BRAiN-M: Bringing Relief to Adolescents Naturally Using Melatonin for Migraine

• Sponsor: Amy Gelfand (Other)
• Overall Status: Completed
• CT.gov ID: NCT02344316
• Collaborator: University of California, Los Angeles (Other)
• Enrollment: 31
• Locations: 2
• Arms: 2
• Duration (Months): 11
• Patients Per Site: 15.5
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

Migraine in adolescents is common and effective and safe preventive treatments are needed. This is a pilot randomized controlled trial of melatonin versus placebo for migraine prevention in adolescents 12-17 years old.

Condition or Disease	Intervention/Treatment	Phase
Migraine in Adolescents	Drug: Melatonin; Other: Placebo	Phase 2

Detailed Description

This is a pilot randomized controlled trial of melatonin vs. placebo for migraine prevention in adolescents 12-17 years old. The main goal of this pilot study is to estimate variance in the outcome measures to help with planning the future fully powered study. Participants will have an in person enrollment visit, followed by phone follow up visits and headache diary data collection via smart phone or internet.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Melatonin for Migraine Prevention in Adolescents: A Pilot Remote Trial: "The BRAiN-M Study"
• Study Start Date: May 1, 2015
• Actual Primary Completion Date: Apr 1, 2016
• Actual Study Completion Date: Apr 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Melatonin Group randomized to melatonin 3 mg orally nightly	Drug: Melatonin; Taken at 9 PM or 1 hour before bedtime, whichever is earlier; Other Names: Rugby melatonin
Placebo Comparator: Placebo Group randomized to placebo orally nightly	Other: Placebo; Matching placebo taken at 9 PM or 1 hour before bedtime, whichever is earlier

Outcome Measures

Primary Outcome Measures

1. Number of Migraine/Migrainous Days Per 28 Day Period [final 4 weeks of treatment]

   Number of Migraine/Migrainous Days Per 28 Day Period in melatonin group and placebo group as measured using an online/mobile device headache diary.

Secondary Outcome Measures

1. Number of Minutes to Sleep Onset [16 weeks]

   Number of minutes to sleep onset as measured by a FitBit.

2. Number of Participants Recruited From Each Recruitment Strategy [During the enrollment period, approximately 1 year]

   Each recruitment strategy will be analyzed for number of participants successfully enrolled.

3. Medication Adherence as Measured by Number of Openings Per Participant [during the "At Home Active Study Period" or Weeks 5-16]

   eCAP tack caps will be used to measure medication adherence and the number of openings will be recorded per participant.

4. Headache Diary Compliance Rate [Weeks 12-16 of the study]

   Number of participants that had ≥85% headache diary compliance during weeks 12-16 of the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age 12-17 years and weight ≥40 kg, to allow consistent dosing for all participants of the melatonin dose that has been found to be effective in adults

2. Resides in California

3. Headache fulfills International Classification for Headache Disorders, Third Edition (beta version)33 criteria for episodic migraine (with or without aura) in adolescents

4. Has been experiencing episodic headaches for at least six months

5. Experiences between 6-14 days of migraine/migrainous headaches per month at baseline (cutoff for chronic migraine is ≥15 days/month)

6. Developmentally able to provide age-appropriate level of assent

7. Has a parent/guardian capable of giving written informed consent

8. Has daily access to a smartphone in order to be able to complete daily study procedures such as diary completion, and to receive text reminders

9. Subject and parent agree the adolescent will not use over-the-counter melatonin, or another migraine preventive medication, while participating in the study

10. Participant and at least one parent speak English

Exclusion Criteria:

1. Currently (or within the last 4 weeks) using any medication or device with migraine preventive properties: i.e. topiramate, amitriptyline, nortriptyline, propranolol, metoprolol, sodium valproate, gabapentin, flunarizine, methysergide, riboflavin, butterbur, coenzyme Q10, or the Cefaly TENS device. For onabotulinum toxin, they will have to have been off it for at least three months

2. Use of other sleep medication or sedating medication, such as benzodiazepines, trazodone, or melatonin receptor agonists

3. History of allergy or adverse event with previous use of exogenous melatonin

4. Previous ineffective trial of melatonin 3 mg nightly for migraine prevention, where the trial duration was at least three months in duration

5. Inability to swallow pills, if this inability persists after instruction on pill-swallowing techniques

6. History of epilepsy or seizure

7. Overuse of acute headache medications, wherein medication overuse is defined33 as ≥4 days per month of barbiturate containing compounds, ≥10 days per month of opioid containing compounds, or ≥10 days per month of triptans or ergot-containing compounds. Those using non-specific analgesics ≥15 days per month would also be excluded

8. Adolescent does not have the cognitive capacity to give verbal assent to participate, or the investigator thinks the adolescent does not have the cognitive capacity to complete the diary, even with parental assistance

9. For females: Pregnancy, lactating or planning to become pregnant during the study. For males: planning to father a child during the study

10. Abnormal neurologic examination findings

11. Serious medical illness of any kind; seriousness as judged by the investigator

12. The investigator does not think the participant can comply with study procedures, or does not think it is medically appropriate for the participant to be in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Headache Research and Treatment Program	Los Angeles	California	United States	90077
2	UCSF Pediatric Brain Center	San Francisco	California	United States	94158

Sponsors and Collaborators

• Amy Gelfand
• University of California, Los Angeles

Investigators

• Principal Investigator: Amy A Gelfand, MD, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

• Fallah R, Shoroki FF, Ferdosian F. Safety and efficacy of melatonin in pediatric migraine prophylaxis. Curr Drug Saf. 2015;10(2):132-5.
• Masruha MR, de Souza Vieira DS, Minett TS, Cipolla-Neto J, Zukerman E, Vilanova LC, Peres MF. Low urinary 6-sulphatoxymelatonin concentrations in acute migraine. J Headache Pain. 2008 Aug;9(4):221-4. doi: 10.1007/s10194-008-0047-5. Epub 2008 Jul 2.
• Masruha MR, Lin J, de Souza Vieira DS, Minett TS, Cipolla-Neto J, Zukerman E, Vilanova LC, Peres MF. Urinary 6-sulphatoxymelatonin levels are depressed in chronic migraine and several comorbidities. Headache. 2010 Mar;50(3):413-9. doi: 10.1111/j.1526-4610.2009.01547.x. Epub 2009 Oct 8.
• Peres MF, Masruha MR, Zukerman E, Moreira-Filho CA, Cavalheiro EA. Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opin Investig Drugs. 2006 Apr;15(4):367-75. Review.
• Peres MF, Sanchez del Rio M, Seabra ML, Tufik S, Abucham J, Cipolla-Neto J, Silberstein SD, Zukerman E. Hypothalamic involvement in chronic migraine. J Neurol Neurosurg Psychiatry. 2001 Dec;71(6):747-51.
• Peres MF, Zukerman E, da Cunha Tanuri F, Moreira FR, Cipolla-Neto J. Melatonin, 3 mg, is effective for migraine prevention. Neurology. 2004 Aug 24;63(4):757.

• Responsible Party: Amy Gelfand, Assistant Professor of Neurology, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02344316
• Other Study ID Numbers: 14-14251
• First Posted: Jan 22, 2015
• Last Update Posted: Sep 9, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Migraine Disorders; Melatonin

Study Results

Participant Flow

Pre-assignment Detail	There was a 28 day baseline run-in prior to randomization.

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	Group randomized to melatonin 3 mg orally nightly Melatonin: Taken at 9 PM or 1 hour before bedtime, whichever is earlier	Group randomized to placebo orally nightly Placebo: Matching placebo taken at 9 PM or 1 hour before bedtime, whichever is earlier
Period Title: Overall Study
STARTED	13	13
COMPLETED	12	11
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Melatonin	Placebo	Total
Arm/Group Description	Group randomized to melatonin 3 mg orally nightly Melatonin: Taken at 9 PM or 1 hour before bedtime, whichever is earlier	Group randomized to placebo orally nightly Placebo: Matching placebo taken at 9 PM or 1 hour before bedtime, whichever is earlier	Total of all reporting groups
Overall Participants	13	13	26
Age (Count of Participants)
<=18 years	13 100%	13 100%	26 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15 (1.2)	14.1 (1.7)	14.5 (1.5)
Sex: Female, Male (Count of Participants)
Female	8 61.5%	8 61.5%	16 61.5%
Male	5 38.5%	5 38.5%	10 38.5%
Region of Enrollment (participants) [Number]
United States	13 100%	13 100%	26 100%

Outcome Measures

1. Primary Outcome

Title	Number of Migraine/Migrainous Days Per 28 Day Period
Description	Number of Migraine/Migrainous Days Per 28 Day Period in melatonin group and placebo group as measured using an online/mobile device headache diary.
Time Frame	final 4 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	Group randomized to melatonin 3 mg orally nightly Melatonin: Taken at 9 PM or 1 hour before bedtime, whichever is earlier	Group randomized to placebo orally nightly Placebo: Matching placebo taken at 9 PM or 1 hour before bedtime, whichever is earlier
Measure Participants	12	11
Mean (Standard Error) [days]	3.6 (0.9)	4.9 (1.7)

2. Secondary Outcome

Title	Number of Minutes to Sleep Onset
Description	Number of minutes to sleep onset as measured by a FitBit.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	Group randomized to melatonin 3 mg orally nightly Melatonin: Taken at 9 PM or 1 hour before bedtime, whichever is earlier	Group randomized to placebo orally nightly Placebo: Matching placebo taken at 9 PM or 1 hour before bedtime, whichever is earlier
Measure Participants	13	13
Mean (Standard Deviation) [minutes]	15.2 (10.7)	17.2 (12)

3. Secondary Outcome

Title	Number of Participants Recruited From Each Recruitment Strategy
Description	Each recruitment strategy will be analyzed for number of participants successfully enrolled.
Time Frame	During the enrollment period, approximately 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	All Participants
Measure Participants	31
Clinic recruitment	6 46.2%
Newspaper advertising	3 23.1%
Social media advertising (eg, Facebook and Google+	11 84.6%
Electronic medical record letter invitation	10 76.9%
Other	1 7.7%

4. Secondary Outcome

Title	Medication Adherence as Measured by Number of Openings Per Participant
Description	eCAP tack caps will be used to measure medication adherence and the number of openings will be recorded per participant.
Time Frame	during the "At Home Active Study Period" or Weeks 5-16

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	Group randomized to melatonin 3 mg orally nightly Melatonin: Taken at 9 PM or 1 hour before bedtime, whichever is earlier	Group randomized to placebo orally nightly Placebo: Matching placebo taken at 9 PM or 1 hour before bedtime, whichever is earlier
Measure Participants	12	12
Mean (Standard Deviation) [Mean Number of Openings]	39 (27)	60 (28)

5. Secondary Outcome

Title	Headache Diary Compliance Rate
Description	Number of participants that had ≥85% headache diary compliance during weeks 12-16 of the study.
Time Frame	Weeks 12-16 of the study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Melatonin	Placebo
Arm/Group Description	Group randomized to melatonin 3 mg orally nightly Melatonin: Taken at 9 PM or 1 hour before bedtime, whichever is earlier	Group randomized to placebo orally nightly Placebo: Matching placebo taken at 9 PM or 1 hour before bedtime, whichever is earlier
Measure Participants	12	11
Count of Participants [Participants]	11 84.6%	10 76.9%

Adverse Events

Arm/Group Title	Melatonin		Placebo
Arm/Group Description
All Cause Mortality
	Melatonin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Serious Adverse Events
	Melatonin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Melatonin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/13 (46.2%)		4/13 (30.8%)
Blood and lymphatic system disorders
Low iron on routine labs	1/13 (7.7%)	1	0/13 (0%)	0
Gastrointestinal disorders
Episode of vomiting	1/13 (7.7%)	1	0/13 (0%)	0
General disorders
Daytime tiredness	2/13 (15.4%)	2	0/13 (0%)	0
Unscheduled medical visit for migraine	2/13 (15.4%)	2	0/13 (0%)	0
Fever	0/13 (0%)	0	1/13 (7.7%)	1
Accident	0/13 (0%)	0	3/13 (23.1%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.