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rTMS as a Treatment for PPA

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ClinicalTrials.gov Identifier: NCT03406429
Recruitment Status : Not yet recruiting
First Posted : January 23, 2018
Last Update Posted : January 23, 2018
Sponsor:
Collaborator:
Massachusetts General Hospital
Information provided by (Responsible Party):
Mark Eldaief, Massachusetts General Hospital

Brief Summary:

The non-fluent/agrammatic (nfvPPA) and the logopenic (lvPPA) variants of Primary progressive aphasia are neurodegenerative diseases characterized by progressive word-finding difficulties and effortful speech. Efforts to slow or halt this progression have been largely unsuccessful. As such, there is a desperate need for novel treatment strategies in PPA.

Repetitive transcranial magnetic stimulation (rTMS) is a safe, non-invasive way of stimulating cortical targets in a focal and reproducible manner. Therapeutic benefits from rTMS have been demonstrated when it is applied in many sequential sessions. For example, repeated sessions of rTMS to left dlPFC is an FDA approved treatment for major depressive disorder. With respect to language, high frequency (rTMS) increases the response rate for picture naming in healthy individuals. rTMS has also been shown to improve the number of correct naming responses in patients with Alzheimer's disease. Further, in a sham controlled study, Cotelli and colleagues demonstrated that in a group of 10 nfvPPA patients high frequency rTMS over the left and right dlPFC during object and action naming tasks improved the percent of correct responses for action, but not object naming. Finally, in a sham controlled single case study, Finocchiaro et al. applied high frequency rTMS to the left inferior mid-frontal gyrus for 3 sessions consisting of five consecutive days (treatment or sham). They found a significant and lasting improvement in the patient's performance on verb production when comparing active rTMS to sham rTMS or baseline. 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 Primary Progressive Aphasia Device: Active rTMS Device: SHAM rTMS Early Phase 1

Detailed Description:

We hope to recruit 15-20 patients with a confirmed diagnosis of either nfvPPA or lvPPA (made by a specialized clinician). Patients must have a mild to moderate language impairment and must be native English speakers. Exclusion criteria include contraindications to receiving 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 30 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 40 study visits, but most commonly 33 visits. Greater than 33 visits will 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 fMRI scan (which will be used for subsequent rTMS targeting). After this, PPA patients will return for four blocks of 20Hz rTMS to left dlpfc: two in which they receive active rTMS and two in which they receive sham rTMS. The following order will be used in all patients: sham-active-sham-active. During each block rTMS (active or sham) will be administered daily for 5 days (Monday through Friday). These visits will last 1 to 1.5 hours each.

Up to five language assessment visits will be performed following each block of rTMS. Typically, there will be three of these assessments, but in cases where there is improvement in language function after rTMS, patients may have up to five post-rTMS visits. These visits will be spread apart by approximately 15 days. During the first of these visits an fMRI will be performed to probe changes induced by rTMS. Scanning will include both resting-state and task fMRI acquisitions. It is estimated that these visits will last approximately 3-4 hours each.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 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: Pilot Study of Repetitive Transcranial Magnetic Stimulation in Patients With Primary Progressive Aphasia.
Estimated Study Start Date : March 1, 2018
Estimated Primary Completion Date : January 1, 2020
Estimated Study Completion Date : January 1, 2021


Arm Intervention/treatment
Experimental: PPA patients
All study participants will carry a diagnosis of Primary Progressive Aphasia (PPA), either the logopenic or the non-fluent variant. All participants will receive the same study interventions in a within-subject crossover design.
Device: Active rTMS
All study participants will receive two blocks of active rTMS. Each block will consist of daily sessions of 20Hz active rTMS delivered to the left dorsolateral prefrontal cortex (dlPFC) over five days (Monday through Friday).

Device: SHAM rTMS
All study participants will receive two blocks of SHAM rTMS. Each block will consist of daily sessions of 20Hz SHAM rTMS delivered to the left dorsolateral prefrontal cortex (dlPFC) over five days (Monday through Friday).




Primary Outcome Measures :
  1. Language Assessment Battery [ Time Frame: Through study completion, an average of 30 weeks ]
    This will include tests of speech production, confrontation naming, sentence completion.



Information from the National Library of Medicine

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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) or agrammatic non-fluent (nfvPPA) variants of 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 DSM criteria.
  4. MRI evidence of significant cerebrovascular disease, hydrocephalus or the presence of a space-occupying intra-cranial mass.
  5. Contraindications to MRI or rTMS including: cardiac pacemaker or pacemaker wires, neurostimulators, implanted pumps, metal in the body (rods, plates, screws, shrapnel, dentures, IUD), surgical aneurysm clips in the head, previous neurosurgery or cochlear implants.
  6. In line with published MGH IRB guidelines for rTMS, pregnancy must be ruled out by urine ß-HCG 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): NCT03406429


Contacts
Contact: Mark C Eldaief, M.D. (617) 726-1728 meldaief@mgh.harvard.edu
Contact: Samantha Krivensky skrivensky@mgh.harvard.edu

Sponsors and Collaborators
Brigham and Women's Hospital
Massachusetts General Hospital

Publications:
Responsible Party: Mark Eldaief, Assistant Professor of Neurology, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT03406429     History of Changes
Other Study ID Numbers: 2017P002319
First Posted: January 23, 2018    Key Record Dates
Last Update Posted: January 23, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Mark Eldaief, Massachusetts General Hospital:
rTMS
PPA

Additional relevant MeSH terms:
Speech Disorders
Aphasia
Aphasia, Primary Progressive
Pick Disease of the Brain
Frontotemporal Dementia
Primary Progressive Nonfluent Aphasia
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