VANCOUVER – Treatment of pediatric patients with amitriptyline, topiramate, or placebo showed no significant difference in reduction of migraine headache frequency, suggesting that pharmacotherapy may need to be reconsidered in this population.
The results of the Childhood and Adolescent Migraine Prevention (CHAMP) study1 were presented at the 2016 Child Neurology Society Annual Meeting in Vancouver, British Columbia, October 26-29, 2016, and simultaneously published in the New England Journal of Medicine.
The CHAMP study sought to identify an efficacious pharmacotherapy option for the treatment of migraine in patients younger than 18 years, as treatment in this population is largely based on consensus rather than scientific evidence.2,3 This is especially troubling, since migraine headache is prevalent in children and adolescents, and poses a significant burden on both the healthcare economy and patient quality of life.4-7
The multicenter, double-blind, placebo-controlled, phase 3 trial enrolled patients from 31 sites across the United States, with end points reflective of a national trend for “clinically meaningful” reduction in headache frequency (≥50%). Participants eligible for randomization had a diagnosis of migraine with or without aura, chronic migraine without continuous headache, a Pediatric Migraine Disability Assessment Scale (PedMIDAS) score of 11 to 139 (range 0-240), and headache frequency of 4 or more days per month, as monitored in a headache diary over a 28-day baseline period.
Following the baseline assessment, eligible participants (N=361) were randomly assigned 2:2:1 to a single dose of oral amitriptyline (1 mg per kg body weight), a single dose of topiramate (2 mg per kg body weight), or placebo taken twice per day (amitriptyline: placebo in the morning, 1 mg amitriptyline in the evening; topiramate: 1 mg topiramate in the morning, 1 mg topiramate in the evening). Doses were increased every 2 weeks for a period of 8 weeks, with modifications based on adverse events. Once the highest dose was achieved, a 16-week maintenance phase was followed up by a 2-week weaning period and a 4-week follow-up period. Participants monitored their headache frequency using a daily headache diary, and headache-related disability was measured using the PedMIDAS. Safety was assessed by reports of adverse events, as well as evaluation with the Child Depression Inventory, Behavior Rating Inventory of Executive Function (BRIEF), and ECG.
Ultimately, 328 participants (mean age 14.2±2.4 years; 68% female) were included in the primary efficacy analysis (amitriptyline, n=132; topiramate, n=130; placebo, n=66). Fifty-two percent of patients in the amitriptyline group achieved ≥50% reduction in headache frequency (28-day baseline [mean headache days 11.4±6.1] compared with the last 28 days of 24-week trial), with 55% and 61% achieving the same in the topiramate and placebo groups, respectively, suggesting that there is no significant difference in efficacy among the two treatments and placebo, both compared with each other and placebo (amitriptyline vs placebo, [odds ratio (OR) 0.71; 98.3% confidence interval (CI), 0.34-1.48, P= .26]; topiramate vs placebo, [OR 0.81; 98.3% CI, 0.39-1.68, P= .48]; amitriptyline vs topiramate, [OR 0.88; 98.3% CI, 0.49-1.59, P= .49]).
Review of secondary outcomes, which were evaluated from a subgroup of patients for whom data were available from baseline and end of study, showed a nonsignificant difference between groups for change in PedMIDAS score (-22.5 (95% CI, -27.6 to -17.4) with amitriptyline, -26.8 (95% CI, -32.2 to -21.5) with topiramate, and -22.6 (95% CI, -30.2 to -15.0) with placebo). No significant between-group difference in headache days was seen from baseline to the final 28 days of the trial, as well.
Notably, more patients in the amitriptyline and topiramate groups dropped out of the study compared with those taking placebo, though this finding was not significant. Twelve serious adverse events were reported in 11 participants during the trial, 5 of which were determined to be treatment related (3 instances of altered mood and 1 incidence of syncope in those treated with amitriptyline, and 1 suicide attempt in the topiramate group). No deaths were reported. The most common adverse events reported in the amitriptyline group were fatigue and dry mouth, while those taking topiramate most commonly experienced paresthesia and weight loss. Other adverse events in the topiramate group included fatigue, dry mouth, impaired memory, aphasia, cognitive disorder, and upper respiratory tract infection.
Ultimately, the trial was stopped early for futility, as an interim analysis suggested that there would be no significant difference in benefit for the preventive medications vs placebo on migraine headache frequency.
Notably, topiramate was recently approved by the US Food and Drug Administration (FDA) for the treatment of episodic migraine in patients aged 12 to 17 years, though these results suggest a questionable benefit in this population.
The authors concluded that the “data do not show a favorable risk-benefit profile for the use of these therapies in pediatric migraine prevention, at least over the 24-week duration of the trial. Our findings also suggest that the adult model of headache treatment, in which amitriptyline and topiramate have been effective, may not apply to pediatric patients.”8
“The study opens the door to many other investigations in order to improve outcomes in children with headaches,” senior author Andrew Hershey, MD, PhD, FAHS, Endowed Chair and Co-Director of Cincinnati Children’s Headache Center, told Neurology Advisor.
See the New England Journal of Medicine site for a full list of disclosures.
For more coverage of CNS 2016, go here.
- Powers SW, Coffey CS, Chamberlin LA, for the CHAMP Investigators. Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N Engl J Med. 27 Oct 2016; doi: 10.1056/NEJMoa1610384. [Epub ahead of print]
- Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, Silberstein S. Practice parameter: pharmacological treatment of migraine headache in children and adolescents: report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology. 2004;63:2215-2224.
- Hershey AD. Current approaches to the diagnosis and management of paediatric migraine. Lancet Neurol. 2010; 9:190-204.
- Stewart WF, Ricci JA, Chee E, Morganstein D, Lipton R. Lost productive time and cost due to common pain conditions in the US workforce. JAMA. 2003;290:2443-2454.
- Bille B. A 40-year follow-up of school children with migraine. Cephalalgia. 1997;17:488-491.
- Powers SW, Patton SR, Hommel KA, Hershey AD. Quality of life in childhood migraines: clinical impact and comparison to other chronic illnesses. Pediatrics. 2003;112:e1-5.
- Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2163-2196.
- Rizzoli P. Preventive pharmacotherapy in migraine. Headache. 2014;54:364-369.