A Randomized, Double-blinded, Sham-controlled Cross-over Study of Theta-burst Transcranial Magnetic Stimulation in Nonfluent/Agrammatic Variant Primary Progressive Aphasia

Transcranial Magnetic Stimulation in Nonfluent/Agrammatic Variant Primary Progressive Aphasia

Sponsors

Lead sponsor: University of British Columbia

Source 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.

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.

Overall Status Not yet recruiting
Start Date September 1, 2018
Completion Date March 1, 2020
Primary Completion Date December 31, 2019
Phase N/A
Study Type Interventional
Primary Outcome
Measure Time Frame
Incidence of treatment-emergent adverse events 6 weeks
Incidence of treatment-emergent adverse events 6 weeks
Incidence of treatment-emergent adverse events 6 weeks
Tolerability levels according to the daily Comfort Rating Questionnaire (CRQ) 6 weeks
Tolerability levels according to the daily Comfort Rating Questionnaire (CRQ) 6 weeks
Tolerability levels according to the daily Comfort Rating Questionnaire (CRQ) 6 weeks
Drop out rate 6 weeks
Drop out rate 6 weeks
Drop out rate 6 weeks
Secondary Outcome
Measure Time Frame
Changes in the Verb and Object Naming Test score 6 weeks
Changes in the Make a Sentence Test score 6 weeks
Changes in the Sentence Comprehension Test score 6 weeks
Changes in the Apraxia of Speech Rating Scale score 6 weeks
Changes in the Clinical Global Impression of Change score 6 weeks
Changes in the Progressive Aphasia Severity Scale rating 6 weeks
Changes in the Western Aphasia Battery rating 6 weeks
Changes in the Montreal Cognitive Assessment Battery score 6 weeks
Changes in the Frontal Assessment Battery score 6 weeks
Changes in the whole-brain functional connectivity measured using functional Magnetic Resonance Imaging (MRI) 6 weeks
Changes in the brain cortical blood oxygenation measured using functional Near Infrared Spectroscopy (fNIRS) 6 weeks
Changes in the brain cortical electrical activity measured using quantitative electroencephalography (EEG) 6 weeks
Enrollment 6
Condition
Intervention

Intervention type: Device

Intervention name: Active iTBS

Description: Intermittent theta burst transcranial magnetic stimulation

Arm group label: Active iTBS

Intervention type: Device

Intervention name: Sham iTBS

Description: Sham intervention

Arm group label: Sham iTBS

Eligibility

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.

Gender: All

Minimum age: 20 Years

Maximum age: N/A

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Fidel Vila-Rodriguez, MD Principal Investigator University of British Columbia
Overall Contact

Last name: Rodrigo A Santibanez, MD

Phone: 1-778-990-4435

Email: [email protected]

Verification Date

August 2018

Responsible Party

Responsible party type: Principal Investigator

Investigator affiliation: University of British Columbia

Investigator full name: Fidel Vila-Rodriguez

Investigator title: Assistant Professor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Arm group label: Active iTBS

Arm group type: Active Comparator

Description: 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).

Arm group label: Sham iTBS

Arm group type: Sham Comparator

Description: 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.

Patient Data No
Study Design Info

Allocation: Randomized

Intervention model: Crossover Assignment

Primary purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Source: ClinicalTrials.gov