Innovative Trial to Test Effect of Light Therapy on Progressive MS-Related Fatigue

Sabeen Toranian

A phase 1, open-label, single center study dubbed NO-FATIGUE (NCT06261528) will test the safety and mechanistic biomarkers behind light therapy as a therapeutic option to help improve fatigue in patients with progressive multiple sclerosis (MS). In the study, investigators will attempt to alleviate fatigue through synchronization of patients’ circadian rhythm, potentially caused by diminished activation of the intrinsically photosensitive retinal ganglion cells (ipRGCs).¹

A total of 10 patients with either primary progressive MS or secondary progressive MS per the 2017 Revised McDonald Criteria will undergo a 2-week screening period that includes using a sleep monitor at home, collecting saliva samples, and completing surveys. After the screening, participants will begin a light therapy program requiring a total of 7 visits to UT Southwestern Medical Center. The visits will occur daily for the first 3 days, followed by additional visits every 2-3 weeks for three more sessions. Each visit will last approximately 3 hours. During the study, participants will also be asked to collect saliva samples, use the home sleep monitor, and complete surveys.

The design of the study was presented as a poster at the 2025 Americas Committee for Treatment & Research in Multiple Sclerosis (ACTRIMS) Forum, held February 27-March 1, in West Palm Beach, Florida. Led by Sabeen Toranian, a medical student at Sam Houston State University College of Osteopathic Medicine, the study will primarily assess the safety of this therapeutic method, with other exploratory end points that cover measures of fatigue, sleepiness, quality of life, disability, circadian rhythms, and sleep outcomes.

After undergoing supervised light therapy, patients in the study will undergo an observation period for 5 weeks for resynchronization and washout. Participants’ circadian rhythm will be measured by the emerging gold standard, the dim light melatonin onset (DLMO), understood to relay information about ipRGC attenuation, while sleep will be measured by several variables collected through actigraphy.

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To be included in the study, patients must have an Epworth Sleepiness Scale (ESS) score of 9 or higher and be able to complete study procedures, as determined by the investigator. Stable dosing of FDA-approved disease-modifying therapy and mood or fatigue treatments for at least three months prior to screening, with plans to maintain this stability during the study, is also required. Exclusions include a sleep onset latency of less than 15 minutes, recent changes to mood or fatigue treatments, unresolved significant medical conditions, or abnormal lab results that could interfere with the study. Other exclusions are drug or alcohol abuse, recent pregnancy, melatonin analog use without a proper washout, MS relapses or demyelinating lesions within the past year, and recent time zone travel or shift work affecting sleep.

Diminished activation of ipRGCs has been increasingly studied in the context of fatigue in MS, as these cells play a key role in non-image-forming visual functions, particularly in circadian rhythms and sleep-wake cycles. The thought is that MS-related damage to pathways involving ipRGCs may impair communication with the SCN, disrupting circadian rhythms. Diminished ipRGC activation reduces the ability to sustain alertness during the day, potentially contributing to the overwhelming fatigue experienced by patients with MS. Furthermore, thinning of the retinal nerve fiber layer and ganglion cell layer, often seen in MS, may reflect damage to ipRGCs, further linking retinal changes with systematic symptoms like fatigue.

Light therapy as a method to improve MS-related fatigue has been tested before, most notably a 2013 prospective study in Tazmania. That study, which featured 198 patients with the disease, showed that personal reported sun exposure was inversely associated with depression scores (ß = –0.26; 95% CI, –0.40 to –0.12; P ≤.001) and fatigue scores (ß = –0.65; 95% CI, –1.23 to –0.07; P = .028). Only high levels of serum 25(OH)D greater than 80 nm were inversely associated with depression scores (ß = –0.64; 95% CI, –1.15 to –0.13; P = .015).²

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REFERENCES
1. Toranian S, Sguigna P, Salter A, et al. Rationale and Design of NO-FATIGUE. Presented at: 2025 ACTRIMS Forum; February 27-March 1; West Palm Beach, FL. ABSTRACT P458.
2. Knippenberg S, Damoiseaux J, Bol Y, et al. Higher levels of reported sun exposure, and not vitamin D status, are associated with less depressive symptoms and fatigue in multiple sclerosis. Acta Neurol Scand. 2014;129(2):123-31. doi:10.1111/ane.12155. Epub 2013 Jun 13.