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TMS for the Treatment of Primary Progressive Aphasia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04188067
Recruitment Status : Not yet recruiting
First Posted : December 5, 2019
Last Update Posted : December 5, 2019
Sponsor:
Collaborator:
National Institute on Deafness and Other Communication Disorders (NIDCD)
Information provided by (Responsible Party):
Alexandra Touroutoglou, Massachusetts General Hospital

Brief Summary:

Primary Progressive Aphasia (PPA) is a progressive syndrome in the family of Alzheimer's disease and related disorders involving devastating language impairments caused by selective neurodegeneration of the brain's language network. Unfortunately, there is no treatment for PPA. An exciting possibility for treatment is non-invasive repetitive transcranial brain stimulation (rTMS), which induces electric currents in degenerating brain networks, making them in some cases more efficient.

Therapeutic benefits from rTMS have been demonstrated when it is applied in many sequential sessions. For example, repeated sessions of rTMS to left dorsolateral prefrontal cortex (dlPFC) is approved by the US Food and Drug administration as a treatment for major depressive disorder. With respect to language, high frequency rTMS increases the response rate for picture naming in healthy individuals and in patients with Alzheimer's disease. Further, in a sham controlled study, Cotelli and colleagues demonstrated that in a group of 10 non-fluent PPA patients, high frequency rTMS over the left and right dlPFC improved the percent of correct responses for action naming. When rTMS was applied for five consecutive days in a sham controlled single case study, Finocchiaro and colleagues showed lasting improvements in language (up to 1 week) in a patient with non-fluent PPA. Trebbastoni and colleagues further showed the same lasting improvements in language (up to 1 week) in a patient with logopenic PPA. Recently, in a sham controlled single case study, Bereau and colleagues applied a more intense rTMS protocol for ten consecutive days and demonstrated significant linguistic improvements in a logopenic PPA patient that lasted for 1 month. These studies have contributed valuable insights into the potential use of rTMS in treating the language symptoms of PPA patients.


Condition or disease Intervention/treatment Phase
Logopenic Variant Primary Progressive Aphasia Non-fluent Variant Primary Progressive Aphasia Semantic Variant Primary Progressive Aphasia Device: ACTIVE rTMS Device: SHAM rTMS Early Phase 1

Detailed Description:

30 patients with a confirmed diagnosis of PPA (non-fluent PPA, logopenic PPA or semantic PPA) (made by a specialized clinician) will be recruited. Patients must have a mild to moderate language impairment and must be native English speakers. Exclusion criteria include contraindications to receiving Magnetic Resonance Imaging (MRI) scanning or rTMS (e.g. metallic or electromagnetically activated implants, cranial mass lesions, surgical aneurysm clips), the presence of significant medical, neurological or psychiatric co-morbid symptoms and patients without study partners.

It will take approximately 4 weeks to complete this research study, but the exact timing will vary according to patient, investigator and equipment availability. Each patient will have a total of up to 21 study visits. Greater than 21 visits may take place in the event that patients' language improves significantly following rTMS in order to test the sustainability of the improvement. Visits will take place at the MGH Martinos Center for Biomedical Imaging.

The first visit (lasting 3-4 hours) will include obtainment of informed consent, baseline assessments, and a baseline MRI scan (which will be used for subsequent rTMS targeting). After this, patients will return for two blocks of 20Hz rTMS to left dorsolateral prefrontal cortex: one in which they receive active rTMS and one in which they receive sham rTMS. Both active and sham rTMS will be delivered as high frequency stimulation (20 hertz, 20Hz). To accomplish this, an rTMS coil capable of delivering active or sham stimulation will be employed. Order of active and sham blocks will be counterbalanced across participants. During each block rTMS (active or sham) will be administered daily for 10 days (Monday through Friday). Neuropsychological testing, including thorough language evaluations, will be done before treatment, after day 1 and day 10 of rTMS treatment. Repeat MRI imaging will be performed after day 1 and day 10 of rTMS treatment. rTMS visit durations will be as follows: Monday (day 1) visit will last approximately 3-4 hours. Tuesday, Wednesday and Thursday and Friday visits (day 2 to day 9) will last approximately 1-2 hours. Friday visit (day 10) will last approximately 5 hours.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Within-subject crossover design
Masking: None (Open Label)
Masking Description: Through use of SHAM rTMS stimulation
Primary Purpose: Other
Official Title: TMS in Primary Progressive Aphasia: Modulation of Brain Networks and Language
Estimated Study Start Date : February 1, 2020
Estimated Primary Completion Date : January 31, 2024
Estimated Study Completion Date : January 31, 2024


Arm Intervention/treatment
Experimental: PPA patients
All study participants will carry a diagnosis of Primary Progressive Aphasia (PPA), either the logopenic, the non-fluent variant or the semantic variant. All participants will receive the same study interventions in a within-subject crossover design.
Device: ACTIVE rTMS
All study participants will receive one block of ACTIVE rTMS. Each block will consist of daily sessions of active rTMS delivered to the left dorsolateral prefrontal cortex over ten days (Monday through Friday).

Device: SHAM rTMS
All study participants will receive one block of SHAM rTMS. Each block will consist of daily sessions of SHAM rTMS delivered to the left dorsolateral prefrontal cortex over ten days (Monday through Friday).




Primary Outcome Measures :
  1. Changes in Language [ Time Frame: Baseline and post treatment Day 10 ]
    This will include observed changes in speech production as a result of the stimulation.

  2. Changes in Brain Network Connectivity [ Time Frame: Baseline and post treatment Day 10 ]
    This will include observed changes in resting-state functional connectivity as a result of the stimulation.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients, age 18-90, who carry a diagnosis of either the logopenic (lvPPA), agrammatic non-fluent (nfvPPA) or semantic (svPPA) variants of Primary Progressive Aphasia (PPA). Patients must have been observed for at least one year by a specialized clinician.
  2. Patients must have at least mild to moderate language impairment.
  3. Patients must be native English speakers.
  4. Patients must have a study partner (e.g. spouse, sibling or adult child) who can accompany them to every study visit.

Exclusion Criteria:

  1. Any history of seizures, unexplained loss of consciousness or a first-degree family member with epilepsy.
  2. Any history of significant co-occurring neurological illness unrelated to neurodegeneration associated with PPA (e.g. multiple sclerosis), or significant medical problems (e.g. poorly controlled diabetes/hypertension or cancer within 5 years).
  3. Active symptoms of major depressive disorder, bipolar disorder, schizophrenia, substance use disorder or significant premorbid intellectual disability according to Diagnostic Statistical Manual (DSM-5) criteria.
  4. Magnetic Resonance Imaging (MRI) evidence of significant cerebrovascular disease, hydrocephalus or the presence of a space-occupying intra-cranial mass.

    Contraindications to MRI or repetitive transcranial magnetic stimulation (rTMS) including: cardiac pacemaker or pacemaker wires, neurostimulators, implanted pumps, metal in the body (rods, plates, screws, shrapnel, dentures, intrauterine device), surgical aneurysm clips in the head, previous neurosurgery or cochlear implants.

  5. In line with published Massachusetts General Hospital (MGH) Institutional Review Board (IRB) guidelines for rTMS, pregnancy must be ruled out by urine ß-Human Chorionic Gonadotropin if answers to screening questions suggest that pregnancy is possible and if female participants are premenopausal and of child-bearing age. Subjects will not be able to enroll if they are breastfeeding.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04188067


Contacts
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Contact: Alexandra Touroutoglou, PhD 6176436348 atouroutoglou@mgh.harvard.edu

Locations
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United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02129
Contact: Alexandra Touroutoglou, PhD    617-643-6348    atouroutoglou@mgh.harvard.edu   
Sponsors and Collaborators
Massachusetts General Hospital
National Institute on Deafness and Other Communication Disorders (NIDCD)

Publications:
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Responsible Party: Alexandra Touroutoglou, Instructor in Neurology, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT04188067    
Other Study ID Numbers: 2019P003391
K23DC016912 ( U.S. NIH Grant/Contract )
First Posted: December 5, 2019    Key Record Dates
Last Update Posted: December 5, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Aphasia
Aphasia, Primary Progressive
Pick Disease of the Brain
Frontotemporal Dementia
Speech Disorders
Language Disorders
Communication Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Dementia
Brain Diseases
Central Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Frontotemporal Lobar Degeneration
TDP-43 Proteinopathies
Neurodegenerative Diseases
Proteostasis Deficiencies
Metabolic Diseases