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

Alzheimer's Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05260177
• Other study ID #: ASIII
• Status: Recruiting
• Phase: N/A
• Start date: September 20, 2022
• Est. completion date: December 1, 2026

Study information

• Verified date: January 2024
• Source: Zealand University Hospital
• Contact: Peter Høgh, MD, Phd
• Phone: 47322809
• Email: phh[@]regionsjaelland.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 62
• Est. completion date: December 1, 2026
• Est. primary completion date: May 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 55 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease

Intervention

Device:
• Light Therapy System (LTS): Active Setting
Exposure for 1 hour á day for consecutive days
• Light Therapy System (LTS): Sham Setting
Exposure for 1 hour á day for consecutive days

Locations

Country	Name	City	State
Denmark	Zealand University Hospital	Roskilde

Sponsors (5)

Lead Sponsor	Collaborator
Zealand University Hospital	Göteborg University, OptoCeutics, Technical University of Denmark, University of Copenhagen

Country where clinical trial is conducted

Denmark, 

References & Publications (8)

Adaikkan C, Middleton SJ, Marco A, Pao PC, Mathys H, Kim DN, Gao F, Young JZ, Suk HJ, Boyden ES, McHugh TJ, Tsai LH. Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron. 2019 Jun 5;102(5):929-943.e8. doi: 10.1016/j.neuron.2019.04.011. Epub 2019 May 7. — View Citation

Adaikkan C, Tsai LH. Gamma Entrainment: Impact on Neurocircuits, Glia, and Therapeutic Opportunities. Trends Neurosci. 2020 Jan;43(1):24-41. doi: 10.1016/j.tins.2019.11.001. Epub 2019 Dec 10. — View Citation

Alawode DOT, Heslegrave AJ, Ashton NJ, Karikari TK, Simren J, Montoliu-Gaya L, Pannee J, O Connor A, Weston PSJ, Lantero-Rodriguez J, Keshavan A, Snellman A, Gobom J, Paterson RW, Schott JM, Blennow K, Fox NC, Zetterberg H. Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease. J Intern Med. 2021 Sep;290(3):583-601. doi: 10.1111/joim.13332. Epub 2021 Jun 26. — View Citation

Benedet AL, Mila-Aloma M, Vrillon A, Ashton NJ, Pascoal TA, Lussier F, Karikari TK, Hourregue C, Cognat E, Dumurgier J, Stevenson J, Rahmouni N, Pallen V, Poltronetti NM, Salvado G, Shekari M, Operto G, Gispert JD, Minguillon C, Fauria K, Kollmorgen G, Suridjan I, Zimmer ER, Zetterberg H, Molinuevo JL, Paquet C, Rosa-Neto P, Blennow K, Suarez-Calvet M; Translational Biomarkers in Aging and Dementia (TRIAD) study, Alzheimer's and Families (ALFA) study, and BioCogBank Paris Lariboisiere cohort. Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum. JAMA Neurol. 2021 Dec 1;78(12):1471-1483. doi: 10.1001/jamaneurol.2021.3671. — View Citation

Herrmann CS. Human EEG responses to 1-100 Hz flicker: resonance phenomena in visual cortex and their potential correlation to cognitive phenomena. Exp Brain Res. 2001 Apr;137(3-4):346-53. doi: 10.1007/s002210100682. — View Citation

Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. doi: 10.1038/nature20587. Erratum In: Nature. 2018 Oct;562(7725):E1. — View Citation

Kasteleijn-Nolst Trenite D, Rubboli G, Hirsch E, Martins da Silva A, Seri S, Wilkins A, Parra J, Covanis A, Elia M, Capovilla G, Stephani U, Harding G. Methodology of photic stimulation revisited: updated European algorithm for visual stimulation in the EEG laboratory. Epilepsia. 2012 Jan;53(1):16-24. doi: 10.1111/j.1528-1167.2011.03319.x. Epub 2011 Nov 16. — View Citation

Martorell AJ, Paulson AL, Suk HJ, Abdurrob F, Drummond GT, Guan W, Young JZ, Kim DN, Kritskiy O, Barker SJ, Mangena V, Prince SM, Brown EN, Chung K, Boyden ES, Singer AC, Tsai LH. Multi-sensory Gamma Stimulation Ameliorates Alzheimer's-Associated Pathology and Improves Cognition. Cell. 2019 Apr 4;177(2):256-271.e22. doi: 10.1016/j.cell.2019.02.014. Epub 2019 Mar 14. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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 Aß42/40 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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	EEG: Spectral feature assessment	Assess spectral features via rs-EEG Fourier power.	Change from Baseline to 6 months and 7.5 months

External Links

•   Carstensen M et al. 40 Hz invisible spectral flicker and its potential use in Alzheimer's light therapy treatment. Proc. SPIE 11221, Mechanisms of Photobiomodulation Therapy XV, 112210L (11 March 2020)