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

Article (PDF Available)inPEDIATRICS 123(3):924-34 · April 2009with41 Reads
DOI: 10.1542/peds.2008-0642 · Source: PubMed
Abstract
Currently, no drugs are Food and Drug Administration-approved for migraine prophylaxis in pediatric patients. The objective of this study was to evaluate the efficacy and safety of topiramate for migraine prevention in adolescents. Adolescents (12-17 years of age) with a >/=6-month history of migraine were assigned randomly to receive 16 weeks of daily treatment with topiramate (50 or 100 mg/day) or placebo. The primary efficacy measure was the percent reduction in monthly migraine attacks, with the use of the 48-hour rule, from the prospective baseline period to the last 12 weeks of the double-blind phase. The 48-hour rule defined a single migraine episode as all recurrences of migraine symptoms within 48 hours after onset. Several secondary efficacy measures were evaluated, including the reduction from baseline in the monthly migraine day rate and the 50% responder rate. Safety and tolerability were also assessed. A total of 29 (83%) of 35 subjects treated with topiramate at 50 mg/day, 30 (86%) of 35 subjects treated with topiramate at 100 mg/day, and 26 (79.0%) of 33 placebo-treated subjects completed double-blind treatment. Topiramate at 100 mg/day, but not 50 mg/day, resulted in a statistically significant reduction in the monthly migraine attack rate from baseline versus placebo (median: 72.2% vs 44.4%) during the last 12 weeks of double-blind treatment. Topiramate at 100 mg/day, but not 50 mg/day, also resulted in a statistically significant reduction in the monthly migraine day rate from baseline versus placebo. The responder rate favored topiramate at 100 mg/day (83% vs 45% for placebo). Upper respiratory tract infection, paresthesia, and dizziness occurred more commonly in the topiramate groups than in the placebo group. The 100 mg/day topiramate group demonstrated efficacy in the prevention of migraine in pediatric subjects. Overall, topiramate treatment was safe and well tolerated.
DOI: 10.1542/peds.2008-0642
2009;123;924Pediatrics
Caryn L. Kurland, Jeff Nye, Eric Yuen, Marielle Eerdekens and Lisa Ford
Donald Lewis, Paul Winner, Joel Saper, Seth Ness, Elena Polverejan, Steven Wang,
Years of Age
and Safety of Topiramate for Migraine Prevention in Pediatric Subjects 12 to 17
Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy
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ARTICLE
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
Donald Lewis, MD
a
, Paul Winner, DO
b
, Joel Saper, MD
c
, Seth Ness, MD, PhD
d
, Elena Polverejan, PhD
d
, Steven Wang, PhD
d
,
Caryn L. Kurland, PhD
d
, Jeff Nye, MD, PhD
d
, Eric Yuen, MD
d
, Marielle Eerdekens, MD
e
, Lisa Ford, MD
d
a
Department of Pediatrics, Division of Pediatric Neurology, Children’s Hospital of the King’s Daughters, Eastern Virginia Medical School, Norfolk, Virginia;
b
Department of
Neurology, Palm Beach Headache Center/Palm Beach Neurology, West Palm Beach, Florida;
c
Department of Neurology, Michigan Head Pain and Neurological Institute,
Ann Arbor, Michigan;
d
Department of Therapeutics, Johnson & Johnson Pharmaceutical Research and Development, Titusville, New Jersey;
e
Department of Therapeutics,
Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium
Financial Disclosure: Dr Lewis received funds from Abbott Laboratories as a scientific advisor for study design and from Pfizer to attend a scientific advisory meeting in 2004 and received research grants from
Abbott Laboratories, Astra Zeneca, Ortho-McNeil and Almirall. Dr Winner received funds from Merck, GlaxoSmithKline, Ortho-McNeil, Pfizer, Allergan, and Astra Zeneca for speaking, advisory board
participation, and consultation and received research grants from GlaxoSmithKline, Ortho-McNeil, Pfizer, Allergan, Novartis, Wyeth, Merck, Forest Laboratories, Elan, Minster Pharmaceuticals, MAP
Pharmaceuticals, Easai, and ReSearch Pharmaceutical Services. Dr Saper received speaking honoraria from GlaxoSmithKline, Merck, Ortho-McNeil, Neuralieve, Allergan, Medtronic, Pfizer, and Advanced
Neuromodulation Systems and received research grants from Pfizer, Endo Pharmaceuticals, GlaxoSmithKline, Neuralieve, ProEthic, Ortho-McNeil, Johnson & Johnson, Merck, Alexa, Allergan, Cypress
Pharmaceutical, Advanced Neuromodulation Systems, MAP Pharmacueticals, Medtronic, Torrey Pines Institute for Molecular Studies, and Schwarz Pharma. Drs Ness, Polverejan, Wang, Kurland, Nye, Yuen,
Eerdekens, and Ford were employees of Johnson & Johnson.
What’s Known on This Subject
Migraine occurs in 10.6% of children and adolescents between the ages of 5 and 15
years and 28% of adolescents between the ages of 15 and 19 years. There are few
well-designed trials evaluating migraine-preventive treatments for pediatric patients.
What This Study Adds
The results of this trial demonstrated that topiramate at 100 mg/day is safe, effective,
and generally well tolerated when used for migraine prevention in patients 12 to 17
years of age.
ABSTRACT
OBJECTIVE. Currently, no drugs are Food and Drug Administration-approved for mi-
graine prophylaxis in pediatric patients. The objective of this study was to evaluate
the efficacy and safety of topiramate for migraine prevention in adolescents.
METHODS. Adolescents (12–17 years of age) with a 6-month history of migraine were
assigned randomly to receive 16 weeks of daily treatment with topiramate (50 or 100
mg/day) or placebo. The primary efficacy measure was the percent reduction in
monthly migraine attacks, with the use of the 48-hour rule, from the prospective
baseline period to the last 12 weeks of the double-blind phase. The 48-hour rule
defined a single migraine episode as all recurrences of migraine symptoms within 48
hours after onset. Several secondary efficacy measures were evaluated, including the
reduction from baseline in the monthly migraine day rate and the 50% responder
rate. Safety and tolerability were also assessed.
RESULTS. A total of 29 (83%) of 35 subjects treated with topiramate at 50 mg/day, 30
(86%) of 35 subjects treated with topiramate at 100 mg/day, and 26 (79.0%) of 33
placebo-treated subjects completed double-blind treatment. Topiramate at 100 mg/
day, but not 50 mg/day, resulted in a statistically significant reduction in the monthly
migraine attack rate from baseline versus placebo (median: 72.2% vs 44.4%) during
the last 12 weeks of double-blind treatment. Topiramate at 100 mg/day, but not 50
mg/day, also resulted in a statistically significant reduction in the monthly migraine day rate from baseline versus
placebo. The responder rate favored topiramate at 100 mg/day (83% vs 45% for placebo). Upper respiratory tract
infection, paresthesia, and dizziness occurred more commonly in the topiramate groups than in the placebo group.
CONCLUSIONS. The 100 mg/day topiramate group demonstrated efficacy in the prevention of migraine in pediatric
subjects. Overall, topiramate treatment was safe and well tolerated. Pediatrics 2009;123:924–934
M
IGRAINE HEADACHES ARE common in children but often are underrecognized and misdiagnosed.
1
The mean
age of onset of migraine is 7.2 years for boys and 10.9 years for girls.
2,3
The prevalence of migraine increases
steadily through childhood, with migraine occurring in up to 10.6% of children and adolescents between the ages
of 5 and 15 years and up to 28% of adolescents between the ages of 15 and 19 years,
4–6
and shifts to female
predominance during adolescence.
1
www.pediatrics.org/cgi/doi/10.1542/
peds.2008-0642
doi:10.1542/peds.2008-0642
This trial has been registered at
www.clinicaltrials.gov (identifier
NCT00210535).
Key Words
migraine prevention, adolescents,
topiramate, prophylactic treatment
Accepted for publication Jul 21, 2008
Address correspondence to Donald Lewis, MD,
Department of Pediatrics, Children’s Hospital
of the King’s Daughters, Eastern Virginia
Medical School, 601 Children’s Lane, Norfolk,
VA 23507-1971. E-mail: dlewis@chkd.org
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2009 by the
American Academy of Pediatrics
924 LEWIS et al
at Indonesia:AAP Sponsored on May 29, 2013pediatrics.aappublications.orgDownloaded from
Migraine often is associated with considerable detri-
ments to pediatric patients’ quality of life.
7,8
In addition,
an evaluation of a clinical trial database involving 1932
adolescents 11 to 18 years of age with migraine found
that most migraine attacks occurred between 6
AM and 6
PM, which potentially would impair school function-
ing.
9,10
No drugs have been approved by the US Food and
Drug Administration for migraine prophylaxis in pediat-
ric patients, and there is a lack of well-designed, placebo-
controlled trials evaluating potential treatments.
1,6,11–14
Topiramate is Food and Drug Administration-approved
for use in adults for migraine prophylaxis.
15
The results
of several randomized, double-blind, placebo-controlled,
clinical trials demonstrated that topiramate at 100 mg/
day was effective, safe, and well tolerated as migraine
prophylaxis for adults.
16–21
Several of those trials also
enrolled adolescents 12 to 17 years of age.
16–19
In a ran-
domized, double-blind, placebo-controlled, pilot study,
topiramate at 100 mg/day showed a trend toward reduc-
tion of migraine days per month, compared with pla-
cebo, for pediatric subjects 6 to 15 years of age.
22
The
objective of this randomized, double-blind, parallel-
group, placebo-controlled study was to evaluate the ef-
ficacy and safety of 2 dosages of topiramate, 50 mg/day
and 100 mg/day, as preventive migraine treatment for
adolescents 12 to 17 years of age.
METHODS
Study Design
The study (study CR002245) was conducted in accor-
dance with the Declaration of Helsinki and followed
International Headache Society guidelines regarding en-
try criteria, treatment duration, end point selection, and
overall study design.
23–25
Each subject and legal represen-
tative gave written consent, according to local require-
ments, after the nature of the study was explained and
before any study-related activity was performed. The
study was conducted at 31 US and non-US sites between
August 10, 2005, and November 11, 2006, after the
protocol was approved at each site by an independent
ethics committee or institutional review board.
This was a randomized, placebo-controlled, double-
blind, parallel-group study that consisted of a pretreat-
ment phase lasting up to 9 weeks, a double-blind phase
lasting 16 weeks, and a taper/exit phase lasting up to 6
weeks (Fig 1). The pretreatment phase of the study
included a screening period lasting up to 1 week, a
4-week washout of disallowed migraine-preventive
medications, and a 4-week prospective baseline period.
Subjects who completed the prospective baseline period
and continued to meet all entry criteria were assigned
randomly (1:1:1) to receive 50 mg/day topiramate, 100
mg/day topiramate, or placebo. During the titration pe-
riod, treatment with topiramate (or matching placebo)
was initiated at 25 mg/day and gradually increased at the
investigators’ discretion to a target dose of either 50
mg/day or 100 mg/day, dosed twice daily, or the maxi-
mal dose tolerated by the subjects. In the event of tol-
erability problems, investigators could recommend dose
reduction or a pause or halt of further dose titration. The
double-blind treatment phase consisted of a 4-week ti-
tration period and a 12-week maintenance period. To
maintain the double-blinding, all subjects received 2
matching tablets at each dose (4 tablets per day). Each
tablet contained either 25 mg of topiramate or placebo,
depending on the group to which the subject was as-
signed. The placebo tablets were identical to the topira-
mate tablets in appearance (in terms of size, markings,
and color). Subjects maintained headache and medica-
tion records during the prospective baseline period, the
double-blind phase, and the posttreatment phase. Par-
ents were advised to assist their children in filling out the
headache and medication records and in checking these
documents for accuracy.
Subjects entered the posttreatment phase at either
completion of the double-blind treatment or discontin-
uation of treatment during the double-blind phase. The
posttreatment phase included a 2-week taper of study
medication, a 4-week medication-free period, and a fol-
low-up visit. Medication was tapered at a rate of 25 mg
of topiramate (or placebo) every 3 days.
With the assumption of a SD of 55% for all 3 treat-
ment groups and a treatment difference of 43% between