Repetitive Transcranial MAgnetic STimulation (rTMS) for MotoR and Mood Symptoms of Parkinson's Disease (MASTER-PD), a Multicenter Clinical Trial

This study is currently recruiting participants.
Verified September 2012 by Beth Israel Deaconess Medical Center
Sponsor:
Collaborators:
University of California, Los Angeles
University of Florida
University Health Network, Toronto
The Cleveland Clinic
Michael J. Fox Foundation for Parkinson's Research
Information provided by (Responsible Party):
Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier:
NCT01080794
First received: March 3, 2010
Last updated: September 5, 2012
Last verified: September 2012
  Purpose

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).


Condition Intervention Phase
Parkinson's Disease
Depression
Device: Repetitive transcranial magnetic stimulation (rTMS)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Repetitive Transcranial MAgnetic STimulation (rTMS) for MotoR and Mood Symptoms of Parkinson's Disease (MASTER-PD), a Multicenter Clinical Trial

Resource links provided by NLM:


Further study details as provided by Beth Israel Deaconess Medical Center:

Primary Outcome Measures:
  • Motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRS Part III) [ Time Frame: pre-treatment; 0,1,3, and 6 months post-treatment ] [ Designated as safety issue: No ]
    To evaluate the motor symptoms in PD.

  • Hamilton Depression Scale (HAM-D) [ Time Frame: pre-treatment; 0,1,3 and 6 months post-treatment ] [ Designated as safety issue: No ]
    To evaluate the mood symptoms in PD.


Secondary Outcome Measures:
  • Clinical Anxiety Scale (CAS) [ Time Frame: pre-treatment; 0,1,3, and 6 months post-treatment ] [ Designated as safety issue: No ]
    To evaluate anxiety in PD.

  • Apathy Evaluation Scale (AES) [ Time Frame: pre-treatment; 0,1,3, and 6 months post-treatment ] [ Designated as safety issue: No ]
    To evaluate apathy in PD.

  • Parkinson's Disease Questionnaire 39 (PDQ-39) [ Time Frame: pre-treatment; 0,1,3, and 6 months post-treatment ] [ Designated as safety issue: No ]
    To assess the quality of life (QOL) in PD.

  • Montreal Cognitive Assessment (MoCA) [ Time Frame: pre-treatment; 0,1,3, and 6 months post-treatment ] [ Designated as safety issue: No ]
    To screen and follow cognitive function in PD.

  • Unified Parkinson's Disease Rating Scale (UPDRS) Parts I, II, and IV [ Time Frame: pre-treatment; 0,1,3, and 6 months post-treatment ] [ Designated as safety issue: No ]
    To assess apathy, cognition, depression, activities of daily living (ADL), quality of life (QOL), and motor symptoms in PD.

  • Beck Depression Inventory (BDI-II) [ Time Frame: pre-treatment; 0,1,3, and 6 months post-treatment ] [ Designated as safety issue: No ]
    To assess mood symptoms in PD.

  • Global Impression Scales [ Time Frame: 0,1,3, and 6 months post-treatment ] [ Designated as safety issue: No ]
  • The number and severity of akk types of adverse events (i.e., serious, treatment-emergent, adverse events of interest, total adverse events) [ Time Frame: Baseline through Month 6 ] [ Designated as safety issue: Yes ]
    To establish the safety and tolerability of rTMS in PD.


Estimated Enrollment: 160
Study Start Date: May 2010
Estimated Study Completion Date: January 2014
Estimated Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Double rTMS
High frequency rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC).
Device: Repetitive transcranial magnetic stimulation (rTMS)

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.

Other Names:
  • Transcranial Magnetic Stimulation
  • Noninvasive Brain Stimulation
  • Magstim Corporation
  • Repetitive transcranial magnetic stimulation (rTMS)
Active Comparator: M1 Active rTMS + DLPFC Sham rTMS
High frequency stimulation of the primary motor cortex (M1) and sham stimulation of the dorsolateral prefrontal cortex (DLPFC).
Device: Repetitive transcranial magnetic stimulation (rTMS)

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.

Other Names:
  • Transcranial Magnetic Stimulation
  • Noninvasive Brain Stimulation
  • Magstim Corporation
  • Repetitive transcranial magnetic stimulation (rTMS)
Active Comparator: DLPFC Active rTMS + M1 Sham rTMS
High frequency stimulation of the dorsolateral prefrontal cortex (DLPFC) and sham stimulation of the primary motor cortex (M1).
Device: Repetitive transcranial magnetic stimulation (rTMS)

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.

Other Names:
  • Transcranial Magnetic Stimulation
  • Noninvasive Brain Stimulation
  • Magstim Corporation
  • Repetitive transcranial magnetic stimulation (rTMS)
Sham Comparator: Double Sham rTMS
Sham rTMS stimulation of the bilateral primary motor cortex (M1) and left dorsolateral prefrontal cortex (DLPFC).
Device: Repetitive transcranial magnetic stimulation (rTMS)

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.

Other Names:
  • Transcranial Magnetic Stimulation
  • Noninvasive Brain Stimulation
  • Magstim Corporation
  • Repetitive transcranial magnetic stimulation (rTMS)

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

Ages Eligible for Study:   21 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01080794

Contacts
Contact: Alvaro Pascual-Leone, M.D., Ph.D. (617) 667-0203 apleone@bidmc.harvard.edu
Contact: Zachary Gray, B.S. (617) 667-0226 zgray@bidmc.harvard.edu

Locations
United States, California
University of California Los Angeles Recruiting
Los Angeles, California, United States
Contact: Allan Wu, M.D.       allanwu@mednet.ucla.edu   
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States
Contact: Hubert Fernandez, M.D.       fernandez@neurology.ufl.edu   
United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Alvaro Pascual-Leone, MD, PhD    617-667-0203    apleone@bidmc.harvard.edu   
United States, Ohio
The Cleveland Clinic Recruiting
Cleveland, Ohio, United States
Contact: Hubert Fernandez, MD       fernanh@ccf.org   
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States
Contact: Diana Dimitrova, PhD    503-494-7269    dimitrov@ohsu.edu   
Principal Investigator: Jau-Shin Lou, MD, PhD         
Canada, Ontario
University Health Network Recruiting
Toronto, Ontario, Canada
Contact: Robert Chen, BChir, MA, MB, MSc       Robert.Chen@uhn.on.ca   
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
University of California, Los Angeles
University of Florida
University Health Network, Toronto
The Cleveland Clinic
Michael J. Fox Foundation for Parkinson's Research
Investigators
Principal Investigator: Alvaro Pascual-Leone, M.D., Ph.D. Beth Israel Deaconess Medical Center
Principal Investigator: Allan Wu, M.D. University of California, Los Angeles
Principal Investigator: Hubert Fernandez, M.D. The Cleveland Clinic
Principal Investigator: Robert Chen, BChir, MA, MB, MSc University Health Network, Toronto
Principal Investigator: Aparna Wagle-Shukla, MD University of Florida
Principal Investigator: Jau-Shin Lou, MD, PhD Oregon Health and Science University
  More Information

Publications:
Friedman JH, Fernandez HH. The nonmotor problems of Parkinson's Disease. The Neurologist 6(1): 18-27, 2000.
Sackheim HA. The cognitive effectsd of electroconvulsive therapy. Cognitive Disorders: Pathophysiology and Treatment. Moos WH and Gamzu ER. New York, Marcel Decker: 183-228, 1992.
Stallings LE, Speer AM, et al. Combining SPECT and repetitive transcranial magnetic stimulation (rTMS)-left prefrontal stimulation decreases relative perfusion locally in a dose dependent manner. Neuroimage 5: S521 Abstract, 1997.
Talairach J, Tournoux P. Co-planar Stereotaxic Atlas of the Human Brain. New York, Thieme Medical Publishers, Inc. 1988.
Tormos JM, Catala MD, et al. Effects of repetitive transcranial magnetic stimulation (rTMS) on EEG. Neurology 50: A317-A318 Abstract, 1998.

Responsible Party: Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT01080794     History of Changes
Other Study ID Numbers: 2010P-000002
Study First Received: March 3, 2010
Last Updated: September 5, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Beth Israel Deaconess Medical Center:
Parkinson's Disease
Depression
Transcranial Magnetic Stimulation

Additional relevant MeSH terms:
Depressive Disorder
Parkinson Disease
Mood Disorders
Mental Disorders
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Depression
Behavioral Symptoms

ClinicalTrials.gov processed this record on April 14, 2014