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Transcranial Magnetic Stimulation in Nonfluent/Agrammatic Variant 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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03153540
Recruitment Status : Unknown
Verified August 2018 by Fidel Vila-Rodriguez, University of British Columbia.
Recruitment status was:  Not yet recruiting
First Posted : May 15, 2017
Last Update Posted : August 10, 2018
Sponsor:
Information provided by (Responsible Party):
Fidel Vila-Rodriguez, University of British Columbia

Brief Summary:
Nonfluent/agrammatic variant primary progressive aphasia (nf/avPPA) is a fatal neurodegenerative disease that begins with isolated language deficits. There is currently no cure or treatment for this disease. Repetitive Transcranial Magnetic Stimulation (rTMS), a noninvasive neuromodulatory technique, is effective in major depression, and studied in many other conditions including nf/avPPA. Here the investigators propose to study the feasibility and change in language and brain function of a newer rTMS protocol (intermittent theta-burst stimulation, iTBS) using a randomized, blinded crossover design: participants will receive active or sham iTBS for two weeks and then switch groups without them or clinicians knowing their group. The investigators hypothesize that brain function and performance with language tasks will change after active iTBS.

Condition or disease Intervention/treatment Phase
Primary Progressive Nonfluent Aphasia Device: Active iTBS Device: Sham iTBS Not Applicable

Detailed Description:

This study is a randomized controlled blinded cross-over treatment trial that involves 20 iTBS treatment sessions (10 active treatment sessions; 10 sham treatment sessions) and the study will last between 6 weeks. There will be 20 treatment visits (Monday-Friday) each lasting 10-40 minutes. Whether the participant is randomly assigned to active or sham treatment, the participant will receive daily 10 minute session of iTBS treatment. Some sessions will include behavioral and neurophysiological measures.

In addition, participants will complete cognitive testing, and neuro-imaging, including functional magnetic resonance (fMRI), functional near infrared spectroscopy (fNIRS) and electroencephalography (EEG) prior to the commencement of iTBS/sham treatment and at post-treatment. Safety and tolerability will be evaluated during daily iTBS treatments.

After 10 iTBS treatment visits over 2 weeks, a clinical assessment will be done to see if the participants are responding to the iTBS treatment with a targeted language assessment and neuro-imaging as described above. After 2 weeks of "wash-out", where the subjects do not receive any treatments, the participants will undergo another 2 weeks of iTBS treatment. On the first iTBS session after the 2-week washout period, participants will undergo a targeted language assessment and EEG/fNIRS. At the final iTBS session at 6 weeks, subjects will again undergo a targeted language assessment, EEG/fNIRS, and fMRI. At that point, after 6 weeks, the cross-over study is finished.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blinded, Sham-controlled Cross-over Study of Theta-burst Transcranial Magnetic Stimulation in Nonfluent/Agrammatic Variant Primary Progressive Aphasia
Estimated Study Start Date : September 1, 2018
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : March 1, 2020


Arm Intervention/treatment
Active Comparator: Active iTBS

Device: MagPro X100 stimulator equipped with the B65 fluid-cooled coil for dominant Inferior Frontal Gyrus (IFG) stimulation (MagPro, Medtronic).

Intervention: 10 sessions daily of iTBS over 2 weeks. Active-iTBS consists of intermittent Theta Burst Stimulation to the dominant IFG (120% of resting motor threshold, bursts of 3 pulses at 50 Hz, bursts repeated at 5 Hz for 600 pulses total over 3 min).

Device: Active iTBS
Intermittent theta burst transcranial magnetic stimulation

Sham Comparator: Sham iTBS

Device: MagPro X100 stimulator applied to dominant inferior frontal lobe.

Intervention: 10 sessions daily of sham iTBS over 2 weeks. Sham sessions involve a click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered.

Device: Sham iTBS
Sham intervention




Primary Outcome Measures :
  1. Incidence of treatment-emergent adverse events [ Time Frame: 6 weeks ]
    Safety will be measured by incidence of treatment-emergent adverse events

  2. Tolerability levels according to the daily Comfort Rating Questionnaire (CRQ) [ Time Frame: 6 weeks ]
    Tolerability will be measured by daily Comfort Rating Questionnaire (CRQ) between sham and active interventions and compared using Chi-square. A mean score across all treatment sessions above 6 on more than 2 items on the CRQ will be considered as severe. A mean score across all treatment sessions between 4 and 6 on more than 2 items on the CRQ will be considered as moderate tolerability. A mean score across all treatment sessions below 4 on the majority of items will be considered as mild tolerability.

  3. Drop out rate [ Time Frame: 6 weeks ]
    Feasibility will be measured by drop out rate. A drop out rate >50% will be considered as an indication of non-feasibility of current protocol.


Secondary Outcome Measures :
  1. Changes in the Verb and Object Naming Test score [ Time Frame: 6 weeks ]
    Verb and Object Naming Test score at baseline and at 2, 4, and 6 weeks

  2. Changes in the Make a Sentence Test score [ Time Frame: 6 weeks ]
    Make a Sentence Test score at baseline and at 2, 4, and 6 weeks

  3. Changes in the Sentence Comprehension Test score [ Time Frame: 6 weeks ]
    Sentence Comprehension Test score at baseline and at 2, 4, and 6 weeks

  4. Changes in the Apraxia of Speech Rating Scale score [ Time Frame: 6 weeks ]
    Apraxia of Speech Rating Scale score at baseline and at 6 weeks

  5. Changes in the Clinical Global Impression of Change score [ Time Frame: 6 weeks ]
    Clinical Global Impression of Change score at baseline and at 2, 4, and 6 weeks

  6. Changes in the Progressive Aphasia Severity Scale rating [ Time Frame: 6 weeks ]
    Progressive Aphasia Severity Scale rating at baseline and at 6 weeks

  7. Changes in the Western Aphasia Battery rating [ Time Frame: 6 weeks ]
    Western Aphasia Battery rating at baseline and at 6 weeks

  8. Changes in the Montreal Cognitive Assessment Battery score [ Time Frame: 6 weeks ]
    Montreal Cognitive Assessment Battery score at baseline and at 6 weeks

  9. Changes in the Frontal Assessment Battery score [ Time Frame: 6 weeks ]
    Frontal Assessment Battery score at baseline and at 6 weeks

  10. Changes in the whole-brain functional connectivity measured using functional Magnetic Resonance Imaging (MRI) [ Time Frame: 6 weeks ]
    fMRI at baseline and at 2 and 6 weeks

  11. Changes in the brain cortical blood oxygenation measured using functional Near Infrared Spectroscopy (fNIRS) [ Time Frame: 6 weeks ]
    fNIRS at baseline and at 2, 4, and 6 weeks

  12. Changes in the brain cortical electrical activity measured using quantitative electroencephalography (EEG) [ Time Frame: 6 weeks ]
    EEG at baseline and at 2, 4, and 6 weeks



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Clinically diagnosed with nonfluent-agrammatic variant primary progressive aphasia (nfvPPA), by 2011 Gorno-Tempini diagnostic criteria.
  • Frontotemporal lobar degeneration modified clinical dementia rating scale (FTLD-CDR) score ≤4 (mild).
  • Is voluntary and competent to consent to treatment, or if demented, to assent and co-consent can be obtained by their legal next-of-kin, legal guardian, or substitute decision maker.
  • Speaks English enough to be able to complete neuropsychological testing.
  • Able to adhere to the treatment schedule.
  • Has a study partner available to answer the Progressive Aphasia Severity Scale (PASS) questionnaire.

Exclusion Criteria:

  • Uncorrected visual or hearing impairment by self report.
  • History of substance dependence or abuse within the last 3 months.
  • Has active suicidal intent.
  • Has a lifetime Mini-International Neuropsychiatric Interview (MINI) diagnosis of major depressive disorder, bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms.
  • Concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump.
  • Any significant neurological disorder other than nfvPPA including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, history of epilepsy, known cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than or equal to 5 minutes in the previous 6 months.
  • Is currently (or in the last 4 weeks) taking lorazepam greater than 2 mg daily (or equivalent) or any dose of an anticonvulsant, due to the potential to limit rTMS efficacy.

Exclusion Criteria for TMS Participation:

- Does not pass the TMS adult safety screening (TASS) questionnaire (e.g. has an intracranial implant)

Exclusion Criteria for MRI Participation:

  • Severe claustrophobia.
  • Cardiac pacemakers or ferromagnetic implants.
  • Pregnant women.

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): NCT03153540


Contacts
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Contact: Rodrigo A Santibanez, MD 1-778-990-4435 rodrigo.santibanez@vch.ca

Sponsors and Collaborators
University of British Columbia
Investigators
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Principal Investigator: Fidel Vila-Rodriguez, MD University of British Columbia
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Responsible Party: Fidel Vila-Rodriguez, Assistant Professor, University of British Columbia
ClinicalTrials.gov Identifier: NCT03153540    
Other Study ID Numbers: H16-01327
First Posted: May 15, 2017    Key Record Dates
Last Update Posted: August 10, 2018
Last Verified: August 2018
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: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Fidel Vila-Rodriguez, University of British Columbia:
Aphasia
Agrammatism
Frontotemporal Dementia
Tauopathies
Neurodegenerative Diseases
Language Disorders
Frontotemporal Lobar Degeneration
Additional relevant MeSH terms:
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Aphasia
Aphasia, Primary Progressive
Pick Disease of the Brain
Frontotemporal Dementia
Aphasia, Broca
Primary Progressive Nonfluent Aphasia
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