Clinical trial NCT03150797
Conditions: Migraine
Keywords: UCSF UCLA melatonin migraine headache
Sponsor: Amy Gelfand
Start date: 2017-08-02; Completion date: 2019-12-01
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This will be a randomized, multi-site double-blind placebo-controlled trial of melatonin (2 different dosing arms) vs. placebo for migraine prevention in adolescents. We intend to enroll approximately 210 participants over 15 months at two sites: UCLA and UCSF. The duration of participation for each participant will be 4 months.

Detailed description:
Participation includes 16 weeks of daily headache diary recording and taking the study pill every night, 1-2 hours before bed. Aside from the initial 1 hour enrollment visit, all remaining study procedures will be completed from home.

During the enrollment visit, history of migraine, questionnaires, a neurologic and physical exam (including weight, blood pressure, pulse, and respiratory rate) will be performed. Girls who have had their first period will undergo a urine pregnancy test and will be instructed to use birth control if they are sexually active.

For the first 8 week phase, participants will be instructed to take one study pill every night, 1-2 hours before bedtime and complete a daily headache diary from a smartphone. Phone call check-ins will occur at week 4 and week 8.

After the first 8 weeks of the study, participants who are eligible for the second phase of the study will be notified by study staff and will be sent the next set of study pills. Again, participants will be instructed to take the study pill every night, 1-2 hours before bedtime and complete a diary entry every evening.

Phone call check-ins will occur at week 12 and week 16. At the final 16 week phone call, additional questionnaires and study completion feedback will be collected.

Arms: arm 1: Melatonin 3mg arm 2: Melatonin 6mg arm 3: Placebo
Interventions: intervention 1: Melatonin intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Melatonin intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
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Amy Gelfand, MD 
Clinical Research Protocol 
MELATONIN FOR ADOLESCENT MIGRAINE PREVENTION STUDY 
THE MAP STUDY 
Protocol Number: 
MAP.1.0 
Version Date: 
March 21, 2017 
Investigational Product: 
Melatonin 
IND Number: 
124,226 
Development Phase: 
Phase II 
Sponsor: 
Amy Gelfand, MD 
1825 4th Street 
5th Floor, 5A 
San Francisco, CA 94158 
Funding Organization: 
Gelfand Salary Support from KL2 Grant  
Irene Perstein Award 
UCSF Weill Institute for the Neurosciences Award 
Principal Investigator: 
Name: Amy Gelfand, MD 
 
Telephone: 415-885-7832 
 
Fax: 415-353-2400 
 
 
E-mail: Amy.Gelfand@ucsf.edu 
 
 
Medical Monitor: 
Name:  
 
Telephone: 
 
Fax: 
 
 
E-mail: 
 
Coordinating Center: 
UCSF 
 
Approval: 
 
 
March 21, 2017 
PI or Sponsor Signature  
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   


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PROTOCOL AGREEMENT 
 
I have read the protocol specified below.  In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing required authorities with complete and timely information, as outlined in the 
protocol.  It is understood that all information pertaining to the study will be held strictly 
confidential and that this confidentiality requirement applies to all study staff at this site. 
Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures 
required to carry out the study in accordance with accepted GCP principles and to abide 
by the terms of this protocol. 
 
Protocol Number: MAP.1.0 
 
Protocol Title:  
Melatonin for Adolescent Migraine Prevention Study. The MAP Study 
 
Protocol Date: March 21, 2017 
 
 
March 21, 2017 
Investigator Signature  
 
Date 
Amy Gelfand, MD  Assistant Professor of Neurology and Pediatrics 
Print Name and Title 
 
Site # 
01 
 
Site Name 
University of California San Francisco 
Address 
Pediatric Headache Program 
 
1825 4th Street 
 
5th Floor, 5A 
 
San Francisco, CA 94158 
Phone Number 
415-885-7832 


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TABLE OF CONTENTS 
 
1 
BACKGROUND .................................................................................................................. 11 
1.1 
Overview of Non-Clinical Studies ............................................................................... 13 
1.2 
Overview of Clinical Studies ....................................................................................... 13 
2 
STUDY RATIONALE ........................................................................................................ 14 
2.1 
Risk / Benefit Assessment ........................................................................................... 15 
3 
STUDY OBJECTIVES ....................................................................................................... 15 
3.1 
Primary Objective ........................................................................................................ 15 
3.2 
Secondary Objectives .................................................................................................. 15 
4 
STUDY DESIGN ................................................................................................................. 165 
4.1 
Study Overview ........................................................................................................... 165 
5 
CRITERIA FOR EVALUATION ...................................................................................... 16 
5.1 
Primary Efficacy Endpoint .......................................................................................... 16 
5.2 
Secondary Efficacy Endpoints ..................................................................................... 16 
5.3 
Safety Evaluations ....................................................................................................... 176 
6 
SUBJECT SELECTION ..................................................................................................... 176 
6.1 
Study Population .......................................................................................................... 176 
6.2 
Inclusion Criteria ......................................................................................................... 176 
6.3 
Exclusion Criteria ........................................................................................................ 17 
7 
CONCURRENT MEDICATIONS .................................................................................... 187 
7.1 
Allowed ........................................................................................................................ 187 
7.2 
Prohibited ..................................................................................................................... 18 
8 
STUDY TREATMENTS ..................................................................................................... 18 
8.1 
Method of Assigning Subjects to Treatment Groups................................................... 18 
8.2 
Blinding ....................................................................................................................... 18 
8.3 
Test and Control Formulation ...................................................................................... 18 
8.4 
Supply of Study Medication at the Site ....................................................................... 18 
8.5 
Study Medication Accountability ................................................................................ 209 
8.6 
Measures of Treatment Compliance ............................................................................ 20 
9 
STUDY PROCEDURES AND GUIDELINES ................................................................. 20 
9.1 
Clinical Assessments ................................................................................................... 20 
9.2 
Clinical Laboratory Measurements .............................................................................. 21 
10 EVALUATIONS BY VISIT ............................................................................................... 21 
10.1 Visit 1 (Screening and Enrollment, Day 1).................................................................. 21 
10.2 8 Week Single Bind Placebo Treatment Phase (Weeks 1-8) .............................. 21 
10.3 Assessment of randomization eligibility (Day 57) ...................................................... 21 
10.4 8-week randomized treatment phase (Weeks 9-16) ..................................................... 21 
10.5 Study Completion (Day 113) ....................................................................................... 21 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ........................ 232 
11.1 Adverse Events ............................................................................................................ 232 


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11.2 Serious Adverse Experiences (SAE) ........................................................................... 244 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS ................................... 254 
12.1 Early Discontinuation of Study Drug ......................................................................... 254 
12.2 Withdrawal of Subjects ................................................................................................ 255 
12.3 Replacement of Subjects .............................................................................................. 25 
13 PROTOCOL VIOLATIONS .............................................................................................. 26 
14 STATISTICAL METHODS AND CONSIDERATIONS ................................................ 276 
14.1 Data Sets Analyzed ...................................................................................................... 276 
14.2 Demographic and Baseline Characteristics ................................................................. 276 
14.3 Analysis of Primary Endpoint...................................................................................... 27 
14.4 Analysis of Secondary Endpoints ................................................................................ 27 
14.5 Interim Analysis ........................................................................................................... 287 
14.6 Sample Size and Randomization ................................................................................. 287 
15 DATA COLLECTION, RETENTION AND MONITORING ........................................ 298 
15.1 Data Collection Instruments ........................................................................................ 298 
15.2 Data Management Procedures ..................................................................................... 298 
15.3 Data Quality Control and Reporting ............................................................................ 298 
15.4 Archival of Data........................................................................................................... 299 
15.5 Availability and Retention of Investigational Records ................................................ 309 
15.6 Monitoring ................................................................................................................... 309 
15.7 Subject Confidentiality ................................................................................................ 309 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ................... 309 
16.1 Protocol Amendments.................................................................................................. 30 
16.2 Institutional Review Boards and Independent Ethics Committees .............................. 30 
16.3 Informed Consent Form ............................................................................................... 31 
16.4 Publications .................................................................................................................. 321 
16.5 Investigator Responsibilities ........................................................................................ 321 
17 REFERENCES .................................................................................................................... 32 
 
APPENDIX 1.  Schedule of Study Visits ........................................................................33 
APPENDIX 2.  Nature’s Bounty Melatonin 3mg Label..................................................34 
APPENDIX 3.  Safeway Compounding Pharmacy .........................................................35 
APPENDIX 4.  Labdoor Safety Review ..........................................................................36 


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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
CFR 
Code of Federal Regulations 
CRF 
case report form 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
IRB 
PedMIDAS 
Institutional Review Board 
Pediatric Migraine Disability Assessment 
IRB 
Institutional Review Board 
PI 
Principal Investigator 
SAE 
SAP 
UCSF 
UCLA 
US 
Serious Adverse Experience 
Statistical Analysis Plan 
University of California, San Francisco 
University of California, Los Angeles 
United States 


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PROTOCOL SYNOPSIS 
TITLE 
Melatonin for Adolescent Migraine Prevention Study.  
The MAP Study 
SPONSOR 
Amy Gelfand, MD 
FUNDING 
ORGANIZATION 
1. Gelfand KL2 Grant Salary Support 
2. Irene Perstein Award  
3. UCSF Weill Institute for the Neurosciences Award 
NUMBER OF SITES 
      2 
RATIONALE 
Safe, effective, and well-tolerated treatments are needed to reduce the 
frequency of migraine attacks in children and adolescents.  Melatonin 
is a natural supplement that has an excellent safety profile and has 
been used to improve sleep in pediatrics.  Melatonin 3 mg orally 
nightly has also been shown in a randomized, placebo-controlled trial 
to be superior to placebo for migraine prevention in adults.  Given the 
excellent safety and tolerability of melatonin and its demonstrated 
efficacy for migraine prevention in adults, we propose to study 
melatonin for migraine prevention in adolescents.   
STUDY DESIGN 
This is a randomized, multi-site double-blind placebo-controlled trial 
of melatonin 3 mg vs. 6 mg vs. placebo orally nightly for migraine 
prevention in adolescents.   We will use a “remote trial” design, 
wherein after the initial in-person enrollment visit all study procedures 
will be done from the comfort of the participant’s own home.  We 
intend to enroll approximately 210 participants over 24-30 months at 
two sites: UCLA and UCSF.   
 
PRIMARY 
OBJECTIVE 
1. To compare the number of migraine/migrainous days in the 
5th-8th weeks of randomized treatment between melatonin 
(combined 6mg + 3mg) vs. placebo.  


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SECONDARY 
OBJECTIVES 
1. To compare the number of migraine/migrainous days in the 
5th-8th weeks of randomized treatment between melatonin 3 
mg vs. placebo.   
2. To compare the number of migraine/migrainous days in the 
5th-8th weeks of randomized treatment between melatonin 6 
mg vs. placebo.   
3. To compare the number of migraine/migrainous days in the 
5th-8th weeks of randomized treatment between melatonin 3 
mg vs. 6 mg.    
4. To compare the mean headache days in 5th-8th randomized 
phase in melatonin (combined) vs. placebo ,  (followed by 
melatonin 3 mg vs. placebo, melatonin 6 mg vs. placebo, and 
melatonin 3 mg vs. melatonin 6 mg using t-tests).    
5. To compare the mean acute medication use days in 5th-8th 
randomized phase in melatonin (combined) vs. placebo,  
(followed by melatonin 3 mg vs. placebo, melatonin 6 mg vs. 
placebo, and melatonin 3 mg vs. melatonin 6 mg using t-tests).   
6. To compare the mean PedMIDAS score (continuous) in 5th-
8th randomized phase in melatonin (combined) vs. placebo,  
(followed by melatonin 3 mg vs. placebo, melatonin 6 mg vs. 
placebo, and melatonin 3 mg vs. melatonin 6 mg using t-tests).   
7. To compare the number of ≥50% responder rate in 5th-8th 
randomized phase in melatonin (combined) vs. placebo 
(Chi-square or Fisher’s exact (if needed),  (followed by 
melatonin 3 mg vs. placebo, melatonin 6 mg vs. placebo, 
and melatonin 3 mg vs. melatonin 6 mg using Chi-square 
(or Fisher’s exact)). 
NUMBER OF 
SUBJECTS 
Approximately 210 subjects  
SUBJECT 
SELECTION 
CRITERIA 
1. Age 10-17—inclusive 
2. Weight ≥40 kg, so as not to require mg/kg based dosing 
3. Meets International Classification of Headache Disorders III 
beta1 
criteria 
for 
migraine 
in 
children/adolescents 
(international standard diagnostic criteria for research) 
4. Lives in the state of California- to allow shipping of study 
medication from our pharmacy 
5. Has at least one parent who speaks English—in order to 
ensure good communication with study team by phone 
6. Has daily access to a smartphone in order to provide daily 
headache diary data 
7. A Parent/Guardian consents and the adolescent is cognitively 
capable of giving assent to participate 
8. Either not on a migraine preventive medication, or if on one 
the dose has been stable for at least 4 weeks prior to 
enrollment, or are willing to wait to start the study until they 


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have reached a stable dose for 4 weeks 
9. Willing to not use OTC melatonin or change migraine 
preventives during the trial 
10. Has ≥1 headache day per week, or 4-28 days of headache in a 
28-day period 
11. Episodic headaches have been present for a minimum of 6 
months—This lowers the likelihood of a secondary cause of 
headaches 
Exclusion Criteria: 
1. Continuous headache  
2. History of seizures/epilepsy 
3. Pregnant/lactating 
4. Concomitant opioid or barbiturate overuse, wherein overuse is 
defined as ≥4 days per month of barbiturate containing 
compounds, ≥10 days per month of opioid containing 
compounds as these may impact sleepiness scales 
5. If in the investigator’s opinion there is a medical or psychiatric 
concern that makes them think the participant should not 
participate 
6. Inability to swallow pills after teaching and practice 
7. History of nocturnal asthma, as evidenced by a having a 
diagnosis of asthma and symptoms that manifest as 
nighttime awakening due to cough, wheeze, and/or 
shortness of breath 
Randomization Criteria: 
1. Had 4-28 migraine/migrainous days in the 28-day period of 
weeks 5-8 of single-blind placebo treatment phase, but not 
continuous headache.  
2. At least 80% compliance with headache diary (i.e. at least 23 
headache diary days) during weeks 5-8 of single-blind placebo 
treatment phase.  
 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
3 mg or 6 mg melatonin orally nightly for the 8 active weeks of study 
treatment. 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Comparable placebo taken orally nightly for the 8 active weeks of 
study treatment. 


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DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be in the study for 16 weeks 
1) 8-week single-blind placebo treatment-phase 
2) 8-week double-blind randomized treatment phase. 
The total duration of the study is expected to be 24-30 months.   
CONCOMMITANT 
MEDICATIONS 
Allowed: All medications are allowed, except specified below, as long 
as the dose is stable for 4 weeks prior to enrollment.  
Prohibited: Overuse of opioid and barbiturate medications, wherein 
medication overuse is defined as ≥4 days per month of barbiturate 
containing compounds and/or  ≥10 days per month of opioid 
containing compounds 
EFFICACY 
EVALUATIONS 
• Headache diary  
• PedMIDAS score (PedMIDAS is a validated score for 
measuring headache related disability in adolescents) 
• 
Cleveland Adolescent Sleepiness Questionnaire score, (a 
validated instrument for measuring excessive daytime 
sleepiness in 11-17 year olds) 
PRIMARY ENDPOINT 
• Number of migraine/migrainous days in the 5th-8th weeks of 
randomized treatment between melatonin (combined 6mg + 
3mg) 
vs. 
placebo. 
 
We 
will 
control 
for 
baseline 
migraine/migrainous day frequency in the 5-8th week of the 
single-blind treatment phase and use an ANCOVA analysis.   
 
SECONDARY 
ENDPOINTS 
• 
Number of migraine/migrainous days in the 5th-8th weeks of 
randomized treatment between melatonin 3 mg vs. placebo.   
• 
Number of migraine/migrainous days in the 5th-8th weeks of 
randomized treatment between melatonin 6 mg vs. placebo.   
• 
Number of migraine/migrainous days in the 5th-8th weeks of 
randomized treatment between melatonin 3 mg vs. 6 mg.    
• 
Mean headache days in 5th-8th randomized phase in melatonin 
(combined) vs. placebo ,  (followed by melatonin 3 mg vs. 
placebo, melatonin 6 mg vs. placebo, and melatonin 3 mg vs. 
melatonin 6 mg using t-tests).    
• 
Mean acute medication use days in 5th-8th randomized phase in 
melatonin (combined) vs. placebo,  (followed by melatonin 3 mg 
vs. placebo, melatonin 6 mg vs. placebo, and melatonin 3 mg vs. 
melatonin 6 mg using t-tests).    
• 
Mean PedMIDAS score (continuous) in 5th-8th randomized phase 
in melatonin (combined) vs. placebo,  (followed by melatonin 3 
mg vs. placebo, melatonin 6 mg vs. placebo, and melatonin 3 mg 
vs. melatonin 6 mg using t-tests).    
• 
≥50% responder rate in 5th-8th randomized phase in melatonin 
(combined) vs. placebo (Chi-square or Fisher’s exact (if needed),  


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(followed by melatonin 3 mg vs. placebo, melatonin 6 mg vs. 
placebo, and melatonin 3 mg vs. melatonin 6 mg using Chi-square 
(or Fisher’s exact)). 
(We will control for the baseline level of these outcomes in all of these 
analyses). 
OTHER 
EVALUATIONS 
Safety outcomes: 
1. Proportion with adverse events between groups 
a. Proportion with serious adverse events between groups 
b. Proportion of adverse events thought to be related to 
the study treatment  
2. Mean Sleepiness score in 5th-8th randomized phase in 
melatonin (combined) vs. placebo,  (followed by melatonin 3 
mg vs. placebo, melatonin 6 mg vs. placebo, and melatonin 3 
mg vs. melatonin 6 mg using t-tests).  
Trial design assessment outcome: 
1. Proportion of participants on melatonin who correctly guessed 
they were on it (just playing chance, 66% should guess 
melatonin) 
2. Proportion of participants on melatonin who guessed their 
dose correctly (by chance 50% 3 mg, 50% 6 mg).  
3. Proportion of participants on placebo who correctly guessed 
they were on placebo (by chance, 33% should guess this) 
4. The same three above but with investigators guessing.  
SAFETY 
EVALUATIONS 
Incidence of adverse events 
PLANNED INTERIM 
ANALYSES  
DATA SAFETY MONITORING PLAN 
The study only includes children without serious medical illness to 
reduce the risk of any possible side effects. In addition, melatonin has 
been studied in children and found to be generally safe and well 
tolerated. Participants or their family member can report an adverse 
event via phone, and serious adverse events will immediately be 
reported to the PI. 
 
The PI will promptly judge each AE’s impact on the risk/benefit ratio 
of the study as well as the risk/benefit ratio for each participant as 
they are reported, so that these ratios will be continuously reassessed 
throughout the study period. Causality will be determined by the PI 
for all AEs reported and all AEs will be carefully documented 
(including AEs determined to be unrelated or only possibly related to 
the study supplement).  AEs will be sent to the DSMB for review at 
the midpoint and end of study. 
In the case of an AE occurring that necessitates breaking the blind, the 
subjects will be discontinued from the study and the data collected 
before discontinuation will be analyzed as “intent to treat”. We have a 


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procedure in place to break the study blind at any time. 
Any serious adverse events will be communicated to the IRB, in 
accordance with their guidelines. 
All serious and non-serious adverse events will be collected in an 
adverse event reporting form and reported to the DSMB as required. 
This information will be summarized and published in the final study 
publication. 
Once the study data are analyzed following the end of the study, 
participants will be sent information about the results and notified of 
their treatment group assignment (melatonin 3 mg, 6 mg or placebo). 
They will be encouraged to discuss with their personal physician the 
possibility of continuing the supplement.  
STATISTICS 
Primary Analysis Plan 
Primary outcome: Number of migraine/migrainous days in the 5th-8th 
weeks of randomized treatment between melatonin (combined 6 
mg+3mg) vs. placebo.   
 
We will control for baseline migraine/migrainous day frequency in the 
5-8th week of the single-blind treatment phase and use an ANCOVA 
analysis.   
Rationale for Number 
of Subjects 
Power calculation: To detect a difference of 1.1 migraine/migrainous 
days (SD 1.8) between groups, as was seen in the adolescent 
topiramate migraine prevention trial that led to FDA-approval of that 
agent in 12-17 year-olds8, we need outcome data on 42 
participants/arm.  We anticipate that 25% of enrolled participants will 
be screened out by the single-blind placebo run-in process, and that 
85% of those who randomize will complete the trial.  Therefore we 
will enroll 70 per arm, or n=210 total.     
 
 


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1 
BACKGROUND 
Migraine affects 6.3% of adolescents (5.0% of boys, 7.7% of girls) 2.   In addition to 
causing significant suffering, migraine causes children and adolescents to miss school and 
can negatively impact school performance3.  Currently, only one migraine preventive is 
FDA-approved in adolescents—topiramate—an anti-epileptic medication that has the 
potential for significant side effects such as cognitive slowing and increased suicidality in 
adolescents.  Safe, effective, and well-tolerated treatments are needed to reduce the 
frequency of migraine attacks in this young age group.  Melatonin is a natural supplement 
that has an excellent safety profile and has been used to improve sleep in pediatrics4.  
Melatonin 3 mg has also been shown in a randomized, placebo-controlled trial to be 
superior to placebo for migraine prevention in adults 5.  Given the excellent safety and 
tolerability of melatonin and its demonstrated efficacy for migraine prevention in adults, 
we propose to study melatonin for migraine prevention in adolescents.  
 
Observational studies support a role for melatonin in the treatment of migraine.  Adults 
with migraine have lower melatonin levels on migraine days compared to non-headache 
days and those with chronic migraine have lower melatonin levels than those with 
episodic migraine 6, 7.   Nocturnal melatonin levels are lower in women with migraine with 
aura whose attacks occur around menses compared to control women. 
There is also experimental evidence supporting a therapeutic role for melatonin in 
migraine prevention, though with some conflicting data.  In a double-blind, randomized, 
placebo-controlled, 3-arm trial with approximately 65 participants per arm, the efficacy of 
3 mg of immediate release melatonin was superior to placebo and comparable to 
amitriptyline 25 mg nightly.  The observed reduction in headache frequency at three 
months was:  2.7 in those treated with melatonin, 2.2 for amitriptyline (p=0.19), and 1.2 
for placebo (p=0.009).  The tolerability of melatonin was comparable to placebo and 
better than amitriptyline 5.  In contrast, in a smaller randomized, double-blind cross-over 
design study of 46 subjects, 2 mg of sustained release melatonin was not different from 
placebo for migraine prevention after 8 weeks of treatment 8.  Mean baseline migraine 
attack frequency (SD) was 4.2±1.2; during the placebo phase it was 2.9±1.4 vs. 2.8±1.6 
during the melatonin treatment phase, p=0.75.   Three participants (7%) had daytime 
tiredness and dizziness during melatonin treatment.  
There are a number of possible reasons for the disparate findings between the two above 
trials, including differences in melatonin dose (3 mg vs. 2 mg) and formulation 
(immediate release vs. sustained release), trial design (parallel-group vs. crossover), 
treatment duration (3 months vs. 8 weeks), difference of outcome measures (headache 
days vs. migraine attacks) and possible under-powering in the smaller study.  Crucially, 
the placebo response in the Peres and colleagues study was in-line with modern, 
adequately powered placebo-controlled migraine preventive studies, while the Alstadhaug 
and colleagues study placebo response was high.  Additional randomized placebo-
controlled trials are needed to clarify the role of melatonin in migraine prevention. 
Uncontrolled studies have generally supported a therapeutic role for melatonin in 
migraine.  In a pilot study of adult patients with migraine or tension-type headache, 
melatonin 4 mg appeared to be an effective dose for migraine prevention.  Forty-nine 


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patients were enrolled, of whom 37 had migraine, and 41 completed the 6-month 
treatment phase.  Headache frequency, and Headache Impact Test scores were statistically 
significantly lower in the migraine group at 6-months of treatment compared to baseline 9. 
Uncontrolled work in pediatrics also suggests melatonin may be useful in the treatment of 
pediatric and adolescent migraine. In one study, 60 pediatric and adolescent participants 
were treated with up to 6 mg melatonin nightly (formulation unspecified).  At three 
months, mean(SD) migraine attack frequency decreased from 15.6±7.6 to 7.1±4.4 per 
month10. In a smaller open-label pediatric study, 14 migraineurs were treated with 3 mg 
melatonin nightly. Ten (71%) had a ≥50% improvement in headache frequency at 3 
months11.  Melatonin was well tolerated in these pediatric studies: in the study where 
children received up to 6 mg of melatonin, 7(12%) had daytime sleepiness vs. 1(7%) in 
the smaller study where they received 3 mg10, 11. 
1.1 Overview of Non-Clinical Studies 
Melatonin is a well-known and well-established substance, and there are no relevant non-
clinical studies or safety concerns pertinent to using this drug for a migraine indication.  
1.2 Overview of Clinical Studies 
Studies of melatonin in adults with migraine: 
In adults, melatonin levels are lower on migraine attack days compared to headache-free 
days.3 In a 2013 study by Peres et al., melatonin given at a dose of 3 mg orally nightly 
was shown to be effective for prevention of episodic migraine in adults in a three-month 
long double-blind randomized placebo-controlled trial4. An earlier study of melatonin for 
migraine prevention in adults was negative, but it was underpowered, had used a lower 
melatonin dose of 2 mg instead of 3 mg nightly, and a prolonged release formulation 
instead of the immediate release formulation used in the 2013 study7. 
Studies of melatonin in children with migraine: 
Open label studies of melatonin in children and adolescents suggest it is beneficial for 
migraine prevention.5, 6  In an open-label neurology clinic-based study of 60 children with 
migraine (ages 5-15 years), the participants were treated with 0.3mg/kg melatonin (max 6 
mg) orally nightly for three months.  Headache frequency dropped from 15.6(±7.6) days 
per month to 7.1(±4.4), p < 0.001.  A ≥50% reduction in headache frequency was seen in 
70% of the participants (95% CI 58-82%).  There was also a statistically significant 
improvement in headache severity, duration, and disability (as measured by PedMIDAS 
score), as well as a decrease in analgesic use after treatment with melatonin. 
In a smaller open-label study of 22 children recruited from a pediatric headache clinic in 
Rome, 14 of the children had migraine and 8 had tension-type headache.  The age range 
was 6-16 years (mean 12.2±2.6) and they were treated with melatonin 3 mg orally nightly 
for three months.  Twenty-one completed the study, 13 of whom had migraine.  Ten of 
these 13 migraineurs experienced a ≥50% decrease in headache frequency5.  In addition, 
of twelve children with post-traumatic headaches treated with melatonin 3-10 mg nightly, 
headaches improved in nine (75%)8. 
 
 


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Safety of melatonin in children and in migraine: 
Melatonin is a safe and well-tolerated sleep aid, even for children5, 9-25. We are aware of 
no serious adverse events ever reported from melatonin supplementation in 
neurodevelopmentally normal children. While a small trial of six children with multiple 
neurologic disabilities raised concern when four developed more frequent seizures on 
melatonin26, subsequent research involving larger numbers of children with 
neurodevelopmental disabilities demonstrated excellent safety9, 12, 20, 22, 24, 27.  In fact 
melatonin treatment has been associated with reduced seizure frequency in children and 
adults with intractable epilepsy14, 19, 28. 
 
In the study of 22 children with headache treated with 3 mg melatonin nightly—there was 
just one child with an adverse event—excessive daytime sleepiness that caused them to 
discontinue the medication5.  In the larger study of 60 children, who were given 0.3mg/kg 
for migraine prevention, serious side effects were not seen.  The side effects seen were: 
12% tiredness (excessive daytime sleepiness 5%), 7% vomiting, 3% mild hypotension, 
and 2% constipation6.   In the Peres et al. positive adult melatonin study, the tolerability of 
melatonin was not different from placebo.   In the Alstadhaug et al. crossover study of 
melatonin 2 mg orally nightly for migraine prevention in adults, the number of 
participants experiencing adverse events was higher in the placebo phase than in the 
melatonin phase. 
 
Melatonin at a dose of 3 mg12, 24or higher20, 21, 23, 24has been used safely with excellent 
tolerability in several randomized pediatric trials.  In a systematic review article of 
melatonin use for children with ADHD, children ranged from 6-14 years and were treated 
with 3-6 mg melatonin nightly—there were no serious adverse events and generally 
adverse events were similar to placebo; of note one child was reported to have severe 
migraine29.  In another study, children treated with melatonin for between 1-4.6 years 
(mean 3.1 years) at a mean dose of 2.7 mg (range 0.3-10 mg) nightly had normal sleep 
quality, mental health scores, and pubertal development30.  Melatonin has even been given 
safely to neonates for its analgesic15, anti-inflammatory16, 17, and anti-oxidant18 
properties.  Furthermore, there is evidence melatonin might be neuroprotective after 
perinatal hypoxic-ischemic injury31. 
At UCSF we conducted a pilot remote RCT of melatonin 3 mg vs. placebo in 12-17 year 
olds (IRB #14-14251.)  We are still completing analysis on that study, however there were 
no serious adverse events and only one participant (out of 26 randomized participants) 
stopped study medication due to daytime tiredness (they were in the melatonin group).   
2 
STUDY RATIONALE 
Safe, effective, and well-tolerated treatments are needed to reduce the frequency of 
migraine attacks in this young age group.  Melatonin is a natural supplement that has an 
excellent safety profile and has been used to improve sleep in pediatrics.  Melatonin has 
also been shown in a randomized, placebo-controlled trial to be superior to placebo for 
migraine prevention in adults.  Given the excellent safety and tolerability of melatonin and 
its demonstrated efficacy for migraine prevention in adults, we propose to study melatonin 
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2.1 Risk / Benefit Assessment 
The most significant potential benefits are a potential reduction in migraine/migrainous 
headache days and reduction in associated disability.  As the placebo response rate in 
pediatric migraine trials is generally high, both participants randomized to melatonin and 
those randomized to placebo may experience the benefit of a decreased number of 
migraine/migrainous headache days.  Other potential benefits include decreased headache 
severity and duration, and decreased need to take acute headache medications.  
Participants also may find it easier to fall asleep at bedtime.  Also, most of the study can 
be completed from home.   
These benefits outweigh the relatively minor potential risks that have been reported with 
the proposed melatonin dosages in developmentally normal pediatric patients—essentially 
sleepiness or drowsiness during the day.   
Participants may not take over the counter melatonin during the study, or 4 weeks prior to 
enrollment. They may; however, be on a different migraine preventive medication as long 
as the dose has been stable for 4 weeks prior to enrollment—hence they have access to 
other effective migraine preventive treatments during the study. They are also allowed to 
use acute migraine treatments as long as there is no concomitant opioid or barbiturate 
overuse. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
To compare the number of migraine/migrainous days in the 5th-8th weeks of randomized 
treatment between melatonin (combined 6 mg+3mg) vs. placebo.  We will control for 
baseline migraine/migrainous day frequency in the 5-8th week of the single-blind 
treatment phase and use an ANCOVA analysis.   
3.2 
Secondary Objectives 
1. To compare the number of migraine/migrainous days in the 5th-8th weeks of 
randomized treatment between melatonin 3 mg vs. placebo.   
2. To compare the number of migraine/migrainous days in the 5th-8th weeks of 
randomized treatment between melatonin 6 mg vs. placebo.   
3. To compare the number of migraine/migrainous days in the 5th-8th weeks of 
randomized treatment between melatonin 3 mg vs. 6 mg.    
4. To compare the mean headache days in 5th-8th randomized phase in melatonin 
(combined) vs. placebo,  (followed by melatonin 3 mg vs. placebo, melatonin 6 mg 
vs. placebo, and melatonin 3 mg vs. melatonin 6 mg using t-tests).    
5. To compare the mean acute medication use days in 5th-8th randomized phase in 
melatonin (combined) vs. placebo,  (followed by melatonin 3 mg vs. placebo, 
melatonin 6 mg vs. placebo, and melatonin 3 mg vs. melatonin 6 mg using t-tests).    
6. To compare the mean PedMIDAS score (continuous) in 5th-8th randomized phase 
in melatonin (combined) vs. placebo,  (followed by melatonin 3 mg vs. placebo, 
melatonin 6 mg vs. placebo, and melatonin 3 mg vs. melatonin 6 mg using t-tests).    
7. To compare the number of ≥50% responder rate in 5th-8th randomized phase in 
melatonin (combined) vs. placebo (Chi-square or Fisher’s exact (if needed),  


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(followed by melatonin 3 mg vs. placebo, melatonin 6 mg vs. placebo, and 
melatonin 3 mg vs. melatonin 6 mg using Chi-square (or Fisher’s exact)).    
4 
STUDY DESIGN 
4.1 
Study Overview 
Randomized, multi-site double-blind placebo-controlled trial of melatonin 3 mg vs. 6 mg 
vs. placebo.   Randomization will be 1:1:1 in blocks of 6 by site.  We will use a “remote 
trial” design, wherein after the initial in-person enrollment visit all study procedures will 
be done from the comfort of the participant’s own home.   
 
We intend to enroll approximately 210 participants over 24-30 months at two sites: UCLA 
and UCSF.   The duration of participation for each participant will be 4 months:  
1) 8-week single-blind placebo treatment-phase  
2) 8-week randomized treatment phase  
5 
CRITERIA FOR EVALUATION 
5.1 Primary Efficacy Endpoint 
1. Mean migraine/migrainous days in weeks 5-8 of randomized treatment phase in 
melatonin treated participants vs. placebo.  
5.2 
Secondary Efficacy Endpoints 
1. Mean migraine/migrainous days in weeks 5-8 of randomized treatment phase in 
melatonin 6 mg vs. placebo.  
2. Mean migraine/migrainous days in weeks 5-8 of randomized treatment phase in 
melatonin 3 mg vs. placebo.  
3. Mean migraine/migrainous days in weeks 5-8 of randomized treatment phase in 
melatonin 6 mg vs. melatonin 3 mg.  
4. Change in mean migraine/migrainous days from weeks 5-8 of single-blind 
treatment phase to weeks 5-8 of randomized treatment phase for each group.   
5. Mean PedMIDAS (headache related disability score) in weeks 5-8 of randomized 
treatment phase in melatonin treated group vs placebo, and in each of the three 
pair-wise group comparisons.  
6. Mean CASQ score in weeks 5-8 of randomized treatment phase in melatonin 
treated group vs. placebo, and in each of the three pair-wise group comparisons.  
7. Number of days acute medication is used in weeks 5-8 of randomized treatment 
phase in melatonin treated group vs. placebo, and in each of the three pair-wise 
group comparisons.  
8. Number of headache days in weeks 5-8 of randomized treatment phase in 
melatonin treated group vs. placebo, and in each of the three pair-wise group 
comparisons.  
 


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5.3 
Safety Evaluations 
1. Incidence of adverse events 
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects with a diagnosis of migraine who meet the inclusion and exclusion criteria will 
be eligible for participation in this study.   
6.2 
Inclusion Criteria 
1. Age 10-17—inclusive 
2. Weight ≥40 kg, so as not to require mg/kg based dosing 
3. Meets International Classification of Headache Disorders III beta1 criteria for 
migraine in children/adolescents (international standard diagnostic criteria for 
research) 
4. Lives in the state of California- to allow shipping of study medication from our 
pharmacy 
5. Has at least one parent who speaks English—in order to ensure good 
communication with study team by phone 
6. Has daily access to a smartphone in order to provide daily headache diary data 
7. A Parent/Guardian consents and the adolescent is cognitively capable of giving 
assent to participate 
8. Either not on a migraine preventive medication, or if on one the dose has been 
stable for at least 4 weeks prior to enrollment, or are willing to wait to start the 
study until they have reached a stable dose for 4 weeks 
9. Willing to not use OTC melatonin or change migraine preventives during the trial 
10. Has ≥1 headache day per week, or 4-28 days of headache in a 28-day period 
Episodic headaches have been present for a minimum of 6 months—This 
lowers the likelihood of a secondary cause of headaches 
6.3 
Exclusion Criteria 
1. Continuous headache  
2. History of seizures/epilepsy 
3. Pregnant/lactating 
4. Concomitant opioid or barbiturate overuse, wherein overuse is defined as ≥4 days 
per month of barbiturate containing compounds, ≥10 days per month of opioid 
containing compounds as these may impact sleepiness scales 
5. If in the investigator’s opinion there is a medical or psychiatric concern that makes 
them think the participant should not participate 
6. Inability to swallow pills after teaching and practice 
History of nocturnal asthma, as evidenced by a having a diagnosis of 
asthma and symptoms that manifest as nighttime awakening due to 
cough, wheeze, and/or shortness of breath 
Randomization Criteria: 
1. Had 4-28 migraine/migrainous days in the 28-day period of weeks 5-8 of single-
blind placebo treatment phase, but not continuous headache.  


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2. At least 80% compliance with headache diary (i.e. at least 23 headache diary days) 
during weeks 5-8 of single-blind placebo treatment phase.  
7 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new preventive therapies.   
7.1 Allowed Medications and Treatments:  
As stated in the exclusionary criteria above, subjects can use their usual acute headache 
medications as long as there is not medication overuse (defined above).  All other 
medications are acceptable. 
7.2 Prohibited Medications and Treatments:  
Overuse of acute headache medications, wherein medication overuse is defined as ≥4 days 
per month of barbiturate containing compounds and/or  ≥10 days per month of opioid 
containing compounds.  
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
Randomization:  1:1:1 to melatonin 3 mg: 6 mg: placebo.  Randomization will be done in 
blocks of 6 by site.  A computer-generated scheme will be used to generate the 
randomization.  
8.2 
Blinding 
Due to the objectives of the study, the identity of test and control treatments will not be 
known to investigators, research staff, or patients. The two melatonin doses and the 
placebo will be indistinguishable in terms of color, appearance, taste, and smell.   
During the study, the blind may be broken only in emergencies when knowledge of the 
patient’s treatment group is necessary for clinical patient management.  
The study blind will be broken on completion of the clinical study and after the study 
database has been locked.  
8.3 
Formulation of Test and Control Products 
8.3.1 
Formulation of Test Product 
The drug product is a commercial melatonin 3 mg tablet that is lawfully marketed in the 
U.S. by Nature’s Bounty. The commercial label is attached to this application.  For the 
purpose of blinding, Safeway Pharmacy will over-encapsulate the tablets using a 
microcrystalline cellulose filler.  We will not make any other changes of any kind to the 
finished marketed Nature’s Bounty melatonin product.  We do not think that 
overencapsulating this melatonin product will effect absorption and we have discussed 
this with the study pharmacist.  While it is possible that absorption will be somewhat 
slower than with the under the tongue method, we do not think this is problematic as we 


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do not think speed of absorption of melatonin will have a role in its efficacy as a migraine 
preventive. 
Those assigned to placebo will take 1 placebo capsule nightly. Those assigned to 
melatonin 3 mg will take one capsule nightly (will contain 1 x 3 mg tablet).  Those 
assigned to melatonin 6 mg will take 1 capsule nightly (will contain 2 x 3 mg tablets).  
 
 
Study Drug 
Placebo 
Active Ingredient, 
mg/mL 
3.36mg melatonin (as per labdoor.com 
analysis—attached) 
N/A 
Other ingredient, 
mg/mL 
Mannitol, Crospovidone, Vegetable Stearic 
Acid, Natural Cherry Flavor, Beet Juice Color, 
Malic Acid, Sucralose, Vegetable Magnesium 
Stearate, Microcrystalline cellulose 
Microcrystalline 
cellulose 
8.3.2 
Formulation of Control Product 
Safeway Pharmacy will make matching placebos capsules using the same gelatin capsules 
and microcrystalline cellulose filler.  They will be visually indistinguishable from the 
over-encapsulated Nature’s Bounty melatonin product.   
8.3.3 
Packaging and Labeling 
Preparations (both active and placebo) will be packaged in white HDPE (high density 
polyethylene plastic) vials topped with cotton balls.  
8.4 
Supply of Study Drug at the Site 
8.4.1 
Dosage/Dosage Regimen 
Participants will take the study drug (either 3 mg melatonin, 6 mg melatonin or placebo) 
at night one hour before bedtime (approximately 21:00 hours).  
8.4.2 
Dispensing 
A medication bottle will be given to participants at the enrollment visit for the single blind 
placebo phase.  For those eligible to continue to the 8-week double blind phase, the 
pharmacy will ship the final study drug bottle to the participant’s home.  
8.4.3 
Administration Instructions  
Participants will take the study drug (either 3 mg melatonin, 6 mg melatonin or placebo) 
orally at night one hour before bedtime (approximately 21:00 hours).  
8.4.4 
Storage 
Pharmacy storage – the pharmacy is capable of monitoring temperature ranges via digital 
USB data loggers that can track humidity, temperature, and dew point.  These reports can be 
regularly downloaded, printed for record, and monitored for consistency.   


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Storage at participants’ homes—Study drug should be stored at the participants’ homes at 
room temperature, 15 to 30ºC (59 to 86ºF).  High humidity and high temperatures should be 
avoided. 
8.5 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by a member of the study site staff.  The 
number of study drug dispensed and returned by the subject will be recorded on the 
Investigational Drug Accountability Record.  The PI will verify these documents 
throughout the course of the study.  In the daily headache diary, participants will also self-
report whether they took the study drug that evening.  Staff will be able to monitor this 
real time.   
8.6 
Measures of Treatment Compliance 
Subjects will be asked to complete a daily headache diary and will be asked whether they 
took the study medication that evening.  The diaries will be monitored by study staff.  
Also, a manual pill count will be performed after each phase of the study.  
9 
STUDY PROCEDURES AND GUIDELINES 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject’s parent/guardian.  Assent from the participant must also be obtained 
prior to conducting any study-related activities. 
9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at screening.    
Dose, route, unit frequency of administration, and indication for administration and dates 
of medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at screening. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at screening. 
9.1.4 
Physical Examination 
A physical examination will be performed by either an investigator or a sub-investigator at 
the screening visit.   
9.1.5 
Vital Signs 
Body temperature, blood pressure, and pulse will be performed after resting for 5 minutes. 


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9.1.6 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation 
to study drug will be recorded on the case report form (CRF). 
9.2 
Clinical Laboratory Measurements  
9.2.1 
Pregnancy Test 
A urine pregnancy test will be obtained from female subjects who are of childbearing age 
and have had their first menstrual period, prior to their participation in the study. 
10 EVALUATIONS BY VISIT 
10.1 Visit 1 (Screening and Enrollment, Day 1) 
We will do a one-time enrollment visit at either UCSF or UCLA.    
 
Consent/assent: At the start of an enrollment visit, potential subjects and their 
parent/guardian will be told about the study by a study investigator and/or study 
coordinator and will be provided with an informed consent document to review.  For 12-
17 year-olds, the informed consent document is addressed to the adolescent and is to be 
signed by both the adolescent and their parent/guardian.  For 10-11 year-olds, the parent 
will sign the consent form and the participant will be provided with a simplified assent 
document.  For this group the participant's assent will be documented by a study team 
member.  Participants and parents/guardians will be given the opportunity to ask questions 
and have them answered to their satisfaction before deciding whether to participate.  
Consent and HIPPA can be signed with paper/pen or via DocuSign.   
 
Enrollment visit data:  
The enrollment visit data will be entered directly into the study database during the 
enrollment visit.  Demographic and logistical information will be collected including 
name, age, sex, race/ethnicity, shipping address, participant smartphone number, parent 
smartphone number, and best times for follow-up calls.  A pediatric headache neurologist 
will review the headache history to ensure the participant meets ICHD criteria for 
migraine with or without aura and will review the current medication list and past medical 
history.   We will measure weight, blood pressure, pulse, and respiratory rate.  There will 
be a general medical examination and a neurologic examination. Girls who have had their 
first period will undergo a urine pregnancy test.  Baseline assessment of the PedMIDAS 
score and CASQ score will be assessed.   Participants will be taught how to use the 
headache diary on their smartphone.  They will be given the study medication for the 
single-blind placebo treatment phase and instructed to take study medication 1 hour before 
bedtime. 
10.2     8-week single-blind placebo treatment phase (Weeks 1-8): 
Participants will take the study medication nightly and complete a headache diary nightly.  
A text message will be sent from the study database each evening to remind them to do 


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these two tasks, and to provide a link to their headache diary.  If they do not complete the 
headache diary, a reminder text will be sent the next morning.  If they do not complete the 
headache diary for three days in a row, a study staff member will call to check in and 
remind them to do it and answer any questions.   There will be a scheduled check in call at 
the four-week mark and again at the 8-week mark.  If they provide headache diary data on 
≥80% of days in each 28-day period, they will receive a $5 gift card each month.  Once 
they have completed the 8-weeks of placebo treatment, they will return their study 
medication in a self-addressed envelope via FedEx.   
 
10.3    Assessment of randomization eligibility (Day 57): 
If the participant meets randomization criteria, the study pharmacy (Safeway) will be 
notified by study staff and the study pharmacy will review the randomization scheme to 
assign treatment and will enter this data into the study database.  The study medication 
will be shipped to the participant’s shipping address via FedEx.   
Study staff will track the shipment via FedEx’s tracking number on their website.  Once 
the package shows as delivered, study staff will enter this information into the study 
database and a text message will be sent to the parent’s smartphone asking them to 
confirm receipt of the study medication.  The date the parent confirms receipt of the study 
medication will be day 1 of the randomized treatment phase.   
 
10.4    8-week randomized treatment phase (Weeks 9-16):  
Participants will take the study medication nightly and complete a headache diary nightly.  
A text message will be sent from the study database each evening at 9:00 PM to remind 
them to do these two tasks, and to provide a link to their headache diary.  If they do not 
complete the headache diary, a reminder text will be sent the next morning.  If they do not 
complete the headache diary for three days in a row, a study staff member will call to 
check in and remind them to do it and answer any questions.   There will be a scheduled 
check in call at the four-week mark and again at the 8-week mark.  If they provide 
headache diary data on ≥80% of days in each 28-day period, they will receive a $5 gift 
card each month.  Once they have completed the 8-weeks of treatment, they will return 
their study medication in a self-addressed envelope via FedEx.    
 
10.5    Study completion (Day 113): 
At the end of the 8-week randomized treatment phase there will be a study completion 
phone visit.  We will again assess the PedMIDAS and CASQ scores.  We will query for 
adverse events, and will solicit participant and parent feedback on the study design.  We 
will remind participants to mail back the study medication bottle using the self-addressed 
FedEx envelope, and once this is received we will perform both a manual pill count and 
compare to the self-report count in their diary.  


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11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency or of greater severity or frequency than expected. 
The study team will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 


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Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
2. death 
3. a life-threatening adverse experience 
4. inpatient hospitalization or prolongation of existing hospitalization 
5. a persistent or significant disability/incapacity 
6. a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  
 
11.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF IRB Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained, after study drug is administered for at least one dose, and will end 
after procedures for the final study visit have been completed. 
 
All serious and non-serious adverse events will be collected in an adverse event reporting 
form.  This information will be supplied to the Data Safety Monitoring Board (DSMB) 
and all adverse event information will be summarized and published in the final study 
publication.  
 


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In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC and DSMB per UCSF IRB guidelines.   
 
During the study, safety will be monitored by a 3-member Data Safety Monitoring Board 
(DSMB) which will be led by a pediatric headache specialist.  The DSMB will review all 
study procedures before the initiation of the study.  They will have the full and final 
authority to stop the study for any safety concern at any point.  They will also review 
study data at the midpoint of the study, and at any subsequent interval that they 
recommend.  Interim reports to the DSMB will be blinded to treatment status, though the 
DSMB may request unblinded information from the investigators at any time for any 
reason.  Reports to the DSMB will be prepared by a UCSF Dept of Epidemiology and 
Biostatistics faculty member who is not otherwise involved in the study and who will not 
communicate with the study investigators regarding any aspect of the DSMB reports. 
 
Serious and unexpected adverse events associated with the use of the study drug or 
procedures will be reported to the IRB and DSMB with subsequent follow-up submission 
of a detailed written report in accordance with the respective policies and procedures of 
the IRB.  http://irb.ucsf.edu/adverse-event  
 
Written IND Safety Reports will be submitted to the FDA as soon as possible and, in no 
event, later than 15 calendar days following the investigator-sponsor’s receipt of the 
respective adverse event information. 
 
The FDA will be notified by telephone or facsimile transmission of a human adverse 
event that is fatal or life-threatening no later than 7 calendar days after receiving the 
respective human adverse event information, followed by the subsequent submission of a 
written IND Safety Report 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the or 
investigator feels that it is not in the subject’s best interest to continue.  The following is a 
list of possible reasons for study treatment discontinuation: 
• Subject withdrawal of consent (or assent) 
• Subject is not compliant with study procedures 
• Adverse event that in the opinion of the investigator would be in the best interest 
of the subject to discontinue study treatment 
• Protocol violation requiring discontinuation of study treatment 
• Lost to follow-up 
• Positive pregnancy test (females) 
• If a subject is withdrawn from treatment due to an adverse event, the subject will 
be followed and treated by the Investigator until the abnormal parameter or 
symptom has resolved or stabilized.   


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All subjects who discontinue study treatment should be encouraged to complete all 
remaining scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  
If the study (in part or in entirety) is discontinued for any reason, the UCSF sponsor-
investigator will notify all other investigators, sub-investigators and study staff within 
FDA guidelines.  Since melatonin at 3mg and at 6mg can be stopped without weaning, 
there will be no further data collected to ensure subject safety.  If part of the study is 
discontinued, subjects will be reconsented with an updated consent as soon as it is 
approved by the IRB.  All parts of the study that have been discontinued will be ended 
within FDA guidelines.   
12.2 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject or the investigator, 
thinks it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.     
12.3 
Replacement of Subjects 
Subjects who withdraw from the study treatment will not be replaced.   
Subjects who withdraw from the study will not be replaced.   
 
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following: 
Failure to meet inclusion/exclusion criteria 
Use of a prohibited concomitant medication 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Investigator will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by the 


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Investigator. A copy of the form will be filed in the site’s regulatory binder and in the 
Investigator’s files. 
14 STATISTICAL METHODS AND CONSIDERATIONS 
14.1 Data Sets Analyzed 
All eligible patients who are randomized and receive at least one dose of the study drug 
(the Safety Population) will be included in the safety analysis. 
Dr. Gelfand will analyze the data using STATA.  As a UCSF KL2 Scholar, she will have 
assistance from the UCSF Dept. of Epidemiology and Biostatistics faculty and CTSI 
consulting services as needed for statistical issues.  
14.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized by dose level: race, 
gender, age, height and weight.   
14.3 Analysis of Primary Endpoint 
Primary outcome: Number of migraine/migrainous days in the 5th-8th weeks of 
randomized treatment between melatonin (combined 6 mg+3mg) vs. placebo.  We will 
control for baseline migraine/migrainous day frequency in the 5-8th week of the single-
blind treatment phase and use an ANCOVA analysis.   
 
Definition of migraine/migrainous day: 
1) Patient had a moderate or severe headache and took a migraine-specific 
medication (triptan or ergot) 
2) Patient had a moderate or severe headache; headache lasted for at least 2 hours, 
and 
a. At least one of the following was present (throbbing quality, movement 
sensitivity, or unilateral/bilateral location) AND 
b. At least one of the following was also present (photophobia, phonophobia, 
nausea or vomiting) 
 
14.4 Analysis of Secondary Endpoints 
Secondary outcome measures will include ≥50% responder rates, tolerability (as measured 
by CASQ scores), and need for use of acute headache medications.  Safety and tolerability 
data will be summarized by treatment group.  Adverse event rates will be coded by body 
system.  Adverse events will be tabulated by treatment group and will include the number 
of patients for whom the event occurred, the rate of occurrence, and the severity and 
relationship to study drug.   
Secondary outcomes: 
(We will control for the baseline level of these outcomes in all of these analyses) 
Effectiveness secondary outcomes: 
1. Number of migraine/migrainous days in the 5th-8th weeks of randomized 
treatment between melatonin 3 mg vs. placebo.   


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2. Number of migraine/migrainous days in the 5th-8th weeks of randomized 
treatment between melatonin 6 mg vs. placebo.   
3. Number of migraine/migrainous days in the 5th-8th weeks of randomized 
treatment between melatonin 3 mg vs. 6 mg.    
4. Mean headache days in 5th-8th randomized phase in melatonin (combined) vs. 
placebo,  (followed by melatonin 3 mg vs. placebo, melatonin 6 mg vs. placebo, 
and melatonin 3 mg vs. melatonin 6 mg using t-tests).    
5. Mean acute medication use days in 5th-8th randomized phase in melatonin 
(combined) vs. placebo,  (followed by melatonin 3 mg vs. placebo, melatonin 6 
mg vs. placebo, and melatonin 3 mg vs. melatonin 6 mg using t-tests).    
6. Mean PedMIDAS score (continuous) in 5th-8th randomized phase in melatonin 
(combined) vs. placebo,  (followed by melatonin 3 mg vs. placebo, melatonin 6 
mg vs. placebo, and melatonin 3 mg vs. melatonin 6 mg using t-tests).    
7. ≥50% responder rate in 5th-8th randomized phase in melatonin (combined) vs. 
placebo (Chi-square or Fisher’s exact (if needed),  (followed by melatonin 3 mg 
vs. placebo, melatonin 6 mg vs. placebo, and melatonin 3 mg vs. melatonin 6 mg 
using Chi-square (or Fisher’s exact)).    
 
Safety outcomes: 
1. Proportion with adverse events between groups 
a. Proportion with serious adverse events between groups 
b. Proportion of adverse events thought to be related to the study treatment  
2. Mean Sleepiness score in 5th-8th randomized phase in melatonin (combined) vs. 
placebo,  (followed by melatonin 3 mg vs. placebo, melatonin 6 mg vs. placebo, 
and melatonin 3 mg vs. melatonin 6 mg using t-tests).  
 
Trial design assessment outcome: 
1. Proportion of participants on melatonin who correctly guessed they were on it 
(just playing chance, 66% should guess melatonin) 
2. Proportion of participants on melatonin who guessed their dose correctly (by 
chance 50% 3 mg, 50% 6 mg).  
3. Proportion of participants on placebo who correctly guessed they were on placebo 
(by chance, 33% should guess this) 
4. The same three above but with investigators guessing.  
14.5 Interim Analysis 
We are not currently planning an interim analysis.  
14.6 Sample Size and Randomization 
To detect a difference of 1.1 migraine/migrainous days (SD 1.8) between groups, as was 
seen in the adolescent topiramate migraine prevention trial that led to FDA-approval of 
that agent in 12-17 year-olds, we need outcome data on 42 participants/arm.  We 
anticipate that 25% of enrolled participants will be screened out by the single-blind 
placebo run-in process, and that 85% of those who randomize will complete the 
trial.  Therefore we will enroll 70 per arm, or n=210 total.  


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15 DATA COLLECTION, RETENTION AND MONITORING 
15.1 Data Collection Instruments 
The UCSF and UCLA Investigators will prepare and maintain adequate and accurate 
source documents designed to record all observations and other pertinent data for each 
subject treated with the study drug.   
Study personnel at each site will enter data from source documents corresponding to a 
subject’s visit into the protocol-specific electronic Case Report Form (eCRF) OR paper 
CRF when the information corresponding to that visit is available.   
For eCRFs: If a correction is required for an eCRF, the time and date stamps track the 
person entering or updating eCRF data and creates an electronic audit trail.  For paper 
CRFs:  If a correction is made on a CRF, the study staff member will line through the 
incorrect data, write in the correct data and initial and date the change.  A copy of the CRF 
will remain at the site at the completion of the study. 
The UCSF and UCLA Investigators are responsible for all information collected on 
subjects enrolled in this study.  All data collected during the course of this study will be 
reviewed and verified for completeness and accuracy by each site’s Investigators.   
After recruitment begins, a monthly call or teleconference between the study team will 
occur to update each site on the status of the study.  A shared, de-identified, password-
protected spreadsheet will keep a record of each site’s enrollment numbers, screen fails, 
Serious and other Adverse Events.  Email and pager numbers will be shared from each 
site in order to communicate in the event of an emergency.  Annually, the UCSF study 
team will travel to UCLA to perform a detailed data and safety review.   
15.2 Data Management Procedures 
The data will be entered into a validated, HIPAA compliant database.  The Data 
Management group will be responsible for data processing, in accordance with procedural 
documentation.  Database lock will occur once quality assurance procedures have been 
completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
15.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis.  
Queries are entered, tracked, and resolved through the EDC system directly.  The study 
database will be updated in accordance with the resolved queries.  All changes to the 
study database will be documented. 
15.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 


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maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures. 
15.5 Availability and Retention of Investigational Records 
The Investigators must make study data accessible to the IRB/IEC, and Regulatory 
Agency (e.g., FDA) inspectors upon request.  A file for each subject must be maintained 
that includes the signed Informed Consent, HIPAA Authorization, Bill of Rights, Assent 
Form and copies of all source documentation related to that subject.  The Investigators 
must ensure the reliability and availability of source documents from which the 
information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of 
the investigational product or for two years after centers have been notified that the IND 
has been discontinued.   
15.6 Monitoring 
Monitoring will be conducted by the PI and study staff.  Additionally, we will request an 
annual review of the data to be conducted by the UCSF Quality Improvement Unit within 
the UCSF Human Research Protection Program.   
http://irb.ucsf.edu/routine-site-visits-and-directed-investigations 
15.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a subject number and subject initials will 
identify all study subjects on CRFs and other documentation. 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet or on a password protected computer. Clinical information 
will not be released without written permission of the subject, except as necessary for 
monitoring by the FDA.  The Investigator must also comply with all applicable privacy 
regulations (e.g., Health Insurance Portability and Accountability Act of 1996, EU Data 
Protection Directive 95/46/EC). 
16.1 Protocol Amendments 
Any amendment to the protocol will be written by the UCSF sponsor-investigator.  
Protocol amendments cannot be implemented without prior written IRB/IEC approval and 
FDA notification if applicable, except as necessary to eliminate immediate safety hazards 


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to patients.  A protocol amendment intended to eliminate an apparent immediate hazard to 
patients may be implemented immediately, provided the IRBs are notified within five 
working days. 
The Sponsor will submit (i.e., in advance of implementing the change) a Protocol 
Amendment to the IND describing any change to a Phase 2 protocol that significantly 
affects the safety of subjects, the scope of the investigation, or the scientific quality of the 
study.  Examples of Phase 2 clinical protocol changes requiring the submission of a 
Protocol Amendment include: 
• Any increase in drug dosage or duration of exposure of individual subjects to the 
investigational drug beyond that described in the current protocol, or any 
significant increase in the number of subjects under study. 
• Any significant change in the design of the protocol (such as the addition or 
deletion of a control group). 
• The addition of a new test or procedure that is intended to improve monitoring for, 
or reduce the risk of, a side effect or adverse event; or the dropping of a test 
intended to monitor the safety of the investigational drug. 
16.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain assurance of 
IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to 
the IRB/IEC.  The IRB/IECs written unconditional approval of the study protocol and the 
informed consent form will be in the possession of the Investigator before the study is 
initiated.  The IRB/IECs unconditional approval statement will be transmitted by the 
Investigator prior to the shipment of study supplies to the site.  This approval must refer to 
the study by exact protocol title and number and should identify the documents reviewed 
and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
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16.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the IRB/IEC.  The consent form generated by the 
Investigator must be approved by the IRB/IEC.  The written consent document will 
embody the elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator keep an 
IRB/IEC-approved copy of the Informed Consent Form for the study file. 
A properly executed, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects (or their parent/guardian/legal representative) must be given ample 
opportunity to inquire about details of the study.  If appropriate and required by the local 
IRB/IEC, assent from the subject will also be obtained.  If a subject is unable to sign the 
informed consent form (ICF) and the HIPAA authorization, a legal representative may 
sign for the subject.   A copy of the signed consent form (and assent) will be given to the 
subjects or the parent/guardian/legal representative of the subject and the original will be 
maintained with the subject’s records. 
16.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by the PI.  The publication or 
presentation of any study results shall comply with all applicable privacy laws, including, 
but not limited to, the Health Insurance Portability and Accountability Act of 1996.  
16.5 
Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after 
notifying the IRB, except when to protect the safety, rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the IRB any AEs that occur in the course of the study, in accordance with 
§21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection as required. 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB all changes in the research activity and all unanticipated 
problems involving risks to subjects or others (to include amendments and IND safety 
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9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312. 
 
17.0     REFERENCES: 
1. 
The International Classificatio of Headache Disorders, 3rd edition (beta version). 
Cephalalgia : an international journal of headache 2013;33:629-808. 
2. 
Bigal ME, Lipton RB, Winner P, et al. Migraine in adolescents: association with 
socioeconomic status and family history. Neurology 2007;69:16-25. 
3. 
Arruda MA, Bigal ME. Migraine and migraine subtypes in preadolescent children: 
association with school performance. Neurology 2012;79:1881-1888. 
4. 
Chang YS, Lin MH, Lee JH, et al. Melatonin Supplementation for Children With 
Atopic Dermatitis and Sleep Disturbance: A Randomized Clinical Trial. JAMA pediatrics 
2016;170:35-42. 
5. 
Peres M, Goncalves A. Double-Blind, Placebo Controlled, Randomized Clinical 
Trial Comparing Melatonin 3 mg, Amitriptyline 25 mg and Placebo for Migraine 
Prevention. Neurology 2013;80:S40.005. 
6. 
Masruha MR, de Souza Vieira DS, Minett TS, et al. Low urinary 6-
sulphatoxymelatonin concentrations in acute migraine. The journal of headache and pain 
2008;9:221-224. 
7. 
Masruha MR, Lin J, de Souza Vieira DS, et al. Urinary 6-sulphatoxymelatonin 
levels are depressed in chronic migraine and several comorbidities. Headache 
2010;50:413-419. 
8. 
Alstadhaug KB, Odeh F, Salvesen R, Bekkelund SI. Prophylaxis of migraine with 
melatonin: a randomized controlled trial. Neurology 2010;75:1527-1532. 
9. 
Bougea A, Spantideas N, Lyras V, Avramidis T, Thomaidis T. Melatonin 4 mg as 
prophylactic therapy for primary headaches: a pilot study. Functional neurology 2016:1-5. 
10. 
Fallah R, Shoroki FF, Ferdosian F. Safety and efficacy of melatonin in pediatric 
migraine prophylaxis. Current drug safety 2015;10:132-135. 
11. 
Miano S, Parisi P, Pelliccia A, Luchetti A, Paolino MC, Villa MP. Melatonin to 
prevent migraine or tension-type headache in children. Neurological sciences : official 
journal of the Italian Neurological Society and of the Italian Society of Clinical 
Neurophysiology 2008;29:285-287. 
12. 
Spilsbury JC, Drotar D, Rosen CL, Redline S. The Cleveland adolescent 
sleepiness questionnaire: a new measure to assess excessive daytime sleepiness in 
adolescents. Journal of clinical sleep medicine : JCSM : official publication of the 
American Academy of Sleep Medicine 2007;3:603-612. 
 


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APPENDIX 1.  SCHEDULE OF STUDY VISITS 
 
VISIT 1 
(Enrollment, Day 1)a 
VISIT 2 PHONE CALL 
(After 4 weeks on 
placebo)a 
VISIT 3 PHONE CALL 
(After 8 weeks on 
placebo)a 
VISIT 4 PHONE CALL 
(After 4 weeks in 
active phase)a 
VISIT 5 PHONE CALL 
(After 4 weeks in 
active phase)a 
Informed Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Complete Physical Exam 
X 
 
 
 
 
Height  
X 
 
 
 
 
Weight  
X 
 
 
 
 
Vital Signs  
X 
 
 
 
 
Pregnancy Test (Urine)  
X 
 
 
 
 
Randomization 
 
 
X 
 
 
Dispensing or Administration of 
Study Drug 
X 
 
X 
 
 
Counting of Returned Study Drug 
 
 
X 
 
X 
Initiate Subject Diary 
X 
 
 
 
 
Subject Diary Review 
 
X 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
Adverse Experiences 
 
X 
X 
X 
X 
a  
3 business 


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APPENDIX 2.  Nature’s Bounty Melatonin 3mg Label 
 
 


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APPENDIX 3.  Safeway Compounding Pharmacy 
 
  


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APPENDIX 4.  Labdoor Safety Review  
 
 


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