A multi-center double-blind pilot comparison of onabotulinumtoxinA and topiramate for the prophylactic treatment of chronic migraine.

Abstract

This multi-center pilot study compared the efficacy of onabotulinumtoxinA with topiramate (a Food and Drug Administration approved and widely accepted treatment for prevention of migraine) in individuals with chronic migraine (CM).
A total of 59 subjects with CM were randomly assigned to one of 2 groups: Group 1 (n = 30) received topiramate plus placebo injections, Group 2 (n = 29) received onabotulinumtoxinA injections plus placebo tablets. Subjects maintained daily headache diaries over a 4-week baseline period and a 12-week active study period. The primary endpoint was the Physician Global Assessment, which measured the treatment responder rate and indicated improvement in both groups over 12 weeks. Secondary endpoints, measured at weeks 4 and 12, included headache days per month, migraine days, headache-free days, days on acute medication, severity of headache episodes, Migraine Impact & Disability Assessment, Headache Impact Test, effectiveness of and satisfaction with current treatment on the amount of medication needed, and the frequency and severity of migraine symptoms. At 12 weeks subjects were re-evaluated and tapered off oral study medications over a 2-week time period. Subjects not reporting a >50% reduction of headache frequency at 12 weeks were invited to participate in a 12-week open label extension study with onabotulinumtoxinA. Of these, 20 subjects, 9 from the Topiramate Group and 11 from the OnabotulinumtoxinA Group, volunteered for this extension from weeks 14 to 26.
This study demonstrated positive benefit for both onabotulinumtoxinA and topiramate in subjects with CM. Overall, the results were statistically significant within groups but not between groups. By week 26, subjects had a reduction of headache days per month compared with baseline. This was a significant within-group finding.
OnabotulinumtoxinA and topiramate demonstrated similar efficacy for subjects with CM as determined by Global Physician Assessment and supported by multiple secondary endpoint measures.

Full text

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Research Submission
A Multi-Center Double-Blind Pilot Comparison of
OnabotulinumtoxinA and Topiramate for the Prophylactic
Treatment of Chronic Migrainehead_179621..32
Roger K. Cady, MD; Curtis P. Schreiber, MD; John A.H. Porter, MD, FAAN; Andrew M. Blumenfeld, MD;
Kathleen U. Farmer, Psy. D
Objective.—This multi-center pilot study compared the efficacy of onabotulinumtoxinA with topiramate (a Food and Drug
Administration approved and widely accepted treatment for prevention of migraine) in individuals with chronic migraine (CM).
Methods.—A total of 59 subjects with CM were randomly assigned to one of 2 groups: Group 1 (n = 30) received
topiramate plus placebo injections, Group 2 (n = 29) received onabotulinumtoxinA injections plus placebo tablets. Subjects
maintained daily headache diaries over a 4-week baseline period and a 12-week active study period.The primary endpoint was
the Physician Global Assessment, which measured the treatment responder rate and indicated improvement in both groups
over 12 weeks.Secondary endpoints,measured at weeks 4 and 12,included headache days per month,migraine days,headache-
free days,days on acute medication,severity of headache episodes,Migraine Impact & DisabilityAssessment,Headache Impact
Test, effectiveness of and satisfaction with current treatment on the amount of medication needed, and the frequency and
severity of migraine symptoms. At 12 weeks subjects were re-evaluated and tapered off oral study medications over a 2-week
time period. Subjects not reporting a >50% reduction of headache frequency at 12 weeks were invited to participate in a
12-week open label extension study with onabotulinumtoxinA.Of these,20 subjects,9 from theTopiramate Group and 11 from
the OnabotulinumtoxinA Group, volunteered for this extension from weeks 14 to 26.
Results.—This study demonstrated positive benefit for both onabotulinumtoxinA and topiramate in subjects with CM.
Overall, the results were statistically significant within groups but not between groups. By week 26, subjects had a reduction of
headache days per month compared with baseline. This was a significant within-group finding.
Conclusion.—OnabotulinumtoxinA and topiramate demonstrated similar efficacy for subjects with CM as determined by
Global Physician Assessment and supported by multiple secondary endpoint measures.
Key words: onabotulinumtoxinA, topiramate, migraine prophylaxis, chronic migraine, physician global assessment
Abbreviations: HIT-6 Headache Impact Test, MIDAS Migraine Impact & Disability Assessment, MIQ Migraine Impact
Questionnaire
(Headache 2011;51:21-32)
From the Headache Care Center, Springfield, MO, USA (R.K. Cady and K.U. Farmer); Citizens Memorial Hospital Neurology
Clinic, Bolivar, MO, USA (C.P. Schreiber); Advance Neurology and Pain, Advance, NC, USA (J.A.H. Porter); The Neurology
Center, Encinitas, CA, USA (A.M. Blumenfeld).
Address all correspondence to R.K. Cady, 3805 S. Kansas Expressway, Springfield, MO 65807, USA.
Accepted for publication September 19, 2010.
Conflicts of Interest:Dr.Roger Cady:Consultant for GlaxoSmithKline,Merck,Ortho-McNeil.Research grants fromAllergan,Endo
Pharmaceuticals, GlaxoSmithKline, Merck, and Wyeth. Dr. John Porter: Consulting Speakers panel with Novartis, Forest, Biogen,
UCB Pharma,Pfizer,TEVA.Dr.Andrew Blumenfeld:Consultant,speaker’s bureau,and research grants fromAllergan.Dr.Curtis
Schreiber and Dr. Kathleen Farmer: None to disclose.
ISSN 0017-8748
doi: 10.1111/j.1526-4610.2010.01796.x
Published by Wiley Periodicals, Inc.
Headache
© 2010 American Headache Society
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INTRODUCTION
Historically migraine has been considered an epi-
sodic pain syndrome.1As such, treatment has largely
focused on terminating or ameliorating symptoms
associated with the acute event of migraine. To this
point during the 1980s and 1990s the Food and Drug
Administration (FDA) approved 9 drugs for acute
treatment of migraine but only divalproate sodium
was approved for migraine prevention.2As an under-
standing of the chronic nature of migraine has
evolved, the importance of preventive therapy has
become increasingly evident.3Consequently, there
have been several clinical trials of preventive therapy
for migraine within the last decade, which has led to
FDA approval of a second anti-epileptic medication
(AED) for the prevention of migraine, topiramate in
2003.4Curiously other AED medications failed to
demonstrate efficacy in preventing migraine despite
presumed advances in understanding migraine patho-
physiology.5,6Whether this reflects limitations in our
scientific understanding of the biology of migraine
prevention, or the methodological limitations in
designing successful and meaningful clinical trials of
pharmacological agents for migraine prevention or
both, is a matter of debate.
OnabotulinumtoxinA (botulinum toxin type A)
was first reported to prevent migraine by Binder in
1991.7Since that time, numerous clinical trials have
been conducted with onabotulinumtoxinA yielding
mixed results.8The American Association of Neurol-
ogy published a consensus paper in 2008 suggesting
thatonabotulinumtoxinA
migraine preventive for episodic migraine and incon-
clusive for chronic migraine (CM).9Since then,
Dodick, Aurora, and Diener reported that in 2
large separate parallel studies on subjects with CM,
statistically significant efficacy for onabotulinum-
toxinA over placebo.10-12Ensuing debate has chal-
lenged whether the findings of this study are truly
clinically relevant although a statistical measure of
meaningful clinical relevance has yet been defined.
Morerecently, onabotulinumtoxinA
licensed by the Medicine and Healthcare Products
Regulatory Agency in the UK for the prophylaxis of
headaches in adults who have CM.13This may suggest
that the debate over the migraine preventive
was ineffectiveasa
hasbeen
potential of onabotulinumtoxinA in CM is becoming
less ambiguous.
The study presented here is designed to approxi-
mate clinical decision making and assimilation of
risks and benefits that clinicians use to assess
migraine preventive medication in the “real world”
clinical care of migraine patients. The primary end-
point in this study is a Global Physician Assessment
based on interviews and diary analyses between
investigator and subject.The authors believe that this
methodology permits a more integrated and relevant
evaluation of efficacy than simply a P value of pre-
specified endpoints. Historically endpoints, such as
the number of migraine episodes or headache days in
a specified time period, have stood as the gold stan-
dard for success of migraine preventive therapy yet
interestingly evidence for these endpoints being clini-
cally meaningful are largely based on consensus. To
this end, the study presented is an effort to help
augment and clarify what has been a murky and often
inconclusive exploration of onabotulinumtoxinA in
the prevention of migraine.
METHODS
Study Design.—This was a 3-center, double-blind
randomized pilot study of onabotulinumtoxinA and
topiramate for preventive treatment of CM defined
as 3-8 attacks of migraine per month with on average
21 days of headache per month.
The study was conducted in compliance with
investigational review board regulations (Sterling
IRB,Atlanta,GA,USA),informed consent,and regu-
lations stemming from the Declaration of Helsinki
and the International Headache Society (IHS) guide-
lines for studies of the prevention of migraine.
Subject and Treatment.—Subjects included male
and female volunteers with documented histories of
CM fulfilling criteria of the Second Edition of the
International Classification for Headache Disor-
ders.14Subjects were randomized to receive injections
of onabotulinumtoxinA plus daily placebo tablets or
topiramate and placebo injections. The investigators
and study coordinators were blinded to study
conditions.
Up to 200 units of onabotulinumtoxinA or
placebo were injected with 100 units into fixed loca-
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tions and up to an additional 100 units in a“follow the
pain” scheme determined at the investigators discre-
tion. Topiramate dosing was initiated at 25 mg daily
and escalated to 100 mg in weekly incremental
changes of 25 mg. The dosage could be further esca-
lated after one month at the discretion of the inves-
tigator to a maximum dosage of 200 mg per day.The
average dosage of onabotulinumtoxinA was 109 units
for the first injection cycle and the average daily
dosage of topiramate was 136 mg by week 12.
Subjects maintained daily headache diaries over
a 4-week baseline period and a 12-week active study
period. At 12 weeks subjects were re-evaluated and
tapered off oral study medications over a 2-week time
period. Subjects not reporting a ?50% reduction of
headache frequency at 12 weeks were invited to par-
ticipate in a 12-week open label extension study with
onabotulinumtoxinA.
Paper diaries were used throughout the study to
record headache frequency, headache severity, start
and stop times of headaches, migraine associated
symptoms, acute treatment medications and proce-
dures, frequency of visits to emergency/outpatient
facilities for headache care, and adverse events. All
subjects completed a Migraine Impact & Disability
Assessment (MIDAS), Headache Impact Test (HIT-
6), and Migraine Impact Questionnaire (MIQ) at
baseline,week 4,and 12.Those continuing in the open
label extension period repeated these tests at week
26. Investigators completed a 9-point Physician
Global Assessment questionnaire at Visit 4 and for
those in the open label extension,the assessment was
also made at week 26.
Inclusion Criteria
• Outpatients, male or female, of any race, between
18 and 65 years of age
• Female subjectsof
with a negative urine pregnancy test who prac-
ticed reliable contraception throughout the study
period
• Subjects met criteria for CM as defined by Second
Edition of the International Classification for
Headache Disorders
• Subjects understood all study requirements
child-bearingpotential
Exclusion Criteria
• Female subjects who were pregnant,breast feeding,
or planning to become pregnant during the time
frame of the study
• Individuals with headache disorders other than CM
• Subjects with medical disorders that increase the
risk with exposure to onabotulinumtoxinA
• Subjects with significant liver or renal impairment
including kidney stones
• Subjects on ketogenic diets
• Subjects who had previously used botulinum toxin
of any type or topiramate regardless of indication
• Subjects with recent evidence of alcohol/drug
abuse or overuse of acute medication
Statistical Analysis.—Statistical analyses were per-
formed using SAS version 9 (SAS Institute Inc.,Cary,
NC, USA).
Sample size was estimated based on a 35% dif-
ference in the proportion of all subjects achieving
treatment response byVisit 4 (regardless of treatment
group assigned) with positive treatment response
being defined as a +2 change in Physician Global
Assessment (alpha = 0.05, 80% power).
Physician GlobalAssessment,Response toTreat-
ment: The Investigator will assess response to treat-
ment using the following 9-point scale:
+4 Clearance of signs and symptoms (about 100%
improvement).
+3 Marked improvement (about 75% improvement).
+2 Moderateimprovement
improvement).
+1 Slight improvement (about 25% improvement).
0 Unchanged.
-1 Slight worsening (about 25% worse).
-2 Moderate worsening (about 50% worse).
-3 Marked worsening (about 75% worse).
-4 Very marked worsening (about 100% worse).
(about 50%
The Physician Global Assessment was calculated
for each subject at weeks 4 and 12 (see Table 4).
Demographic data were analyzed using two-
sided chi-square test or Fisher exact test. Physician
GlobalAssessment and MIQ were analyzed using the
Wilcoxon signed rank test. Changes from baseline in
Headache
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headache diaries or MIQ scores were analyzed using
ANCOVA/rank ANCOVA based on baseline vari-
ability. Paired t-test/Wilcoxon signed rank test was
used to assess the within group tests for the MIQ.
The study funder generated the random alloca-
tion sequence. A sealed card marked with the sub-
ject’s study number was delivered via FedEx to the
Midwestern study site. A research coordinator, not
involved with the study,would open the card,note the
treatment assignment, dilute the compound, fill the
syringe,and hand the medication to the study coordi-
nator who assisted the investigator with the injec-
tions. Both the study coordinator and the physician
were blinded to the treatment allocation number
until the completion of week 12, the end of the
blinded study.
RESULTS
Demographics.—There were 59 subjects enrolled
(first patient in on 9-2-04 and last patient out on 8-8-
06) and were randomized into 2 groups:(Group 1) 30
received topiramate plus placebo injections and
(Group 2) 29 received onabotulinumtoxinA injec-
tions plus placebo tablets. The mean age was 39.6
years with a range of 19.6 to 64.0;91.5% were women
(54/59). Racially, 94.9% (56/59) were Caucasian. At
baseline every subject reported at least one problem
with a body system (58/59,neurological;39/59,psychi-
atric).A physical/neurological abnormality was found
in 13.6% (8/59). The median number of years that
subjects suffered with migraine was 16.There were 16
subjects (27%) who identified themselves as smokers:
9 in the Topiramate Group smoked 9.8 cigarettes per
day, 7 in the OnabotulinumtoxinA Group smoked
21.4 cigarettes per day.
The average baseline headache characteristics
were similar between the 2 groups with 21.1 days per
month with headache, 8.9 headache-free days per
month, 11.1 migraine days per month, 14.5 days per
month on headache medication, and the severity of
headache being rates as 2.8 on a 3-point scale (see
Tables 1-3).
Participant Flow Diagram
Double Blind Study
Open Label
OnabotulinumtoxinA
Randomly
AssignedWeek 4Week 12Week 14 Week 26
Group 1
Group 2
30
29
27
28
22
22
94
8 11
Primary Endpoint.—The Treatment Responder
Rate based on the Physician GlobalAssessment indi-
cated that physicians noted improvement in subjects
of both groups over time. There was no statistically
significant difference between groups (see Table 4)
yet the majority of subjects in both groups exhibited
improvement. At week 4, in the Topiramate Group,
20/27 (74.0%) had improved compared with 17/28
(60.7%) in the OnabotulinumtoxinA Group.At week
Table 1.—Baseline Characteristics Between Groups
Headache Diary
Mean
Total
n = 59
Group 1
Topiramate
n = 30
Group 2
OnabotulinumtoxinA
n = 29
Headache days/month
Headache-free days/month
Migraine days/month
Days on headache meds
Headache severity
21.1
8.9
11.1
14.5
2.8
20.5
9.5
10.3
15.1
2.7
21.8
8.2
11.9
13.9
2.9
Three-point scale: mild, moderate, severe.
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12, in the Topiramate Group, 17/24 (70.8%) had
improved compared with 19/24 (79.2%) in the
OnabotulinumtoxinA Group.
Secondary Endpoints.—Headache
mean number of days per month with headache
dropped at week 4 by 4.4 days (from 20.5 to 16.1) for
Days.—The
the Topiramate Group and by 3.0 days (from 21.8
18.8) for the OnabotulinumtoxinA Group. This
change was not significant between groups but was
significant within groups (see Fig. 1).At week 12, the
mean number of days per month with headache
dropped by 8.1 days to 12.4 in the Topiramate Group
Table 2.—Baseline Characteristics Between Groups
Study Questionnaire
MeanTotal
Group 1
Topiramate
Group 2
OnabotulinumtoxinA
MIDAS total scoren = 57
62.67
n = 54
65.09
n = 59
n (%)
18 (30.5)
33 (54.2)
31 (52.5)
26 (44.0)
n = 58
7 (12.0)
24 (41.4)
n = 58
320.43
115.58
n = 29
59.17
n = 27
65.63
n = 30
n (%)
5 (16.7)
17 (56.7)
14 (46.6)
11 (36.7)
n = 29
5 (17.2)
9 (31.0)
n = 30
194.20
137.20
n = 28
66.29
n = 27
64.56
n = 29
n (%)
13 (44.8)*
15 (51.7)
17 (58.6)*
15 (51.7)*
n = 29
2 (6.8)
15 (51.7)
n = 28
455.68
93.21
HIT-6 score
Effectiveness of current treatment
Prescription meds, dissatisfied
Non-prescription meds, dissatisfied
Frequency of symptoms, dissatisfied
Severity of symptoms, dissatisfied
Current preventive tx
Satisfied
Does not apply
Money spent on migraine meds (previous 3 months)
Prescription
Non-prescription
*P < .05 (Wilcoxon).
HIT-6 = Headache Impact Test; MIDAS = Migraine Impact & Disability Assessment; tx, treatment.
Table 3.—Interference of Migraine Pain at Baseline Between Groups
Mean
Study Questionnaire
Total
Group 1
Topiramate
Group 2
OnabotulinumtoxinA
Presenteeism (days/month worked with migraine)n = 53
27.6
n = 54
n = 27
24.9
n = 27
Quite a bit + extremely
n (%)
11 (40.7)
9 (33.3)
14 (51.8)
12 (44.4)
10 (37.0)
17 (62.9)
n = 26
30.3
n = 27Interference
n (%)
22 (40.7)
20 (37.1)
27 (51.8)
30 (55.5)
24 (44.4)
33 (61.1)
n (%)
11 (40.7)
11 (40.7)
14 (51.8)
18 (66.7)
14 (51.8)
16 (59.2)
Work
Sleep
Mood
Daily activities
Recreational activities
Enjoyment of life
Headache
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and by 8.0 days to 13.8 in the OnabotulinumtoxinA
Group. This change was not significant between
groups but was significant within groups (see Fig. 1).
OPEN LABEL ONABOTULINUMTOXINA
TREATMENT (WEEK 14 TO 26).—At week 12,
subjects in both groups who had not reduced the
number of headache days per month by ?50% were
considered non-responders and were given the option
to participate in an open label onabotulinumtoxinA
study. Of the 48 subjects who completed the study at
week 12, 12/24 (50.0%) in the Topiramate Group and
9/24 (37.5%) in the OnabotulinumtoxinA Group had
Table 4.—Physician Global Assessment-Response to Treatment
Change from Baseline
Group 1
Topiramate
n (%)
Group 2
P-value
OnabotulinumtoxinA
n (%)
Week 4
No change
Slight improvement
Moderate improvement
Marked improvement
Week 12
No change
Slight improvement
Moderate improvement
Marked improvement
n = 27
4 (14.8)
8 (29.6)
9 (33.3)
3 (11.1)
n = 24
5 (20.8)
1 (4.2)
6 (25.0)
10 (41.7)
n = 28
9 (32.1)
10 (35.7)
3 (10.7)
4 (14.3)
n = 24
3 (12.5)
5 (20.8)
4 (16.7)
10 (41.7)
.3221 (Wilcoxon)
.9914 (Wilcoxon)
Fig 1.—Change from baseline: headache diary. *P ? .05 (t-test within group).
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at least a 50% reduction in headache days per month,
according to the headache diaries. Of the remaining
27 subjects,20 agreed to continue with the open label
onabotulinumtoxinA study, 9 from the Topiramate
Group and 11 from the OnabotulinumtoxinA Group.
By week 26, there were 4 remaining subjects in the
Topiramate Group and 8 in the OnabotulinumtoxinA
Group.These subjects had a reduction of the number
of headache days per month compared to baseline
but, according to reports in the diaries, the Topira-
mate Group had an increase of the average number
of headaches days compared with week 14 (1.5 days)
while those in the OnabotulinumtoxinA Group
had an average reduction (1.04 days) of headache
days. This was a significant within-group finding
(P = .0148).
Headache-Free Days.—The mean number of
headache-free days per month increased at week 4 by
4.4 days (from 9.5 to 13.9) for the Topiramate Group
and by 3.0 days (from 8.2 to 11.2) for the Onabotuli-
numtoxinA Group. This change was not significant
between groups but was significant within groups (see
Fig. 2). At week 12, the mean number of headache-
free days per month increased by 8.1 days (to 17.6) in
theTopiramate Group and by 8.0 days (to 16.2) in the
OnabotulinumtoxinA Group. This change was not
significant between groups but was significant within
groups (see Fig. 2).
Migraine Disability Assessment.—The average
MIDAS total score at week 12 had dropped by 26.67
points for the Topiramate Group and by 38.48 points
for the OnabotulinumtoxinA Group.This change was
not significant between groups but was significant
within groups (see Fig. 3).
Headache Impact Assessment.—The
HIT-6totalscoreatweek4haddroppedby5.87points
for the Topiramate Group and by 4.84 points for the
OnabotulinumtoxinAGroup.Thischangewasnotsig-
nificant between groups but was significant within
groups (see Fig. 4). At week 12, the score lessened
further by 6.00 points for the Topiramate Group and
by 6.29 points for the OnabotulinumtoxinA Group.
Thischangefrombaselinewasnotsignificantbetween
groups but was significant within groups (see Fig. 4).
Money Spent on Migraine Medication.—At week
12, the amount of money spent on prescription drugs
over the previous 3 months had decreased by $121.05
for the topiramate subjects and $497.60 for onabotu-
linumtoxinA subjects.This change was not significant
between groups but was significant within groups (see
Table 5).
Concerning non-prescription drugs, at week 12,
subjects estimated the amount of money spent over
the previous 3 months had lessened by $86.86 for the
topiramate subjects and $63.50 for the onabotulinum-
toxinA subjects. This change was not significant
between groups but was significant within groups (see
Table 5).
average
Fig 2.—Change from baseline: headache diary. *P ? .05 (t-test
within group).
Fig 3.—Change from baseline. *P ? .05 (signed rank within
group). MIDAS = Migraine Impact & Disability Assessment.
Headache
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Multiple other endpoints potentially useful to
clinician/investigators to evaluate subject response
were also collected.These included self-evaluation of
presenteeism, interference of migraine at work, and
changes in sleep, mood, performance of daily recre-
ational activities, and enjoyment of life. All evalua-
tions listed above demonstrated significant positive
change within groups over baseline. While clinician/
investigators may have been able to integrate these
changes into a cogent understanding of benefit or risk
for a specific subject, the statistical basis for these
evaluations has not been established and thus the
details of the clinical evaluation is not reported on in
this manuscript.
Safety Assessments.—The number of subjects who
discontinued the study was 15, 8 topiramate subjects
and 7 onabotulinumtoxinA subjects, half of whom
listed adverse events as the reason for dropping out.
Yet at baseline, before the study began, a majority of
subjects from both groups had identified side effects
(see Table 5).
Fig 4.—Change from baseline. *P ? .05 (signed rank within
group); ‡P ? .05 (t-test within group). HIT-6 = Headache
Impact Test.
Table 5.—Safety Assessment Study Questionnaire
n (%)
Group 1
Topiramate
Group 2
OnabotulinumtoxinA
Baseline
Mild fatigue
Nausea
Difficulty concentrating or with memory
Mood swings
Week 12
Mild fatigue
Nausea
P-value (c2)
Difficulty concentrating or with memory
Mood swings
n = 30
22 (73.3)
22 (73.3)
19 (63.3)
12 (40.0)
n = 22
15 (68.2)
6 (27.3)
n = 29
20 (69.0)
20 (69.0)
14 (48.3)
14 (48.3)
n = 22
16 (72.7)
13 (59.1)
.0331*
11 (50.0)
6 (27.3)
13 (59.1)
4 (18.2)
Side Effects of Current Preventive Migraine Treatment:Very Satisfied + Somewhat Satisfied
n (%)
Baselinen = 30
3 (10.0)
n = 22
9 (40.9)
n = 29
4 (13.8)
n = 22
10 (45.5)
Week 12
P-value (Wilcoxon).2171
*P ? .05.
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At week 12, the 4 most commonly reported
adverse events (see Table 5) were mild fatigue,
nausea, difficulty concentrating or with memory, and
mood swings.The only significant difference between
groups was nausea, reported by 27.3% of topiramate
subjects and 59.1% of onabotulinumtoxinA subjects
(see Table 5).
When asked to rate the influence of current pre-
ventive treatment side effects, at baseline, 36.7% of
topiramate subjects and 55.2% of onabotulinum-
toxinA subjects stated that the question did not apply.
At week 12, there was a non-significant change
toward being more satisfied with the side effects
experienced with the current treatment from 10% to
40.9% among topiramate subjects and from 13.8% to
45.5% among onabotulinumtoxinA subjects.
DISCUSSION
This multi-center pilot study is positive for its
primary endpoint of Physician Global Assessment of
efficacy and demonstrated similar clinical benefits for
both onabotulinumtoxinA and topiramate in subjects
with CM. These data support the conclusions of a
pilot, single-center study by Mathew and Jaffri.15
The validity of the Physician Global Assessment
in this study was supported by significant correlations
with multiple predefined secondary endpoints,includ-
ing analyses of subjects’ diaries and improvement in
disability scales. The diary review demonstrated sta-
tistically significant decreases in headache days and
reduction in acute medication usage from baseline.
Further,there was a statistically significant increase in
headache-free days.This was true for both topiramate
and onabotulinumtoxinA. In addition, both interven-
tions demonstrated statistically significant improve-
ment in MIDAS scores at week 12 (see Fig. 3).Finally
there were potentially relevant clinical improvements
in quality of life, sleep, work and recreational activi-
ties. Given the scope of these changes it appears that
the Physician Global Assessment of the subject cor-
related well with other more traditional statistical
measurements of success for preventive therapy
defined in this study as secondary endpoints.
Both therapies were generally well tolerated and
neither had any associated serious adverse events.
Interestingly, adverse events were quite similar for
both medications with only slight differences were
noted between the two therapies (see Table 5).
Retention rates for this study were relatively high
for the first 12 weeks following the baseline period.
Because fewer subjects were eligible to continue in
the open label extension, the statistical power of any
conclusions for this phase of the study is significantly
less.The open label extension should be viewed as an
exploratory effort to assess if onabotulinumtoxinA
might be beneficial in subjects failing to respond to
topiramate. No conclusive statement can be made
based on the limited number of subjects in this phase
of the study. The most common reasons for study
withdrawal were adverse events (53.3%; 8 out of 15)
but there were no statistical differences in withdrawal
rates between the onabotulinumtoxinA and topira-
mate groups and only minor differences in specific
adverse events between the 2 groups.
Comparisonsbetween
onabotulinumtoxinA groups suggested earlier onset
of efficacy for topiramate but trended toward greater
efficacy for onabotulinumtoxinA at 12 weeks. At
week 12,12/24 (50.0%) of theTopiramate Group and
9/24 (37.5%) of the OnabotulinumtoxinA Group
were eligible to continue in the open label extension
with onabotulinumtoxinA. Of those originally ran-
domized to topiramate there was statistical improve-
ment at week 14 after open label injection with
onabotulinumtoxinA (see Fig. 1). For the group
receiving onabotulinumtoxinA as initial therapy, a
second injection did not demonstrate increased effi-
cacy at week 14 nor week 26, but there was no wors-
ening of headache frequency. These results must be
tempered by the small numbers,the open label design
of the extension study, and study design.
The value of a study approximating clinical deci-
sionmakingbyutilizingaglobalphysicianratingscale
is that it permits physicians to integrate and weigh the
relative value of various treatment attributes when
assessingefficacy. Forexample,ifaspecificsubjecthad
only a moderate reduction of migraine attacks but
acute attacks became more effectively treated with
acute intervention resulting in reduction of headache
and migraine days and improvement in disability, the
investigator could define the subject as a treatment
success. Thus, this research methodology more accu-
the topiramateand
Headache
29

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rately mirrors clinical practice by allowing positive
and/ornegativeoutcomes
weighted,in the context of the individual subject.This
is in contradistinction to more traditional research
methodologies where a single primary endpoint is
prespecified and success or failure of the patient is
determined by that variable alone.Accordingly, if the
primary endpoint was for example a 50% reduction in
migraine frequency, then a subject with a 40% reduc-
tion in migraine frequency but meaningful improve-
mentindisabilityscores,improvedtreatmentoutcome
of acute intervention, improvement in quality of life
measures, and significant reduction in acute medica-
tion need would be deemed a study failure. This
paradox opens a debate as to whether the methodol-
ogy commonly used in regulatory preventive medica-
tion studies adequately reflects the real medical needs
of patients and clinicians.
At the core of such a debate is the understand-
ing of migraine itself. It is becoming increasingly
obvious that within the migraine population there is
a spectrum of clinical subtypes that share a common
clinical symptomatology but not necessarily share
the same underlying pathophysiology or treatment
need. For example, the pathophysiology of infre-
quent acute migraine and CM are likely unique
from one another and certainly therapeutic need is
distinctly different. In addition, one needs to con-
sider the role of numerous co-morbid diseases and
psychosocial consequences that become increasing
more prevalent as migraine becomes more chronic.
This in turn has the potential to alter efficacy needs
for individual patients. Finally, as an understanding
of migraine is emerging to suggest that episodic
migraine can evolve into a chronic disease (CM)
there is a need to assess positive or negative
attributes of preventive therapies between as well as
during acute episodes of migraine.
Ironically, in 1988 the IHS diagnostic criteria for
headache and facial pain syndromes defined migraine
only in its episodic form.16This is despite defining
episodic and chronic definitions for both tension-type
and cluster headache. In the 2004 revision of the IHS
classificationtaxonomy,
included and the episodic migraine was considered a
precursor to CM.14Since then, a more operational
tobeappropriately
criteria forCM were
diagnostic scheme has been proposed where for the
first time different clinical phenotypes of primary
headache are acknowledged as co-existing in defining
CM.17
The primary question is whether migraine-
related neurological disruption exists only during
attacks of IHS migraine or are there clinical, mean-
ingful, neurological, and physiological alterations
evident between attacks of migraine, especially
evident as migraine becomes more chronic.This ques-
tion has critical implications to understanding, effec-
tive management, and meaningful scientific study of
this disease especially in regard to preventive therapy.
Preventive medications are generally taken on a
daily basis and presumably exert pharmacological
effects between as well as during migraine attacks.
The current regulatory methodology of assessing only
attack-related benefit may be unlikely to observe the
totality of clinical response. Yet Physician Global
Assessment in conjunction with an ability to weigh
quality of life evaluations is more likely to detect
these potentially positive or negative outcomes asso-
ciated with preventive treatment. To elaborate this
point,in thisstudynumerous
migraine endpoints such as improvement in disability
scores, decreases in acute medication usage, efficacy
of non-prescription medications, and quality of life
measures were statistically improved.Clinically these
treatment attributes are an important part of the
equation for clinicians and patients attempting to
evaluate the effectiveness of a specific migraine pre-
ventive treatment.
OnabotulinumtoxinA has been studied as a
migraine preventive in several clinical trials with
sometimes mixed results.This may be because of the
novelty of this product in terms of pharmacological
mechanisms and delivery. The most recent large
scale multi-center study called the Phase III Re-
search Evaluating Migraine Prophylaxis Therapy
(PREEMPT) study was a positive study for subjects
with CM.12,13It reduced the number of headache days,
acute medication usage, and increased the number of
migraine-free days over placebo.Interestingly,studies
of subjects with episodic migraine have not been con-
vincingly positive, suggesting disease differences
between episodic and CM.
non-regulatory
30
January 2011

Page 11

Other studies have demonstrated significant
improvement of many quality of life factors with
onabotulinumtoxinA vs placebo.18These include
improvement in MIDAS and HIT-6 scores, sleep,
work, and recreational activities. While important,
clinically they have doubtful relevance for current
standards of regulatory approval.
There are several limitations to this study. One
limitation might be that the investigators in the study
were more sophisticated in evaluation of migraine
response and that Physician Global Assessment by
these investigators does not reflect clinical assessment
of the broader population of physicians treating
migraine.This criticism should however be tempered
by the number of objective measures observed in the
study, which also support efficacy of onabotulinum-
toxinA and topiramate.
A second concern is the use of active compara-
tor rather than placebo and if the positive results
reflect regression to the mean. Placebo rates are
stated to be 21-23.5% in trials of migraine preven-
tive medications19,20and in general lower response
rates are observed in placebo controlled double-
blinded studies. Consequently, without an active
placebo arm the precise benefit of active treatment
arms cannot be fully assessed. On the other hand,
topiramate has multiple positive studies and is
approval by the FDA for migraine prevention. In
the recent PREEMPT studies, onabotulinumtoxinA
demonstrated statistical superiority over placebo
with a reduction of headache days, which is quite
similar to that noted in this study (-8.4 days vs 8.1
days, respectively). Finally, because the intent of this
study was to approximate clinical practice the use of
a comparator rather than placebo would seem to
parallel clinical practice.
Despite these limitations, this study supports
onabotulinumtoxinA as an effective preventive treat-
mentforCMwithafrequencybetween3and8attacks
per month. It adds to a body of other studies with
similarconclusions.21,22However,thereareotherclini-
calstudiesthatdonotshowefficacyevenwhensimilar
subjects are enrolled in the study.23This suggests that
methodological issues as well as pathophysiological
considerations of migraine as it becomes increasingly
chronified need to be addressed.
CONCLUSIONS
Topiramate and onabotulinumtoxinA demon-
strated significant efficacy in treating subjects with
CM. Improvements for both medications were noted
on a number of clinically relevant measures and
reflected in positive Physician Global Assessment of
efficacy. The results of this study support onabotuli-
numtoxinA as a useful therapy for patients with fre-
quent migraine and raise important questions about
methodologies and efficacy endpoints used to study
migraine preventive medications. Clearly further
study of onabotulinumtoxinA and topiramate are
warranted.
Acknowledgments: The authors wish to acknowl-
edge the contributions of M.E.Beach and Candace Shade
for their help with preparing the article, and of Murray
Jensen for performing the statistical analyses.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Roger Cady
(b) Acquisition of Data
Roger Cady,Curt Schreiber,John Porter,Andrew
Blumenfeld
(c) Analysis and Interpretation of Data
Roger Cady,Andrew Blumenfeld, Kathy Farmer
Category 2
(a) Drafting the Manuscript
Roger Cady, Kathy Farmer
(b) Revising It for Intellectual Content
Roger Cady, Curt Schreiber, Andrew Blumen-
feld, Kathy Famer
Category 3
(a) Final Approval of the Completed Manuscript
Roger Cady
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