality of life (QOL) in Parkinson's Disease. The PDQ-39 mean scores were reported for each group at each time point. The PDQ-39 Score Range is 0 - 156, where higher the score indicates greater impact on quality of life. | Pre-treatment; Post-treatment 0,1,3, and 6 months. | 
| Montreal Cognitive Assessment (MoCA) | To screen and follow cognitive function in Parkinson's Disease. The MoCA mean scores were reported for each group at each time point. The MoCA Score Range is 0 - 30, where 26-30 indicates normal cognition. | pre-treatment; 0,1,3, and 6 months post-treatment | 
| Unified Parkinson's Disease Rating Scale (UPDRS) Parts I, II, and IV | To assess apathy, cognition, depression, activities of daily living (ADL), quality of life (QOL), and motor symptoms in Parkinson's Disease. The UPDRS I, II, IV total mean scores were reported for each group at each time point. The UPDRS I, II, IV scores were added together for each patient, with a total score range of 0 - 91, where higher the score indicates greater severity of the symptoms. | Pre-treatment; Post-treatment 0,1,3, and 6 months. | 
| Beck Depression Inventory (BDI-II) | To assess mood symptoms in Parkinson's Disease. The BDI-II mean scores were reported for each group at each time point. The BDI-II Score Range is 0 - 63, where higher the score indicates greater severity of the mood symptoms. | Pre-treatment; Post-treatment 0,1,3, and 6 months. | 
| Global Impression Scales | To assess symptom severity and treatment response in Parkinson's Disease. The CGI mean scores were reported for each group at each time point. The CGI Score Range is 1 - 8, where higher the score indicates greater severity of illness or worsening of illness. | Pre-treatment; Post-treatment 0,1,3, and 6 months. | 
| The Number All Types of Adverse Events. | To establish the safety and tolerability of rTMS in Parkinson's Disease. | Baseline through Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's Disease, Depression, Transcranial Magnetic Stimulation