Study on the Effect of 40 Hz Non-Invasive Light Therapy System

Study Overview
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Brief Summary
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The ALZLIGHT STAGE III Study is a continuation of the ALZLIGHT Pilot - Study on Safety, Feasibility and Neural Activation of Non-Invasive Light Therapy System. As with the first two stages, this study will examine whether entrainment of 40 Hz neural oscillation by novel 40 Hz Invisible Spectral Flicker is a potential therapy for Alzheimer's Disease. In order to examine this, 62 patients with mild to moderate Alzheimer's Disease will be recruited. The patients will be exposed to the Non-Invasive Light Therapy System for 1 hour a day for 6 months. The effect will be measured by a combination of electroencephalography, cognitive testing, functional magnetic resonance imaging, magnetic resonance spectroscopy and actigraphy.

Detailed Description
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Recent studies in mouse models of Alzhimer's Disease (AD) have shown that exposure to 40 Hz stroboscopic light therapy for one hour a day, resulted in slowing disease progression and lead to multiple neuroprotective effects such as cognition and memory recovery, and even scavenged both tau and Aβ protein species. Hence, the 40 Hz stroboscopic light therapy has a considerable potential for treatment of humans. This study will utilize a novel way of masked light by alternating the spectral composition of a white light, rendering the flicker invisible to the conscience perception, while still entraining 40 Hz oscillations in the brain. In the study, 62 patients with probable mild to moderate AD will be exposed to either invisible spectral flickering light through the Light Therapy System (LTS) (active setting) or continuous non-flickering white light (sham setting) for 1 hour each day. The sham setting is a high quality sham intervention as subjects will be blinded to the setting, both appear as white light. The study will last 8½ months for each participant and consist of 3 periods: Enrollment period of 1 month, an intervention period of 6 months, and a 1½ month post-interventional follow-up period. In order to test whether the LTS intervention is a potential treatment for AD, cognition will be measured by neuropsychological tests at baseline and at follow-ups. To get a better understanding of the potential effects, markers of efficacy based on MRI, MRS, EEG and blood samples will be tested. The results from this study will increase the understanding of the impact of gamma oscillations in the human brain, and how it can be utilized as a novel and important tool for the treatment of neurodegenerative diseases.

Official Title
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ALZLIGHT Stage III - Study on the Effect of 40 Hz Non-Invasive Light Therapy System

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Device: Light Therapy System (LTS): Active Setting
* Device: Light Therapy System (LTS): Sham Setting


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult competent person, able to understand the nature of the study and give written informed consent. Diagnosed with probable mild to moderate AD based on NIA-AA diagnostic criteria. Age > 55 years. Females must be post-menopausal. Fluent in Danish. > 8 years of normal school education Pass a color-blindness test (Ishihara color test) Have visual and auditory capabilities, and language skills necessary for neuropsychological testing. Participants must have a designated caregiver, who is available to the participant and can provide the necessary assistance with using the LTS device and the Actigraph wearable at home and assist with clinical visits and other practical issues Exclusion Criteria: Profound visual impairment (visual acuity > 0.5) provided correction with spectacles, if needed Significant abnormalities related to important parts of the brain, e.g., the visual system, prefrontal cortex, or hippocampus, or relevant lesions detected by pre-trial imaging. Prior history of significant diseases related to the visual system or the brain. Medication: Use of any antiepileptic drugs, neuromodulating drugs or high dose of sedatives will be excluded. Prior history of substance abuse within the past 2 years. Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol (at the discretion of the PI)

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A parallel-group randomized (1:1), double-blinded, placebo-controlled, clinical trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active<br>Exposure to LTS device set to 40 Hz invisible spectral flicker for 1 hour a day for consecutive days | Device: Light Therapy System (LTS): Active Setting<br>* Exposure for 1 hour á day for consecutive days<br>|
| Sham Comparator: Sham<br>Exposure to LTS device set to continuous color matched white light for 1 hour a day for consecutive days | Device: Light Therapy System (LTS): Sham Setting<br>* Exposure for 1 hour á day for consecutive days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gamma oscillations assessment | Determine the total gamma power at 40 Hz, with no concomitant LTS device stimulation, assess changes in the gamma power at 40 Hz. | Change from Baseline to 6 months and 7.5 months | 
| Induction of 40 Hz Gamma oscillations | Estimate the change in electrical field patterns by EEG SSVEP, assess the difference between placebo and treatment for power spectral density signal to noise ratio at baseline measured by EEG SSVEP | Change from Baseline to 6 months and 7.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognition and memory assessment | Assess changes in cognition measured by the Alzheimer's Disease Assessment Scale -Cognitive Subscale plus Executive Functioning and Functional Ability (ADAS Cog plus EF & FA). The score ranges from 0 to 135. A higher score reflects greater cognitive impairment. | Change from Baseline to 6 months and 7.5 months | 
| Cognition and memory assessment | Assess changes in cognition measured by the Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL). The score ranges from 0 to 78. A higher score reflects a better outcome. | Change from Baseline to 6 months and 7.5 months | 
| Cognition and memory assessment | Assess changes in cognition measured by the Montreal Cognitive Assessment (MoCA). The score ranges from 0 to 30. A higher score reflects a better outcome. | Change from Baseline to 6 months and 7.5 months | 
| Connectivity measures | rs-fMRI Connectivity: Estimate the temporal correlation between cortical regions, assess changes in correlation between cortical regions from baseline to 6 months and 7.5 months | Change from Baseline to 6 months and 7.5 months | 
| Connectivity measures | EEG Connectivity: Estimate the temporal correlation between cortical regions, assess changes in correlation between cortical regions from baseline to 6 months and 7.5 months | Change from Baseline to 6 months and 7.5 months | 
| MR Spectroscopy | MR Spectroscopy biomarkers: Assess changes from baseline to 6 months and 7.5 months | Change from Baseline to 6 months and 7.5 months | 
| Sleep Quality | Assess changes from baseline to 6 months and 7.5 months of total sleep time in minutes, measured by actigraphy data and self-reported sleeping patterns (self-reported sleep quality scores based on patient's subjective report alone are often inaccurate). Unit: total sleep time in minutes | Change from Baseline to 6 months and 7.5 months | 
| Sleep Quality | Assess changes from baseline to 6 months and 7.5 months of wakefulness after sleep onset, measured in minutes of wakefulness after a patient has fallen asleep based on actigraphy data. Unit: total time of wakefulness in minutes | Change from Baseline to 6 months and 7.5 months | 
| Biomarkers of Alzheimer's Disease | Assess changes in biomarkers of Alzheimer's Disease in blood sampled from the participants from baseline to 6 months and 7.5 months. Markers of AD will be measured via ultrasensitive assays using fluid-based biomarkers such as plasma levels associated with amyloid pathology (plasma Aβ42/40 ratio), tau (plasma P-tau181 and P-tau231), neurodegeneration (plasma neurofilament light), and astrocytic function (glial fibrillary acidic protein). | Change from Baseline to 6 months and 7.5 months | 
| Safety Assessment | Estimate the safety of the LTS therapy, assess device- and procedure-related adverse events (DR/PR-AEs) including serious AEs (SAEs) occuring at any time during the trial | 9 months | 
| Feasibility assessment | Investigate whether participants can meet the requirements of sitting in front of the LTS device for 1 hour per day. The feasibility of the LTS intervention will be measured by the amount of time (in minutes) of correct device use per day and through a self-report of usage via a compliance/feasibility questionnaire (structured interview on participant's self-reported usage and perception of the LTS device). Unit: minutes per day of usage | Baseline to 6 months | 
| Compliance assessment | Investigate the tolerability of the LTS intervention through questionnaires (structured interviews) measured by the number of protocol breaches in total, i.e., not complying with one hour of light stimulation per day during the intervention period, and qualitative assessment based on the compliance/feasibility questionnaire (structured interview on participant's self-reported usage and perception of the LTS device). Unit: number of total protocol breaches | Baseline to 6 months | 
| MRI Atrophy assessment | Assess changes from baseline to 6 months and 7.5 months of global atrophy (ventricular volume and hippocampal volume) using advanced MR techniques on structural MRI data, i.e., including but not limited to voxel-based analysis. | Change from Baseline to 6 months and 7.5 months | 
| MRI perfusion assessment | Assess MRI perfusion: Changes from baseline to 6 months and 7.5 months. | Change from Baseline to 6 months and 7.5 months | 
| EEG: Spectral feature assessment | Assess spectral features via rs-EEG Fourier power. | Change from Baseline to 6 months and 7.5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gamma Entrainment, 40 Hz, Invisible Spectral Flicker, LED, Light Therapy, Brain Stimulation, Gamma Oscillations, Gamma Induction