Clinical trial NCT01080794: rTMS for Motor and Mood Symptoms of Parkinson's Disease
Official title: Repetitive Transcranial Magnetic Stimulation (rTMS) for Motor and Mood Symptoms of Parkinson's Disease (MASTER-PD), a Multicenter Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Parkinson's Disease
Depression
Keywords: Parkinson's Disease
Depression
Transcranial Magnetic Stimulation
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: University of California, Los Angeles
name: University of Florida
name: University Health Network, Toronto
name: The Cleveland Clinic
name: Michael J. Fox Foundation for Parkinson's Research
First posted: 2010-03-04
Enrollment: 61
Sex: ALL
Minimum age (years): 21
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Motor Subscale of the Unified Parkinson's Disease Rating Scale (UPDRS Part III)
timeFrame: Pre-treatment; Post-treatment 0,1,3, and 6 months.
measure: Hamilton Depression Scale (HAM-D)
timeFrame: Pre-treatment; Post-treatment 0,1,3, and 6 months.
Secondary outcomes:
measure: Clinical Anxiety Scale (CAS)
timeFrame: Pre-treatment; Post-treatment 0,1,3, and 6 months.
measure: Apathy Evaluation Scale (AES)
timeFrame: Pre-treatment; Post-treatment 0,1,3, and 6 months.
measure: Parkinson's Disease Questionnaire 39 (PDQ-39)
timeFrame: Pre-treatment; Post-treatment 0,1,3, and 6 months.
measure: Montreal Cognitive Assessment (MoCA)
timeFrame: pre-treatment; 0,1,3, and 6 months post-treatment
measure: Unified Parkinson's Disease Rating Scale (UPDRS) Parts I, II, and IV
timeFrame: Pre-treatment; Post-treatment 0,1,3, and 6 months.
measure: Beck Depression Inventory (BDI-II)
timeFrame: Pre-treatment; Post-treatment 0,1,3, and 6 months.
measure: Global Impression Scales
timeFrame: Pre-treatment; Post-treatment 0,1,3, and 6 months.
measure: The Number All Types of Adverse Events.
timeFrame: Baseline through Month 6
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Cleveland
country: United States
facility: The Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Alvaro Pascual-Leone, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Allan Wu, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: The Cleveland Clinic
name: Hubert Fernandez, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University Health Network, Toronto
name: Robert Chen, BChir, MA, MB, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida
name: Aparna Wagle-Shukla, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Oregon Health and Science University
name: Jau-Shin Lou, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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