Investigating the Effect of Repetitive Transcranial Magnetic Stimulation (rTMS) as a Treatment for Alzheimer's Disease

The main objective of this study is to investigate the effects of repetitive Transcranial Magnetic Stimulation (rTMS) treatment on patients with probable early or moderate Alzheimer's disease.

Study Overview

• Status: Unknown
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Device: rTMS active treatment; Device: rTMS sham treatment

Detailed Description

Upon meeting the inclusion criteria and providing informed consent, each participant will complete a series of cognitive assessments and rTMS treatments at the TMS Lab at Riverview Health Center (PE-450).

After enrollment, patients at each site will be assigned using stratified block randomization into either active or sham treatment arms with different duration of treatment (either 2 weeks or 4 weeks).

rTMS at frequency of 20 Hz will be used to stimulate the dorsolateral prefrontal cortex (DLPFC) of each patient in the real groups. Prior to the first treatment, and once per week during treatment, the patient's motor threshold will be measured using single pulses of TMS, noting the intensity necessary to cause a small twitch in the thumb finger. Then, the 70 mm cooled coil will be placed on the head at a location for optimal stimulation of the DLPFC at an intensity of 90-100% of the motor threshold. The 20 Hz rTMS treatment will incorporate 30 pulses per train, with 25 trains per side of the brain per session (total of 750 pulses per side per session). The trains will have a duration of 1.5 seconds, with an intertrain interval of 10 seconds. Each TMS treatment session will take approximately 10 to 25 minutes.

The DLPFC will be located on each patient using our Brainsight neuronavigation system from a reference MRI scan. If we cannot retrieve a valid previous clinical MRI scan or a valid ordered research MRI scan, a reference head model will approximate the patient's anatomy.

The treatments will be administered daily (5 days/week) either for 4 weeks or 2 weeks. The same protocol will also be used while doing sham stimulation.

To prevent un-blinding, the Magstim sham coil will be used; it provides the same sound and tactile sensory experience as those of the real coil, but it attenuates the strength of the induced electrical field in the brain well below the threshold required to stimulate neurons. In addition, during the treatment, only the designated research assistant and the patient will be present. It should also be noted that the only people who know the grouping are: the rTMS administrator (who also groups the patients) at each site and the sites' coordinator. The patients' grouping info will be in a secure folder in a locked cabinet to which only the rTMS administrator and the three sites coordinator will have the key.

Participants will be assessed six times during the study. This will occur at weeks 0, 3, 5, 13, 21, and 29 for the 4 week treatment groups, and weeks 0, 3, 5, 11, 19, and 27 for the 2 week treatment group. Each assessment will involve a set of nine assessment tools, including ADAS-Cog as the primary outcome measure and various other tasks and questionnaires to measure cognition, memory, caregiver burden, symptoms, and treatment tolerability.

For Winnipeg and Montreal sites only: The immediate effects (i.e. within 3 minutes) after participants receive the rTMS treatment will be assessed with a 1-minute semantic fluency test at four time points. This will occur at before and immediately after rTMS intervention in Week 1 and at weeks 5 and 13 for the 4 week treatment groups, and before and immediately after rTMS intervention in Week 1 and at weeks 5 and 11 for the 2 week treatment group.

Patients who are randomized to the sham treatment will be unblinded at the 6 month follow up and offered either 2-weeks or 4-weeks treatment; the patients and/or their family can choose the duration of treatment. As such, the 12 month assessment will be an unblinded follow up only of those initially randomised to one of the real groups (2-weeks or 4-weeks of treatment).

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Zahra Moussavi, PhD; Phone Number: 204-474-7023; Email: Zahra.Moussavi@Umanitoba.ca

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia
      • Recruiting
      • Monash University
      • Contact: Paul Fitzgerald, PhD; Phone Number: 61 3 9076 6552; Email: paul.fitzgerald@monash.edu
• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3L 2P4
      • Recruiting
      • Riverview Health Center
      • Contact: Zahra Moussavi, Ph.D.; Phone Number: 204-478-6163; Email: Zahra.Moussavi@Umanitoba.ca
      • Contact: Cristina Francisco, Ph.D; Email: cristina.francisco@umanitoba.ca
      • Principal Investigator: Zahra Kazem-Moussavi, Ph.D.
  • Quebec
    • Montreal, Quebec, Canada
      • Recruiting
      • McGill University
      • Contact: Lisa Koski, PhD; Phone Number: 42612 (514) 934-1934; Email: lisa.koski@mcgill.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Individuals must have a MoCA score between 7 and 25, indicating mild cognitive impairment or dementia, a CDR score of 1-2, and a CSDD score of 18 or less.
• Participants must have probable early or moderate Alzheimer's disease as confirmed by their treating neurologist, geriatrician, or psychiatrist, and/or by the study doctors.
• Participants must be +55 years old.
• Participants must be taking a stable dose of an acetylcholinesterase inhibitor for at least 3 months prior to study entry with no plans to change medication for the duration of the study. Or if participants decide to stop taking their Alzheimer's disease related medication, they must wait a minimum of 6 weeks prior to the start of the intervention.

Exclusion criteria:

• Psychiatric conditions/disorders, or current neurological or medical disorders, other than AD, that could interfere with the subjects' cooperative participation (e.g. Severe agitation, prominent anxiety)
• Mental retardation
• Impaired visual and auditory acuity that confounds performance in cognitive tests
• Being diagnosed explicitly by other forms of dementia
• Confounding psychiatric disorders (e.g., schizophrenia, bipolar affective disorder) or current neurological, systemic, or medical disorders (e.g., liver disease, congestive heart failure, severe COPD) that may impair cognition and/or could affect attention span.
• Use of benzodiazepines or other hypnotics during the study and preceding two weeks
• Use of drugs with anticholinergic properties
• Pharmacological immunosuppression
• Participation in a clinical trial with any investigational agent within two weeks prior to study enrollment
• Current alcohol abuse
• History of epileptic seizures or epilepsy
• Contraindication for receiving TMS treatment according to a TMS questionnaire.
• Clinically significant abnormal laboratory findings which have not been approved by the Principal Investigator.
• Inability to adequately communicate in English in Manitoba and Australia sites and either English or French in Montreal site.
• Previous treatment with rTMS within the past 3 months
• A change in medication for AD, mood disorders, or pain during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 4 weeks active treatment; 4 weeks of rTMS active treatment applied using an active rTMS coil.	Device: rTMS active treatment; Repetitive Transcranial Magnetic Stimulation uses magnetic pulses to active neurons.
Experimental: 2 weeks active treatment; 2 weeks of rTMS active treatment applied using an active rTMS coil.	Device: rTMS active treatment; Repetitive Transcranial Magnetic Stimulation uses magnetic pulses to active neurons.
Sham Comparator: 4 weeks sham treatment; 4 weeks of rTMS sham treatment applied using a modified rTMS coil which does not stimulate the brain.	Device: rTMS sham treatment; A fake treatment designed to mimic the sensations of rTMS
Sham Comparator: 2 weeks sham treatment; 2 weeks of rTMS sham treatment applied using a modified rTMS coil which does not stimulate the brain.	Device: rTMS sham treatment; A fake treatment designed to mimic the sensations of rTMS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) change	Standard measure of cognitive symptoms, a popular tool that measures the severity of dementia symptoms. The primary outcome measure will be the change in the score from the baseline at 5 weeks.	Weeks 0 and 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stroop Test	Measures a person's attention by having them read colour names when the colour of the text doesn't match.	Weeks 0, 3, 5, 11, 19, and 27 for the 2 week group and weeks 0, 3, 5, 13, 21, and 29 for the 4 week groups
Digit Span Test	Memory test asking the participant to remember a sequence of numbers and repeat them back.	Weeks 0, 3, 5, 11, 19, and 27 for the 2 week group and weeks 0, 3, 5, 13, 21, and 29 for the 4 week groups
Verbal Fluency Test (VFT)	Fluency test where the participant has to name as many words a possible that match a certain criteria.	Weeks 0, 3, 5, 11, 19, and 27 for the 2 week group and weeks 0, 3, 5, 13, 21, and 29 for the 4 week groups
Neuropsychiatric Inventory-Questionnaire (NPI-Q)	Caregiver questionnaire that assesses severity of symptoms	Weeks 0, 3, 5, 11, 19, and 27 for the 2 week group and weeks 0, 3, 5, 13, 21, and 29 for the 4 week groups
Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL)	Caregiver questionnaire that assesses patient's ability to handle daily activities	Weeks 0, 3, 5, 11, 19, and 27 for the 2 week group and weeks 0, 3, 5, 13, 21, and 29 for the 4 week groups
Zarit Burden Interview (ZBI)	Caregiver questionnaire that assesses the burden of the patient on the caregiver	Weeks 0, 3, 5, 11, 19, and 27 for the 2 week group and weeks 0, 3, 5, 13, 21, and 29 for the 4 week groups
Treatment Satisfaction Questionnaire for Medication (TSQM)	Assessment that asks directly if the participant is satisfied with the treatment	Weeks 3, 5, 11, 19, and 27 for the 2 week group and weeks 0, 3, 5, 13, 21, and 29 for the 4 week groups
Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) effect over time	Standard measure of cognitive symptoms, a popular tool that measures the severity of dementia symptoms.	Weeks 0, 3, 11, 19, and 27 for the 2 week group and weeks 0, 3, 13, 21, and 29 for the 4 week groups
Semantic Fluency Test (SFT)	Fluency test where the participant has to name as many animals in 1 minute (Winnipeg and Montreal sites only)	Before and immediately after rTMS intervention in Week 1, at weeks 5 and 11 for the 2 week group and before and immediately after rTMS intervention in Week 1, at weeks 5, and 13 for the 4 week groups
Clinical Dementia Rating (CDR) sum of boxes	Assesses the severity of cognitive and functional decline related to Alzheimer's disease and other dementias	Week 27 for the 2 week group and week 29 for the 4 week group

Collaborators and Investigators

• Sponsor: University of Manitoba
• Investigators: Principal Investigator: Zahra Moussavi, PhD, Department of Biomedical Engineering, University of Manitoba

Publications and helpful links

General Publications

• Moussavi Z, Koski L, Fitzgerald PB, Millikin C, Lithgow B, Jafari-Jozani M, Wang X. Repeated Transcranial Magnetic Stimulation for Improving Cognition in Alzheimer Disease: Protocol for an Interim Analysis of a Randomized Controlled Trial. JMIR Res Protoc. 2021 Aug 9;10(8):e31183. doi: 10.2196/31183.
• Moussavi Z, Rutherford G, Lithgow B, Millikin C, Modirrousta M, Mansouri B, Wang X, Omelan C, Fellows L, Fitzgerald P, Koski L. Repeated Transcranial Magnetic Stimulation for Improving Cognition in Patients With Alzheimer Disease: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial. JMIR Res Protoc. 2021 Jan 8;10(1):e25144. doi: 10.2196/25144.

Study record dates

Study Major Dates

• Study Start: November 1, 2016
• Primary Completion (Anticipated): June 1, 2022
• Study Completion (Anticipated): July 1, 2022

Study Registration Dates

• First Submitted: September 13, 2016
• First Submitted That Met QC Criteria: September 18, 2016
• First Posted (Estimate): September 21, 2016

Study Record Updates

• Last Update Posted (Actual): February 26, 2021
• Last Update Submitted That Met QC Criteria: February 24, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: B2016:077

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data will be shared with two other institutes: McGill and Monash Universities, who are part of the same team.
• IPD Sharing Time Frame: 2016-12-01 till 2021-12-30
• IPD Sharing Access Criteria: Data are shared over a database that is only accessible by the sites of the study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR