Clinical trial NCT03597529
Conditions: Migraine
Sponsor: Amy Gelfand
Start date: 2017-09-25; Completion date: 2019-12-01
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Existing treatments for acute migraine are not effective for all children and adolescents, and can cause side effects. Investigator propose a dose-finding study of melatonin for acute migraine treatment in children and adolescents to determine the best dose to bring forward in a future fully-powered efficacy trial.

Detailed description:
This pilot randomized trial is a dose-finding study to determine which dose of melatonin is most effective for treating acute migraine in children and adolescents who have episodic migraine. Investigator will identify the most effective dose to pull forward into a future fully-powered placebo-controlled efficacy study. If both doses are equally effective, Investigator will bring forward the best tolerated dose. If doses are equally well tolerated, Investigator will bring forward the lowest effective dose, as this will minimize cost to families should this treatment become widely adopted.

Arms: arm 1: melatonin 2mg (equal to or over 40kg) melatonin 1mg (under 40kg) Melatonin: melatonin arm 2: melatonin 8mg (equal to or over 40kg) melatonin 4mg (under 40kg) Melatonin: melatonin
Interventions: intervention 1: Melatonin
Intervention descriptions: intervention 1: melatonin

Protocol documents:
Prot_SAP_000.pdf: 
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AMY GELFAND, MD 
Clinical Research Protocol 
CHOCOlate MeLatonin for AdolescenT MigrainE: 
The CHOCOLATE Study 
Protocol Number: 
CHOCOLATE.01 
Version Date: 
02/05/2018 
Investigational Product: 
Melatonin 1mg – 8mg, formulation by Good Day Chocolate 
IND Number: 
124,226 
NCT Number:  
NCT03597529 
Development Phase: 
Phase 2 
Sponsor: 
Amy Gelfand, MD 
Assistant Professor of Neurology and Pediatrics 
University of California, San Francisco 
550 16th Street, Fourth Floor 
San Francisco, CA 94158 
Funding Organization: 
Funding is provided by the UCSF Pediatric Headache 
Program discretionary funds, and the product is donated by 
Good Day Chocolate 
Principal Investigator: 
Name: Amy Gelfand, MD 
Telephone: 415-885-7832 
Fax: 415-353-2400 
E-mail: Amy.Gelfand@ucsf.edu 
Coordinating Center: 
UCSF 
 
 
Approval: 
 
 
 
Amy Gelfand M.D. 
Assistant Professor of Neurology and Pediatrics, UCSF 
02/05/2018 
 
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 
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: CHOCOLATE.01 
 
Protocol Title: The CHOCOLATE Study: CHOCOlate MeLatonin for AdolescenT MigrainE 
 
Protocol Date: 02/01/2018 
 
 
02/01/2018 
 
Investigator Signature 
Date 
 
Amy Gelfand M.D. 
Assistant Professor of Neurology and Pediatrics 
Print Name and Title 
 
 
Site Name 
UCSF Pediatric Headache Program 
University of California, San Francisco (UCSF) 
Address 
 
550 16th Street, Fourth Floor 
San Francisco, CA 94158 
 
Phone Number 
415-885-7832 
 
 
 


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The CHOCOLATE Study: CHOCOlate MeLatonin for AdolescenT MigrainE 
 
 
 
Principal Investigator 
Amy Gelfand, MD 
Assistant Professor of Neurology and Pediatrics 
University of California, San Francisco 
San Francisco, CA 
 
UCSF Co-Investigator 
William Qubty, MD 
Assistant Professor of Neurology and Pediatrics 
University of California, San Francisco 
San Francisco, CA 
 
Additional Support 
Laura Dapkus- Study Coordinator 
Elaina Allen- Biostatistics 


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TABLE OF CONTENTS 
1 
BACKGROUND ................................................................................................................11 
1.1 
Overview of Non-Clinical Studies..............................................................................11 
1.2 
Overview of Clinical Studies ......................................................................................11 
2 
STUDY RATIONALE .......................................................................................................12 
2.1 
Risk / Benefit Assessment ..........................................................................................12 
3 
STUDY OBJECTIVES ......................................................................................................12 
3.1 
Primary Objective ......................................................................................................12 
3.2 
Secondary Objectives .................................................................................................13 
4 
STUDY DESIGN ................................................................................................................13 
4.1 
Study Overview ..........................................................................................................13 
5 
CRITERIA FOR EVALUATION ....................................................................................13 
5.1 
Primary Efficacy Endpoint .........................................................................................13 
5.2 
Secondary Efficacy Endpoints ....................................................................................13 
5.3 
Safety Evaluations ......................................................................................................14 
6 
SUBJECT SELECTION ...................................................................................................14 
6.1 
Study Population ........................................................................................................14 
6.2 
Inclusion Criteria ........................................................................................................14 
6.3 
Exclusion Criteria .......................................................................................................14 
7 
CONCURRENT MEDICATIONS ...................................................................................14 
7.1 
Allowed and Prohibited Medications .........................................................................15 
8 
STUDY TREATMENTS ...................................................................................................15 
8.1 
Method of Assigning Subjects to Treatment Groups ..................................................15 
8.2 
Blinding......................................................................................................................15 
8.3 
Test and Control Formulation .....................................................................................15 
8.4 
Supply of Study Medication at the Site ......................................................................16 
8.5 
Study Medication Accountability ...............................................................................16 
8.6 
Measures of Treatment Compliance ...........................................................................16 
9 
STUDY PROCEDURES AND GUIDELINES.................................................................16 
9.1 
Clinical Assessments ..................................................................................................17 
10 EVALUATIONS BY VISIT ..............................................................................................17 
10.1 Visit 1 .........................................................................................................................17 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ........................18 
11.1 Adverse Events ...........................................................................................................18 
11.2 Serious Adverse Experiences (SAE) ..........................................................................20 
11.3 Medical Monitoring ....................................................................................................20 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS ...................................20 
12.1 Early Discontinuation of Study Drug ...............................................................20 


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12.3 Withdrawal of Subjects ...............................................................................................20 
12.4 Replacement of Subjects ............................................................................................21 
13 PROTOCOL VIOLATIONS ............................................................................................21 
14 STATISTICAL METHODS AND CONSIDERATIONS ...............................................21 
14.1 Data Sets Analyzed ....................................................................................................21 
14.2 Demographic and Baseline Characteristics.................................................................21 
14.3 Analysis of Primary Endpoint ....................................................................................22 
14.4 Analysis of Secondary Endpoints ...............................................................................22 
14.5 Interim Analysis .........................................................................................................22 
14.6 Sample Size and Randomization ................................................................................22 
15 DATA COLLECTION, RETENTION AND MONITORING .......................................22 
15.1 Data Collection Instruments .......................................................................................22 
15.2 Data Management Procedures ....................................................................................23 
15.3 Data Quality Control and Reporting ...........................................................................23 
15.4 Archival of Data .........................................................................................................23 
15.5 Availability and Retention of Investigational Records ...............................................23 
15.6 Monitoring .................................................................................................................23 
15.7 Subject Confidentiality ...............................................................................................23 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ...................24 
16.1 Protocol Amendments ................................................................................................24 
16.2 Institutional Review Boards and Independent Ethics Committees .............................24 
16.3 Informed Consent Form .............................................................................................25 
16.4 Publications ................................................................................................................25 
16.5 Investigator Responsibilities ......................................................................................25 
17 REFERENCES .........................................................................................................26 


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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 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
PI 
Principal Investigator 
SAE 
SAP 
UCSF 
US 
Serious Adverse Experience 
Statistical Analysis Plan 
University of California, San Francisco 
United States 
VAS (Visual Analog Scale) 
ICHD (International Classification of Headache Disorders) 


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PROTOCOL SYNOPSIS 
 
TITLE 
The CHOCOLATE Study: CHOCOlate MeLatonin for AdolescenT MigrainE 
SPONSOR 
Investigator Initiated Study (Dr. Amy Gelfand) 
FUNDING 
ORGANIZATION 
Funding is provided by the UCSF Pediatric Headache Program 
discretionary funds, and the product is donated by Good Day 
Chocolate 
NUMBER OF SITES 
1 
RATIONALE 
Migraine is common in children and adolescents. 
It causes pain and suffering and disability. 
Acute medications exist but do not work for everyone and may cause 
side effects. Some patients and parents will prefer a natural 
supplement for acute treatment rather than a prescription or over-the- 
counter pharmacologic agent. 
Melatonin has recently been shown to be effective for migraine 
prevention in adults and some early work suggests it may also be 
effective for migraine prevention in children and adolescents. Some 
migraine treatments that are helpful as preventives can also be helpful 
acutely. This is a dose-finding study to begin to examine whether 
melatonin might also be helpful acutely for treating migraine in 
children and adolescents. 
STUDY DESIGN 
This pilot randomized trial is a dose-finding study to determine which 
dose of melatonin is most effective for treating acute migraine in 
children and adolescents who have episodic migraine. We will 
identify the most effective dose to pull forward into a future fully- 
powered placebo-controlled efficacy study. If both doses are equally 
effective, we will bring forward the best tolerated dose. If doses are 
equally well tolerated, we will bring forward the lowest effective 
dose, as this will minimize cost to families should this treatment 
become widely adopted. 
PRIMARY 
OBJECTIVE 
To determine a change in mean VAS score between baseline and 2-hr 
time point in low-dose vs. high-dose group. 


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SECONDARY 
OBJECTIVES 
• 
To determine a change in mean VAS score between baseline 
and 2-hr time point in low-dose vs. high-dose group in the < 40 
kg and the ≥40 kg subgroups. (We will also do sensitivity 
analyses of completers who were awake for the 2-hr time point). 
• 
To determine the tolerability/side effects of high-dose vs. low-dose 
in the group over all, and in weight-based strata. 
• 
To determine the proportion of participants who get to mild/no 
pain by 2 hrs (overall and by weight group), and who remain at 
mild/no pain from 2-24 hours 
• 
To determine the proportion of participants who get to 
mild/no of each of: pain, photophobia, phonophobia, 
nausea, vomiting at 30, 60, 90, and 120 minutes and 24 
hours; both overall and in weight based strata. 
• 
To determine the proportion of parents/participants who 
found the treatment useful, and who preferred it over 
other treatments they'd tried. 
• 
Using logistic regression, we will examine for possible 
predictors of treatment efficacy (sex, age, nap, nap duration, 
etc). 
• 
To determine the proportion of participants who needed rescue 
medication between 2-24 hrs, both overall and by weight- based 
strata. 
NUMBER OF 
SUBJECTS 
100 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
1. Meet ICHD criteria for episodic migraine in children and adolescents, 
with at least 1 migraine attack per month on average. 
2. Age 3-17 years 
3. Dissatisfaction with previous acute treatments, for one or more of the 
following reasons: a) One or more previously tried acute medications have 
not been effective, or adequately effective, b) previously tried acute 
treatments have caused side effects, or C) patient/family would prefer a 
natural supplement for acute treatment over medication treatment 
4. If of driving age, teen participant agrees not to drive for at least 8 hours 
after treating with melatonin. 
Exclusion Criteria: 
1. Allergy or intolerance to melatonin, or to chocolate. 
2. Opioid or barbiturate overuse as defined in ICHD 
3. Pregnant/lactating 


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TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Good Day Chocolate melatonin 1-8mg per attack, taken my mouth 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
N/A 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Participation duration depends on how long it takes to treat two 
migraine headache attacks. In total, it will take approximately 2-3 
hours to complete the study. Enrollment will take place over 24 
months. 
CONCOMMITANT 
MEDICATIONS 
Allowed: All 
Prohibited: N/A 
Acute migraine medications such as ibuprofen (Motrin), 
acetaminophen (Tylenol), naproxen (Aleve) or a triptan (for 
example, sumatriptan) may be taken during the study, but we will 
ask participants to try to wait 2 hours after they take the study 
treatment, in order to see if the study treatment is effective. 
EFFICACY 
EVALUATIONS 
VAS pain scores between baseline and 2-hr time point 
PRIMARY ENDPOINT 
To determine a change in mean VAS score between baseline and 2-hr 
time point in low-dose vs. high-dose group. 
SECONDARY 
ENDPOINTS 
• 
To determine a change in mean VAS score between baseline 
and 2-hr time point in low-dose vs. high-dose group in the < 40 
kg and the ≥40 kg subgroups. (We will also do sensitivity 
analyses of completers who were awake for the 2-hr time point). 
• 
To determine the tolerability/side effects of high-dose vs. low-dose 
in the group over all, and in weight-based strata. 
• 
To determine the proportion of participants who get to mild/no 
pain by 2 hrs (overall and by weight group), and who remain at 
mild/no pain from 2-24 hours 
• 
To determine the proportion of participants who get to 
mild/no of each of: pain, photophobia, phonophobia, 
nausea, vomiting at 30, 60, 90, and 120 minutes and 24 
hours; both overall and in weight based strata. 


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• 
To determine the proportion of parents/participants who 
found the treatment useful, and who preferred it over 
other treatments they'd tried. 
• 
Using logistic regression, we will examine for possible 
predictors of treatment efficacy (sex, age, nap, nap duration, 
etc). 
• 
To determine the proportion of participants who needed rescue 
medication between 2-24 hrs, both overall and by weight- based 
strata. 
OTHER 
EVALUATIONS 
Headache Diary 
SAFETY 
EVALUATIONS 
Incidence of adverse events. 
PLANNED INTERIM 
ANALYSES 
Serious adverse events will be monitored by the PI and the UCSF IRB 
on an ongoing basis throughout the study. 
STATISTICS 
Primary Analysis Plan 
To detect a mean difference of 3 cm (SD 3) on the change in VAS 
between doses, an effect size that has been considered clinically 
meaningful in previous pediatric migraine work, we would anticipate 
needing 2-hour outcome data on 16 individuals per arm for subjects 
treating only one attack. However, we will be able to control within 
subject variability to a degree by having subjects treat two attacks, and 
thus will revise the estimate to needing outcome data on 12 per group. 
We will use generalized estimating equations (GEE) to compare mean 
change from baseline to 2-hour time-points in high-dose vs. low-dose, 
controlling for repeated measures. 
Rationale for Number 
of Subjects 
Assuming 15% drop-out, and adding an extra 20% data-loss for those 
who will be asleep at the 2-hour time point assessment, we anticipate 
needing to enroll 19 participants per dosing arm. As we wish to be 
able to perform this analysis both for the group overall (i.e. all “high 
dose” vs. all “low dose”), and for the <40 kg and ≥40 kg subgroups 
individually, we will need to enroll a total of 76 participants. 
19 @ < 40 kg, given 1 mg at each of 2 attacks 
19 @ < 40 kg given 4 mg at each of 2 attacks 
19 @ ≥40 kg given 2 mg at each of 2 attacks 
19 @ ≥40 kg given 8 mg at each of 2 attacks 


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1 
BACKGROUND 
Migraine is common in children and adolescents. It affects 5% of children by age ten and 
prevalence increases further in adolescence. In addition to causing pain, migraine causes children 
and teens to miss school and can impact their school performance. While acute medications exist 
for treating migraine in children and adolescents, they do not work for all children and can cause 
significant side effects. In addition, some patients and parents prefer a natural supplement for 
acute migraine treatment rather than a prescription or over-the-counter pharmacologic agent (e.g. 
sumatriptan or ibuprofen). Additional safe, well- tolerated and effective acute migraine 
treatments are needed to help those who do not respond to existing therapies, experience 
significant side effects from existing therapies, or who prefer not to be taking prescription acute 
medications. 
 
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 
Melatonin is effective for migraine prevention in adults and data suggest it may also be effective 
for migraine prevention in children and adolescents. Our clinical experience suggests melatonin 
may also be helpful for treating acute migraine in children and adolescents, even among some 
who do not respond to other acute agents. There are several possible mechanisms by which 
melatonin might help migraine acutely. Melatonin may help children get to sleep, and sleep 
seems to be helpful in terminating migraine attacks. Melatonin may also have direct, acute 
analgesic effects. It has been used to treat acute procedural pain in children, without significant 
safety issues, even when administered at a high-dose of 10mg/kg IV to neonates who were 
undergoing endotracheal intubation (i.e. a dose of about 30 mg IV for a typical 3 kg neonate). 
There are melatonin receptors in both the thalamus (part of the ascending nociceptive pathway) 
and the periaqueductal grey (part of the descending anti-nociceptive pathway). There are also 
melatonin receptors in the hypothalamus, a part of the brain thought to be involved in generating 
migraine attacks. In animals, melatonin has been shown to decrease the amount of trigeminal 
nociceptive activation induced by cortical spreading depression, suggesting it could be effective 
acutely for migraine. 
 
It is already established that certain agents that are traditionally thought of as useful for migraine 
prevention can also be useful for treating acute migraine—such as sodium valproate. The 
reverse also appears to be true, for example the NSAID naproxen is effective for acute migraine 
treatment but also can be effectively used as a migraine preventive. The question now arises 
whether melatonin—known to be effective for migraine prevention in adults and likely in 
children—can also be effective acutely for migraine. 
 
This proposed pilot trial is a dose finding study to determine which dose of melatonin is most 
effective at treating acute migraine in children and adolescents who have episodic migraine. The 


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doses being studied here are well within the range of what has been safely studied in children 
before.  We propose, depending on weight, to give between 1 mg and 8 mg of melatonin, once, 
at onset of headache. Each participant would treat two attacks. As noted above, neonates have 
safely been given 10mg/kg IV for peri-procedural pain management. Children undergoing 
auditory brainstem response tests were given 5-20 mg. Doses of 0.25-0.5 mg/kg have been given 
for MRI sedation—which would equate to about 15 mg for a 30 kg child. In another study, 
children were given 10 mg for MRI sedation. Our clinical experience suggests that for acute 
migraine treatment, 1-4 mg of melatonin would be adequate for children < 40 kg, and 2-8 mg for 
children and adolescents >40 kg. We propose to study a melatonin formulation that is an edible 
(i.e. chewable) milk-chocolate based formulation. We consider this formulation to have three 
potential advantages: 
 
1. More rapid onset than a tablet/capsule formulation, potentially allowing for faster relief 
and in turn potentially a higher chance or relief, as treating when the pain is still mild has 
been shown to predict efficacy of other acute migraine treatments. 
2. Young children who cannot yet swallow pills will be able to take this formulation. 
3. Children who are nauseated during migraine attacks may still find a chocolate-based 
formulation palatable and be willing to take it during an attack. 
 
 
2 
STUDY RATIONALE 
This pilot study is a dose finding study to determine what dose of melatonin seems effective for 
treating acute migraine in children and adolescents with episodic migraine. We will identify the 
most effective dose to pull forward into a future fully-powered placebo-controlled efficacy study. 
If doses are equally effective, we will bring forward the best tolerated dose. If equally well 
tolerated, we will bring forward the lowest effective dose, as this will minimize cost to families 
should this treatment become widely adopted. 
 
2.1 
Risk / Benefit Assessment 
 
2.2 
Very low risks to participating in this study, and inconvenience to the participant/family is 
minimized as most/all study activities can be completed from the participant's home. 
 
3 
STUDY OBJECTIVES 
 
3.1 
Primary Objective 
To determine a change in mean VAS score between baseline and 2-hr time point in low-dose vs. 
high-dose group. 
 
3.2 
Secondary Objectives 
• 
To determine a change in mean VAS score between baseline and 2-hr time point in low- 
dose vs. high-dose group in the < 40 kg and the ≥40 kg subgroups. (We will also do 
sensitivity analyses of completers who were awake for the 2-hr time point). 


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• 
To determine the tolerability/side effects of high-dose vs. low-dose in the group over all, and 
in weight-based strata. 
• 
To determine the proportion of participants who get to mild/no pain by 2 hrs (overall and 
by weight group), and who remain at mild/no pain from 2-24 hours 
• 
To determine the proportion of participants who get to mild/no of each of: pain, 
photophobia, phonophobia, nausea, vomiting at 30, 60, 90, and 120 minutes and 24 
hours; both overall and in weight based strata. 
• 
To determine the proportion of parents/participants who found the treatment 
useful, and who preferred it over other treatments they'd tried. 
• 
Using logistic regression, we will examine for possible predictors of treatment efficacy 
(sex, age, nap, nap duration, etc). 
• 
To determine the proportion of participants who needed rescue medication between 2-24 hrs, both 
overall and by weight- based strata. 
 
4 
STUDY DESIGN 
 
4.1 
Study Overview 
This randomized pilot trial is a dose finding study to determine which dose of melatonin is most 
effective for treating acute migraine in children and adolescents who have episodic migraine. 
Participants will be randomized to a higher-dose or a lower-dose, stratified by weight (< 40 kg 
and ≥40 kg). They will treat 2 acute headache attacks and will complete a symptom diary for 
those 2 attacks and then return the diary to the study center. Randomization will be done in 
blocks of 4 to ensure equal group size and will be stratified by weight (< 40 kg or ≥40 kg). 
 
5 
CRITERIA FOR EVALUATION 
 
5.1 
Primary Efficacy Endpoint 
To determine in a randomized trial which dose of melatonin, “high dose” vs. “low dose”, is more 
effective at two-hours for acute migraine head pain in children and adolescents who have 
episodic migraine. 
 
5.2 
Secondary Efficacy Endpoints 
• 
To determine a change in mean VAS score between baseline and 2-hr time point in low- 
dose vs. high-dose group in the < 40 kg and the ≥40 kg subgroups. (We will also do 
sensitivity analyses of completers who were awake for the 2-hr time point). 
• 
To determine the tolerability/side effects of high-dose vs. low-dose in the group over all, and 
in weight-based strata. 
• 
To determine the proportion of participants who get to mild/no pain by 2 hrs (overall and 
by weight group), and who remain at mild/no pain from 2-24 hours 
• 
To determine the proportion of participants who get to mild/no of each of: pain, 
photophobia, phonophobia, nausea, vomiting at 30, 60, 90, and 120 minutes and 24 
hours; both overall and in weight based strata. 
• 
To determine the proportion of parents/participants who found the treatment 


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useful, and who preferred it over other treatments they'd tried. 
• 
Using logistic regression, we will examine for possible predictors of treatment efficacy 
(sex, age, nap, nap duration, etc). 
• 
To determine the proportion of participants who needed rescue medication between 2-24 hrs, both 
overall and by weight- based strata. 
 
5.3 Safety Evaluations 
Although there is substantial safety data for the use of melatonin in children and adolescents (as 
cited above), safety will be carefully monitored throughout this study by review of the headache 
diary forms by the investigator team. 
 
6 
SUBJECT SELECTION 
 
6.1 
Study Population 
Subjects ages 3-17 inclusive with a diagnosis of episodic migraine who meet the inclusion and 
exclusion criteria will be eligible for participation in this study. 
 
6.2 
Inclusion Criteria 
 
1. Meet ICHD criteria for episodic migraine in children and adolescents, with at least 1 
migraine attack per month on average. 
2. Age 3-17 years 
3. Dissatisfaction with previous acute treatments, for one or more of the following reasons: a) 
One or more previously tried acute medications have not been effective, or adequately 
effective, b) previously tried acute treatments have caused side effects, or C) patient/family 
would prefer a natural supplement for acute treatment over medication treatment. 
4. If of driving age, teen participant agrees not to drive for at least 8 hours after treating with 
melatonin. 
 
6.3 
Exclusion Criteria 
1. Allergy or intolerance to melatonin, or to chocolate. 
2. Opioid or barbiturate overuse as defined in ICHD 
3. 
Pregnant/lactating 
 
7 
CONCURRENT MEDICATIONS 
There are no concurrent medication restrictions except as above in the exclusion criteria.. 
 
7.1 
Allowed Medications and Treatments 
Standard therapy for migraine is allowed except for treatments noted in the exclusion criteria 
described above. Acute migraine medications such as ibuprofen (Motrin), acetaminophen 
(Tylenol), naproxen (Aleve) or a triptan (for example, sumatriptan) may be taken during the 


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study, but we will ask participants to try to wait 2 hours after they take the study treatment, in 
order to see if the study treatment is effective. 
 
 
8 
STUDY TREATMENTS 
 
8.1 
Method of Assigning Subjects to Treatment Groups 
Randomization will be done in blocks of 4 to ensure equal group size and will be stratified by 
weight (< 40 kg or ≥40 kg). 
 
8.2 
Blinding 
This is an open label study and there is no blinding 
 
8.3 
Formulation of Test and Control Products 
 
 
8.3.1 
Formulation of Test Product 
Chocolate melatonin pieces, developed by Good Day Chocolate 
Table 1: Formulation of melatonin 
 
 
 
 
 
 
 
8.3.2 
Formulation of Control Product 
There is no control product, all participants will receive chocolate melatonin. 
 
 
8.3.3 
Packaging and Labeling 
Study drug is supplied in bulk from the manufacturer to the study team. The investigator team 
will place 1-8 pieces into each pill bottle, as determined by the randomization scheme. Each 
participant will receive two study treatment bottles—one for attack 1 and one for attack 2. The 
study team will label these bottles with the study ID number, and the attack they are intended for: 
i.e. “Attack 1” or “Attack 2” or “Extra” (in case they drop some or decide to treat a different 
attack). Participants randomized to receive either 1mg or 2mg will receive 4 extra pieces. Those 
randomized to 4mg or 8mg will get 8 extra pieces., 
Melatonin 
Active Ingredient, mg/mL 
Melatonin 1mg per piece 
Other ingredient, mg/mL 
Chamomile extract 


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Supply of Study Drug at the Site 
Good Day Chocolate has donated the chocolate melatonin and the site will store it in a locked 
cabinet at room temperature. 
 
8.3.4 
Dosage/Dosage Regimen 
19 participants @ < 40 kg, given 1 mg at each of 2 attacks 
19 @ < 40 kg given 4 mg at each of 2 attacks 
19 @ ≥40 kg given 2 mg at each of 2 attacks 
19 @ ≥40 kg given 8 mg at each of 2 attacks 
 
8.3.5 
Dispensing 
The investigators will give the participants the study bottles at their clinic visit, or the study 
bottles will be sent to them. 
 
8.3.6 
Administration Instructions 
The study team will instruct the participant and a parent as to how and when to take the study 
chocolates. 
 
8.4 
Supply of Study Drug at the Site 
Good Day Chocolate will send the chocolate to the site and the site will repackage the chocolate 
pieces into study pill dispending bottles. 
 
8.4.1 
Storage 
The study bottles will be stored in a locked cabinet at room temperature. 
 
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 principal investigator will verify these documents throughout the 
course of the study. 
 
8.6 
Measures of Treatment Compliance 
Participants will be asked how many chocolate pieces they took for each attack and they will be 
asked how many of the Extra Pieces were either dropped/thrown away and how many were kept 
for a future or other attack. 
 
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 


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by the subject’s parent or legal guardian. Age appropriate assent will be obtained from the child 
or adolescent prior to conducting any study-related activities. 
 
9.1 
Clinical Assessments 
 
9.1.1 
Concomitant Medications 
Pertinent concomitant medication and concurrent therapies will be documented at 
Baseline/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, sex, race) will be recorded at Screening. 
 
9.1.3 Medical History 
Relevant medical history will be recorded at Screening. 
 
9.1.4 
Physical Examination 
Participants will have had physical examinations performed as part of their clinical care at the 
UCSF Pediatric Headache program. No additional physical examinations will be needed for 
study purposes. 
 
9.1.5 
Vital Signs 
See 9.1.4 
 
9.1.6 
Adverse Events 
Participants and parents will be able to report adverse events at any time during 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). 
 
9.1.7 
Pregnancy Determination 
During enrollment, female subjects who are of childbearing age will be asked if they could be 
pregnant. 
 
10 EVALUATIONS BY VISIT 
 
10.1 Visit 1 
Baseline data will be collected by either an investigator and/or the study coordinator either in- 
person in the clinic, via a recommendation by their doctor or another member of the study team, 
or via phone for those enrolling remotely. All participants will have already been verified to  
meet ICHD criteria for episodic migraine. Headache duration, history, preventive medication  
use pattern, acute medication use pattern, aura status, family history, associated symptoms, 
comorbidities, pregnancy status and other variables will be assessed via questioning either in the 
clinic, chart review or via phone/text. 


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Participants will be instructed to treat two migraine attacks with their assigned melatonin dose. 
For those randomized to either 1mg or 2mg, they will receive 4 extra pieces in case they drop or 
lose any, or would like to use a different headache to track in the event that they take the 
melatonin and then something comes up where they are unable to track that headache for 24 
hours. 
 
For those randomized to 4mg or 8mg, they will receive 8 extra pieces. Participants are instructed 
that they are able to keep any unused pieces for a future attack but will be asked to return the 
empty bottles. Families will be asked to write down on the front cover of the headache diary  
how many of the extra pieces were either kept for later attacks, or were lost/dropped/thrown 
away. Alternatively, the study team will ask the families and record this for them. The diary asks 
how many chocolate pieces were taken for each attack. 
 
Migraine attacks should be separated by at least 24 hours’ headache freedom in between. 
 
Participants will be provided with the Good Day sleep chocolate product and told their randomly 
assigned dose (either 1mg or 4mg for under 40kg, and either 2mg or 8mg for greater than or 
equal to 40kg). They will be given three bottles: 
• Bottle 1 is labeled Attack #1 and will have their exact dose (as described above) 
• Bottle 2 is labeled Attack #2 will have their exact dose (as described above) 
• Bottle 3 is labeled Extra and will have either 4 or 8 pieces so they can have enough extra 
pieces if they drop or lose some of the pieces from bottle 1 or 2, as well as so they can 
use some if they want to treat another attack (they have been instructed to only use the 
dose they are assigned to) 
 
Chocolate melatonin supplies will be given to the parents for all young children who, in the 
opinion of the investigator, may need additional supervision. If a child were to eat all of the 
chocolate melatonin pieces at once, this would still be considered a safe amount, as neonates 
have been safely given 10mg/kg IV melatonin3. 
 
They will also be given a paper headache diary (either in person or shipped). They will be 
instructed to treat as early as possible in an attack, i.e. ideally while the pain is still mild, 
however they will still be permitted to treat even if the pain has reached the moderate or severe 
levels. Participants will be asked to treat attacks that occur at home (or attacks that are not yet 
treated when they reach home), or that occur at another location where they can stay for at least 8 
hours if needed, so as to ensure driving after dosing will not be necessary (for older teens), and 
that headache diaries will be available, and participants can sleep after dosing if desired. 
 
Participants will record baseline pain intensity (and other migraine symptom intensity) at time 
zero, i.e. right before they dose the melatonin. They will be asked not to take other acute 
medications for two hours, and to record pain intensity (and other symptom intensity) at 30, 60, 
90 min and the two-hour time marks. If they fall asleep, parents/caretakers will be instructed not 
to wake them for data collection, as sleep may be a mechanism by which melatonin helps acute 


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migraine. They will resume data collection as soon as they first awaken. They will be asked to 
collect data also at 4 hours and 24 hrs, and to record any acute medication used between 2-24 
hours. They will also be asked to record their impressions about the treatment’s efficacy, side 
effects, and whether or not they slept after dosing and if so for how long. 
 
Study staff will contact participants until they complete the study to remind them about when to 
treat an acute attack and to answer any questions. Participants may be sent ‘retention’ packages 
(small office supplies, pens, or other small items) to remind them about the study. At the 
completion of the study, participants will be asked to mail back the headache diary in a pre-paid 
FedEx envelope. A $5 gift card will be given to participants once they mail back the diary. 
 
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 in the current 
protocol or of greater severity or frequency than expected based on the information in the 
protocol. 
The study team will collect AE information in the headache diary data. Adverse events will be 
recorded in the patient CRF. Adverse events will be described by 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 


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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. 
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: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 


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• 
a persistent or significant disability/incapacity 
• 
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 
CHR Guidelines. The collection period for all SAEs will begin after informed consent is 
obtained and end after procedures for the final study visit have been completed. 
 
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. 
 
11.3 Medical Monitoring 
Dr. Amy Gelfand should be contacted directly at these numbers to report medical concerns or 
questions regarding safety. 
Phone: (415) 860-2202 
Pager: (415) 443-2089 
 
 
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 subject’s 
parent/guardian, or the investigator think that it is not in the subject’s best interest to continue. 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed 
and treated by the Investigator team until the abnormal parameter or symptom has resolved or 
stabilized. 
All subjects who discontinue study treatment should tell the study site. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
 
12.3 
Withdrawal of Subjects from the Study 
A subject may be discontinued from study treatment at any time if the subject, the subject’s 
parent/guardian, or the investigator think that 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. 


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12.4 
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 
Investigator. A copy of the form will be filed in the site’s regulatory binder. 
 
14 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a Statistical Analysis Plan (SAP) will be written 
describing analyses that will be performed. 
 
Data Sets Analyzed 
All eligible patients who are randomized into the study and receive at least one dose of the study 
drug (the Safety Population) will be included in the safety analysis. 
 
14.1 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized by dose level: sex, age, 
and weight. 
 
14.2 Analysis of Primary Endpoint 
We will use generalized estimating equations (GEE) to compare mean change from baseline to 
2-hour time-points in high-dose vs. low-dose, controlling for repeated measures. 
 
14.3 Analysis of Secondary Endpoints 
 
Safety and tolerability data will be summarized by treatment group. 


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Adverse event rates will be coded by body system and MedDra classification term. 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. 
 
14.4 Interim Analysis 
There is no planned interim analysis. 
 
14.5 Sample Size and Randomization 
Participants will be randomized based on weight (over or under 40kg). Randomization will be in 
blocks of 4.  Nineteen participants per arm will be randomized in each of the four treatment 
arms. 
 
 
19 @ < 40 kg, given 1 mg at each of 2 attacks 
19 @ < 40 kg given 4 mg at each of 2 attacks 
19 @ ≥40 kg given 2 mg at each of 2 attacks 
19 @ ≥40 kg given 8 mg at each of 2 attacks 
15 DATA COLLECTION, RETENTION AND MONITORING 
 
15.1 Data Collection Instruments 
Data will be entered by the participant (headache diary) and by study staff (demographics, pill 
counts etc.). Subjects will not be identified by name in the study database, but by subject 
number. The study team will be responsible for data processing, in accordance with procedural 
documentation. Database lock will occur once quality assurance procedures have been 
completed. 
 
Every effort will be made to keep participant data secure, though there is some risk of loss of 
privacy. The main privacy loss risk would be that it could be revealed than a child or adolescent 
has migraine and is taking a treatment for it. While sometimes migraine is stigmatized as being 
“just a headache” and the sufferer can be seen as a “complainer”, by being part of a medical 
research study on migraine treatment that might give legitimacy to the condition and thereby the 
sufferer. 
 
15.2 Data Management Procedures 
The data will be entered into a validated REDCap database. The study team 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. 


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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. 
 
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 maintained. 
Databases are backed up by the database administrator in conjunction with any updates or 
changes to the database. 
 
15.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the IRB 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 and Assent Form and copies of all source 
documentation related to that subject. The Investigator 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 visits will be conducted by the investigator according to the U.S. CFR Title 21 Parts 
50, 56, and 312 and ICH Guidelines for GCP (E6). 
By signing this protocol, the Investigator 
grants permission to appropriate regulatory authorities to conduct on-site monitoring and/or 
auditing of all appropriate study documentation. 
 
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 submitted to the Sponsor. 
Additional subject confidentiality issues (if applicable) are covered in the Clinical Study 
Agreement. 
 
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 and code sheets linking a patient’s name to a patient identification number will be 
stored separately in another locked file cabinet. Clinical information will not be released without 


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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 investigator. Protocol amendments cannot 
be implemented without prior written IRB approval except as necessary to eliminate immediate 
safety hazards 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. 
 
16.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the UCSF IRB prior to study 
initiation. Serious adverse experiences regardless of causality will be reported to the IRB in 
accordance with the standard operating procedures and policies of the IRB, and the Investigator 
will keep the IRB informed as to the progress of the study. The Investigator will obtain 
assurance of IRB compliance with regulations. 
Any documents that the IRB 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. The 
IRB’s 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’s unconditional 
approval statement will be implemented 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 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 and written verification that the modification was 
submitted and subsequently approved should be obtained. 
The IRB 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; an annual update and/or request 
for re-approval; and when the study has been completed. 
 
 
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. 


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The consent form generated by the Investigator must be approved by the IRB. 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. 
A properly executed, written, informed consent will be obtained from each subject’s 
parent/guardian prior to entering the subject into the trial. Information should be given in both 
oral and written form and subjects (or their legal representatives) must be given ample 
opportunity to inquire about details of the study. 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 subject or 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 mutual agreement among the study investigators. 
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 Sponsor (or designee), 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 Sponsor or designee 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 with the Sponsor (or designee). 
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 and the Sponsor (or designee) all changes in the research activity 
and all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 


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10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
 
References: 
 
1. 
Victor TW, Hu X, Campbell JC, Buse DC, Lipton RB. Migraine prevalence by age and 
sex in the United States: a life-span study. Cephalalgia : an international journal of headache 
2010;30:1065-1072. 
2. 
Ambriz-Tututi M, Rocha-Gonzalez HI, Cruz SL, Granados-Soto V. Melatonin: a 
hormone that modulates pain. Life sciences 2009;84:489-498. 
3. 
Gitto E, Aversa S, Salpietro CD, et al. Pain in neonatal intensive care: role of melatonin 
as an analgesic antioxidant. Journal of pineal research 2012;52:291-295. 
4. 
Posa L, De Gregorio D, Gobbi G, Comai S. Targeting melatonin MT2 receptors: A novel 
pharmacological avenue for inflammatory and neuropathic pain. Curr Med Chem 2017. 
5. 
le Grand SM, Patumraj S, Phansuwan-Pujito P, Srikiatkhachorn A. Melatonin inhibits 
cortical spreading depression-evoked trigeminal nociception. Neuroreport 2006;17:1709-1713. 
6. 
Marseglia L, Manti S, D'Angelo G, et al. Potential Use of Melatonin in Procedural 
Anxiety and Pain in Children Undergoing Blood Withdrawal. Journal of biological regulators 
and homeostatic agents 2015;29:509-514. 
7. 
Schmidt CM, Knief A, Deuster D, Matulat P, am Zehnhoff-Dinnesen AG. Melatonin is a 
useful alternative to sedation in children undergoing brainstem audiometry with an age 
dependent success rate--a field report of 250 investigations. Neuropediatrics 2007;38:2-4. 
8. 
Wassmer E, Fogarty M, Page A, et al. Melatonin as a sedation substitute for diagnostic 
procedures: MRI and EEG. Developmental medicine and child neurology 2001;43:136. 
9. 
Johnson K, Page A, Williams H, Wassemer E, Whitehouse W. The use of melatonin as 
an alternative to sedation in uncooperative children undergoing an MRI examination. Clinical 
radiology 2002;57:502-506. 
10. 
Goadsby PJ, Zanchin G, Geraud G, et al. Early vs. non-early intervention in acute 
migraine-'Act when Mild (AwM)'. A double-blind, placebo-controlled trial of almotriptan. 
Cephalalgia : an international journal of headache 2008;28:383-391. 
11. 
Richer L, Craig W, Rowe B. Randomized controlled trial of treatment expectation and 
intravenous fluid in pediatric migraine. Headache 2014;54:1496-1505. 
12. 
Brousseau DC, Duffy SJ, Anderson AC, Linakis JG. Treatment of pediatric migraine 
headaches: a randomized, double-blind trial of prochlorperazine versus ketorolac. Annals of 
emergency medicine 2004;43:256-26