Bright Light Treatment at Home to Improve Symptom Management of Fibromyalgia Syndrome
Phase: NA
Conditions: Fibromyalgia, FMS
Sponsor: University of Michigan

BRIGHT LIGHT TREATMENT AT HOME TO IMPROVE 
SYMPTOM MANAGEMENT OF FIBROMYALGIA 
SYNDROME 
 
 
 
 
 
IRB Approval Date: February 22, 2021 
NCT03794908 
 

BRIGHT LIGHT TREATMENT AT HOME TO IMPROVE 
SYMPTOM MANAGEMENT OF FIBROMYALGIA 
SYNDROME 
Protocol Number: HUM00151160 
National Clinical Trial (NCT) Identified Number:  NCT03794908 
Principal Investigator: Helen Burgess, PhD 
Sponsor: NINR 
Funded by: Grant #R21 NR0169301-01A1 
 
Initial Version: 23 August 2018 
 
Version Number:  10.0 
February 17 2021/AKL (MR) 
 
 
 
 

NIH Behavioral and Social Clinical Trial Protocol Template   
 

  
1 
PROTOCOL SUMMARY .............................................................................................................................................................. i 
1.1 
Synopsis ................................................................................................................................................................................... i 
1.2 
Schema................................................................................................................................................................................... ii 
 
ii 
1.3 
Schedule of Activities ...................................................................................................................................................... 1 
2 
INTRODUCTION ............................................................................................................................................................................ 0 
2.1 
Study Rationale .................................................................................................................................................................. 0 
2.2 
Specific Aims ....................................................................................................................................................................... 0 
2.3 
Background .......................................................................................................................................................................... 0 
3 
Risk-Benefit Assessment ........................................................................................................................................................... 2 
3.1 
Known Risks ........................................................................................................................................................................ 2 
3.2 
Unknown risks ..................................................................................................................................................................... 4 
3.3 
Potential Benefits .............................................................................................................................................................. 4 
3.4 
Risk-benefit Assessment ............................................................................................................................................... 4 
4 
OBJECTIVES AND ENDPOINTS .......................................................................................................................................... 4 
5 
STUDY DESIGN ............................................................................................................................................................................. 5 
5.1 
Overall Design .................................................................................................................................................................... 5 
5.2 
Randomization .................................................................................................................................................................... 6 
6 
STUDY POPULATION ................................................................................................................................................................ 6 
6.1 
Inclusion Criteria ................................................................................................................................................................ 6 
6.2 
Exclusion Criteria .............................................................................................................................................................. 6 
6.3 
Lifestyle Considerations ................................................................................................................................................ 7 
6.4 
Screen Failures .................................................................................................................................................................. 7 
6.5 
Strategies for Recruitment and Retention ............................................................................................................ 8 
7 
STUDY INTERVENTION(s) ...................................................................................................................................................... 9 
7.1 
Study Intervention Delivery .......................................................................................................................................... 9 
7.2 
Fidelity ................................................................................................................................................................................... 10 
7.3 
Measures to Minimize Bias ........................................................................................................................................ 10 
7.4 
Concomitant Therapy .................................................................................................................................................... 10 
7.5 
Contraindicated Therapy ............................................................................................................................................. 11 

  
8 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................................................................... 11 
8.1 
Discontinuation of Study Intervention ................................................................................................................... 11 
8.2 
Participant Discontinuation/Withdrawal from the Study .............................................................................. 11 
9 
STUDY ASSESSMENTS AND PROCEDURES ......................................................................................................... 12 
9.1 
Assessments ..................................................................................................................................................................... 12 
9.2 
Safety Assessments ...................................................................................................................................................... 14 
9.3 
Adverse Events ................................................................................................................................................................ 15 
9.4 
Unanticipated Problems .............................................................................................................................................. 16 
10 
STATISTICAL CONSIDERATIONS ................................................................................................................................... 17 
10.1 
Sample Size & Power Analysis ............................................................................................................................... 17 
10.2 
Specific Aim 1 ................................................................................................................................................................... 17 
10.3 
Specific Aim 2 ................................................................................................................................................................... 17 
10.4 
Exploratory Aim ................................................................................................................................................................ 18 
11 
Supporting Information & Operational Considerations ............................................................................................. 18 
11.1 
Informed Consent Process ........................................................................................................................................ 18 
11.2 
Data Retention .................................................................................................................................................................. 18 
11.3 
Quality Assurance and Quality Control ............................................................................................................... 19 
11.4 
Safety Monitoring Committee Members.............................................................................................................. 19 
12 
REFERENCES .............................................................................................................................................................................. 20 
13 
Optional Sub-study: Apple Watch & Sleep Phase Identification ......................................................................... 32 
13.1 
Sub-study Introduction ................................................................................................................................................. 32 
13.2 
Sub-study Risk-Benefit Assessment ..................................................................................................................... 32 
13.3 
Sub-Study Population ................................................................................................................................................... 32 
13.4 
Sub-Study Procedures ................................................................................................................................................. 33 
13.5 
Sub-study Incentive ....................................................................................................................................................... 33 
13.6 
Sub-study Reference .................................................................................................................................................... 33 

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i 
1 PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Title: 
Bright Light Treatment At Home To Improve Symptom Management of 
Fibromyalgia Syndrome 
Study Description: 
A double-blinded RCT looking at the effect of light therapy on 
symptoms associated with fibromyalgia syndrome  
Primary Objective 
Fibromyalgia Impact Questionnaire-Revised 
Secondary Objectives 
PROMIS Pain Intensity 
Heat pain sensitivity – threshold 
Heat pain sensitivity - tolerance 
Study Population: 
Men and women ages 18 or older with fibromyalgia 
Phase: 
N/A 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Michigan Medicine Sleep and Circadian Research Laboratory, a 
renowned facility housed within the Depression Center at the Rachel 
Upjohn Building  
Description of Study 
Intervention: 
The study intervention is daily exposure to bright light therapy.  
Participants will self-administer the therapy at home for 60 minutes 
each day for 4 consecutive weeks. 
Study Duration: 
3 years 
Participant Duration: 
5 weeks 

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ii 
1.2 SCHEMA 
 
 
 
 
Sample protocol for average 12 to 8am sleeper. [ ] = subject times in lab. Qs = questionnaires. Pain Ts = Pain 
Sensitivity Tests (heat, ischemia).  All visits with Qs and Pain Ts will be scheduled for the same time of day. 

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1.3 SCHEDULE OF ACTIVITIES 
OnCore Study 
Phase 
On Study 
On Arm/On Treatment 
Off 
Study 
Study Phase 
Practice 
Baseline 
Treatment 
 
Day Number1 
1 
2 
3 
4 
5 
6 
7 
8 
98 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
239 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
3710 
Visit Number 
V1 
V2 
 
 
 
 
 
 
V3 
 
 
 
 
 
 
V4 
 
 
 
 
 
 
V5 
 
 
 
 
 
 
V6 
 
 
 
 
 
 
V7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Pressure  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anthropometrics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vision testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Receive WatchPat2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Breathalyzer 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Urine drug screen 
(dipstick)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
confirmation4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
expectation 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Seasonality 
Questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complex Medical 
Symptom Index 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multidimensional 
Inventory of 
Subjective 
Cognitive 
Impairment 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Questionnaires5 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MEQ6 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
BDI-II7 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Heat pain test 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Ischemic pain test 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Accelerometry & 
Sleep Log 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AppleWatch and 
app (substudy-
optional) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Daily medication 
log 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Treatment (active 
or placebo) in AM 
@ home & Log 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Treatment fidelity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
SAFTEE 
questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Treatment 
satisfaction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Follow-up 
questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 All outcome assessment visits have a ± 7 day window; 2 Participants receive WatchPat (a study-provided device) on D1 and return it to the lab for data download on D2; 3 Urine drug screen via dipstick is conducted using study-provided supplies; 4 Participants go 
through an extensive pre-screening process in the days prior to enrollment; 5 Battery includes: FIQR, PROMIS physical function, pain interference, pain intensity, sleep disturbance, anxiety, anger, pain catastrophizing, Fibromyalgia Fatigue, Insomnia Severity 
Index, Negative Affect, Catastrophizing & depression; 6 Morning-eveningness questionnaire; 7 Beck Depression Inventory; 8 Baseline visit; 9 mid-treatment assessment; 10 post-treatment assessment 
 

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2 INTRODUCTION 
2.1 STUDY RATIONALE  
Fibromyalgia syndrome (FMS) is characterized by chronic widespread pain, sleep disturbance, 
fatigue, and cognitive dysfunction [7,8]. People with FMS report high distress, disability, 
unemployment, reliance on medical services, and poor quality of life [9, 10]. FMS is also related to 
medical [11,12] and psychiatric comorbidities [13,14]. Estimates suggest that FMS affects more 
than 6.5 million Americans [15,16], and represents an important public health problem [17]. 
Development of effective treatments has been hampered by an incomplete understanding of the 
etiology and pathophysiology of FMS. Pharmacological agents have been tested, but findings 
indicate only small effects [18,19] with a high rate of dropout due to adverse side-effects [18]. Non-
pharmacological alternatives (cognitive behavioral therapy [CBT], exercise) have also been tested, 
but with only small to modest effects [20-22]. Thus, an urgent need exists to develop adjunctive 
approaches to manage FMS symptoms that have optimal treatment effects, minimal side effects, are 
readily available and affordable, and are easily implemented by patients without extensive support 
from specialized personnel. 
2.2 SPECIFIC AIMS 
SPECIFIC AIM 1: To determine the effect of bright versus dim (placebo) morning light treatment on 
function, pain intensity, and pain sensitivity in individuals with FMS. 
Hypothesis 1: Function, pain intensity and pain sensitivity will improve significantly more 
in the bright light treatment group than in the dim (placebo) light treatment group, at mid- 
treatment and at post-treatment. 
SPECIFIC AIM 2: To determine the effect of bright vs. dim (placebo) morning light treatment on 
potential treatment mediators: morningness-eveningness, sleep, mood, pain catastrophizing, 
analgesic medication use. [All outcomes associated with Specific Aim 2 are exploratory.] 
Hypothesis 2: Morningness will increase, sleep will improve, and mood, pain 
catastrophizing, and analgesic medication use will reduce significantly more in the bright 
light treatment group than in the dim (placebo) light treatment group, at mid-treatment and 
at post-treatment. 
Hypothesis 3: Changes in these potential mediators will be associated with changes in 
function, pain intensity, and pain sensitivity, at mid-treatment and at post-treatment (both 
groups combined). 
EXPLORATORY AIM: To explore whether sleep apnea severity and/or subject sex moderate treatment 
effects. 
2.3 BACKGROUND  
2.3.1 
Fibromyalgia and the Need for Adjunct Chronic Pain Management Strategies 
Fibromyalgia syndrome (FMS) is characterized by chronic widespread pain, sleep disturbance, 
fatigue, and cognitive dysfunction [7, 8]. People with FMS report high distress, disability, 
unemployment, reliance on medical services, and poor quality of life [9, 10]. FMS is more prevalent 

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in women than men (9:1 [7]), and is the second most common disorder diagnosed in rheumatology 
practices [57]. FMS affects ~2-6% of the US population [15, 16], or more than 6.5 million 
Americans, representing an important public health problem. FMS appears due to amplification in 
the central processing of pain, with an increase in pain facilitating signals and reduction in pain 
inhibitory signals [58, 59]. A range of pharmacological agents have been tested for FMS, including 
antidepressants, antiepileptics, and opioid analgesics, but recent meta-analyses indicate they have 
small incremental effects over placebo in reducing pain [18, 19], and small to negligible effects on 
fatigue, sleep, and quality of life [18]. Also, many patients drop out of treatment because of 
intolerable side effects [18]. Nonpharmacological treatments such as cognitive behavioral therapy 
(CBT) to teach adaptive coping skills [20] and exercise to increase functional capacity [60] appear 
effective in reducing pain and distress compared to control conditions, but again with small to 
modest effects [20-22]. Such psychosocial interventions also require the availability and 
affordability of specialized personnel for delivery and high patient motivation to maintain 
substantial changes in behavior. Thus, there is an urgent need to develop adjunctive approaches to 
manage FMS symptoms that have optimal treatment effects but low side effects, and which are 
readily available, affordable, practical, and easily implemented by patients without extensive 
support from specialized personnel. 
2.3.2 
Later (Delayed) Circadian Timing and More Eveningness is Associated with Greater 
Pain in FMS.  
The central circadian clock is located in the suprachiasmatic nuclei (SCN [61]) in the hypothalamus. 
Circadian timing in humans can be estimated from the onset of melatonin secretion in dim light 
(DLMO, [62]), and from the Morningness-Eveningness Questionnaire (MEQ) [63] which correlates 
with the DLMO (e.g. r=-0.70, [3]). On average, the central circadian clock has a period of ~24.2 h 
[64, 65] and therefore requires phase advances (shifts earlier) to remain synchronized to the 
external 24 hour day. Much of this daily shifting is accomplished through light captured by retinal 
photoreceptors [66-68], which transmit the light signal to the SCN [69]. Light in the evening shifts 
rhythms later (phase delay, more eveningness) and light in the morning shifts rhythms earlier 
(phase advance, more morningness) [70, 71]. Thus, morning light is essential for corrective 
advances, whereas evening light exacerbates the endogenous tendency to drift later (promotes 
misalignment). Correct circadian timing is essential for optimal sleep, function, mental and physical 
health [72- 75]. Centrally controlled circadian timing is likely to impact pain sensitivity via: (1) 
circadian control of melatonin secretion - a potent anti-inflammatory that modulates opioid and 
GABA receptor function [76-79], and reduces FMS pain [28-30]; and (2) via the paraventricular 
nucleus, the SCN sends afferents to the amygdala, part of the descending pain system [23, 24, 80]. 
To date, 3 studies have examined circadian timing (melatonin rhythm) in FMS (all n≤10). Two 
studies reported later circadian timing in FMS vs. controls [25, 26]. A third found no difference, but 
patients stabilized their sleep timing before assessment which likely masked any preexisting delays 
[81]. In a large sample (n=1,548) of FMS patients, those with more eveningness reported worse 
symptoms, even after controlling for age, sex, and employment [27]. Thus, delayed circadian timing 
may relate to FMS pain, and advancing circadian timing (more morningness) could reduce pain. 
2.3.3 
Morning Bright Light May Reduce Pain via Advances in Circadian Timing (More 
Morningness)  
Bright light causes shifts in circadian timing [82, 83]. Phase advances of ~1 h are seen after a week 
of a 1 hour pulse of bright light after usual wake time [1, 2]. Morning bright light is used to treat 
winter depression [5, 84- 86], nonseasonal depression [87-89], improves mood in controls [90], 
and increases sleep efficiency [89, 91]. Phase advances and reductions in depression occur within 
the first few days of treatment [86, 92, 93]. These effects are attributed mostly to circadian phase 

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advances, but bright light also has rapid mood enhancing effects (e.g.[4]). Two published studies 
examined effects of bright light on pain. In one, a light visor was tested in FMS (n=14) [94]. No 
changes in pain, affect, or sleep were observed, but subjects reported the bright light was more 
efficacious than no bright light. There were no measures of compliance. Subjects found the visor 
uncomfortable, and the light source was above the eyes, while people often gaze down. In the other 
study, 14 days of a 1 h morning bright light treatment from a light box reduced abdominal pain and 
headache [95]. There are no other studies testing bright light for chronic pain, except for our 
studies. 
2.3.4 
Poor Sleep and Negative Affect: Potential Mediators?  
Pain degrades sleep quality/quantity [96-100], and sleep quality/quantity influence pain [101]. 
Sleep disturbance is common in FMS [102], and in FMS patients poor sleep on one night predicts 
greater pain the next day [103]. Sleep quality in FMS also predicted pain 1 year later [104]. Sleep 
disturbance also predicts the risk of pain-free women developing FMS >10 years later, even after 
controlling for psychological well-being (OR 2.05-3.43) [44, 105]. Improving sleep in FMS reduces 
pain [50, 52, 54-56, 106]. Research also indicates significant relationships between negative affect 
(NA), such as anxiety, anger and depressive symptoms, and chronic pain intensity (r=0.29 to 0.51) 
[107-110]. In a sample of FMS patients (n=462), cross-sectional correlations among pain intensity, 
depressive symptoms, and function ranged from r=0.22 to 0.43 [111]. Anxiety is also related to 
elevated FMS pain [112, 113]. In treatment studies for FMS, depression predicted poorer outcomes 
[114], and changes in cognitive and affect factors during therapy for FMS were significantly related 
to changes in pain and function (r’s>0.35) [115]. While sleep and NA impact pain, delayed circadian 
timing and more eveningness negatively impacts NA [31, 32] and sleep [35, 36]. Even small 1-2 
hour circadian delays negatively impact sleep [38, 39], are associated with depression [37, 74, 116-
120], and increase NA in controls [33, 34]. Thus, circadian timing may directly, and indirectly (via 
sleep, NA) influence pain. 
3 RISK-BENEFIT ASSESSMENT 
3.1 KNOWN RISKS 
3.1.1 
Distress when sharing personal information  
Participants might feel uncomfortable at having to share personal information during the pre-
screening process and in response to the questionnaires.  Participants may refuse to answer any 
question with which they are uncomfortable.  In the case of eligibility assessment, failure to answer 
certain questions may preclude enrollment. 
3.1.2 
Brief moderate intensity acute pain associated with pain sensitivity testing 
Participants will experience brief, moderate intensity pain during both the ischemic and heat pain 
sensitivity assessments.  Participants have total control over the duration of their exposure, and 
thus may end the task by indicating when they have reached their limit.  Both pain sensitivity 
testing paradigms have been used previously in numerous studies involving both healthy and 
chronic pain patients without incident [126, 145]. 
3.1.3 
Discomfort and disrupted sleep from WatchPat 
Participants might experience discomfort from the wearing the WAtchPat, an FDA-approved device 
for the in-home assessment of obstructive sleep apnea.  It is widely used in clinical practice, and the 

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PI has worn the device herself and found that her sleep was only mildly disturbed by the presence 
of the equipment.  Participants will be told of the potential for mild sleep disruption in return for 
the benefit of an assessment for sleep apnea.  The data from the WatchPat will be downloaded by 
the study team and reviewed by the Co-I, Dr. Cathy Goldestein (MD).  Individuals will be referred to 
treatment for sleep apnea if their WatchPat evaluation suggests an apnea/hopopnea index (AHI) ≥ 
15 which reflects the presence of at least mild obstructive sleep apnea. 
3.1.4 
Side effects of morning light treatment 
While light therapy is a relatively benign therapy, some individuals will report headache, eyestrain, 
nausea and agitation [86], but often these side effects spontaneously remit [86, 141], and are rarely 
cause for discontinuation of therapy.  Likewise, the circadian phase shifts (~1-2 hours) resulting 
from active morning light treatment may lead to transient feelings akin to jet lag after crossing 1-2 
time zones including transient sleepiness, fatigue and headache.  These symptoms are similar to 
those one might experience on a Monday morning after a late weekend.  It is expected that these 
feelings of “jet lag” will be short lived and the circadian phase shifts likely complete within the first 
few days of morning light treatment.  Side effects to treatment will be assessed (SAFTEE; see 
Section 9.2, Safety Assessments) the day after session #1, and weekly thereafter. 
A rare, but serious side effect is mania in bipolar patients who overexpose themselves to light [86, 
141]; individuals with bipolar depression are excluded from this study, and all participants are 
instructed to limit their light treatment to 1 hour/day.  Note that mania in response to morning 
light treatment is so rare that light treatment has even been clinically tested in bipolar patients and 
found to be safe [158]. 
The device used in this study, the Re-timer®, is commercially available and in use by the general 
population.  The device meets international ultraviolet and blue light hazard safety standards. The 
light intensities used in this study are greater than most indoor light, but much dimmer than 
sunlight on a bright day. 
3.1.5 
Worsening of pain, affect and/or sleep overall 
The overall risk level of this study is minimal; however, participants may experience a worsening of 
their FMS or changes in their mood by the mere act of changing their daily routine.  To minimize the 
potential worsening of pain and mood, participants are closely monitored throughout the study.  
During the baseline phase, if an individual seems to be deteriorating significantly in terms of pain, 
emotional or sleep condition, the PI and study team will refer them to appropriate treatment, and 
potentially withdraw them from further participation.   
Weekly visits that include a standardized side effects assessment (SAFTEE) will ensure that any 
exacerbations will be documented and addressed in real-time.  Furthermore, participant are told to 
immediately contact the study team (24-hour availability) if they experience any unexpected or 
significant deleterious changes in their condition. 
3.1.6 
Confidentiality and privacy risks 
The risk of research data or PHI being accessed without study or clinical care need is very low given 
the standard safeguards used by Michigan Medicine, and by those on the study team.  Access to 
study records is granted on a need-basis by the lab manager or PI.  Interviews, the informed 
consent process and study visits will be conducted in private spaces within the Sleep and Circadian 
Research Laboratory by PEERRS and GCP-trained staff.   

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OBJECTIVES 
Timeframe 
PROMIS Pain Intensity 
Post-treatment @ 5 weeks 
Heat pain sensitivity – threshold 
Heat pain sensitivity – tolerance 
 
5 STUDY DESIGN  
5.1 OVERALL DESIGN 
Study Design 
• 
Double-blinded, placebo-controlled randomized trial 
• 
Parallel groups 
 
Study Arms 
• 
Control Group:  placebo (dim light) therapy delivered via the Re-Timer® 
• 
Experimental Group: bright light therapy delivered via the Re-Timer® 
 
An optional sub-study looking at use of an app paired with an Apple Watch to identify changes in 
sleep and circadian phase across the study period will be offered to eligible participants of the main 
study.  Details are located in the appendix (Section 13). 
 
This study is designed as a 5-week protocol.  Potential participants are pre-screened using both an 
online survey and a telephone interview.  Eligibility is confirmed at the first visit.  On Day 1, 
subjects will come to the lab, complete the consent process, confirm eligibility and receive a 
WatchPAT device to wear as they sleep at home that night. On Day 2, subjects will return to the lab 
and complete a practice session of questionnaires and pain tests. They will also receive a wrist 
activity monitor, daily sleep logs and event logs while they sleep ad lib at home, following their 
usual sleep schedule. On Day 9 (baseline), subjects will complete the questionnaires and pain tests 
and have their wrist actigraphy and daily logs reviewed. Then they will be randomized to either 
bright or dim (placebo) Re-timer® and treatment expectations will be assessed. Subjects will begin 
their light treatment the next morning at home. Then there will be weekly lab visits for wrist 
activity monitor and Re-timer® data downloads and subjects will receive feedback on their 
adherence to the light treatment. On Day 23 subjects will also complete questionnaires and pain 
tests for the mid-treatment assessment, to help us assess treatment duration effects. On Day 37 
subjects will also complete a post-treatment assessment and treatment satisfaction rating.  
 
Data collection for the entire study will occur over 18-24 months with a plan to enroll 6 
subjects/month except in Nov and Mar when seasonal time changes restrict the enrollment period 
thus contributing to potentially fewer accruals during those months.  For example, an individual 
could be enrolled the week after a seasonal time change, but we are unlikely to enroll someone 
whose study duration would span the time change because of the confounding effects on individual 
sleep habits and circadian rhythms. 

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5.2 RANDOMIZATION 
Participants are will be stratified by sex and randomized to either the experimental study arm 
(Bright Light Therapy) or the control study arm (Dim Light Therapy, placebo) at Baseline (Day 9). 
 
 
6 STUDY POPULATION 
The population under study includes male and female patients with fibromyalgia who are willing to 
travel to the lab for multiple visits across the study duration.  We plan to enroll 80 people with FMS 
for a final sample of n=60 (~80% women, 30 per group), assuming ~25% attrition during the 37-
day study. We have chosen inclusion/exclusion criteria to permit as many people with FMS as 
possible to participate safely, while ensuring the treatment and outcome measures are not 
significantly confounded, to maximize generalizability of findings. 
 
We will assess for FMS at the phone screening using the ACR 2011 Diagnostic criteria ([135, 136]): 
no other disorder is present to explain the pain, symptoms must have been present ≥3 months, and 
the pain must meet widespread (widespread pain index, WPI) and symptom severity (SS) criteria 
(WPI≥7 & SS≥5 or WPI=3-6 & SS ≥9). To characterize the sample, information will also be gathered 
about the onset of FMS pain, medical interventions to date, exacerbating and ameliorating factors, 
and medications used currently and in the past. 
 
6.1 INCLUSION CRITERIA 
• 
Adults ≥18 years 
• 
Meet ACR 2011 FMS Diagnostic criteria for fibromyalgia syndrome 
• 
Ability to understand English well enough to participate 
• 
Ability to travel to study 
• 
Current stable therapeutic regimen (e.g. medications, cognitive behavioral therapy, physical 
therapy, etc.) for at least 30 days prior to enrollment 
6.2 EXCLUSION CRITERIA 
• 
Significant chronic disease (including but not limited to uncontrolled diabetes, advanced 
liver disease, cancer, kidney failure, significant cardiovascular disease*, seizures) that might 
otherwise confound study outcomes and/or procedures 
• 
Retinal pathology or history of eye surgery 
• 
Use of photosensitizing medications 
• 
Severe hearing or memory problems 
• 
Any light treatment in the past year 
• 
Pending medical leave applications at workplace 
• 
Past or present psychotic, bipolar disorders or acute suicidal ideation (relevant items from 
the SCID-5-RV, [137]) 
• 
Current alcohol or substance abuse problems (SCID, urine drug screen), 
• 
Current pregnancy, breastfeeding, or actively trying to get pregnant** 
• 
Night work or travel outside the eastern time zone within 1 month of the study 
• 
Other research participation 

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• 
Frequent number of special events during study period special events (weddings, concerts, 
exams, etc). 
• 
Current melatonin use – individuals must be off for at least 30 days prior to enrollment and 
for the duration of the study 
• 
Self-reported allergy to plastics 
*This does not include hypertension (unless measurement is greater than or equal to 140/90 
mmHg at the screening visit). If excluded for this reason, participants will be referred to their 
primary care physician. 
**Bright light therapy is not contraindicated for pregnant or breastfeeding individuals, and in fact, 
has been used to treat peri/post-partum depression in these women; however, pregnancy and 
breastfeeding can independently (of FM) impact sleep and mood thereby confounding many study 
measures including pain report and pain sensitivity.   
 
6.3 LIFESTYLE CONSIDERATIONS 
6.3.1 
Alcohol Use 
Participants are asked to refrain from alcohol consumption for 24 hours prior to their study visits.  
Any participant breathalyzing positive will be: 
• 
Rescheduled to start the study anew if positive test occurs at Visit 3 (between days 1-9)- 
(prior to initiation of light treatment). 
• 
Withdrawn from the study if positive test occurs at any Visit 4-7 (after day 16) –  
(after initiation of light treatment). 
6.3.2 
Sleep-wake patterns 
Additionally, participants are asked to maintain their usual sleep-wake patterns as documented 
during the initial week of activity monitoring (approximately Days 2-9), and to refrain from 
napping in the 4 hours immediately after light therapy, which counteracts the effects of the light 
treatment. 
6.3.3 
Medication and Concomitant therapies 
Participants are asked to maintain their current (from time of enrollment) treatments including all 
medications and non-pharmacological strategies throughout their participation in the study. 
6.3.4 
Naps 
Participants are asked not nap within 4 hours of completing their treatment. 
6.4 SCREEN FAILURES 
Participants will be considered a screen failure if: 
• 
Urine drug screen at baseline indicates current or recent drug use not accounted for 
by their self-reported medications 
• 
Their blood pressure exceeds 140/90 mmHg upon measurement 
• 
Study team learns of any new exclusion criterion that arises during the first two 
study visits 

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6.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
The eligibility criteria were designed to include as many people with FMS as possible, meaning that 
contraindications to the proposed treatments or inability to fulfill study requirements are the two 
primary reasons why someone would not be able to participate.  Our recruitment avenues are 
designed to reach individuals with FMS living within routine driving distance of the Sleep and 
Circadian Research Lab. 
6.5.1 
Recruitment 
Community/internet advertisements: Our online recruitment strategies will include craigslist.com, 
Facebook, and umclinicalresearch.org, the University of Michigan Research Registry.  We will also 
place IRB approved fliers on The University of Michigan Campus and surrounding Ann Arbor, 
Detroit, and Ypsilanti communities.  Subjects may also be recruited via word of mouth as a result of 
community/internet advertisements. 
Previous research participants: IRB fliers will also be sent to participants who have previously 
participated in Dr. David Williams’ (co-investigator on grant) fibromyalgia research studies and 
have indicated they are willing to be contacted about future research studies. 
Support Groups and the Fibromyalgia Seminar: IRB-approved fliers will also be sent to local support 
groups and be available at the bi-weekly Fibromyalgia Seminar 
(https://medicine.umich.edu/dept/cpfrc/events/fibromyalgia-seminars) held at Domino’s Farms 
(across the street from the Sleep and Circadian Research Lab).  If research staff are available, they 
will attend select seminars to talk to potential participants in person. 
6.5.2 
Data Direct/EMERSE 
We will use two of the online self-serve tools provided by the University of Michigan Data Office for 
Clinical and Translational Research to access clinical data as a means of identifying potential 
participants with fibromyalgia and/or chronic pain.  Once identified, these individuals will be 
approached initially via an introductory letter, email, or text inviting them to contact the study team 
for information. 
6.5.3 
Pre-screening 
Prospective participants will participate in series of pre-screening surveys: first they complete an 
online survey (REDCap) to determine basic suitability (e.g. meeting criteria for FMS, desired 
schedule, etc.) for the FibroLight study followed by a telephone interview during which screening 
questions for psychiatric disorders, and other potentially sensitive exclusion criteria are discussed.  
The PI and/or lab manager will review the pre-screening (both REDCap & phone interview) 
information to confirm preliminary eligibility.  Once deemed eligible at this stage, prospective 
participants will be scheduled for the initial study visit at which additional screening procedures 
will occur. 
6.5.4 
Accrual 
We intend to enroll 80 people with FMS with the intent of achieving a final sample size of n=60.  
With an accrual period of approximately 18 months we will strive for 6 new participants each 
month. 

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6.5.5 
Retention 
Our pilot data suggest that this is a motivated population who respond well to frequent contact and 
support.  We use daily texts as a means of promoting treatment adherence, but also as a way of 
maintaining contact throughout the study period. 
Weekly visits allow for more personal contact between the study team and participant.  Individual 
sleep and treatment data are shared with participants to help promote adherence and retention. 
6.5.6 
Participant incentives 
Participants will be paid a total of $670 for study their participation. This payment includes 
incentive for participation and completion of study procedures in addition to covering costs 
associated with traveling to the 7 laboratory visits. The schedule of payments is as follows: 
• 
$50 for completing the 1 night wearing the WatchPAT device and returning it to the 
research staff 
• 
$100 for completing each week of the study (up to $500) 
• 
$50 bonus for completing the study (at Visit 7) 
• 
$10 travel stipend for each visit (up to $70) 
Participants will be paid only for the parts of the study they complete. 
 
7 STUDY INTERVENTION(S) 
7.1 STUDY INTERVENTION DELIVERY 
Both the study intervention and the placebo intervention are self-administered by the participants 
in their own homes.  Participants will be randomized and receive their Re-Timer® at study visit 3 
(approximately Day 9), and will start their 1-hour daily morning light treatment (regardless of 
study arm) the next morning within a few minutes of their assigned wake up time, determined as 
their average wake time from the baseline week of activity monitoring, or up to 1 hour earlier to 
accommodate their morning schedule (work, child care) [1, 2]. Participants will be provided with 
an alarm set to the start of the light treatment, and will also use their own alarm as a backup. A light 
log to note light on/off times and any interruptions to light treatment will be provided.  Participants 
are also given a list of written reminders to charge the Re-timer®, only turn it on during the 
scheduled time, and not to nap in the 4 hour window after the light treatment. Subjects will be 
instructed to maintain their baseline sleep duration. 
 
7.1.1 
Control (placebo) intervention 
• 
Dim-light therapy via the Re-Timer®  
• 
Daily use 
• 
For the first hour after waking 
o Can wake up 1 hour earlier than usual for therapy 
• 
60 minutes/day 
• 
Fill out treatment log 
7.1.2 
Study intervention 
• 
Bright light therapy via the Re-Timer® 
• 
Daily use 

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• 
For the first hour after waking 
o Can wake up 1 hour earlier than usual for therapy 
• 
60 minutes/day 
• 
Fill out treatment log 
7.1.3 
Re-Timer® Storage 
The Re-Timer® glasses will be stored in the locked PI office when distributed.  Participants will be 
asked to store the device in its provided storage case and away from extreme cold or heat while it is 
in their possession.  Each pair will be wiped clean with alcohol swabs between participants. 
 
7.2 FIDELITY 
• 
Participants will complete a daily treatment log indicating times of use and any 
interruptions or alterations to the treatment session 
• 
Use time of the Re-Timer® (both arms) and activity monitor data will be downloaded and 
reviewed weekly at study visits 4, 5, 6 and 7.  Data will be reviewed by PI or lab manager 
(unblinded) and shared with the participant. 
• 
Participants will receive daily text prompts asking Yes/No question completion of light 
therapy.  
• 
Re-Timers® will be custom fitted to each participant to ensure proper placement and 
delivery of light therapy. 
7.3 MEASURES TO MINIMIZE BIAS 
7.3.1 
Randomization 
Participants will be stratified by age (18-29 vs. 30 and older) and randomized in a 1:1 ratio to one 
of the two study arms. 
7.3.2 
Blinding 
The outcome assessors and participants will be blinded to condition.  The PI and lab manager will 
remain unblinded, and perform the fidelity and side effects assessments (SAFTEE).  Participants are 
asked and reminded throughout the study to only speak about their light treatment with either the 
PI or lab manager. 
7.4 CONCOMITANT THERAPY 
Patients are allowed to continue their usual care, including medications and non-pharmaceutical 
therapies throughout the study.  All concomitant treatments must be stable for at least 30 days 
prior to enrollment, and be maintained throughout the study period.  Allowable therapies include, 
but are not limited to: 
• 
Prescribed hypnotics, over-the-counter sleep aids, anti-epileptics, antidepressants, opioid 
analgesics, and muscle relaxants; melatonin is NOT allowed 
• 
Psychological interventions (e.g. cognitive behavioral therapy, counseling, etc.) are 
permitted only if treatment started at least 30 days prior to enrollment and will continue 
throughout the study duration 

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• 
Physical therapy and exercise, etc. are permitted only if started at least 30 days prior to 
enrollment and will continue throughout the study duration 
7.5 CONTRAINDICATED THERAPY 
Current use of melatonin is an exclusion criterion.  Participants must be melatonin-free for at least 
30 days prior to enrollment. 
8 STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
8.1 DISCONTINUATION OF STUDY INTERVENTION 
Use of the Re-Timer® will be stopped in the event of any of: 
• 
Hospitalization of the patient due to a significant decline in health 
• 
Any new diagnosis that would be considered part of the original exclusion criteria for this 
study 
• 
At the request of the patient to discontinue therapy 
• 
At discretion of Dr. Goldstein after review of side effects/SAFTEE data and speaking to 
participant 
 
Reasons for discontinuation will be documented, and all outcome assessments will proceed as 
scheduled, if possible. 
 
8.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Reasons why a subject might be withdrawn from the study: 
• 
Subject request 
• 
Subjects who begin treatment for sleep apnea during the study period 
• 
Positive breathalyzer test at the study visit 4 or later (approximately Day 16 onward) 
• 
Start of new treatment or therapy during study period 
• 
Significant study intervention non-compliance, i.e. inability or unwillingness to complete 
study intervention or outcome assessments  
• 
Any clinical event or other medical condition or situation such that continued participation 
in the study would not be in the best interest of the subject 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) any time after the first two study visits (approximately Day 3 onward) 
• 
Lost-to-follow up 
 
If possible, reasons for withdrawal will be documented.  Data from dropouts or withdraws will be 
kept until the end of the study, including study analyses. Subjects who are excluded from the study 
during the screening phase will be informed of their reason for exclusion in general terms only, in 
order to prevent bias and enrollment of other subjects who do not meet specific criteria. Due to 
heavy recruitment via word of mouth, informing subjects of their specific reason for exclusion could 
impact validity of this research. 
 

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9 STUDY ASSESSMENTS AND PROCEDURES 
9.1 ASSESSMENTS  
9.1.1 
Demographics 
Participants will complete a basic demographics survey 
9.1.2 
Clinical history & Concomitant Medications 
Participants will fill out medical history and concomitant medication forms to document co-
morbidities, clinical history related to fibromyalgia, and to evaluate for any contraindicated 
medications 
 
9.1.3 
Blood Pressure 
Participants will have their blood pressure measured as part of the screening procedures. Upon an 
initial reading of 140/90 mmHg or higher, participants will be asked to lay down for 10 minutes 
and then re-evaluated. If participant blood pressure remains above this level, they will be dropped 
from the study and advised to contact their primary care physician as soon as possible.  
9.1.4 
Height & Weight 
Participant height and weight will be measured in the clinic. 
9.1.5 
Vision Testing 
Participants will undergo a brief vision test that involves standing a set distance from a standard 
Snellen-type eye chart as well as a screening for color-blindness using a common color vision test 
that involves looking at a circular pattern comprised of many dots of various colors, brightness and 
sizes.   
9.1.6 
WatchPat 
The WatchPAT device consists of a wrist monitor and finger probe. Subjects will wear the 
WatchPAT device for 1 night of sleep and return it to the lab the next day. The WatchPAT device is 
FDA approved to assess the severity of any sleep disordered breathing, which will be used in the 
study’s data analytical approach. Dr. Goldstein (co-investigator) will inform the subjects of the 
results and refer them for treatment if necessary (apnea-hypopnea index ≥15). Subjects who begin 
treatment prior to the end of the study will be dropped, however, due to delays in seeing a 
physician and receiving a CPAP machine (≥ 4 weeks), this is unlikely to affect many subjects. 
9.1.7 
Wrist Activity Monitor and Sleep & Medication Log 
After the WatchPAT night, subjects will be required to wear a wrist activity monitor, the Actiwatch 
Spectrum, which looks like a wrist watch, for the entirety of the study. This will record movement 
and sleep patterns. After the light treatment starts (see below), study staff will download data from 
the wrist monitor during the weekly appointments to confirm subjects are waking at the assigned 
light treatment time and not napping in the 4 hours after the light treatment. 
 
In conjunction with the activity monitor, participants will be asked to fill out a daily sleep log that 
queries in-bed time, other factors related the previous night’s sleep, and any medications used 
during the previous 24 hours. 
9.1.8 
Treatment expectation 
Participants will complete a brief survey about their expectation for treatment 

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9.1.9 
Surveys 
Participants will be asked to complete questionnaires that assess pain, function, mood and sleep:  
• 
Fibromyalgia Impact Questionnaire, Revised (FIQ-R) 
• 
PROMIS Fatigue-Fibromyalgia Profile 
• 
PROMIS Physical Function (Item Bank v2.0 SF 8b) 
• 
PROMIS Pain Interference (Item Bank v1.0 SF 8a) 
• 
PROMIS Pain Intensity – 3-item, numeric rating scale 
• 
Morningness-Eveningness Questionnaire (MEQ) 
• 
PROMIS Sleep Disturbance (Item Bank v1.0 SF 8b) 
• 
PROMIS Sleep-related Impairment (Item Bank v1.0 SF 8a) 
• 
Insomnia Severity Index (ISI) 
• 
Patient Health Questionnaire (PHQ) 
• 
PROMIS Anxiety (Item Bank v1.0 SF 8a) 
• 
PROMIS Anger (Item Bank v1.1 SF 5a) 
• 
Pain Catastrophizing Scale 
• 
SAFTEE questionnaire to assess treatment side effects 
• 
Beck Depression Inventory - II 
• 
Seasonality Questionnaire 
• 
Complex Medical Symptom Index 
• 
Multidimensional Inventory of Subjective Cognitive Impairment 
• 
Treatment expectation 
• 
Treatment satisfaction 
• 
Follow-up Questionnaire on study experience 
• 
Health history questionnaire 
• 
For Females Only Questionnaire 
9.1.10 Pain sensitivity testing 
Participants will undergo two different quantitative sensory testing paradigms to evaluate pain 
sensitivity. 
 
• 
Heat Pain Test: Pain threshold and tolerance will be assessed during a heat pain task using a 
Medoc TSAII NeuroSensory Analyzer. We will use an ascending method of limits protocol 
[126]. Four trials each will be conducted for threshold and tolerance, with each trial 
conducted sequentially at 1 of 4 different non-overlapping sites on the non-dominant 
ventral forearm. An interval of 30 secs between successive stimuli will be used. For pain 
threshold trials, the probe will start at an adaptation temperature of 32°C, with temperature 
increasing at a ramp rate of 0.5°C/sec until the subject indicates that the stimulus feels 
“painful”. For each tolerance trial, the probe will start at an adaptation temperature of 40°C, 
with temperature increasing at a ramp rate of 0.5°C/sec until the subject indicates 
tolerance. Means of the 4 trials will be derived. Subjects can stop at any time, and the Medoc 
device has a 52°C automatic cutoff to prevent injury. 
• 
Ischemic Pain Test: Pain threshold and tolerance will be assessed during an ischemic pain 
task [144, 145].  Subjects will engage in 2 minutes of dominant forearm muscle exercise 
using a hand dynamometer at 50% of max grip strength (determined earlier), and then 
raise their dominant forearm overhead for 15 secs. A blood pressure (BP) cuff will be 
inflated on the dominant bicep to 200 mmHg SBP, and will remain inflated until tolerance is 
reached (max 480 secs). Threshold is time elapsed from task onset to when sensation is first 

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described as painful. Tolerance is time elapsed from task onset to subjects’ desire to 
terminate the task. 
 
9.2 SAFETY ASSESSMENTS 
9.2.1 
SCID Screening & Beck Depression Index for suicidality 
At screening, all potential participants will be assessed for suicidal thoughts and behaviors with the 
SCID, and will be excluded.  Weekly administration of the Beck Depression Inventory (BDI-II) will 
be used to assess suicidality throughout the trial; participants with significant suicidality will be 
excluded.   
For any potential subject in whom we detect concerning suicidal thoughts/behaviors (defined 
according to the BDI-II or SCID), the PI will be notified and a risk assessment of the patient will be 
conducted, including the identification of risk factors (e.g., substance abuse, active psychosis, 
hopelessness), mitigating factors (e.g., social support, degree of control over suicidal thoughts, 
religious beliefs against suicide) and the level of suicidal ideation/behavior (documented in the 
SCID).  An intervention plan will be formulated, taking into account the level of risk and treatment 
resources available to the potential participant.  This could include monitoring by family, contact 
with a treating clinician (with the patient’s permission), follow-up phone calls, or urgent evaluation 
in the psychiatric emergency room.  For individuals without a treating clinician, referrals to 
available community resources will be made. 
9.2.2 
SAFTEE for treatment side effects 
Either the PI or the lab manager (unblinded) will administer the SAFTEE (Systematic Assessment 
for Treatment Emergent Events) the first morning after light treatment, and thereafter at weekly 
study visits.   
If a participant reports a significant worsening of symptoms as indicated by a score of 4 (“bothered 
quite a bit”) or 5 (“bothered extremely”), or endorses any of the following trigger points, the study 
team will contact Dr. Goldstein as soon as possible who will then contact the participant for 
additional information, and make the ultimate decision to retain or withdraw the participant from 
the study, and/or refer them to appropriate treatment. 
9.2.2.1 
Trigger Point Items from the SAFTEE 
• 
Loss of consciousness (2 or more) 
• 
Seizures (2 or more) 
• 
Difficulty swallowing (3 or more) 
• 
Chest pain (2 or more) 
• 
Shortness of breath (2 or more) 
• 
Rapid heart rate (2 or more) 
• 
Irregular heart beat (2 or more) 
9.2.3 
Changes in Clinical Status 
Symptom surveys will be scored in relative real-time allowing for ongoing monitoring of symptoms 
and overall clinical status.  Participants showing a 25% worsening of a symptom (e.g. mood state) 
will be flagged and presented to the PI for review.  Participants showing a 50% worsening in a 
symptom will be flagged and presented to co-I, Dr. Goldstein for review and possible referral to 

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treatment.  Of note, in the PI’s previous studies, it is very rare that participants experience a 50% 
worsening.   
9.3 ADVERSE EVENTS 
The Data Safety and Monitoring Plan is the definitive source for this project’s strategy for upholding 
data integrity and participant safety.  Briefly, this project is considered to be “minimal risk” because 
the probability and magnitude of harm or discomfort anticipated in the research are not greater 
than those ordinarily encountered in daily life or during the performance of routine physical and 
psychological examinations or tests. Safety of subjects will be ensured by the continued monitoring 
of their mental health and medical status.  Subjects will all have access to treatment-as-usual 
services to address any study-induced adverse effects or other clinical concerns. 
NINR has requested an Independent Monitoring Committee consisting of an M.D. physician (board-
certified in sleep medicine) and familiar with sleep and circadian treatments, a Ph.D. biostatistician 
with extensive experience in clinical trials, and a Ph.D. experienced clinical researcher and 
psychologist also be formed to review the study.  
The PIs will provide quarterly updates to the Committee on study performance including subject 
accrual and status of subjects. For any non-serious adverse events (protocol deviations, non-
compliance, and other events that meet reporting criteria, see below), the Study Monitors and IRB 
will be notified on a quarterly basis and provided with event information and steps taken to resolve 
the situation. The efforts of the Committee will supplement the ongoing data inspections conducted 
by the PIs, who will inspect the data weekly and review it with the research team at weekly 
meetings.  
9.3.1 
Adverse Events 
Serious adverse events will be reported per occurrence to the Study Monitors, IRB, and NINR, 
within 3 business days or sooner. We agree to abide by the resulting directives of the Study 
Monitors, IRB, and NINR, and if requested the study will be suspended until the Study Monitors, IRB 
and NINR resolve the concerns to their satisfaction. The PIs will be responsible for rectifying any 
study problems and notifying all parties as to the resolution of the situation.  
9.3.1.1 
Adverse events definition 
Any unfavorable or unintended symptom, sign, or disease associated with a medical treatment or 
procedure that may or may not be related to the treatment or procedure. Adverse events can be 
related to the treatment or to the disorder being treated (e.g. pain exacerbation), as well as to a 
concurrent disorder or treatment (e.g. MDD or its treatment), or they could be entirely unrelated to 
any of these (e.g., motor vehicle accident).  
9.3.1.2 
Serious adverse event definition 
In this study, we will use the FDA definition of serious adverse events (SAE, e.g., death, 
hospitalization, emergency room visits, suicide plans or attempts). Adverse events and SAE will be 
systematically assessed at each lab visit. Again, any SAE, whether or not related to study 
intervention, will be reported to the Study Monitors, IRB, and NINR within 3 business days or 
sooner. In addition, the PIs will prepare an annual report on data collection and occurrence of any 
adverse events for review by the Study Monitors, IRB, and NINR. Any initial SAE report will be 
followed by submission of a completed resolution report to the Study Monitors, IRB, and NINR. 

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In the event that a patient withdraws from the study or the investigators decide to discontinue a 
patient due to SAE, the patient will be monitored by the PIs via ongoing status assessment until: 
• 
A resolution is reached (i.e., the problem has resolved or stabilized with no further 
changes expected) 
• 
The SAE is determined to be clearly unrelated to the study intervention, or  
• 
The SAE results in death 
Should a large number of unexpected SAEs occur, we will modify or terminate the trial if the events 
are severe. We will also monitor safety alerts, defined as events that are relevant to the study 
populations and pose safety risks to study subjects. Examples of safety alerts would include a 
sudden increase in pain symptoms, change in the type of pain experienced, a clinically significant 
increase in patient depression or anxiety, or certain responses on the SAFTEE. Both SAEs and safety 
alerts will be tracked using a standardized form recording the date of the event, type of event, 
attribution of the event (e.g., judgment regarding whether it was intervention related), whether the 
event was resolved or controlled, and the resolution date.  
9.3.1.3 
Adverse events grading scale 
(0)  No adverse event or within normal limits 
(1)  Mild adverse event – did not require treatment 
(2)  Moderate adverse event – resolved with treatment 
(3)  Severe adverse event – resulted in inability to carry on normal activities and required 
professional medical attention 
(4)  Life threatening or disabling adverse event 
(5)  Fatal adverse event 
9.3.1.4 
 Adverse event attribution scale 
• 
Definite: The adverse event is clearly related to the investigational agent(s)  
• 
Probable: The adverse event is likely related to the investigational agent(s)  
• 
Possible: The adverse event may be related to the investigational agent(s)  
• 
Unlikely: The adverse event is doubtfully related to investigational agent(s)  
• 
Unrelated: The adverse event is clearly not related to investigational agents(s) 
9.4 UNANTICIPATED PROBLEMS 
Unanticipated problems, in general, will include any incident, experience, or outcome that meets 
ALL of the following 3 criteria: 
• 
It is unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol, informed consent document, or other research materials; 
and (b) the characteristics of the subject population being studied. 
• 
It is related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research). 
• 
It suggests that the research places subjects or others at a risk of unknown harm or 
addition/increased frequency of harms (including physical, psychological, economic, 
legal, or social harm) than was previously known or recognized. 

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10 STATISTICAL CONSIDERATIONS  
10.1 SAMPLE SIZE & POWER ANALYSIS 
We will enroll 80 adults (≥18 years) with FMS. We conservatively estimate ~25% attrition (final 
n=60) which includes dropouts (failed drug tests not accounted for by medications, illness, job 
offers, family crises), and noncompliance (<25% of morning light [121]), based on light treatment 
trials (4 week bright light treatment 6% attrition [121], 12 week bright light treatment 19% 
attrition [159]). Subjects who obtain only 25% of the prescribed light (15 min/day) should still 
obtain some benefit, as only 12-20 mins of morning light can be effective [4, 160, 161]. Our primary 
outcome measure is the FIQR. If we assume a 22% decrease in FIQR with the bright Re-timer® as 
per our pilot study, a 5% decrease with dim light (control arm), and baseline mean and SD FIQR 
from a large FMS sample (mean 62.4, SD 14.1 [162]), then using a two-sample t-test for differences 
at the final time point with 30 subjects/group, we will have 81.7% power (α=0.05). This is adequate 
for a pilot study to estimate effect sizes for a future larger trial.  
10.2 SPECIFIC AIM 1 
To determine whether baseline to mid- to post-treatment changes in FIQR (primary outcome 
measure), PROMIS Physical Function, Pain Interference, Pain Intensity, heat pain threshold and 
tolerance, ischemia pain threshold and tolerance are greater in bright vs. dim light conditions.  
First, balance in randomization (baseline FIQR, age, sex, race/ethnicity, season) between the two 
arms will be examined using descriptive measures (mean, SD for continuous variables; percentages 
for categorical variables) and differences tested with t-tests and Chi-square tests. If imbalances 
occur, we will use propensity score based corrections in regressions. 
Second, we will use linear mixed effects regression models with subject specific intercepts and 
slopes to account for variability in average levels at baseline and changes over time. Light Condition 
(bright vs. dim light) x Time (baseline, mid-treatment, post-treatment with baseline as reference 
time) interactions will test whether changes in outcomes depend on treatment. These analyses will 
be intent-to-treat. We will also focus on the time course of outcome changes: modeling quadratic 
terms to determine: (1) whether both baseline to mid- and/or mid- to post-treatment changes in 
variables are significant, (2) the relative degree of change in each treatment interval indexed by 
appropriate contrasts of regression coefficients. These analyses will determine when significant 
outcome changes occur during treatment. 
10.3 SPECIFIC AIM 2 
To determine whether baseline to mid- to post-treatment changes in morningness-eveningness, sleep, 
NA, pain catastrophizing, and analgesic medication use are greater in the bright vs. dim light 
conditions.  
We will examine the time course of changes in these variables using the analyses described for Aim 
1. We will also test the degree to which baseline to mid- to post-treatment changes in these 
variables are associated with baseline to mid- to post-treatment changes in function, pain intensity 
and pain sensitivity with a regression.  These analyses will identify potential treatment mediators 
to fully test in a future larger study. 

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10.4 EXPLORATORY AIM 
To explore whether obstructive sleep apnea severity and/or subject sex moderate treatment effects. 
 The analyses described above for Aim 1 will be rerun to test Light Condition x OSA (normal to mild 
AHI<15 vs. moderate to severe AHI≥15) x Time for outcomes. We anticipate recruiting ≥20% males 
(see Human Subjects), and will examine possible sex differences in response to bright light 
treatment by testing Light Condition x Sex x Time interactions similar to analyses used in Aim 1. 
[Note:  Descriptions of planned analyses are illustrative. Actual analyses may differ from those 
described here.] 
11 SUPPORTING INFORMATION & OPERATIONAL CONSIDERATIONS 
11.1 INFORMED CONSENT PROCESS 
The recruitment and informed consent process is designed to provide information about study 
participation multiple times and in different format.  Individuals expressing interest will be 
provided with a verbal explanation of study procedures and the risk-benefit profile or be able to 
read basic study information on the umhealthresearch.org website.  From there, individuals are 
provided with an IRB-approved copy of the consent document to review at their leisure.   
The informed consent dialog will take place at the initial study visit (Day 1).  It will consist of a 
dialog between the study team and the potential participant.  The discussion will focus on the 
voluntary nature of research, expectations for participation, a discussion of the risks and benefits 
associated with being in the study, and include time for questions.  Individuals will have an 
opportunity to see the study materials (e.g. activity monitor, WatchPat, etc.) prior to signing the 
consent document. 
The physical location for the consent dialog will be private research space within the Sleep and 
Circadian Research Laboratory.  
11.2 DATA RETENTION 
Research data will be retained for both study record-keeping purposes and for future unspecified 
research use according to IRBMED guidelines for federally-funded projects.  All paper and 
computer records will be identified by the subject ID code rather than name or other identifier.  
Consent documents and other forms with identifiers will be stored in a separate double-locked 
setting.   
Data from participants who withdraw from the study will be retained in the study database. 
11.2.1 Study-record keeping 
Hard copies of the data will be maintained for 7 years after which they will be destroyed.  Files will 
be stored in double-locked environment and access-limited under the purview of the PI.  All 
research records will be identified by subject ID; pre-screening records will be scrubbed of 
identifiers and date shifted to preserve confidentiality.   

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Study database records will be identified by subject ID, and the link between identifiers and subject 
ID will be maintained by the PI and lab manager.  The link will be destroyed after submission of 
the NIH final report or publication of the primary outcomes manuscript, whichever is later. 
11.2.1.1 Protected Health Information (PHI) 
We will abstract basic eligibility and contact information from the Michigan Medicine electronic 
medical records system, MiChart.  These data will be stored separately from study data, and will 
retained with identifiers throughout the duration of the study.  Once the study concludes, the 
identifiers will be destroyed. 
11.2.2 Data for future unspecified research use 
De-identified study databases will be locked and archived for future unspecified research.  These 
data will be used for analyses related to the main study, new analyses, and in grant proposals for 
new research. 
• 
The data will be stored on Michigan Medicine servers in REDCap and/or statistical datasets 
that are stripped of identifiers  
• 
Access to data will be at the discretion of the PI 
• 
Any data shared with collaborators will shared using secure data transfer methods (e.g. 
MiShare) 
11.3 QUALITY ASSURANCE AND QUALITY CONTROL 
11.3.1 Quality Control of Data Collection 
The study will use the Michigan Medicine instance of REDCap, a web-based electronic data capture 
system that is secure and HIPAA-compliant.  Access is restricted to individuals with a Michigan 
Medicine Level 2 password, and can then be further restricted by role within the study database.  
Data validation and data quality rules will be implemented to minimize errors in data capture, entry 
and analysis.  
REDCap provides automated export procedures to common statistical packages in which 
automated syntax can be used to score questionnaire responses thereby reducing errors associated 
with hand calculations or Excel formulas.  It is standard procedure in the Burgess Lab that all data 
manipulations are double-checked and initialed by a second study team member. 
Weekly team meetings in which data are reviewed will further serve as a quality assurance 
measure.  Data reviewed will include information about mental and physical health symptoms of 
participants, and various psychological characteristics gleaned from the questionnaire battery and 
participant report.   
11.4 SAFETY MONITORING COMMITTEE MEMBERS 
Todd Arnedt, PhD 
James Abelson, MD, PhD 
Philip Boonstra, PhD 
Associate Professor of Psychiatry 
Professor of Psychiatry 
Research Asst. Professor of 
Biostatistics, School of Public 
Health 

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tarnedt@med.umich.edu 
jabelson@med.umich.edu 
philb@umich.edu 
 
 
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Appendix 1 
 
13 OPTIONAL SUB-STUDY: APPLE WATCH & SLEEP PHASE IDENTIFICATION 
13.1 SUB-STUDY INTRODUCTION 
The FDA-approved method of longitudinal sleep tracking in the ambulatory environment is 
actigraphy.  Although actigraphy is highly useful, consumer available wearable devices are less 
expensive, easily interface with mobile health applications, and may be more acceptable to patients.  
As such, we have developed an app that houses algorithms to estimate sleep stages when applied to 
raw heart rate and acceleration data from the Apple Watch.  Our algorithm demonstrated excellent 
sensitivity and specificity (80% and 76%) when compared to the gold standard for sleep 
measurement (polysomnogram, PSG) (Walch unpublished).  Additionally, mathematical models 
that use light exposure and movement to estimate circadian phase have been well-described and 
also available through the same app (Walch 2016). 
 
Therefore, we aim to use the Apple Watch and our app in a subgroup of participants from the main 
study, Bright Light Treatment at Home to Improve Symptom Management of Fibromyalgia 
Syndrome, to identify changes in sleep and circadian phase over the 5-week study period.  This data 
may be used to assist in validating the Apple Watch App, and may also be used in HUM00122578. 
13.2 SUB-STUDY RISK-BENEFIT ASSESSMENT 
Participation in this sub-study does not appreciably alter the risk-benefit profile of the main study 
as the only additional risk is that of small increased in burden associated with wearing the Apple 
Watch and using the app.  Some people might find wearing the study watch, plus their own watch 
(if applicable) and the accelerometer a bit annoying.  The Apple Watches themselves are 
comfortable to wear, and don’t pose any additional comfort risks. 
Participation in this sub-study also requires downloading the study app onto one’s personal cell 
phone.  Some individuals might find this intrusive.  Overall, these risks are no different than those 
associated with using the Apple Watch and affiliated apps on their own. 
The risk to privacy and confidentiality are likewise similar to those listed for the main study and 
typical consumer use of a smart watch and app.  The investigators will protect all study data as 
described in Sections 3.1.6 and 11.3 
Participants in the main study are under no obligation to also enroll in this sub-study.  Declining 
enrollment will not change the relationship between the participant and the study team.   
13.3 SUB-STUDY POPULATION 
Participants for this sub-study will be drawn from those individuals already presenting for 
enrollment into the main study.   

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13.3.1 Eligibility Criteria 
Inclusion criteria include all of those associated with the main study, plus the following: 1) 
enrollment in the main study; 2) ownership of an iPhone; 3) ability to operate a mobile application 
on said iPhone; and 4) a willingness to wear an Apple Watch. 
13.4 SUB-STUDY PROCEDURES 
At visit 1, consented individuals will be given a study Apple Watch, and work with the study team to 
download the app on their personal cell phones.  They will receive instructions on how to wear the 
Apple Watch (e.g. which wrist, when, how often, how/when to charge it, etc.), and how to use the 
app to enter light exposure information.  
The app uses the innate heart rate and accelerometer data from the Apple Watch, and will be 
transmitted via HTTP request from the phone.  While most of the data collection will be passive; 
participants will be asked to press an indicator button prior to onset of sleep on some nights.   
13.5 SUB-STUDY INCENTIVE 
Participants will receive $40 per week of wearing the Apple Watch (up to $200 total) in addition to 
the remuneration in place for the main study.  
13.6 SUB-STUDY REFERENCE 
Walch OJ, Cochran A, Forger D. A global quantification of “normal” sleep schedules using 
smartphone data.  Sci Adv 2016;2(5):e1501705