Clinical trial NCT03715465
Conditions: Delayed Sleep Phase Syndrome
Sponsor: University of Michigan
Start date: 2019-02-15; Completion date: 2021-11-05
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will test whether measuring the circadian clock during treatment of delayed sleep-wake phase disorder results in greater improvements in sleep compared to estimating the circadian clock.

Detailed description:
The study is a randomized, controlled, parallel double-blind 4-week trial of 0.5 mgs of exogenous melatonin timed to either 3 h before actual dim light melatonin onset (DLMO) based on in-home measurement (M-DLMO, n = 25) or 3 h before DLMO estimated at 2 h before average sleep onset time based on actigraphy and sleep diary (E-DLMO, n = 25) in adult participants with delayed sleep-wake phase disorder. All participants will receive melatonin 0.5 mgs. Outcomes include change in DLMO, subjective and objective sleep parameters, and daytime symptoms.

As of January 7, 2020, the Insomnia Severity Index was removed from the IRB-approved protocol. No data were collected for this measure.

Arms: arm 1: Four weeks (28 days) of nightly melatonin 0.5 mg fast dissolve tablets timed to be administered 3 hours before estimated dim light melatonin onset. arm 2: Four weeks (28 days) of nightly melatonin 0.5 mg fast dissolve tablets timed to be administered 3 hours before measured dim light melatonin onset.
Interventions: intervention 1: Melatonin 0.5 MG intervention 2: Dim Light Melatonin Onset (salivary)
Intervention descriptions: intervention 1: Melatonin tablet intervention 2: Test to determine the time of melatonin onset in saliva under dim light conditions

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL PROTOCOL 
 
 
 
The Clinical Utility of DLMO in the Treatment of Delayed Sleep-Wake Phase 
Disorder: A Randomized Trial 
 
 
 
Study Agents:  Melatonin 0.5 mg 
 
 
HUM #: 00145052 
 
IND: 141269 
 
Principal Investigator:  Leslie Swanson, Ph.D. 
 
Co-Investigators:  J. Todd Arnedt, Ph.D., Helen Burgess, Ph.D., Deirdre Conroy, Ph.D., 
Shelley Hershner, M.D. 
 
Institution: University of Michigan 
 
Version and Date: 7.0, 3/18/2022 
 
 


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Table of Contents 
1 
INTRODUCTION ...................................................................................................... 6 
1.1 
INDICATION ........................................................................................................ 6 
1.2 
BACKGROUND AND RATIONALE ................................................................. 6 
1.3 
HYPOTHESIS ....................................................................................................... 8 
1.4 
PREVIOUS HUMAN EXPERIENCE ................................................................. 8 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................ 9 
2.1 
OBJECTIVES ........................................................................................................ 9 
2.2 
ENDPOINTS ........................................................................................................ 10 
2.2.1 
PRIMARY ENDPOINT ................................................................................ 10 
2.2.2 
SECONDARY ENDPOINT .......................................................................... 10 
3 
STUDY DESIGN ...................................................................................................... 10 
4 
SUBJECT SELECTION .......................................................................................... 10 
4.1 
SUBJECT RECRUITMENT .............................................................................. 10 
4.1.1 
INCLUSION CRITERIA .............................................................................. 11 
4.1.2 
EXCLUSION CRITERIA............................................................................. 11 
5 
STUDY TREATMENTS.......................................................................................... 12 
5.1 
ALLOCATION TO TREATMENT .................................................................. 12 
5.2 
BREAKING THE BLIND .................................................................................. 13 
5.3 
DRUG SUPPLIES ............................................................................................... 13 
5.3.1 
FORMULATION, PREPARATION AND DISPENSING ........................ 13 
5.3.2 
DRUG STORAGE AND DRUG ACCOUNTABILITY ............................ 13 
5.4 
CONCOMITANT MEDICATIONS .................................................................. 13 
6 
STUDY PROCEDURES .......................................................................................... 14 
6.1 
SCREENING VISIT ............................................................................................ 14 
6.2 
TREATMENT STUDY PERIOD ...................................................................... 14 
VISIT 1 (DAY 1) .............................................................................................................. 14 
6.2.1 
FOLLOW-UP (WEEKS 1-4) ........................................................................ 14 
7 
ASSESSMENTS ....................................................................................................... 15 
7.1 
PRIMARY ENDPOINT ASSESSMENTS ........................................................ 16 
7.2 
SECONDARY ASSESSMENTS ........................................................................ 16 
8 
ADVERSE EVENT REPORTING ......................................................................... 17 
PROTECTION AGAINST STUDY RISKS ..................................................................... 20 
9.1 
SAMPLE SIZE DETERMINATION ................................................................ 22 
9.2 
DATA ANALYSIS ............................................................................................... 22 
9.2.1 
ANALYSIS OF PRIMARY ENDPOINT .................................................... 22 
9.2.2 
ANALYSIS OF SECONDARY ENDPOINTS ............................................ 22 
10 MONITORING ......................................................................................................... 23 
10.1 
DATA AND SAFETY MONITORING PLAN ................................................. 23 
10.2 
FREQUENCY OF DATA AND SAFETY MONITORING ................................ 23 
11 DATA HANDLING AND RECORD KEEPING .................................................. 24 
11.1 
CRFS / ELECTRONIC DATA RECORD ........................................................ 24 
11.2 
RECORD RETENTION ..................................................................................... 24 
12 ETHICS ..................................................................................................................... 25 
12.1 
IRB/FDA ............................................................................................................... 25 
12.2 
INSTITUTIONAL REVIEW BOARD (IRB) ................................................... 25 


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12.3 
SUBJECT INFORMATION AND CONSENT................................................. 25 
12.4 
STUDY DISCONTINUATION CRITERIA ..................................................... 25 
12.4.1 
STOPPING RULES FOR SAFETY REASONS ........................................ 25 
12.4.2 
RULES FOR DISCONTINUATION OF A SUBJECT ............................. 26 
13 REFERENCES ......................................................................................................... 27 
14 APPENDIX ............................................................................................................... 29 
 
List of Tables 
Table 1. Protocol Activities  
Table 2. Study-Specific AE Reporting Timeline  
 


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PROTOCOL SYNOPSIS  
 
Sponsor:  American Sleep Medicine Foundation 
Name of Finished Product: N/A 
Study Title:  The Clinical Utility of DLMO in the Treatment of Delayed Sleep-Wake 
Phase Disorder: A Randomized Trial 
Study Phase: 3 
Primary Objective:  The objective of the proposed study is to evaluate the clinical utility 
of obtaining field-based dim light melatonin onset (DLMO) to time melatonin 
administration for patients with delayed sleep-wake phase disorder. Note that the efficacy 
of the intervention used to time the administration of melatonin is being tested, not the 
efficacy of melatonin per se.    
Study Design: The study is a randomized, controlled, parallel double-blind 4-week trial 
of 0.5 mgs of exogenous melatonin timed to either 3 h before actual dim light melatonin 
onset (DLMO) based on in-home measurement (M-DLMO, n = 25) or 3 h before DLMO 
estimated at 2 h before average sleep onset time based on actigraphy and sleep diary (E-
DLMO, n = 25) in adult participants with delayed sleep-wake phase disorder. All 
participants will receive melatonin 0.5 mgs. Outcomes include change in DLMO, 
subjective and objective sleep parameters, and daytime symptoms.  
Study Population: Adults 18-65 years of age who meet diagnostic criteria for current 
delayed sleep-wake phase disorder.   
Diagnosis and Main Criteria for Inclusion: To be enrolled in the study, participants 
must be 18-65 years of age, and meet diagnostic criteria for delayed sleep-wake phase 
disorder (DSWPD) per the International Classification of Sleep Disorders-3 (ICSD-3). 
Diagnostic criteria include: (1) have evidence of a delayed phase of the sleep-wake pattern 
on daily sleep diaries and actigraphy maintained for at least 7 days (e.g., a ≥ 2 h delay in 
the timing of habitual sleep episode between work/school and free days); (2) report 
difficulty falling asleep and difficulty awakening at desired/required times for ≥ 3 months.   
Test Product; Dose; and Mode of Administration: Melatonin; 0.5 mgs; oral fast 
dissolve 
 
Reference or Placebo Therapy; Dose; and Mode of Administration: N/A (all 
participants will receive melatonin 0.5 mgs).  
Duration of Treatment: 4 weeks (28 days) 
Variables: Time of DLMO in minutes; Epworth Sleepiness Scale score (ESS); 
Multidimensional Fatigue Inventory score (MFI-20); Short-Form Health Survey (SF-12); 


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from diary and actigraphy: total sleep time, initial sleep latency, sleep onset time, sleep 
offset time.  
Statistical Methods: Statistical analyses will include 2-tailed t-tests and linear mixed 
models to test group differences on outcomes.  
  
 
 


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1 
INTRODUCTION 
1.1 
Indication 
Treatment of delayed sleep-wake phase disorder by timing melatonin administration to 
either measured or estimated dim light melatonin onset.   
1.2 
Background and Rationale  
Delayed sleep-wake phase disorder is common and debilitating  
The most common circadian rhythm sleep-wake disorder, delayed sleep-wake phase 
disorder (DSWPD) is estimated to affect up to 7-16% of adolescents and young adults, and 
more than 10% of patients presenting to sleep clinics with insomnia symptoms (American 
Academy of Sleep Medicine 2014). The prototypical patient with delayed sleep-wake phase 
disorder presents with chronic difficulty falling asleep and waking at required or socially 
desired times (American Academy of Sleep Medicine 2014). When free to select their own 
sleep schedule, patients with DSWPD have significantly later sleep onset and wake times 
relative to convention, with preserved sleep quality and normal sleep duration (American 
Academy of Sleep Medicine 2014). Delay of the circadian timing system relative to the 
required or socially desired timing of the sleep episode is posited to be one of the major 
etiological factors (Micic et al. 2016). This is corroborated by numerous studies, which 
show delays ranging from 2-6 h in DSWPD patients’ circadian phase relative to normal 
sleepers (Oren et al. 1995, Ozaki et al. 1996, Shibui et al. 1999, Uchiyama et al. 2000, 
Watanabe et al. 2003).  
The inability to maintain a sleep-wake schedule consistent with social and 
occupational requirements often leads to chronic sleep loss and significant daytime 
impairments. Consequences of DSWPD are wide-ranging and include absenteeism and 
presenteeism, and impairment in social and family life (Rajaratnam et al. 2015). Indeed, role 
disability is greater, and quality of life is more impaired, in adults with DSWPD relative to 
other chronic disorders, including sleep apnea, migraine, and depression (Nagtegaal et al. 
2000).   
 
Effective treatment of DSWPD is challenging under current treatment paradigms 
Despite its prevalence, treatment of DSWPD is challenging. Effective treatment requires 
correcting the circadian phase so that it is optimally aligned with the desired sleep-wake 
schedule. Treatment options include light therapy, hypnotic medications, prescribed sleep-
wake scheduling, timed physical activity, and wakefulness promoting medications. Among 
the available treatment options, the American Academy of Sleep Medicine (AASM) Clinical 
Practice Guideline for treatment of DSWPD in adults recommends only one therapy: timed 
exogenous melatonin (Auger et al. 2015). As noted in both the Clinical Practice Guideline 
and its accompanying editorial, there is a significant lack of research on clinical populations 
with circadian sleep-wake rhythm disorders, and treatment of circadian rhythm sleep-wake 
disorders such as DSWPD, with a particular need for field-based studies (Auger et al. 2015). 
Previous placebo-controlled studies of melatonin for DSWPD in adults show improvements 
in objectively measured sleep parameters, including increased total sleep time, reduced sleep 
onset latency, advanced DLMO time, and an advanced time of sleep onset time for 
melatonin relative to placebo (Kayumov et al. 2001, Mundey et al. 2005, Rahman et al. 
2010).  


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However, on average, these improvements are relatively modest and development of 
treatment protocols that enhance the efficacy of melatonin therapy is needed. Clinical 
strategies that allow for home-based measurement of DLMO and the administration of 
melatonin personalized to each patient’s DLMO hold promise to improve the efficacy of 
melatonin. Indeed, evidence from laboratory-based studies of healthy adults suggests that 
melatonin must be administered at the correct time in the phase response curve relative to 
the individual’s circadian phase to achieve a shift in circadian timing (Burgess et al. 2008, 
Burgess et al. 2010). One previous study has demonstrated the importance of the timing of 
melatonin administration in maximizing phase advances in adults with DSWPD, with a 
more robust phase advance observed for earlier administration times (Mundey et al. 2005). 
Nevertheless, to date, no study has evaluated the clinical superiority of timing the 
administration of melatonin to an individual’s circadian time vs. clock time using a 
randomized design. 
 
Dim light melatonin onset can be readily measured in the field    
The time of melatonin onset in dim light (or dim light melatonin onset; DLMO) is the gold 
standard circadian marker (Lewy et al. 1989) and most reliable circadian phase marker in 
humans (Klerman et al. 2002). Dim light melatonin onset can be obtained via blood, urine, 
or saliva; advantages of saliva relative to other methods include practicality and reliability 
(Benloucif et al. 2008). Historically, research utilizing DLMO has been conducted in 
laboratory settings, which limits clinical utility. However, our group has pioneered the 
development of, and established the validity for, a kit for home-based saliva sampling to 
measure DLMO in the field. Dr. Burgess (Co-I) has developed a novel in-home DLMO kit, 
which she has validated against laboratory DLMOs, with a very high correlation between 
the in-home and in-laboratory DLMOs (r = 0.91, p < 0.001), and excellent compliance, as 
92% of the in-home samples were valid (Burgess et al. 2015). Crucially, Dr. Burgess has 
also validated the kit in adults with DSWPD, with high correlations (r = 0.93, p < 0.001) 
relative to in-laboratory DLMOs and high compliance, as 83% of the in-home samples were 
valid (Burgess et al. 2016). In conjunction with Dr. Burgess, Dr. Swanson (PI) has used the 
in-home DLMO kit with postpartum women with depression, with excellent compliance 
(98% of the DLMOs were valid; (Swanson et al. 2017)).  
 
Objective of the proposed study 
The objective of the proposed study is to evaluate the clinical utility of obtaining field-based 
DLMO in the treatment of DSWPD using a randomized controlled study design. Our central 
hypothesis is that timing exogenous melatonin administration using measured DLMO will 
result in a more robust treatment response after 4 weeks of therapy relative to timing 
exogenous melatonin administration using an estimation of DLMO. The rationale for the 
proposed project lies in the critical need to understand whether use of objective circadian 
markers, particularly field-based markers, enhances treatment outcomes in DSWPD to 
reduce the burden of this circadian rhythm sleep disorder. This proposal leverages our 
unique expertise with field-based, validated in-home assessment of DLMO and clinical 
treatment of DSWPD. We plan to test our central hypothesis with a double-blind 
randomized trial of measured DLMO (M-DLMO, n = 25) vs. estimated DLMO (E-DLMO, 
n = 25) for timing exogenous melatonin administration in adults with DSWPD.  


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1.3 
Hypothesis 
Specific Aims  
Aim 1: Compare pre- to post-treatment changes in DLMO in M-DLMO vs. E-DLMO 
conditions.  
 
Hypothesis 1: Participants in the M-DLMO condition will show greater improvements in 
DLMO (i.e., greater advance of DLMO) relative to participants in the E-DLMO condition 
after 4 weeks of exogenous melatonin. 
 
Aim 2: Compare pre- to post-treatment changes in objective and subjective sleep parameters 
and daytime symptoms in M-DLMO vs. E-DLMO conditions.  
 
Hypothesis 2: Participants in the M-DLMO condition will show greater improvements in 
objective (per wrist actigraphy) and subjective (per daily sleep-wake diary) sleep parameters 
(specifically, total sleep time, initial sleep latency, sleep onset time, sleep offset time) after 4 
weeks of exogenous melatonin. They will also show greater improvements in daytime 
symptoms.   
1.4 
Previous Human Experience 
Melatonin is designated as a dietary supplement by the FDA. A recent, randomized, double-
blind clinical trial to assess the toxicology of chronic melatonin tested 10 mg of oral 
melatonin administered daily for 28 days (n = 30) versus placebo (n = 10) in healthy adults 
(Seabra et al. 2000). Measurements included the following laboratory tests: complete blood 
count, urinalysis, sodium, potassium and calcium levels, total protein levels, albumin, blood 
glucose, triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density 
lipoprotein (LDL), and very low-density lipoprotein (VLDL), urea, creatinine, uric acid, 
glutamic-oxalacetic transaminase phosphate, gama-glutamic transaminase, T3, T4, TSH, 
LH/FSH, cortisol, and melatonin serum concentrations. Additional measurements included 
the Epworth Sleepiness Scale, and participants were also asked about side effects. No 
toxicological changes were noted in participants in the melatonin group. There were no 
differences between melatonin and placebo on any of the laboratory tests or Epworth 
Sleepiness Scale. There were no differences between melatonin and placebo in side effects. 
The most common side effects reported in the melatonin group included somnolence and 
headache.     
 
Other studies in healthy adults have investigated psychomotor performance and melatonin. 
One of the studies examined the effects of 5 mg of oral melatonin vs. placebo on driving 
performance using a randomized, placebo-controlled, double-blind, crossover design in 20 
healthy adults (Suhner et al. 1998). Measures included a medical examination, subjective 
sleepiness, body sway measurement, and a standardized driving computer battery (which 
tested attention, reaction time, power of concentration, and sensomotor coordination). All 
measures were administered 60 minutes after the melatonin was ingested. No differences 
were observed between melatonin and placebo on any of the driving performance measures, 
although subjective sleepiness was greater in the melatonin group vs. placebo. A second 
study evaluated the psychomotor effects of time-release oral melatonin 6 mg in 23 healthy 
adults; measures included serial reaction time, logicial reasoning, serial subtraction, and 


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multitask (Paul et al. 2003). Participants completed testing 7 hours after ingestion of 
melatonin. Melatonin did not impair performance on any task.    
 
Melatonin has also been investigated in human clinical populations. A recent randomized, 
double-blind, placebo-controlled study of oral melatonin 6 mg vs placebo, taken daily for 3 
months, on depression symptoms in adult females who were undergoing surgery for breast 
cancer found that melatonin reduced depressive symptoms, and there were no differences on 
side effects between the groups (Hansen et al. 2014). In a randomized, double-blind, 
placebo-controlled trial of 12 weeks of oral melatonin 3 mg (60 participants) vs. placebo (59 
participants) and amitriptyline 25 mgs (59 participants) for the prevention of migraine 
headaches in adults, participants in the melatonin group reported a similar rate of side 
effects/adverse events to placebo, with the most common side effect of sleepiness; further, 
melatonin was equal, or superior to, amitriptyline on the migraine endpoints (Goncalves et 
al. 2016). In a trial of 1 or 3 mg of oral melatonin vs. placebo nightly for 12 months in 81 
postmenopausal women with osteopenia, melatonin was not different from placebo with 
respect to side effects/adverse events; further, no hangover effect affecting balance- and 
muscle function was found following the intake of melatonin (Amstrup et al. 2015). 
 
Melatonin has also been studied in adult humans as a treatment of delayed sleep-wake phase 
disorder (the indication for the present study). One of the earliest randomized controlled, 
trials was a crossover study conducted in 8 adults with delayed sleep wake phase syndrome, 
which evaluated oral melatonin 5 mgs vs placebo nightly for 4 weeks. Results indicated that 
melatonin was produced at a significantly earlier sleep onset time and wake time relative to 
placebo, with no next-day hangover effects (Dahlitz et al. 1991). Later randomized, 
controlled trials in adults with delayed sleep-wake phase syndrome have demonstrated the 
efficacy of melatonin for this disorder, including: 20 participants randomized to 4 weeks of 
nightly oral melatonin 5 mg or placebo, which found that melatonin produced improvements 
in sleep onset latency, with no difference from placebo in sleepiness, fatigue, and alertness 
(Kayumov et al. 2001); 30 participants in a crossover trial studying 2 weeks of nightly 5 mg 
oral melatonin vs. placebo, showing that melatonin produced significant advancement of the 
endogenous melatonin profile, advance of sleep onset, and shortened sleep latency 
(Nagtegaal et al. 1998); in 20 participants in a crossover trial of 4 weeks of nightly oral 
melatonin (5 mg) or placebo, melatonin improved sleep continuity and depression symptoms 
(Rahman et al. 2010); and for 13 participants who were randomized to 4 weeks of nightly 
oral melatonin (0.3 or 3 mg) or placebo, melatonin (regardless of dose) advanced the 
circadian phase of exogenous melatonin and sleep onset (Mundey et al. 2005). The dose of 
melatonin (0.5 mgs) was selected based on work by Burgess (Co-I; (Burgess et al. 2010)) 
and others (Mundey et al. 2005), which has shown similar phase shifting effects between 
smaller (0.3-0.5 mgs) and larger (3.0 mg) doses. As earlier administration produces maximal 
phase shifts, we propose to use the lowest effective dose to minimize possible soporific 
effects of taking melatonin during waking hours.     
 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The objective of the proposed study is to evaluate the clinical utility of obtaining field-based 
DLMO in the treatment of DSWPD using a randomized controlled study design. Our central 


Leslie Swanson  
UM HUM 00145052  
PROTOCOL VERSION # 6.0   
 
Page 10 of 29 
 
hypothesis is that timing exogenous melatonin administration using measured DLMO will 
result in a more robust treatment response after 4 weeks of therapy relative to timing 
exogenous melatonin administration using an estimation of DLMO. The rationale for the 
proposed project lies in the critical need to understand whether use of objective circadian 
markers, particularly field-based markers, enhances treatment outcomes in DSWPD to 
reduce the burden of this circadian rhythm sleep disorder. This proposal leverages our 
unique expertise with field-based, validated in-home assessment of DLMO and clinical 
treatment of DSWPD. We plan to test our central hypothesis with a double-blind 
randomized trial of measured DLMO (M-DLMO, n = 25) vs. estimated DLMO (E-DLMO, 
n = 25) for timing exogenous melatonin administration in adults with DSWPD.  
 
2.2 
Endpoints 
Endpoints were selected to include those identified as “critical” and “important” by the 
AASM Clinical Practice Guideline (Auger et al. 2015). 
 
2.2.1 
Primary Endpoint  
The primary endpoint is change in time of DLMO from pre- to post-treatment. 
 
2.2.2 
Secondary Endpoint 
Secondary endpoints include:  
• Change in sleep parameters per wrist actigraphy and sleep diary (specifically, total 
sleep time, initial sleep latency, sleep onset time, sleep offset time) from pre- to post-
treatment.  
•  Change in daytime symptoms and functioning (as assessed by the Epworth 
Sleepiness Scale, Multidimensional Fatigue Inventory-20, Sheehan Disability Scale, 
Patient Health Questionnaire-9, Generalized Anxiety Disorder-7) from pre- to post-
treatment.   
• Change in self-report sleep quality and symptoms (as assessed by the Pittsburgh 
Sleep Quality Index, Morningness Eveningness Questionnaire, PROMIS-Sleep 
Disturbance scale, PROMIS-Sleep Related Impairment scale). 
 
3 
STUDY DESIGN  
Overview of research design 
This study is a randomized, controlled, parallel double-blind 4-week trial of 0.5 mg of 
exogenous melatonin (Emens et al. 2015) timed to either 3 h before actual DLMO based on 
in-home measurement (M-DLMO, n = 25) or 3 h before DLMO estimated at 2 h before 
average sleep onset time based on actigraphy and sleep diary (E-DLMO, n = 25). Note that 
the intervention tested is the method used to time melatonin administration--not melatonin 
per se, as all participants will receive the same dose of melatonin for the duration of the 
study.   
 
4 
SUBJECT SELECTION 
4.1 
Subject Recruitment 
Fifty participants will be recruited over 2 years. Recruitment will occur within the greater 
Ann Arbor community, the Michigan Medicine Behavioral Sleep Medicine (BSM) clinics, 


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affiliated with the Michigan Medicine Sleep Disorders Center, where Drs. Swanson (PI), 
Arnedt (Co-I), and Conroy (Co-I) provide direct clinical care, and the University of 
Michigan’s University Health Service (UHS) Collegiate Sleep Disorders Clinic (CSDC), 
directed by Dr. Hershner (Co-I). The UHS provides health care to all students enrolled at 
University of Michigan (> 40,000 students). Between the CSDC and BSM Clinics, an 
average of 63 new patients are seen per month, 8 of whom are diagnosed with DSWPD. 
Thus, we anticipate a pool of at least 95 patients annually from which we will recruit to meet 
our enrollment target of 25 participants per year.  
4.1.1 
Inclusion Criteria 
1. 18-65 years of age 
2. ICSD-3 diagnosis of DSWPD: (1) have evidence of a delayed phase of the sleep-wake 
pattern on daily sleep diaries and actigraphy maintained for at least 7 days (e.g., a ≥ 2 h 
delay in the timing of habitual sleep episode between work/school and free days); (2) 
report difficulty falling asleep and difficulty awakening at desired/required times for ≥ 3 
months.   
3. Female participants of childbearing potential (i.e., they are not permanently sterilized 
(hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or postmenopausal 
(12 months with no menses without an alternative medical cause) by report) must agree 
to use a reliable method of contraception from the screening visit until 4 weeks after the 
study has completed. Acceptable methods of birth control during participation in the 
study include: oral contraceptives, patch contraceptives, injection contraceptives, male 
condom with spermicide, diaphragm or cervical cap with spermicide, vaginal 
contraceptive ring, intrauterine device, surgical sterilization (bilateral tubal ligation), 
vasectomized partner(s), or total sexual abstinence.  
4.1.2 
Exclusion Criteria 
1. Hypersensitivity to melatonin or any other component of the product   
2. Suspicion of a sleep disorder other than DSWPD per interview (Edinger et al. 2004) and 
medical record review (when available) 
3. Presence of chronic psychiatric conditions which may directly influence sleep per 
interview and medical record review (when available), including:  
• current illicit drug use, 
• current alcohol or drug abuse, 
• bipolar disorder, 
• psychotic disorder. 
4. Presence of unstable chronic medical condition which may directly influence sleep (e.g., 
chronic pain, thyroid conditions) 
5. Current or past history of medical conditions which may affected by melatonin per self-
report and medical record review (when available), such as  
• Hypertension or hypotension  
• diabetes,  
• clotting/bleeding disorders,  
• epilepsy/seizures,  
• autoimmune disorders,  
• conditions requiring immunosuppressive management such as transplant.  


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6. Per self-report or medical record review (when available), current use of medications 
which may have interactions with melatonin:  
• nifedipine,  
• anti-hypertensive medications (including, but not limited to, chlortalidone, 
chlorothiazide, hydrochlorothiazide, indapamide, metolazone, Lisinopril, 
Benazepril, captopril, candesartan, losartan, amlodipine, diltiazem);  
• immunosuppressants (including, but not limited to, prednisone,  budenoside, 
prednisolone, cyclosporine, tacrolimus, sirolimus, everolimus, azathioprine, 
leflunomide, mycophenolate);  
• sedative or hypnotic medications (including, but not limited to, zolpidem, 
suvorexant, butabarbital, quazepam, estazolam, flurazepam, triazolam, 
eszopiclone, temazepam, secobarbital, doxepin, zaleplon);  
• antidiabetes drugs (including, but not limited to, insulin, metformin, glyburide, 
glipizide, glimepiride, repaglinide, nateglinide, rosiglitazone, pioglitazone, 
canagliflozin, dapagliflozin, liraglutide);  
• anticoagulant/antiplatelet (including, but not limited to, heparin, warfarin, 
rivaroxaban, dabigatran, apixaban, edoxaban, enoxaparin, fondaparinux, 
clopidogrel, ticagrelor, prasugrel, dipyridamole, dipyridamole/aspirin, 
ticlodipine, eptfibatide.)  
• CYP4501A2 strong or moderate inhibitors or inducers (including, but not limited 
to, floroquinolones such as ciprofloxacin, fluvoxamine, verapamil, St. John’s 
wort, modafinil, nafcillin, omeprazole) 
7. Pregnancy (as determined by urinary pregnancy test at screening for women of child-
bearing potential) or self-report of breastfeeding 
8. Self-report of routine night shift work 
9. Self-report of past month travel or planned travel during the study across more than one 
time zone 
10. Self-report of use of melatonin in the past month 
11. Current use of medications that may interfere with the measurement of melatonin 
(NSAIDs if used daily, and beta-blockers, (Benloucif et al. 2008)) per self-report and 
medical record review (when available) 
 
5 
STUDY TREATMENTS 
5.1 
Allocation to Treatment 
Eligible participants will be randomized using the minimization method (Pocock et 
al. 1975) in a 1:1 ratio to M-DLMO or E-DLMO. Assignment to condition will be balanced 
by age and baseline sleep onset time on free days. For allocation of participants, a computer 
program (the Treatment Assignment System, created by UM’s Consulting for Statistics, 
Computing, and Analytics Research) will be used by the study coordinator to generate the 
group assignment at enrollment for each participant.  
Participants will be blinded to the specific study hypotheses and to their group 
assignment. The study clinician will be blinded to group assignment. The study coordinator, 
who communicates the time of melatonin administration to the study clinician, will not be 
blinded to the actual DLMO of participants in the M-DLMO condition; however, they will 
be blinded to the actual DLMO of participants in the E-DLMO condition until their 
participation is complete.   


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Due to individual variation in melatonin levels or errors in the saliva collection 
process, it is possible that DLMO will not be able to be determined for a small proportion of 
participants. To retain these participants in the protocol, if they are randomly assigned to the 
M-DLMO condition, the study coordinator may change their assignment to the E-DLMO 
condition. Data for these participants will be examined post-hoc upon completion of the 
study using sensitivity analyses before determining whether to retain or discard their data 
from analyses.   
 
5.2 
Breaking the Blind 
The randomization can be broken, if necessary per the physicians caring for the subject to 
ensure subject safety.   
 
5.3 
Drug Supplies 
5.3.1 
Formulation, Preparation and Dispensing 
Melatonin 0.5 mgs in a fast dissolve tablet manufactured by Natrol®, LLC (21411 Prairie 
St. Chatsworth, CA 91311) will be dispensed by study staff to participants. The 
manufacturer is providing the melatonin for this study free of charge. They will be provided 
with a 14-day supply at the start of the study and at the first follow-up treatment visit (week 
1).   
5.3.2 
Drug Storage and Drug Accountability 
Melatonin will be stored in the Sleep and Circadian Research Laboratory in a locked 
cabinet, to which only study staff will have access. Melatonin will be provided by study staff 
to participants in bottles equipped with a TrackCap to monitor the date and time at which the 
bottle was opened. Reconciliation of medication will be tracked at each study visit by pill 
count completed by study staff and by download of the TrackCap data at each study visit.  
 
5.4 
Concomitant medications 
Medications that may interact with melatonin will not be allowed during the study (list of 
possible interactions obtained from the Food, Herbs, and Supplements Database available at 
https://naturalmedicines.therapeuticresearch.com). Participants enrolled in the study will not 
be allowed to take alcohol, nifedipine, anti-hypertensive medications (including, but not 
limited to, chlortalidone, chlorothiazide, hydrochlorothiazide, indapamide, metolazone, 
lisinopril, benazepril, captopril, candesartan, losartan, amlodipine, diltiazem); 
immunosuppressants (including, but not limited to, prednisone,  budenoside, prednisolone, 
cyclosporine, tacrolimus, sirolimus, everolimus, azathioprine, leflunomide, mycophenolate); 
sedative or hypnotic medications (including, but not limited to, zolpidem, suvorexant, 
butabarbital, quazepam, estazolam, flurazepam, triazolam, eszopiclone, temazepam, 
secobarbital, doxepin, zaleplon); antidiabetes drugs (including, but not limited to, 
metformin, glyburide, glipizide, glimepiride, repaglinide, nateglinide, rosiglitazone, 
pioglitazone, canagliflozin, dapagliflozin, liraglutide); anticoagulant/antiplatelet (including, 
but not limited to, heparin, warfarin, rivaroxaban, dabigatran, apixaban, edoxaban, 
enoxaparin, fondaparinux, clopidogrel, ticagrelor,    prasugrel, dipyridamole, 
dipyridamole/aspirin, ticlodipine, eptfibatide); CYP4501A2 strong or moderate inhibitors or 
inducers (including, but not limited to, floroquinolones such as ciprofloxacin, fluvoxamine, 


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verapamil, St. John’s wort, modafinil, nafcillin, omeprazole). If they require one of the 
medications on this list, they will be discontinued from the study.  
6 
STUDY PROCEDURES 
6.1 
Screening Visit  
Potential participants will be screened for initial eligibility using an in-person diagnostic 
interview, including the Mini-International Neuropsychiatric Interview (M.I.N.I) and a sleep 
interview. In order to maintain the integrity of the data, participants screening visits will not 
be scheduled around the start or end of daylight savings time.  
 
During second level screening, participants will complete health history and demographic 
forms (including current and past medical history, and current medications) and female 
participants of childbearing potential will complete a urine pregnancy test. Participants who 
meet eligibility criteria following completion of the forms and pregnancy screen will 
maintain self-selected sleep-wake schedules at home for approximately 7-14 days with daily 
sleep-wake diaries and actigraphy monitoring to evaluate study criteria for DSWPD and 
determine full eligibility.  
 
Participants who are eligible for the study following full screening will complete baseline 
study questionnaires and complete an orientation to the in-home DLMO collection protocol. 
Participants who do not meet eligibility criteria will be provided referrals for clinical care 
through the CSDC or BSM clinics.  
 
6.2 
Treatment Study Period 
Visit 1 (Day 1)  
Participants will have their first session with the study clinician at Visit 1. Prior to the 
session, study staff will meet with the participant to download their actigraphy. Study 
staff will provide the study clinician with the initial clock time at which each participant 
should take melatonin. The initial clock time of melatonin administration for participants 
assigned to the M-DLMO condition will be set at 3 h before their measured baseline DLMO. 
The initial clock time of melatonin administration for participants assigned to the E-DLMO 
condition will be set at 5 h before their average time of sleep onset at baseline per most 
recent 7 days of actigraphy. Participants be provided with a 14-day supply of melatonin 0.5 
mgs, which they will begin taking that evening.  
 
During the first visit, study staff will query whether participants have had any changes in 
their medications or medical history since the screening, and review concomitant 
medications.  Participants’ baseline sleep diary and actigraphy data will be reviewed by the 
study clinician. The study clinician will provide them with specific instructions regarding 
when to take melatonin, their bed time, their wake time, and when to dim ambient lighting 
and electronic devices to their lowest usable level (timed to be approximately 60 minutes 
before their scheduled bedtime). They will be provided with a handout summarizing this 
information.  
6.2.1 
Follow-up (Weeks 1-4) 
Participants will continue to take melatonin 0.5 mg at the scheduled time daily for the 4 
weeks of the study. At approximately Week 1, they will be provided with an additional 14-


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day supply of melatonin. Each follow-up session (approximately Weeks 1-4) will follow an 
identical protocol:  
1. Study staff will meet with the participant to query the following: review previously 
reported medications and current use of previously reported medications; any new 
medications; any side effects from the melatonin; any unexpected medical conditions 
since their last visit; any new medical diagnoses or changes in medical history since their 
last visit. They will also meet with the participant to download their actigraphy, 
TrackCap data, and complete a pill count. Compliance with melatonin administration 
timing per TrackCap, the pill count, changes in medical history or medications, and side 
effect information, will be provided to the study clinician. Only melatonin administration 
deviations ≥ 30 minutes will be considered non-compliant and be reported as protocol 
deviations.  
2. During the follow-up treatment session, the study clinician will review side 
effects/adverse events, compliance with bed and wake times, adherence to melatonin 
administration time, and address any barriers to compliance. Participants will be 
instructed to advance the time of melatonin administration by 1 h and their bed-wake 
schedule by 1 h (without altering their total time in bed from their baseline average) at 
each weekly treatment session until they reach their desired bed-wake schedule. The 
study clinician may also choose to adjust the melatonin administration time or time in 
bed schedule using their discretion and clinical judgement as needed.  At each follow-up 
session, participants will be provided with a handout summarizing the main components 
of the session.  
7 
ASSESSMENTS  
Table 1. Protocol Activity by Visit  
Protocol Activity 
Screen/ 
Baseline 
Visit 1 
Follow-up 
1 
Follow-
up 2 
Follow-up 
3 
Follow-up 4 
(Final) 
  
 
Day 1  
Day 7 ± 5 
business 
days  
Day 14 ± 
5 
business 
days  
Day 21 ± 5 
business 
days   
Day 28 ± 5 
business days  
Week (approximate) 
0 
1 
2 
3 
4 
5 
Visit #  
0 
1 
2 
3 
4 
5 
Informed Consent  
X 
  
  
  
  
  
Interview and Medical History  
X 
  
 
 
 
 
Pregnancy Test (females of 
childbearing potential) 
X 
  
  
  
  
  
Randomization 
X 
  
  
  
  
  
DLMO 
X 
 
 
 
 
X 
Daily sleep diary 
X 
X 
X 
X 
X 
X 
Wrist actigraphy 
X 
X 
X 
X 
X 
X 


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7.1 
Primary Endpoint Assessments 
Protocol activity and assessments are summarized in Table 1 above.  
Primary endpoint: change in the time of DLMO from pre- to post-treatment.  
 
To assess time of DLMO, all eligible participants (regardless of group assignment) will 
undergo in-home salivary DLMO collection at pre- and post-treatment, using the protocol 
established by Dr. Burgess (Co-I) (Burgess et al. 2015). Participants will be oriented to the 
collection procedures during their clinic visit. Participants will be in dim light starting 30 
minutes prior to the first sample collection. Collection begins 6 hours prior to participants’ 
habitual sleep onset per their most recent week of actigraphy at baseline. At post-treatment, 
collection begins 6 hours prior to participants’ bed time as assigned at the final treatment 
session. Samples are collected via Salivette every 30 minutes until bedtime (13 samples 
total). They are provided with a kit, which includes: a checklist of procedures; a test tube 
rack; a toothbrush; a nightlight; blue-blocking Uvex glasses (with an Actiwatch attached to 
monitor compliance of use); an iPod programmed to alarm at collection times; a light 
medallion (an Actiwatch with light sensor worn around the neck to monitor compliance with 
light exposure); Salivette collection vials equipped with Track Cap, which will record when 
the vial was opened; and a label dispenser with pre-labeled labels. Participants wear the 
blue-blocking glasses throughout the dim light saliva collection and are required to remain 
seated in the 10 minutes before each sample. When the iPod alarms, participants brush their 
teeth without toothpaste, collect saliva by chewing on the Salivette, and deposit it in the vial. 
Participants are informed about the compliance measures utilized in the study. Samples will 
be stored in participants’ freezers until they can be transported to our facility. Samples are 
centrifuged for two minutes, frozen, and assayed using Bühlmann Laboratory 
radioimmunoassay (ALPCO Diagnostics, Salem, NH) at Solidphase Inc. To ensure 
consistency and to minimize the effects of sleep schedule changes on the weekends/days off 
of work, whenever possible, all participants will complete DLMO collection on the third 
night of their typical workday sleep schedule (e.g., DLMO collection will occur on a 
Wednesday, Thursday, or Friday night for participants who work a traditional Monday-
Friday schedule).    
7.2 
Secondary Assessments  
Secondary Assessments: 1. Change from pre- to post-treatment in sleep parameters (total 
sleep time, initial sleep latency, sleep onset time, sleep offset time) measured using wrist 
actigraphy and daily sleep diaries; 2. Change in daytime symptoms and functioning 
(Epworth Sleepiness Scale, Multidimensional Fatigue Inventory-20, Sheehan Disability 
Scale, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7,) from pre- to post-
Melatonin Treatment 
 
X 
X 
X 
X 
X 
Adverse Event  Assessment  
 
 
X 
X 
X 
X 
Concomitant Medication Assessment 
X 
X 
X 
X 
X 
X 
Daytime functioning and sleep self-
report measures 
X 
 
 
 
 
X 


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treatment, 3. Change in self-report sleep quality and symptoms (as assessed by the 
Pittsburgh Sleep Quality Index, , Morningness Eveningness Questionnaire, PROMIS-Sleep 
Disturbance scale, PROMIS-Sleep Related Impairment scale). 
Wrist Actigraphy Assessments: The Actiwatch Spectrum Plus will be worn by participants 
daily throughout the protocol for wrist actigraphy monitoring to approximate objective 
sleep/wake patterns. The Actiwatch Spectrum Plus is a kinesiology ambulatory recorder 
manufactured by Philips Respironics (Bend, Oregon), and is exempt from FDA 
premarket submission. Actigraphy data will be scored using Actiware®-Sleep software 
following standard scoring procedures (Patel et al. 2015).   
Sleep Diary Assessments: Participants will maintain daily self-report sleep-wake diaries 
daily throughout the treatment protocol.  
Daytime Symptoms Assessments: Participants will complete the self-report questionnaires 
(Epworth Sleepiness Scale, Multidimensional Fatigue Inventory-20, Sheehan Disability 
Scale, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7,) to assess 
daytime symptoms.  
Sleep Quality and Symptoms:  Participants will complete the self-report questionnaires (the 
Pittsburgh Sleep Quality Index, Morningness Eveningness Questionnaire, PROMIS-
Sleep Disturbance scale, PROMIS-Sleep Related Impairment scale) to assess sleep 
quality and symptoms. 
 
Exploratory Assessment: Conners Adult ADHD Rating Scale-Short Form (Change from 
pre- to post-treatment) 
8 
ADVERSE EVENT REPORTING 
 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a subject participating in an 
investigational study or protocol regardless of causality assessment.  An adverse event can be an 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
syndrome or disease associated with or occurring during the use of an investigational product 
whether or not considered related to the investigational product. 
 
These events may be: 
 
a. Definitely related: clearly associated with study drug/treatment 
b. Probably related:  likely associated with study drug/treatment 
c. Possibly related:  may be associated with study drug or other treatment 
d. Unlikely to be related, or 
e. Definitely not related to the study drug/treatment 
 
For reporting purposes, an AE should be regarded as definitely or probably related to the 
regimen if the investigator believes that at least one of following criteria are met: 
 
a. There is a clinically plausible time sequence between onset of the AE and the administration 
of the study drug or treatment. 


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b. There is a biologically plausible mechanism for the study drug or treatment causing or 
contributing to the AE. 
c. The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or 
procedures.  
d. A potential alternative cause does not exist. 
 
Serious Adverse Events (SAE):  An adverse drug experience occurring at any dose that results 
in any of the following outcomes: 
 
a. 
Death 
b. 
A life-threatening adverse drug experience 
c. 
Inpatient hospitalization or prolongation of existing hospitalization 
d. 
A persistent or significant disability &/or incapacity 
e. 
A congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. A 
serious adverse experience includes any experience that is fatal or immediately life threatening, 
results in a persistent or significant disability/incapacity, requires or prolongs in-patient 
hospitalization, or is a congenital anomaly, cancer, or overdose. 
Other important medical events that may not result in death, not be life-threatening, or not 
require hospitalization may be considered a serious adverse experience when, based upon 
appropriate medical judgment, the event may jeopardize the subject/patient and may require 
medical or surgical intervention to prevent one of the outcomes listed previously. 
 
Expected adverse events are those adverse events that are listed in the protocol and the study 
informed consent document. 
 
Unexpected adverse events are those that are not anticipated in the study informed consent.  
This includes adverse events for which the specificity or severity is not consistent with the 
description in the informed consent. 
 
Unanticipated problem: Per FDA Procedural Guidance for Clinical Investigators, Sponsors, and 
IRBs (January 2009), A serious problem that has implications for the conduct of the study 
(requiring a significant and usually safety-related, change in the protocol such as revising 
inclusion/exclusion criteria or including a new monitoring requirement, informed consent or 
investigator’s brochure). 
 
Unanticipated problem Reporting: Per 21 CFR 312.66, 312.53 (c)(1)(vii), and 56.108(b)(1), 
should an Unanticipated problem occur during the investigation, the investigator will 
promptly report all unanticipated problems involving risks to human subjects or others to 
IRBMED /FDA. 
 
The severity or grade of an adverse event may be measured using the following definitions: 


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Mild:  Noticeable to the subject, but does not interfere with subject’s expected daily activities, 
usually does not require additional therapy or intervention, dose reduction, or discontinuation of 
the study. 
Moderate:  Interferes with the subject’s expected daily activities, may require some additional 
therapy or intervention but does not require discontinuation of the study. 
Severe: Extremely limits the subject’s daily activities and may require discontinuation of study 
therapy, and/or additional treatment or intervention to resolve. 
Event reporting:  Information regarding potential adverse events (AE) will be collected by 
participant report at each study assessment/follow-up. Dr. Swanson will ensure that all 
protocol deviations, AEs, and SAEs are reported to the IRB and FDA according to the 
applicable regulatory requirements. AEs will be reported according to the study-specific 
reporting timeline outlined below. Only related adverse events will be reported.  
 
Potential Risks of the Study:  
 
1 Risk: Breach of confidentiality 
Likelihood of risk: Rare 
Seriousness to the subject: Minimal 
2.  Risk: Saliva collection. There is a risk of choking on salivette chewing swab.  
Likelihood of risk: Rare 
Seriousness to the subject: Serious 
3. Risk: Actigraphy. Minimal risks exist with actigraphy. It is possible that participants 
may experience some discomfort from the band. 
Likelihood of risk: Infrequent 
Seriousness to the subject: Minimal  
4. Risk: Clinical interview and questionnaires.  Participants may feel psychological 
discomfort when being interviewed or completing questionnaires related to their 
insomnia, mood, or health.  
Likelihood of risk: Rare 
Seriousness to the subject: Minimal 
5. Risk: Melatonin side effects. The safety of melatonin has been well-documented in both 
animal and human studies, with no studies showing evidence of serious adverse events 
from melatonin. Possible side effects include drowsiness, headache, dizziness, or nausea.  
Likelihood of risk: Infrequent 
Seriousness: Minimal  
 
Potential Benefits: 
Potential benefits of the proposed research to the participants include an active treatment for 
DSWPD, thus many can expect to experience improvement in their sleep and related 
functioning during the day. The study could potentially identify a more effective treatment 
for DSWPD than the current standard of care. Additionally, we will have other treatment 
referral services in place in the event that we identify other potential sleep disorders, such 
insomnia. Thus, the risks associated with participating are reasonable in light of the potential 
benefits to the participants and others.  


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Protection against Study Risks 
Informed Consent Process. All subjects will provide written informed consent prior to 
beginning participation in the study. The consent process will inform potential subjects 
about the study, indicates that their participation is voluntary, and they have the right to stop 
participation at any time. Risks are enumerated in the informed consent form and described 
orally during the consent process.  
 
Protection Against Risks.    
Melatonin side effects:  To minimize side effects from melatonin, a very small dose 
of melatonin (0.5 mgs) is utilized in the study, and for a short period of time (28 days). 
Further, individuals who take medications for which there are known interactions with 
melatonin, or who have medical conditions for which melatonin is contraindicated, will be 
excluded from participation in the study. Participants will be provided with written and 
verbal instructions to avoid driving or operating heavy machinery until they know how the 
melatonin will affect their alertness.   
 
Saliva sample collection: Participants will be shown how to use the saliva collection 
swab to minimize the risk of choking. 
 Actigraphy: Participants will be instructed on how to dry the band should it become 
wet to minimize discomfort.  
Violation of Confidentiality: To minimize the risk to confidentiality, we will ensure 
that data are protected and coded only by subject identification number. Further, only 
highly trained study team members will be interacting with participants or have access to 
study data. These protections are likely to be very effective in preventing loss of 
confidentiality. 
Psychological discomfort: To minimize this risk, all interviews and questionnaire 
completion will be completed by skilled research staff in private offices. Participants 
will also be informed that they do not have to answer every question to participate in the 
study.  
Although we do not anticipate screening or enrolling participants who are at risk for suicide, 
should the participant report suicidal ideation (on interview, the Patient Health 
Questionnaire-9, or in clinical interaction or any other study interaction), participants will be 
further screened for suicide risk using the Columbia Suicide Severity Rating Scale (C-
SSRS). Note that the majority of cases in our current and previous research studies are 
generally determined to be minimal risk- no immediate threat to self or others, no plan in 
place, no means to carry out threat, etc. For minimal risk cases (positive answers to 
questions 1 or 2 on C-SSRS suicidal ideation scale with negative answers to questions 3-5), 
staff will express concern to the participant and provide resources (including a pamphlet 
from the National Suicide Prevention Lifeline, the phone number for Michigan Medicine 
Psychiatric Emergency Services), and referral information for treatment depending on the 
situation. For moderate risk (positive answers to question 3 on C-SSRS with negative 
answers to questions 4 and 5) or high/imminent risk (positive answers to questions 4 or 5 on 
C-SSRS) cases, Dr. Swanson (PI) will be immediately paged for consultation; Drs. Arnedt 
and Conroy (Co-Is) may also be paged if Dr. Swanson is unavailable/as necessary. For 


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moderate and high/imminent risk cases, staff will first discuss their concerns with the 
participant and ask their permission to arrange a liaison with study staff (i.e., as noted above, 
Drs. Swanson, Arnedt, or Conroy) for further assessment. If the participant refuses 
consultation, staff and the on-call supervisor determine safety plans and resources and notify 
medical staff and/or authorities in some cases. 
 
Table 2. Study-Specific AE Reporting Timeline  
 
 
 
Reportable Events 
 
Timing of Report to IRB and FDA 
Unanticipated problem involving risks to 
subjects or others related to this research 
study 
Serious: within 7 days 
Non-serious: with scheduled continuing 
review 
Any physical, social, or psychological harm 
attributable to participation in this research 
study (e.g., an injury occurring during a 
study visit, infection at the site of a blood 
draw if antibiotics are required) 
Serious: within 7 days 
Non-serious: with scheduled continuing 
review 
Death while on study regardless of 
relatedness 
Within 7 days 
Privacy violation or breach of 
confidentiality 
Within 7 days  
Protocol deviations not related to an adverse 
event 
With scheduled continuing review 
Unanticipated problem related to the 
research that is not a serious adverse event 
With scheduled continuing review 
Expected, minor side effects commonly 
associated with melatonin use: 
• Dizziness 
• Sleepiness 
• Headache 
• Nausea  
• Transient depression 
• Insomnia 
• Nightmares or vivid dreams 
• Diarrhea 
• Irritability 
 
With scheduled continuing review 
Other serious events not attributable to the 
research except death as noted above 
With scheduled continuing review 


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9. DATA ANALYSIS/STATISTICAL METHODS 
9.1 
Sample Size Determination 
We based our sample size estimation on the number of participants necessary to detect a 1 h 
change in DLMO; the sample size required to detect this change at 90% power with an alpha 
of 0.05 is 23 per group. Thus, our proposed sample of 25 participants per group (50 total) 
should be adequate to detect a clinically meaningful change in DLMO.  
9.2 
Data Analysis 
Descriptive analyses will be completed by graphical and numerical summarization of key 
variables. Treatment groups will be compared on pre-treatment demographic and clinical 
variables using t-tests, chi-square tests, and Fisher’s exact tests as appropriate. Variables that 
emerge as potential confounders from this analysis will be controlled for in the final 
analyses. Weekly averages will be calculated for total sleep time, initial sleep latency, sleep 
onset time, and sleep offset time for each week of the study for both actigraphy and sleep 
diary.   
9.2.1 
Analysis of Primary Endpoint 
Change in DLMO from pre- to post-treatment will be calculated in minutes for each 
participant. A 2-tailed t-test will evaluate the difference between the change in DLMO 
between the two groups.  
9.2.2 
Analysis of Secondary Endpoints 
Linear mixed models using a repeated measures group X time (weeks of study) model will 
be used to determine between-group main effects and interactions with week of study for the 
following actigraphy and sleep diary variables: sleep onset time, initial sleep latency, total 
sleep time, sleep offset time, wake after sleep onset, and sleep efficiency. T-tests (2-tailed) 
will compare group differences in the change from pre- to post-treatment on the following: 
ESS score; SF-12 score; MFI-20 score.  
 
 
 


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10 MONITORING 
10.1 
Data and Safety Monitoring Plan 
At  each follow-up visit, study staff will query participants about each of the following: review 
previously reported medications and current use of previously reported medications; any new 
medications; any side effects from the melatonin; any unexpected medical conditions since 
their last visit; any new medical diagnoses or changes in medical history since their last visit.  
Side effects and adverse events will be reviewed with the participant by the study clinician at 
each follow-up visit. The PI will have oversight of the  medical history data, medications, and 
side effect data for each participant. Only changes to medications/medical history/side effects 
which occur after the first treatment session/treatment initiation will be recorded. Changes to 
medications/medical history/side effects deemed by the PI to be possibly, probably, and 
definitely related to melatonin use will be reported as adverse events.   
  
The PI will be primarily responsible for monitoring data integrity. Monitoring is intended to 
protect participants’ rights and safety, and to ensure the integrity and quality of the data 
collected. The PI will ensure that all relevant IRBMED and FDA policies, procedures, and 
stipulations are followed by the study team.  
10.2 
 Frequency of Data and Safety Monitoring  
Study staff will inform the PI of potentially related unexpected events as soon as they occur. 
The PI will be informed of related serious adverse events as soon as they occur and will 
notify the IRB and FDA within 7 days of notification.  
 
 


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11 DATA HANDLING AND RECORD KEEPING 
11.1 
CRFs / Electronic Data Record 
All data, including Case Report Forms, will be collected and maintained in REDCap.  
11.2 
Record Retention 
Per 21 CRF §312.62, study records will be retained for 2 years after the investigation is 
discontinued. 
 


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12 ETHICS 
12.1 
IRB/FDA 
Prior to study commencement, an Investigator Initiated Investigational New Drug (IND) 
will be submitted to the Food and Drug Administration (FDA), for review and approval. The 
study will also be reviewed and approved by the Institutional Review Board (IRBMED, 
University of Michigan, Ann Arbor, MI). 
This study will be carried out in compliance with the protocol and the principles of good 
clinical practice, as described below: 
12.2 
Institutional Review Board (IRB) 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to be provided to subjects, must be reviewed by a properly constituted 
Institutional Review Board (IRB). Any amendments to the protocol must be reviewed and 
approved by IRBMED. 
12.3 
Subject Information and Consent 
The study team member will explain to each subject (or legally authorized representative) 
the nature of the study, its purpose, the procedures involved, the expected duration, the 
potential risks and benefits involved and any discomfort it may entail.  Each subject will be 
informed that participation in the study is voluntary and that he/she may withdraw from the 
study at any time and that withdrawal of consent will not affect his/her subsequent medical 
treatment or relationship with the treating physician. 
This informed consent will be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing 
and dating it, and should be given a copy of the signed document. If the subject cannot read 
or sign the documents, oral presentation may be made or signature given by the subject’s 
legally appointed representative, if witnessed by a person not involved in the study, 
mentioning that the patient could not read or sign the documents. No patient can enter the 
study before his/her informed consent has been obtained. 
The informed consent form is considered to be part of the protocol, and will be submitted for 
IRB approval. 
12.4 
STUDY DISCONTINUATION CRITERIA 
12.4.1 
Stopping Rules for Safety reasons 
The trial will be stopped if any serious adverse events occur that could possibly be related to 
the intervention.  


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12.4.2 
Rules for Discontinuation of a Subject 
In the event a patient drops out of the study or is discontinued due to protocol violations, all 
attempts will be made to exit the patient in accordance with the protocol requirements. 
 


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13 REFERENCES 
 
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14 APPENDIX 
 
In order to maintain participant and study staff’s safety, the following protocol changes may 
be made during a viral outbreak or pandemic, per clinical judgement and in line with all 
institutional guidance/requirements with subjects:  
 
1. 
We will follow all institutional guidance/requirements regarding in person contact 
with subjects. 
2. 
When appropriate, participants will be provided with all materials necessary so 
that they may complete their study participation, including intervention sessions, 
remotely per sponsor allowance for Virtual Clinic Visits per clinician/subject 
discretion/institutional or government allowance to reduce or eliminate in-person 
contact with the study team. Specifically, we will provide the participant with 
enough supplies to complete post treatment in-home saliva collection and a 28-day 
supply of melatonin.  
3. 
We will continue to screen participants for initial eligibility; all screening will take 
place remotely and will not involve any in-person interactions with participants. 
Participants will complete e-consent through REDCap to provide their written 
consent prior to completion of remote screening.  
4. 
Further screening for participants who meet initial eligibility will be deferred until 
in-person interactions with participants may be resumed. Participants who passed 
the initial eligibility screen and completed e-consent will be re-consented in-
person at their, in-person second eligibility screen.   
5. 
Screening interviews and intervention sessions may take place via an online video 
system (i.e., BlueJeans, Zoom Health), or over the phone.