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Network-based rTMS in Alzheimer's Disease

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: NCT04263194
Recruitment Status : Active, not recruiting
First Posted : February 10, 2020
Last Update Posted : February 10, 2020
Sponsor:
Collaborators:
I.R.C.C.S. Fondazione Santa Lucia
Ministero della Salute, Italy
Information provided by (Responsible Party):
Debora Brignani, IRCCS Centro San Giovanni di Dio Fatebenefratelli

Brief Summary:
Severe alterations of brain networks connectivity have been described in Alzheimer's disease (AD). Repetitive Transcranial Magnetic Stimulation (rTMS) has gained evidence as an effective tool to modulate brain networks connectivity, leading to a recovery or reorganization of both local and remote brain regions functionally connected to the stimulated area. The investogators propose an innovative tailored network-based rTMS treatment to ameliorate cognitive symptoms in mild AD, through the boosting of connectivity within brain networks affected by AD pathophysiology. The combination of the proposed intervention with an integrated multi-modal imaging approach will allow to evaluate the neural mechanisms underlying the clinical response to the treatment and to define quantitative markers of clinical impact on AD. If successful, the present proposal would immediately impact on patient's quality of life, with important implications for the time and costs of delivery of rehabilitative services.

Condition or disease Intervention/treatment Phase
Alzheimer Disease, Late Onset Alzheimer Disease Cognitive Deterioration Device: rTMS Device: Sham rTMS Not Applicable

Detailed Description:
Currently, no effective cure is available for Alzheimer's disease (AD). Repetitive Transcranial Magnetic Stimulation (rTMS) has gained increasing attention as a potential treatment for various neurological and psychiatric disorders, but available rTMS studies are flawed by inaccurate anatomical targeting, inadequate sample size, unsatisfactory controls and lacking blindness. To date, the elective target area of rTMS interventions in AD has been the dorsolateral prefrontal cortex (DLPFC), a core area of the Central Executive network (CEN), which plays a key role in regulating executive functions, attention and working memory. While the CEN has recently been described as dysfunctional in AD, AD pathophysiology has been mainly associated with the breakdown of the Default Mode network (DMN) and with structural disconnection of its parietal nodes. The DMN plays a crucial role in episodic memory retrieval and incorporates various brain regions, among which parietal areas are highly connected with the rest of the brain. The present multicenter, double-blind, randomized and placebo-controlled study has the ambition to provide evidence of the efficacy of two tailored network-based rTMS treatments in mild AD, through the enhancement of connectivity of CEN and DMN. Innovative integrated multi-modal imaging investigations will further enrich this proposal allowing to identify quantifiable markers underlying the clinical impact of rTMS on AD.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: After recruitment, patients will be randomized and assigned to one of three rTMS treatments: DMN (N=20), CEN (N=20) or placebo (N=20). The rTMS treatment will consist of 2 phases: an intensive phase and a maintenance phase. The intensive phase will involve 3 weeks of treatment, 5 days per week (15 sessions in total). The maintenance will consist of 1 session of treatment every 2 weeks for 5 months (10 sessions in total). Overall, the patients will undergo 25 sessions of rTMS delivered over 6 months. At baseline (T0), at the end of the intensive phase (T1) and at the end of the maintenance phase (T2) all patients will undergo a clinical and cognitive assessment and a multi-modal imaging data collection.
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Masking Description: The study will be a double blind trial, i.e. both patients and clinicians involved in the assessment will be blind to treatment allocation.
Primary Purpose: Treatment
Official Title: Novel Tailored Network-based rTMS Treatments in Alzheimer's Disease: an Integrated Multiimaging Approach
Actual Study Start Date : March 21, 2019
Estimated Primary Completion Date : September 21, 2021
Estimated Study Completion Date : March 21, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Default Mode Network (DMN)
The treatment will consist in the individually tailored stimulation of a DMN node (i.e. left inferior parietal lobe).
Device: rTMS
25 min of high frequency (20 Hz) repetitive TMS applied at 100% of resting motor threshold (rMT).

Experimental: Central Executive Network (CEN)
The treatment will consist in the individually tailored stimulation of a CEN node (i.e. left dorsolateral prefrontal cortex).
Device: rTMS
25 min of high frequency (20 Hz) repetitive TMS applied at 100% of resting motor threshold (rMT).

Placebo Comparator: Placebo
The treatment will consist in targeting the upper part of the scalp (i.e. CZ) while using a sham rTMS coil.
Device: Sham rTMS
Placebo intervention will consist in the same procedure but using a sham rTMS coil.




Primary Outcome Measures :
  1. Change in ADAS-Cog scale scores [ Time Frame: At baseline (T0), up to 4 weeks (T1), through study completion, an average of 6 months (T2) ]
    A brief neuropsychological assessment used to assess the severity of cognitive symptoms of dementia

  2. Change in TMS-evoked cortical responses (TEPs) [ Time Frame: At baseline (T0), up to 4 weeks (T1), through study completion, an average of 6 months (T2) ]
    A novel probe of treatment induced cortical modulations. TEPs will serve as markers of reactivity of the stimulated area, whereas the spreading of their cortical activation will serve as an index of connectivity between targeted cortex and functionally connected areas underlying DMN or CEN.


Secondary Outcome Measures :
  1. Change in CANTAB battery scores [ Time Frame: At baseline (T0), up to 4 weeks (T1), through study completion, an average of 6 months (T2) ]
    The scores on two tests of CANTAB battery (www.cambridgecognition.com)

  2. Change in Associative Learning test (PAL) [ Time Frame: At baseline (T0), up to 4 weeks (T1), through study completion, an average of 6 months (T2) ]
    A measure of episodic memory

  3. Change in Spatial Working Memory test (SWM) [ Time Frame: At baseline (T0), up to 4 weeks (T1), through study completion, an average of 6 months (T2) ]
    A measure of executive functions



Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Mini-Mental State Examination score >=18, <=24
  • Anti-cholinesterase treatment for at least 3 months prior the start date

Exclusion Criteria:

  • Enrollment in other clinical and pharmacological trials
  • Previous evidence of any other CNS disorder (e.g. epilepsy, infectious diseases, frontotemporal, Parkinson or Pick's disease)
  • History of major psychiatric disorders
  • History of alchol or substance abuse
  • Stress-related skin problems
  • Current consumption of psychiatric medication
  • Presence of metal implants or any implanted electronics

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): NCT04263194


Locations
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Italy
IRCCS Centro San Giovanni di Dio Fatebenefratelli
Brescia, Lombardia, Italy, 25125
Sponsors and Collaborators
IRCCS Centro San Giovanni di Dio Fatebenefratelli
I.R.C.C.S. Fondazione Santa Lucia
Ministero della Salute, Italy
Investigators
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Principal Investigator: Debora Brignani IRCCS Centro San Giovanni di Dio Fatebenefratelli
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Responsible Party: Debora Brignani, Principal Investigator, IRCCS Centro San Giovanni di Dio Fatebenefratelli
ClinicalTrials.gov Identifier: NCT04263194    
Other Study ID Numbers: GR-2016-02364718
First Posted: February 10, 2020    Key Record Dates
Last Update Posted: February 10, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Debora Brignani, IRCCS Centro San Giovanni di Dio Fatebenefratelli:
TMS
rTMS
Alzheimer Disease
Additional relevant MeSH terms:
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Alzheimer Disease
Late Onset Disorders
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Disease Attributes
Pathologic Processes