- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03778151
Repetitive TMS of the Default Mode Network in AD (TMS-AD)
Repetitive TMS of the Precuneus: a Randomized Double-blinded Placebo-controlled Trial in Alzheimer's Disease Patients.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by severe disruption of large-scale brain networks connectivity. AD pathophysiology has been mainly associated with a breakdown of the Default Mode Network (DMN) and with a structural disconnection of parietal nodes. It has been shown that the precuneus (PC), a central hub of the DMN, is involved in successful episodic memory retrieval, working as a key area of the network activated by recognition memory. Recent anatomical works have shown that medial parietal regions are interconnected with the medial temporal region, which is implicated in memory retrieval. In particular, the PC was identified as a region demonstrating strong functional interconnectivity with the hippocampal formation. This is of particular relevance because PC is altered in AD. At early clinical stages of AD, PC is selectively vulnerable to early amyloid deposition, and plays a critical role in the conversion towards dementia.
Hypothesis: a novel therapeutic intervention for AD is repetitive Transcranial Magnetic Stimulation (rTMS). rTMS is a non- invasive approach that can be used to induce long lasting modulation of specific brain functions, inducing neuroplastic changes not only in the cortical site of stimulation, but also in remote interconnected areas. In a recent double blind randomized cross-over clinical pilot study, we found that a two-week course of daily high-frequency rTMS (20 Hz) treatment targeting the DMN (Stimulation site: PC) was able to induce an improvement in episodic memory compared to placebo. Indeed, TMS-EEG measurements showed that rTMS treatment, applied over the DMN, was capable to modulate the cortical activity in both the targeted areas (PC) as well as in functional connected regions of the DMN (Koch et al., 2018).
Specific aims: to investigate clinical efficacy and safety of DMN rTMS applied during 6 months in mild AD patients. To provide novel evidence that non-invasive treatment of network dysfunction, through stimulation of the PC, will represent an effective strategy to enhance cognitive functions and lead to substantial slowing of cognitive and functional decline in patients with mild AD. The findings yielded by the present project will have a potential strong impact on clinical practice of AD patients. Since rTMS is well tolerated and relatively low-priced, a positive result could lead to a fast application of the present proposal to the clinical experience. If successful, the proposed project will provide support for a novel treatment for cognitive dysfunction in AD patients.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
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Rome, Italy, 00179
- Giacomo Koch
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Rome, Italy, 00179
- Santa Lucia foundation
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- The patient and the responsible caregiver have signed the Informed Consent Form.
- The patient has probable AD, diagnosed according to NINCDS-ADRDA criteria.
- The patient is a man or woman, aged ≤ 85 years.
- The patient has a CDR total score of 0.5 or 1 (mild) and MMSE score of 18-26 (inclusive) at Screening.
- Has at least one identified adult caregiver
The patient has been treated with acetylcholinesterase inhibitor (AChEI), i.e., donepezil, galantamine, or rivastigmine, at the time of Screening
- For at least 3 months
- The current dosage regimen must have remained stable for ≥ 8 weeks
- It must be planned that the dosage regimen will remain stable throughout participation in the study
- The patient is able to comply with the study procedures in the view of the investigator.
Exclusion Criteria:
- Significant neurodegenerative disorder of the central nervous system other than Alzheimer's disease
- Significant intracranial focal or vascular pathology seen on brain MRI scan
- History of seizure (with the exception of febrile seizures in childhood)
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision (DSM IV-TR) criteria met for any of the following within specified period:
- Major depressive disorder (current)
- Schizophrenia (lifetime)
- Other psychotic disorders, bipolar disorder, or substance (including alcohol) related disorders (within the past 5 years)
- Metal implants in the head (except dental), pacemaker, cochlear implants, or any other non-removable items that are contraindications to MR imaging.
Treatment currently or within 3 months before Baseline with any of the following medications:
- Typical and atypical antipsychotics (i.e. Clozapine, Olanzapine)
- Antiepileptics drugs (i.e. Carbamazepine, Primidone, Pregabalin, Gabapentin)
- Memantine
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: TRANSCRANIAL MAGNETIC STIMULATION
repetitive TRANSCRANIAL MAGNETIC STIMULATION (rTMS) will be applied over the precuneus to modulate DMN activity.
The rTMS treatment will consist of two phases: an intensive phase and a maintenance phase.
The intensive phase will involve 2 weeks of treatment, 5 days per week (10 sessions, 1.600 pulses per day for a total of 16.000 pulses).
The maintenance phase will consist of 1 session of treatment every week for 5 months (21 sessions, 100.800 pulses in total).
|
daily treatment session of REPETITIVE TRANSCRANIAL MAGNETIC STIMULATIO will be applied over precuneus for 20 minutes of consecutive blocks of 20Hz pulses for two seconds followed by 28 seconds of no stimulation.
Other Names:
|
Sham Comparator: SHAM TRANSCRANIAL MAGNETIC STIMULATION
SHAM TMS will be applied over the precuneus.
The SHAM protocol will consist of two phases: an intensive phase and a maintenance phase.
The intensive phase will involve 2 weeks of treatment, 5 days per week (10 sessions, 1.600 pulses per day for a total of 16.000 pulses).
The maintenance phase will consist of 1 session of treatment every week for 5 months (21 sessions, 100.800 pulses in total).
|
daily treatment session of REPETITIVE TRANSCRANIAL MAGNETIC STIMULATIO will be applied over precuneus for 20 minutes of consecutive blocks of 20Hz pulses for two seconds followed by 28 seconds of no stimulation.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Clinical Dementia Rating scale (CDR) sum of boxes
Time Frame: change from baseline to Week 24
|
global cognition
|
change from baseline to Week 24
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog)
Time Frame: change from baseline to Week 24
|
global cognition
|
change from baseline to Week 24
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Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
Time Frame: change from baseline to Week 24
|
functional activities
|
change from baseline to Week 24
|
Neuropsychiatric Inventory (NPI)
Time Frame: change from baseline to Week 24
|
behavioural symptoms
|
change from baseline to Week 24
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Frontal Assessment Battery (FAB)
Time Frame: change from baseline to Week 24
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frontal lobe functions
|
change from baseline to Week 24
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Immediate and delayed total recall score from the Rey Auditory Verbal Learning test (RAVLT)
Time Frame: change from baseline to Week 24
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memory
|
change from baseline to Week 24
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Cortical activity (TMS-EEG)
Time Frame: change from baseline to Week 24
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neurophysiological marker
|
change from baseline to Week 24
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Collaborators and Investigators
Investigators
- Study Director: Caterina Motta, Santa Lucia foundation
Publications and helpful links
General Publications
- Koch G, Bonni S, Pellicciari MC, Casula EP, Mancini M, Esposito R, Ponzo V, Picazio S, Di Lorenzo F, Serra L, Motta C, Maiella M, Marra C, Cercignani M, Martorana A, Caltagirone C, Bozzali M. Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease. Neuroimage. 2018 Apr 1;169:302-311. doi: 10.1016/j.neuroimage.2017.12.048. Epub 2017 Dec 19.
- Di Lorenzo F, Ponzo V, Bonni S, Motta C, Negrao Serra PC, Bozzali M, Caltagirone C, Martorana A, Koch G. Long-term potentiation-like cortical plasticity is disrupted in Alzheimer's disease patients independently from age of onset. Ann Neurol. 2016 Aug;80(2):202-10. doi: 10.1002/ana.24695. Epub 2016 Jul 8.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- RC-2018
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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