Light Therapy as Treatment for Fatigue in Multiple Sclerosis
Phase: NA
Conditions: Multiple Sclerosis, Relapsing-Remitting
Sponsor: Massachusetts General Hospital

 
 
 
LIGHT THERAPY FOR THE TREATMENT 
OF MS-ASSOCIATED FATIGUE 
Protocol 
NCT03060759  
 
August 8, 2018 

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Light Therapy for Multiple Sclerosis Fatigue 
Detailed Protocol; version 3 
I. 
BACKGROUND AND SIGNIFICANCE:  
Historical background, rationale behind the proposed research, 
and potential benefits to patients and/or society.  
Fatigue is the most commonly reported symptom among people living 
with multiple sclerosis (pMS).1-4 More than a quarter of pMS state fatigue 
is their most disabling symptom.5 Despite the impact of fatigue in MS, 
there are few effective treatment options. Many pMS seek non-
pharmacological options for their symptoms but have limited evidence 
upon which to make important treatment decisions.  
Fatigue may have multiple mechanisms in MS including dysfunction of 
the dopaminergic neurons in the basal ganglia,6,7 endocrine 
dysfunction due to suppression of the hypothalamic pituitary adrenal 
axis,8 cytokine induction in a continuous, pro-inflammatory state of the 
brain,9 and/or reduced function of the frontal cortices.6 We hypothesize 
that supplemental exposure to bright white light will be associated with 
a reduction in MS-associated fatigue. In a prospective study following 
pMS, self-reported sunlight exposure was correlated with lower levels 
of fatigue.10 Although causality cannot be determined from that study, 
this suggests a possible therapeutic benefit of light for fatigue in pMS. 
Light therapy has also been associated with reduction of fatigue in 
other neurological and medical disorders including Parkinson’s 
disease11, traumatic brain injury12, seasonal affective disorder13 and 
cancer-related fatigue14. If mechanisms of fatigue are overlapping 
across disorders in which bright LT has shown therapeutic benefits, LT 
may be an unrecognized therapeutic option for fatigue among pMS. 
The beneficial effects of light on fatigue may be mediated through its 
direct alerting effects or through its effects as the main synchronizer of 
the circadian system.  
II. 
SPECIFIC AIMS 
Objectives and hypotheses to be tested:  
1. To determine whether bright white light (BWL) (active condition) 
compared to dim red light (DRL) (control condition) will reduce self-
reported fatigue among pMS when administered twice daily in one-hour 
sessions for four consecutive weeks.  
Hypothesis 1:  Bright white LT will reduce the average self-reported 
fatigue score on the Fatigue Severity Score (FSS) by ≥10 points among 
pMS with fatigue, compared to pMS treated with dim red LT.  
2. To determine the feasibility and tolerability of LT as an intervention 
strategy to reduce fatigue in pMS by reporting the adherence data with 
the study intervention and participant-reported side effects.  
Hypothesis 2:  LT will be both feasible and well-tolerated in pMS. 
III. 
SUBJECT SELECTION:  
A. Inclusion/Exclusion Criteria: 
a. Inclusion Criteria: (1) relapsing remitting or secondary 

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progressive MS based on McDonald Criteria (2010)15 (2) ≥18 
and ≤70 years old, (3) presence of fatigue defined as FSS ≥36 
on screening (range 7-63 possible points).16  
b. Exclusion criteria: (1) change in an anti-depressant, (2) 
fatigue medication regimen, or MS disease modifying therapy 
up to 4 weeks prior to study screening, (3) Beck Depression 
Inventory II score >20, (4) shift work, (5) use of 
photosensitizing medication, (6) presence of eye trauma or 
acute optic neuritis within the preceding 3 months or presence 
of macular degeneration or other retinal disease, (7) history of 
traumatic brain injury or (8) probable (untreated) sleep apnea 
based on Berlin questionnaire (9) significant anemia (10) 
history of mania, (11) MS relapse in the preceding four weeks, 
(12) current pregnancy, (13) known photosensitivity (14) other 
complicating illness preventing study completion.  Patients will 
be withdrawn from study participation if they experience a 
clinical relapse requiring hospitalization or treatment with 
steroids during the study period. They will also be withdrawn 
if there is a change in disease modifying therapy for MS, 
depression or fatigue during the study period.  
B. Subject Recruitment:  
Participants will be recruited from the MS Clinic at Massachusetts 
General Hospital (MGH). 700 pMS are followed in this clinic. In 
preliminary screening, ~2/3 of MS patients at MGH have a FSS ≥36 
(mean 45.9, standard deviation 15.2 points) and will be eligible for 
participation. We will use flyers placed throughout the hospital as well 
as letters to eligible patients in order to assist with recruitment. We 
will use MGH’s Research Subject Volunteer Program (RSVP), a 
participant matching service, to identify subjects with enthusiasm for 
the project. If the participant is a patient of the principal investigator, 
a research physician or study coordinator will explain the study so 
they do not feel obligated to participate. Subjects between 18-70 
years old will be recruited for they study. For older subjects, best 
clinical judgment will be used to determine if participation is feasible.  
IV. 
SUBJECT ENROLLMENT:  
A. Methods of enrollment, procedures for obtaining informed 
consent, and randomization: Following a redcap screening survey 
(Beck Depression Inventory, Fatigue Severity Scale, Berlin 
Questionnaire, Inclusion/exclusion criteria) and a baseline visit, 
eligible participants will be consented and randomized using a 
computer-based randomization generator 1:1 to (a) white LT (10,000 
lux), or (b) dim red LT (<300 lux). Dim red LT is a widely accepted 
controlled condition in clinical studies of LT. In attempt to reduce 
placebo effect, the participants will be informed that this study will 
examine the effect of two different light spectra on fatigue and that 
one will be placebo. They will be informed that they will not know the 

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group they are in. Informed written consent will be obtained at the 
time of enrollment at the screening/baseline visit.  
V. 
STUDY PROCEDURES:  
A. Study visits and parameters to be measured, data to be 
collected and when the data is to be collected:  
Interested patients will be identified through the MS clinic at 
MGH, the RSVP, the Partners Clinical Trials website or alerted by 
flyer/letter. Following a phone call to explain the details and 
requirements of the study, interested participants will undergo a 
screening survey administered through redcap, link sent by email. 
This survey will include questions regarding the inclusion/exclusion 
criteria, the Fatigue Severity Scale (≥36), the Beck Depression 
Inventory (≤20), and the Berlin Questionnaire to screen the 
participant for eligibility. Participants who are eligible and remain 
willing to participate will then be scheduled for an in-person visit with 
either the principal investigator (PI) or another physician involved in 
the study for a baseline visit. The following assessments will be 
administered by the study PI/research physician at the baseline visit: 
(1) the Kurtrzke Extended Disability Status Scale (EDSS), (2) FSS, 
(3) Pittsburg Sleep Quality Index (PSQI), (4) Epworth Sleepiness 
Scale (ESS), (5) Multiple Sclerosis Quality of Life-54 (MSQOL-54). 
Additionally data will be obtained from patient report and chart 
review on the patient’s history of RRMS or SPMS including time from 
diagnosis, 
disease 
modifying 
therapy, 
baseline 
neurologic 
symptoms, imaging features such as presence or absence of spinal 
cord lesions as well as data on medical comorbidities and 
medications used. Data on the use of caffeine, alcohol and tobacco 
will also be collected. The participants most recent Vitamin D level 
will also be obtained from their medical record. This will be collected 
in order to assess whether response to light therapy differs amongst 
patients with differing levels of vitamin D deficiency. Studies in 
patients with MS fatigue show mixed results regarding the 
relationship of fatigue with vitamin D level and supplementation 19-21.  
At the baseline visit, participants will be randomized to BWL 
or DRL. The research coordinator will be aware of the assignment 
and will distribute the appropriate light therapy boxes during the visit. 
The PI and research physician will be blinded to treatment 
assignment so as not to bias follow-up visit assessments. The group 
assignments will be kept in an excel file that only the research 
coordinator has access to to maintain blindedness.  
After randomization the subjects will begin the study period. The 
study period will include a 2-week baseline period without any light 
therapy treatment, a four week treatment period and a four week 
follow-up (wash-out) period. Throughout the study period, 
participants will record their fatigue using the Visual Analogue 
Fatigue Scale (VAFS) four times daily, starting after waking up, and 

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every four hours thereafter (at least 3x per day). The VAFS is a 
simple, validated 10-point scale ranging from 1 to 10 in which 
participants can report their fatigue as a snapshot at that particular 
moment.18 Data collection will occur by participants in self-report 
fashion on paper that will be returned to the study staff at then end 
of the study period. During the entirety of the study period including 
baseline and wash-out, patients will also collect a sleep diary which 
requires filling out once per day (<1 minute). During the four week 
treatment period patients will record their use of light therapy in a log 
as well as any side effects they are experiencing. Patients will be 
instructed to sit in front of the light box with eyes approximately 18.5 
inches from the light source.  They will use the box for one hour twice 
per day, in the morning starting two hours after awakening and in the 
evening starting 3 hours before bedtime. Eyes should be open while 
using LT but patients do not have to look directly at the light and can 
eat, read, watch television etc. during use.  
There will be two visits with the principal investigator (PI) 
including the baseline visit described above, a visit with the PI at the 
end of the treatment period in which participants will perform a FSS, 
MSQOL-54 and discuss their experiences with LT. Final follow up 
surveys (FSS and MSQOL54) will be sent using redcap by email 
following the 4-week washout period. Patients will be reminded not 
to reveal their treatment assignment to the examining blinded 
physician.   
 
B. Device to be used: The light box used for LT (SunRay by The 
Sunbox Company, Gaithersburg, Maryland, USA) is approximately 
15.5” tall x 23” wide x 3.25” deep and is designed to stand on a desk 
or tabletop. It can be used both in the home or office. The light is 
delivered at a downward angle to maximize the effectiveness. The 
box runs on 124 watts and contains full spectrum 5000k 10,000 lux 
bulbs. Bright light treatment requires at least 2,500 lux to be 
effective.17 
 
 
The lights are tested by the supply company before 
 
distribution to ensure they meet advertised levels of lux 
 
output. Lights are turned on by the study team to make 
 
sure they work before being provided to study participants. 
 
In cases where bulbs burn out, they are replaced with new 
 
bulbs purchased from the same supply company.  
 
 
VI. 
BIOSTATISTICAL ANALYSIS:  
Specific data variables, study endpoints, statistical methods, 
power analysis  
The primary outcome measure will be change in the average FSS after 

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the 4-week study period in the bright light “active” versus the dim light 
“control” groups. There are no available data on FSS in response to 
bright LT in pMS. To test the specific aim of change of 15 points, we 
used the conventional values of =0.05 and =0.80 for 2-tailed tests of 
probability with equally sized groups. For a difference in 15 points, with 
an estimated standard deviation of 15.2 points and mean of 45.9 points 
from preliminary data collection at the MGH MS Clinic, we require a 
minimum of 15 people in either group. The primary aim will compare the 
mean change in FSS scores before initiation and after completion of LT, 
in an intention to treat analysis comparing the active and control 
condition groups. The secondary outcome measure will be a change in 
the global VAFS scores after light therapy in both groups. Frequencies 
will be used to describe baseline characteristics across treatment arms. 
X2 statistics or Fisher’s exact test will be used to compare the differences 
between groups. VAFS will be evaluated using a mixed-effects model 
which accounts for correlation between repeated measurements. 
Participant logbooks will be used to generate summary statistics and to 
graphically display fatigue patterns throughout the day among pMS in 
both groups. Logbooks will also be used to qualitatively assess the 
safety and tolerability of LT.  
RISKS AND DISCOMFORTS:  
Device 
complications/malfunctions 
and 
Psychosocial 
(non-
medical risks) 
We anticipate light therapy to be well-tolerated. Potential side effects of 
light therapy include triggering photosensitivity in those prone to 
migraines as well as triggering mania in those with a history of mania 
(mania is an exclusion criteria to trial participation). Patients may find it 
burdensome to devote two hours per day to light therapy but may also 
be motivated to try this potential treatment for a disorder with minimal 
current treatment options. Patients may also find the frequent VAFS 
tracking burdensome although this has been used successfully in the 
past in trials of light therapy in Parkinson’s disease patients11. We do not 
anticipate device malfunction to lead to any risks or safety issues. 
Should the device stop working, participants will be given instructions on 
how to contact the research team to obtain a new device.  
VII. 
POTENTIAL BENEFITS 
Potential benefits to participating individuals and to society 
Participants may benefit by improvement of their fatigue severity with 
light therapy. Society and patients with MS stand to benefit if LT is found 
to be an effective, feasible, and tolerable non-pharmacologic therapy for 
a very common problem among MS patients for which there are 
currently limited treatment options. Data gathered from this study will be 
essential to inform a larger randomized study of LT for fatigue reduction 
in pMS in general or among subgroups of pMS with promising 
preliminary results. 
VIII. 
MONITORING AND QUALITY ASSURANCE  

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A. Independent monitoring of source data: If participants in the bright 
white LT do not self-administer the intervention, it may underestimate 
the effect of LT. Participants will be called two weeks after the 
commencement of the light therapy treatment phase by the research 
coordinator, including addressing challenges to completion of LT. 
Honest reporting of LT use will be encouraged.  
B. Safety Monitoring: As above, participants will be called two weeks 
after the commencement of the light therapy treatment phase to 
assess for tolerability problems with light therapy. They will be 
encouraged to contact the research team immediately to report  any 
potential side effects of light therapy. The research coordinator will 
be available by phone during regular business hours, and the PI will 
be available to patients at all times by page.  
C. Outcomes Monitoring: Outcomes including therapy efficacy, 
tolerability and feasibility will be reviewed at each treatment visit.  
D. Adverse Event Reporting Guidelines: Patients will monitor 
adverse events/side effects on a daily basis and will be instructed 
how to contact the research coordinator or PI at any time to report 
adverse events. As above the research coordinator will review 
potential adverse events two weeks after the commencement of the 
light therapy treatment phase with patients and the research 
physicians will review treatment/side effect logs at the two post-
treatment follow-up visits.  
IX. 
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