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Gelfand AA, Qubty W, Patniyot I, et al. Home-Based Trials in Adolescent Migraine: A Randomized Clinical Trial. JAMA Neurol. 2017;74(6):744–745. doi:10.1001/jamaneurol.2017.0285
Randomized trials are needed to identify safe and effective migraine preventive treatments for children. Conventional trials typically require frequent in-person study visits.1 Many families decline study participation, citing time and distance.2 Home-based trials are a novel, participant-centered design innovation wherein most or all study procedures are completed remotely using technology.
Melatonin is safe and effective for migraine prevention in adults.3 In this pilot study, we assessed the feasibility of a home-based trial of melatonin for adolescent migraine prevention.
We conducted a randomized, double-blind, placebo-controlled pilot study of melatonin, 3 mg (Rugby Laboratories), vs placebo for migraine prevention in children aged 12 to 17 years. Participants were recruited via our clinic, flyers, social media, print advertisements, and parent letters (Table 1). Screening occurred on our study website; eligible participants were invited for a 1-time study center enrollment visit. Diagnosis of migraine by International Classification of Headache Disorders, 3rd edition (beta version) criteria4 was confirmed by a pediatric headache neurologist. Remaining study procedures were conducted from home. The institutional review board of the University of California, San Francisco approved this study (clinicaltrials.gov identifier: NCT02344316). Parents provided written informed consent and adolescents provided assent.
Participants received a nightly text message on their smartphone that linked to a secure web-based electronic headache diary. Study staff monitored diary compliance and provided reminders. After a 28-day baseline, those with 80% or greater diary compliance and the requisite number of headaches were randomized to melatonin or placebo for 12 weeks. Study medication was shipped to homes. Participants recorded sleep using Fitbits (Fitbit Inc). Sleep data synced to participants’ smartphones or computers and automatically transferred to the study database via application program interface calls. Adverse events were assessed via telephone twice monthly. The enrollment goal was 30 participants.
The aims of this study were to (1) determine the success vs cost of various recruitment strategies, (2) demonstrate enrollment feasibility, (3) estimate study completion rate, (4) estimate variance in headache outcomes using home-trial methodology, and (5) assess adverse events. Mann-Whitney, χ2, and Fisher exact tests as well as multivariable linear regression were used.
Initially, adolescents with 6 to 14 migraine/migrainous days per month not taking prevention therapy were eligible. However, after 4 months, only 17 of 128 participants (13.3%) passed screening and only 10 enrolled. The main reasons for screen failure were (1) too many (n = 51) or too few (n = 38) headaches and/or (2) taking prevention therapy (n = 48). We broadened inclusion criteria to allow participants with stable prevention and 2 to 24 migraine days per month. We also increased social media advertisements. Thereafter, 20 additional participants enrolled in 7 weeks. A 31st enrolled entirely remotely using telemedicine as a proof of principle. Twenty-six fulfilled randomization criteria; 5 had too few migraine/migrainous days to randomize.
Baseline characteristics were similar between groups, except the Pediatric Migraine Disability Assessment score (headache-related disability) was higher in the melatonin group. Outcome data were available for 23 of 26 participants (89%). Mean migraine days was lower in the melatonin group vs the placebo group in the final 4 weeks of treatment (the primary outcome measure) but was not statistically significant (mean [SE] days, 3.6 [0.9] vs 4.9 [1.7]; difference, −1.3; 95% CI for difference, −5.1 to 2.6). Adjusted mean (SE) days with migraine was 3.1 (1.3) in the melatonin group and 5.4 (1.4) in the placebo group (difference, −2.3; 95% CI for difference, −6.3 to 1.8). Sleep outcomes did not differ. There were no serious adverse events (Table 2). Three participants withdrew (2 from placebo group and 1 from melatonin group).
This pilot study demonstrates the feasibility of home-based trials for adolescent migraine. With optimized inclusion criteria and social media recruiting, we exceeded our enrollment goal. Web-based electronic headache diaries and physiologic data from a wearable device proved feasible for collecting data and allowed for timely data collection and compliance monitoring. The study completion rate was excellent (89%).
There were no serious adverse events. Migraine days in the final 4 weeks were lower in the melatonin group compared with the placebo group, which could be due to chance. A fully powered study is merited. Based on the observed variance, we would need 75 participants per arm to detect a difference of 2.3 migraine days per month.
Home-based trials can accelerate neurological therapeutic development and may be preferable for certain patient populations.
Corresponding Author: Amy A. Gelfand, MD, MAS, Pediatric Headache Program, Department of Neurology, University of California, San Francisco, Mission Hall Box 0137, 550 16th St, 4th Floor, San Francisco, CA 94158 (firstname.lastname@example.org).
Published Online: April 24, 2017. doi:10.1001/jamaneurol.2017.0285
Author Contributions: Dr Gelfand had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gelfand, Pletcher, Goadsby, Cummings.
Acquisition, analysis, or interpretation of data: Gelfand, Qubty, Patniyot, Grimes, Pletcher, Cummings.
Drafting of the manuscript: Gelfand, Grimes, Goadsby.
Critical revision of the manuscript for important intellectual content: Gelfand, Qubty, Patniyot, Pletcher, Cummings.
Statistical analysis: Gelfand, Grimes.
Obtained funding: Gelfand, Cummings.
Administrative, technical, or material support: Gelfand, Qubty, Patniyot, Pletcher.
Supervision: Gelfand, Pletcher, Goadsby.
Conflict of Interest Disclosures: Dr Gelfand has received research support from eNeura and Allergan, travel expenses from Teva, consulting fees from Zosano and Eli Lilly, and personal fees from Up-to-Date. Her spouse has received research support from Genentech, MedDay, and Quest Diagnostics and has received personal compensation for medical-legal consulting as well as consulting fees from Genentech. Dr Pletcher has received research support from Zoll. Dr Goadsby has received grants and personal fees from Allergan, Amgen, and Eli Lilly and Company; personal fees from Akita Biomedical, Alder Biopharmaceuticals, Autonomic Technologies, Avanir Pharma, Cipla, Colucid Pharmaceuticals, Dr Reddy’s Laboratories, eNeura, Electrocore LLC, Novartis, Pfizer, Promius Pharma, Quest Diagnostics, Teva Pharmaceuticals, Trigemina, and Scion; and personal fees for medical-legal consulting from Journal Watch, Up-to-Date, and Oxford University Press. In addition, Dr Goadsby has a patent pending for magnetic stimulation for headaches assigned to eNeura. Dr Cummings has consulted for Eli Lilly, Merck, Radius, Amgen, Sermonix, Regeneron, Calico, Grail, Google Research, and Verily. No other disclosures were reported.
Funding/Support: Dr Gelfand received salary support and research funding for this study from grant 8KL2TR000143-09 from the National Center for Advancing Translational Sciences. Additional funding was provided by the Migraine Research Foundation; the University of California, San Francisco Clinical and Translational Science Institute; the Irene Perstein Award; and a philanthropic donation to the University of California, San Francisco Pediatric Headache Program.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We acknowledge Jessica Litwin, MD (Department of Neurology, University of California, San Francisco), for her assistance in discussions with Dr Gelfand regarding the role of melatonin in pediatric sleep, Andrew Charles, MD (Department of Neurology, University of California, San Francisco), for his insights into migraine preventive trial design, and Laura Dapkus, BS (Pediatric Headache Program, Department of Neurology, University of California, San Francisco), for her assistance as the study coordinator.
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