Randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of topiramate for migraine prevention in pediatric subjects 12 to 17 years of age

Background:  No drugs are currently approved by the Food and Drug Administration for the use of migraine prophylaxis in pediatric patients. 

Objective:  To evaluate the safety and efficacy of topiramate for migraine prevention in patients 12 to 17-years-old.

Methods:  This was a randomized, placebo-controlled, double-blind, parallel-group study.
Subjects were enrolled from 31 US and non-US sites between August 10, 2005 and November 11, 2006.  They underwent random assignments with stratification according to age.  Subjects were included if they were between the ages of 12 and 17 and had a history of migraine.  Subjects were excluded if they were currently taking topiramate, had previously failed to achieve relief from topiramate, or were unable to distinguish migraines from other headaches.  Subjects meeting criteria, who were currently taking migraine prophylactic medication, went on a two week taper off these drugs followed by a two week medication-free period.  All subjects then went through a four-week prospective baseline period followed by a double-blind treatment phase.  The treatment phase consisted of a four-week titration period followed by a 12-week maintenance period where they received either placebo, topiramate 50mg, or topiramate 100mg; groups consisted of 33, 35, and 35 subjects, respectively.  The primary efficacy end point was the percent reduction in the monthly migraine attack rate over the last 12 weeks of the double-blind treatment phase compared to the prospective baseline period.  Secondary endpoints included (1) percent reduction in monthly migraine attack rate from prospective baseline to the last 4 weeks of the treatment phase (2) percent reduction in monthly migraine day rate from the prospective baseline to the last 12 weeks of the treatment phase (3) responder rate.  With the assumption of a SD of 55% for all three treatment groups, 34 subjects in each group were needed to detect a treatment difference of 43% with an 80.8% power and a 2 sided alpha level of 0.25.  An intent-to-treat efficacy analyses was used.

Results:  Twenty-six, 29, and 30 subjects from the placebo, topiramate 50mg, and topiramate 100mg groups, respectively, completed the double blind phase.  The primary outcome in the 100mg, 50mg, and placebo groups was 72.2%, 44.6%, and 44.4%, respectively.  This difference was significant for the topiramate 100mg group vs placebo (P=0.016) only.  The secondary outcomes supported the primary outcomes: percent reduction monthly migraine attack rate: 100% for 100mg group (P=0.015 vs placebo), 65.5% for the 50mg group, and 61.4% for the placebo.  The percent reduction in monthly migraine day rate was significantly reduced (P=0.002) for the 100mg group vs placebo.  Responder rate was 83%, 46%, and 45% for the 100mg (P=0.002 vs placebo), 50mg (P=0.957 vs placebo), and placebo, respectively.  No significant difference occurred between groups for rescue medication rate.  Authors’ concluded that 100mg daily of topiramate is safe and efficacious in preventing migraines in pediatrics 12 to 17-years-old. 

Strengths:  An appropriate study design was utilized.  Methods of assignment were clearly described and inclusion and exclusion criteria were appropriate.

Weaknesses:  There were several conflicts of interest which may have skewed authors’ interpretation of results.  Baseline differences in gender appeared to differ between groups but were not analyzed statistically.  A carry-over effect may have occurred for those patients taking migraine prophylactic medication prior to enrollment even though a washout period was used.  A sample size was not met in all groups to achieve an 80.8% power.  Additionally, even if this power was achieved, the 43% treatment difference and SD of 55% is too large.  Also, the description of the calculation for the primary outcomes is not clearly explained and may have been more complex than was necessary.  Intent-to-treat analysis was used which may have made results appear less efficacious.  This study did not assess whether or not guardians of the children had a role in record keeping.  Medication compliance as well as control of diet, environment, or migraine triggers was not controlled for in this study.  This study would have further benefitted if a more thorough analyses of rescue medication was done (e.g. type of medication), if migraine severity was rated on a scale, and if school days missed were outcomes measured.

Conclusion:  Topiramate does appear to be safe in pediatric patients ages 12 to 17 based on this study.  Further randomized, controlled trials are needed which account for the limitations mentioned.  However, if a pediatric patient is resistant to other medications, a well-monitored trial of topiramate beginning at 50mg and titrating up to 100mg would be reasonable. 

Lewis D, Winner P, Saper J, Ness S, et al.  Randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of topiramate for migraine prevention in pediatric subjects 12 to 17 years of age.  Pediatrics. 2009; 123(3): 924-34.

Lindsey Koliscak, PharmD Candidate