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BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHEORIGINAL ARTICLE
From the Jefferson Headache Center, Thomas Jefferson University, Philadel-phia, Pa (S.D.S.); The Neurology & Headache Treatment Center, Alexandria,Va (S.R.S.); Department of Neurology, University of Washington MedicalCenter, Seattle (S.M.L.); Ottawa Headache Centre, Ottawa, Ontario (S.N.C.);and Allergan, Inc, Irvine, Calif (R.E.D., C.C.T.). A complete list of participantsin the BoNTA-039 Study Group appears at the end of this article.
Dr Silberstein is on the advisory panel and speakers bureau and receivesresearch support from Allergan, Inc; he is on the advisory panel or speakersbureau or serves as a consultant for Abbott Laboratories, AstraZenecaPharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, Johnson &Johnson, Merck & Co, Inc, Metis, NPS Pharmaceuticals, Ortho-McNeil Phar-maceutical, Inc, Pfizer Inc, Pozen, Inc, UCB Pharma, and X-Cel Pharmaceuti-cals; and he receives research support from Abbott Laboratories, Astra-Zeneca Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, Johnson &Johnson, Medtronics, Inc, Merck & Co, Inc, NPS Pharmaceuticals, Pfizer Inc,Pozen, Inc, UCB Pharma, and X-Cel Pharmaceuticals . Dr Stark has served as aprincipal investigator and subinvestigator for Allergan, Inc, for the past 4years. Dr Lucas is a consultant for Allergan, Inc, AstraZeneca Pharmaceuti-cals, Biogen Idec, GlaxoSmithKline, Merck & Co, Inc, Ortho-McNeil Pharma-ceutical, Inc, Pfizer Inc, and Serono Pharmaceuticals Ltd. Dr Christie hasreceived a research grant, consultancy fees, and honoraria from Allergan, Inc.Dr Turkel and Mr DeGryse are employed by and own stock in Allergan, Inc.
This study was sponsored by Allergan, Inc, Irvine, Calif.
Address reprint requests and correspondence to Stephen D. Silberstein, MD,Jefferson Headache Center, Thomas Jefferson University Hospital, 111 S11th St, Suite 8130, Philadelphia, PA 19107 (e-mail: [email protected]).
2005 Mayo Foundation for Medical Education and Research
For edit orialcomment, see
page 1119
Botulinum Toxin Type A for the Prophylactic Treatment
of Chronic Daily Headache:
A Randomized, Double-Blind, Placebo-Controlled Trial
STEPHEN D. SILBERSTEIN, MD; STUART R. STARK, MD; SYLVIA M. LUCAS, MD, PHD; SUZANNE N. CHRISTIE, MD;
RONALD E. DEGRYSE, MS, MA; AND CATHERINE C. TURKEL, PHARMD, FORTHE BONTA-039 STUDY GROUP
OBJECTIVES: To identify a treatment-responsive population forbotulinum toxin type A (BoNTA) and to evaluate the safety andefficacy of 3 different doses of BoNTA as prophylactic treatmentof chronic daily headache (CDH).
PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled study of BoNTA in patients with CDH was conductedfrom July 6, 2001, through November 7, 2003, at 28 NorthAmerican study centers. Eligible patients were injected withBoNTA at 225 U, 150 U, 75 U, or placebo and returned foradditional masked treatments at day 90 and day 180. Patients
were assessed every 30 days for 9 months. The primary efficacyend point was the mean change from baseline in the frequency ofheadache-free days at day 180 for the placebo nonrespondergroup.
RESULTS: For this study, 702 patients were enrolled and random-ized. The primary efficacy end point was not met. Mean improve-ments from baseline at day 180 of 6.0, 7.9, 7.9, and 8.0 head-ache-free days per month were observed in the placebononresponder group treated with BoNTA at 225 U, 150 U, 75 U, orplacebo, respectively (P=.44). An a prioridefined analysis ofheadache frequency revealed that BoNTA at 225 U or 150 U hadsignificantly greater least squares mean changes from baselinethan placebo at day 240 (8.4, 8.6, and 6.4, respectively; P=.03analysis of covariance). Only 27 of 702 patients (3.8%) withdrewfrom the study because of adverse events, which generally weret ransient and mild t o moderate.
CONCLUSIONS: Although the primary efficacy end point was notmet, all groups responded to treatment. The 225 U and 150 Ugroups experienced a greater decrease in headache frequencythan the placebo group at day 240. The placebo response washigher than expected. BoNTA was safe and well tolerated. Furtherstudy of BoNTA prophylactic t reatment of CDH appears warranted.
Mayo Clin Proc. 2005;80(9) :1126-1137
ANCOVA = analysis of covariance; BoNTA = botulinum toxin type A;CDH = chronic daily headache; ICHD = International Classification ofHeadache Disorders; MIDAS = Migraine Disabilit y Assessment
Chronic daily headache (CDH) describes a heteroge-neous group of headache disorders that occur morethan 15 days per month in the absence of structural orsystemic disease and often are associated with considerable
disability.1-4 In population-based surveys, CDH affects ap-
proximately 4% to 5% of the general population,2,5,6 with
0.5% experiencing severe headaches daily.7 Chronic daily
headache is encountered frequently at major tertiary head-
ache centers, where it is responsible for headaches in up to
40% of patients.4,8 Analgesic overuse is a common risk
factor for CDH.1,8,9
More than 70% of patients with CDH previously had
experienced intermittent migraine that progressed eventu-
ally to headaches that occurred more frequently and/or
lasted longer,1,10-12 ie, transformed migraine. This shift from
episodic to chronic headache may involve progressive
changes to the central nociceptive sys-
tem,3 and preliminary evidence sug-
gests that repeated migraine may result
in recurrent damage and structural al-teration, leading to a decreased thresh-
old for further migraine attacks in this population.13 Pre-
ventive treatments for patients with chronic disabling mi-
graines are needed to reduce the frequency and/or severity
of headaches, slow disease progression, decrease the need
for medication for acute headache and for health care ser-
vices, and reduce the potentialfor medication overuse.14,15
Very few well-designed studies have evaluated prophylactic
headache treatment in patients with CDH.1,16-18
To date, no drug has received regulatory approval for
the prevention of headaches in patients with migraine and
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BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHE
CDH. Numerous agents, encompassing various classes, are
used for prophylactic treatment of migraine (episodic
migraine and CDH). These classes include -blockers, cal-cium channel blockers, serotonin antagonists, antidepres-
sants, nonsteroidal anti-inflammatories, and antiepilep-
tics.19,20 Viewed collectively, they offer limited effectivenessand poor tolerability due to adverse events.19-22
Botulinum toxin type A (BoNTA) (BOTOX, Allergan,
Inc, Irvine, Calif), a focally administered neurotoxin, in-
hibits the release of acetylcholine at the neuromuscular
junction and is used therapeutically in disorders character-
ized by muscle hyperactivity.23 In preclinical models,
BoNTA has been shown to inhibit the release of nocicep-
tive mediators, such as glutamate, substance P, and calcito-
nin gene-related peptide, from nociceptive fibers.24-26 Re-
sults from several clinical trials suggest that BoNTA may
be an effective and safe preventive headache medication
for migraine and CDH.27-29
The objectives of this exploratory phase 2 trial were to
(1) identify a treatment-responsive population for BoNTA,
(2) evaluate the safety and efficacy of 3 different BoNTA
doses compared with placebo with use of a fixed injection-
site protocol, and (3) evaluate any BoNTA dose response in
the prophylactic treatment of CDH in a severely disabled
population of patients.
PATIENTS AND METHODS
STUDY DESIGNA randomized, double-blind, placebo-controlled, parallel-
group clinical study of 3 fixed-dose treatments of BoNTAcompared with placebo in the treatment of patients with
CDH was conducted from July 6, 2001, through November
7, 2003. The study was conducted at 28 North American
study centers. Before study initiation, the investigators re-
ceived appropriate institutional review board approval.
This study was conducted in compliance with the ethical
principles that originated in the Declaration of Helsinki
regarding biomedical research on human subjects and in-
formed consent regulations.
PARTICIPANT CHARACTERISTICS
Inclusion Criteria. Patients were men and women aged
18 to 65 years who experienced headaches on more than 15days during a 30-day baseline screening period. Headaches
could include any combination of migraines: those with or
without aura, migrainous headache, probable migraine,
and/or episodic or chronic tension-type headaches (as de-
fined by the International Headache Societys 1988 Inter-
national Classification of Headache Disorders [ICHD]-I).30
Patients had to be medically stable and willing and able to
give written informed consent. Patients taking long-term
medication (including long-term prophylactic headache
medications) had to be stable (no change in dose or dosing
regimen) for at least 3 months immediately before the
baseline period. Acute headache pain medication to relieve
headaches could be taken as needed. Patients had to be
willing to continue taking current medications during thecourse of the study, complete the entire course of the study,
and comply with study instructions including the daily use
of an electronic diary for data collection.
Exclusion Criteria. Patients were excluded from the
study if they had any medical condition (eg, neuromuscular
disorders) or used any agent that might expose them to risk
if they received BoNTA, had an infection or skin problem
at any of the injection sites, or had a known allergy or
sensitivity to the study medication or to its components.
Patients also were excluded if they had cluster headache or
chronic paroxysmal hemicrania, analgesic rebound head-
ache (as per the investigators discretion, since at the time
the study was conducted, no agreed-upon definition was
available), headache secondary to head trauma or whiplash
injury, a history of complicated migraine (eg, migrainous
infarction, hemiplegic migraine, ophthalmoplegic mi-
graine, or basilar migraine), a Beck Depression Inventory
score greater than 24, previous therapy with botulinum
toxin of any serotype, an injection of anesthetics or corti-
costeroids into the study-targeted muscles during the 30
days immediately before the baseline period, or if they
overused or abused symptomatic medication, alcohol, or
drugs in the investigators opinion. Concurrent or long-
term use of muscle relaxants (eg, cyclobenzaprine, cariso-
prodol, or benzodiazepines) during the 3 months before thescreening period was prohibited. Women who were preg-
nant or nursing or were unable or unwilling to use a reliable
form of contraception during the study were excluded.
TREATMENT SCHEDULEAND PROTOCOLThe overall duration of the study for each patient was 11
months. This included a 30-day screening (baseline) pe-
riod, followed by a 30-day placebo run-in period and a
9-month treatment period divided into 3 double-blind
treatment cycles each of 3 months duration. During the
baseline period, patients were screened for eligibility and
recorded data about specified headache characteristics in a
validated electronic headache diary using a telephone inter-active voice capture system daily (Phase Forward, Waltham,
Mass). Calls to the electronic diary system were to be com-
pleted daily throughout the study; the criterion for diary
compliance at baseline was 80% on a weekly basis. The
timing and duration of headache episodes, headache medica-
tion use, and other associated headache characteristics were
evaluated after the baseline period. Patients who continued
to meet inclusion/exclusion criteria were enrolled and re-
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BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHE
TABLE 1. BoNTA Dose or Placebo Inject ed per Muscle*
225 150 75 Placebo
Frontalis (4 sites) 30 20 10 0Corrugator (2 sites) 15 10 5 0
Temporalis (4 sites) 30 20 10 0Splenius capitis (2 sites) 30 20 10 0Trapezius (4 sites) 60 40 20 0Semispinalis capitis (2 sites) 30 20 10 0Suboccipital region (2 sites) 30 20 10 0
*Botulinum toxin type A (BoNTA) or placebo was injected bilaterallyinto the identified pericranial muscle groups at the indicated dose.
The dilution factor for the BoNTA 225 U group was 7.5 U/0.1 mL.The dilution factor for the BoNTA 150 U group was 5.0 U/0.1 mL.The dilution factor for the BoNTA 75 U group was 2.4 U/0.1 mL.
BoNTA (U)
Muscle area
ceived a single-blind placebo injection into 20 sites encom-
passing 7 muscle areas, including the frontalis, corrugator,
temporalis, splenius capitis, trapezius, semispinalis capitis,
and the suboccipital region (Table 1). The injection proto-
col used was a fixed-site approach, similar to that de-
scribed by Blumenfeld et al.31 Specified characteristics of
patients headaches were recorded again for 30 days using
electronic diaries. Patients were not informed about whether
they were injected with BoNTA or placebo. At the end of the
placebo run-in period, patients were classified as a placebo
responderif their number of headache days had changed
from 16 or more to less than 16 or if their number of
headache days decreased 30% or more from baseline. All
other patients were considered placebo nonresponders.
After the placebo run-in period, patients within the 2
groups (responders, nonresponders) were randomized atday 0 and received the first of 3 masked BoNTA treatments
(at 225 U, 150 U, or 75 U) or placebo. Patients returned for
2 additional masked treatments at day 90 and at day 180.
Patients were assessed subsequently at 30-day intervals
after each treatment through day 270. Patients were in-
jected with BoNTA or placebo using the same injection
protocol as used during the placebo run-in period. The
same volumes of study medication or placebo were in-
jected into the same muscles and muscle sites. If a patient
exited the study at any visit before day 270, all exit proce-
dures and evaluations were completed at that visit.
INTERVENTIONEach vial of BoNTA contained 100 U ofClostridium botu-
linum toxin type A, 0.5 mg of albumin (human), and 0.9 mg
of sodium chloride in a sterile, vacuum-dried form with
no preservative. Each vial of placebo contained 0.9 mg
of sodium chloride in a sterile, vacuum-dried form with
no preservative. All vials were reconstituted with 0.9%
sterile, preservative-free saline. The vials were reconsti-
tuted by using the volume of diluent assigned to each
specific randomization number to attain specific BoNTA
doses of 225 U, 150 U, or 75 U (1.33 mL, 2.0 mL, or 4.0 mL,
respectively).
BLINDINGAND RANDOMIZATION
The placebo run-in was a single-masked treatment where-by the investigator, but not the patient, knew that the treat-
ment administered was a placebo. This was a double-blind
study; therefore, neither the investigator nor the patient
knew which treatment was given at day 0, day 90, and day
180. On the basis of their baseline telephone diary data,
patients were randomized electronically within each group
(placebo nonresponder or placebo responder) to receive
BoNTA at 225 U, 150 U, or 75 U, or placebo in a ratio of
1:1:1:1 in blocks of 8.
To maintain the blinding, an individual with no other
study responsibilities reconstituted the study medication
and drew the study drug into the syringes for use. This
person diluted 3 vials of study medication and drew the
study drug into 7 syringes (1 for each muscle) for use. The
syringes then were given to the investigator for injection.
BoNTA injections and evaluations were performed by
the same investigator throughout the study whenever pos-
sible. If it was impossible for the same investigator to
monitor a given patient, then injections and evaluations
were to overlap between the investigators for at least 1 visit
when possible.
PRIORAND CONCOMITANT THERAPYThe use of any concurrent medication (eg, prescription
[including prophylactic medications] or over-the-counter[including herbal remedies]) was recorded along with the
reason that a medication was taken. Also, patients recorded
medications they had taken for treatment of each headache
by using their telephone diary as part of their daily call to
the integrated voice response system.
EFFICACY END POINTSBaseline data comprised the diary data collected daily dur-
ing the 30 days preceding the placebo run-in period (ie,
days 60 to 30). Each headache episode was characterized
by the recording in the diary of the headache start and stop
time, characteristics, symptoms, and medications taken. A
headache day was defined as the occurrence of a headacheepisode of any type or length in the 24-hour period from
midnight (inclusive) at the start of the day to midnight (not
inclusive) at the end of the day. A headache-free day was
defined as a complete day during which no headache was
recorded. The primary efficacy end point was the mean
change from baseline in the frequency of headache-free
days for the 30-day period ending on day 180 for the
placebo nonresponder group.
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BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHE
A secondary efficacy end point was the proportion of
patients with a decrease from baseline of 50% or more in
the frequency of headache days (per 30-day period) at day
180 for the placebo nonresponder group. Other variables
evaluated per 30-day period included the frequency of any
type of headaches, the proportion of patients with a de-crease from baseline of 50% or more headaches, the fre-
quency of migraine headaches of any severity, the propor-
tion of patients with a decrease from baseline of 50% or
more in migraine headaches, the proportion of patients
with a decrease from baseline of 2 or more migraine head-
aches, and the frequency of moderate to severe migraine
headaches.
For this analysis, the definition ofheadache frequency
was determined by several a prioridefined parameters. A
headache episode was determined by a diary entry of the
headache start and/or stop times and/or headache charac-
teristics, headache symptoms, and/or medications taken for
headaches. If the headache stopped 3 days after starting, it
was counted as 1 headache and 3 headache days. If a
patient recorded multiple headaches during the course of 1
day, the day was counted as 1 headache day, and the
frequency was recorded in relation to the number of head-
aches as defined by viable start and stop times. If the
headache was a migraine, it had to meet ICHD 1.1 or 1.2
criteria. For any 2 consecutive migraines, if the period of
time between the stop time of the first headache and the
start time of the second was less than 24 hours, they were
considered 1 continuous migraine headache. If the head-
ache met the criteria for probable migraine, the 24-hour
rule was not used and it counted as 2 headaches.Also evaluated was the number of days that medication
for acute headache was used during the study. Quality-of-
life questionnaires were distributed; patients were to com-
plete the Migraine Disability Assessment (MIDAS) at days
60, 90, 180, and 270, and the Headache Pain-Specific
Quality of Life Questionnaire was to be completed at days
60, 0, 90, 180, and 270.
SAFETY MEASURESAt each visit after treatment at day 0, adverse event infor-
mation was recorded, indicating the date of onset, resolu-
tion date (if applicable), severity (mild, moderate, or se-
vere), duration, frequency, relationship to study treatment,action taken regarding study treatment, treatment re-
quired (if any), and outcome. The relationship between an
adverse event and the study treatment was assessed by
the investigator as none, possible, probable, or definite.
Safety was assessed by reports of adverse events, physical
and neurologic examinations, and clinical laboratory tests
for the pooled population (placebo nonresponders and
placebo responders).
STATISTICAL ANALYSESThe as-treated population for both the safety and efficacy
analyses included all patients treated with the second injec-
tion at day 0 (randomization), regardless of subsequent
injections. They were analyzed in the responder or non-
responder group indicated by baseline and placebo run-indata, regardless of which group they were assigned to
during randomization. Data recorded in the patients dia-
ries were used in the analysis of outcome measurements.
Multiple comparison adjustments were made by using the
OBrien-Fleming group sequential method to set the sig-
nificance level at .048 for the primary analysis at day 180.
All other hypothesis tests used a type I error of=.05 to
determine statistical significance, except that treatment-by-
subgroup interactions were examined at the .10 level.
For the frequency of headache-free days at baseline and
its change from baseline in the nonresponder group, com-
parisons among all treatment groups were done with the
Kruskal-Wallis test, and pairwise comparisons between
treatment groups were done with the Wilcoxon rank sum
test.32 If there were significant baseline differences among
treatments in the primary variable, the baseline value of the
variable was included as a covariate in an analysis of
covariance (ANCOVA) of the variable.
An analysis of variance (with type III sums of squares)
modeling response was used for treatment-by-subgroup
interactions for several factors (eg, age, sex, race, time
since disease onset, chronic headache subtype, base-
line MIDAS total days score, and baseline prophylactic
treatment).
The proportion of patients with a decrease from baselineof 50% or more headache days per 30-day period was
analyzed by using the observed data with Pearson 2 orFisher exact tests. Additional secondary end points in-
cluded the changes from the baseline period to time points
other than day 180 (days 30, 60, 90, 120, 150, 210, 240, and
270). For the secondary efficacy variable, as for the pri-
mary variable, supplemental analyses using imputed data
for missing values were performed.
The primary analysis used observed data. When the
data reported were incomplete, certain a prioridefined
rules were applied. For example, if a patient recorded
diary data for at least 10 days but for less than 30 days in a
30-day study period, the number of headache-free daysfor the 30-day period was prorated and rounded to a
whole number.
RESULTS
PATIENT DEMOGRAPHICSAND BASELINE CHARACTERISTICSAmong 1200 screened patients, 702 (mean age, 43.4 years;
582/702 [82.9%] female) were enrolled, entered into the
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BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHE
TABLE 2. Baseline Characteristics (All Enrolled Patients)*
225 150 75 PlaceboBaseline characteristic (n=182) (n=168) (n=174) ( n=178) P value
Age (y)
Mean 42.4 43.7 43.7 43.7 .61Range 18-65 21-65 20-64 18-64
Mean (SD) years since onset 13.6 (11.9) 12.7 (10.8) 14.2 (13.2) 14.2 (12.9) .96Mean (SD) No. of headaches during
30-day baseline period 14.1 (8.5) 13.2 (8.8) 13.9 (7.4) 13.8 (9.6) .61Mean (SD) No. of migraines or probable
migraines per 30-day period at baseline 10.8 (7.5) 10.0 (7.4) 10.5 (6.6) 10.5 (8.5) .61No. (%) of patients using prophylactic
headache medications 93 (51.1) 85 (50.6) 84 (48.3) 86 (48.3) .93No. (%) of patients overusing pain
medication for acute headache 78 (42.9) 67 (39.9) 74 (42.5) 77 (43.3) .92Mean (SD) MIDAS score 56.0 (50.8) 52.0 (45.8) 50.7 (49.2) 59.9 (57.5) .63
*BoNTA = botulinum toxin type A; MIDAS = Migraine Disability Assessment.
BoNTA (U)
placebo run-in period, and subsequently randomized to
active treatment or placebo at day 0. At the end of the
baseline period, 498 patients were no longer enrolled for
the following reasons: 15 or fewer headache days (26%),
withdrew consent (20%), not enough diary calls (17%),
Beck Depression Inventory score greater than 24 (7%), lost
to follow-up (7%), personal reasons (4%), unstable chronic
medications (3%), taking exclusionary medications (2%),
medication overuse (1%), screen failure due to abnormal
laboratory results (1%), and other (12%).
At the end of the placebo run-in period, of 702 patients,
538 (76.6%) were classified as placebo nonresponders and
164 (23.4%) as placebo responders. Subsequently, patients
within each group were randomized to receive BoNTA at225 U (n=182), 150 U (n=168), 75 U (n=174), or placebo
(n=178). No statistically significant differences in demo-
graphic and other baseline characteristics were found
among the 4 treatment groups (Table 2).
Patient Disposition. A total of 71.9% (387/538) of the
placebo nonresponders and 75.6% (124/164) of the placebo
responders completed the study. Of the patients who dis-
continued (27.2% [191/702]), 10.5% (74/702) did so for
lack of efficacy, 7.4% (52/702) for administrative reasons,
3.8% (27/702) for adverse events, 0.4% (3/702) for proto-
col violation, and 4.3% (30/702) for other reasons; 5
patients (0.7%) discontinued the study because they were
administered incorrect doses of BoNTA. The placebogroup alone accounted for 43% (32/74) of the patients who
discontinued for lack of efficacy.
Type and Severity of Headaches. Each headache was
classified as migraine (ICHD-II level 1) or nonmigraine
(ICHD-II level 2; eg, tension-type headache). Patients in
the BoNTA 225 U, 150 U, 75 U, and placebo groups
experienced mean headache days per 30-day period at
baseline of 23.6, 23.6, 24.0, and 24.1, respectively (pooled
placebo nonresponder and placebo responder group). The
mean age at onset of CDH was 29.1 years, and the mean
time since onset was 13.7 years. The CDH diagnosis sub-
type, based on a clinical interview and assigned by the
investigator, was not recorded for approximately 30.9%
(217/702) of patients because this was part of a protocol
amendment that was initiated midway through the study.
Among the 485 of 702 patients (69.1%) who had their CDH
subtype classified, 77.3% (375) were classified as having
transformed migraine, followed by 18.4% (89) with
chronic tension-type headache, 3.3% (16) with new daily
persistent headache, and 1% (5) with other. No patients
were diagnosed as having hemicrania continua. All but 5
patients experienced at least 1 migraine or probable mi-graine during the baseline period, suggesting that the pa-
tients were migraineurs, even though this diagnosis was not
recognized by the investigator for all patients. A history of
migraine was recorded for almost half of all patients
(48.9%). The mean number of headaches experienced dur-
ing the 30-day baseline period was 14.1, 13.2, 13.9, and
13.8 for the 225 U, 150 U, 75 U, and placebo groups,
respectively. The mean number of migraine or probable
migraine headaches experienced during the (30-day)
baseline period was approximately 10.5 headaches for all
treatment groups. The mean baseline MIDAS score for all
patients (54.7) indicated that most patients experienced
moderate to severe disability.Medication Use at Baseline. Almost half the patients
(49.6% [348/702]) used prophylactic headache medica-
tions, yet met the inclusion criteria of 16 days or more of
headaches per 30-day period: 262 of 524 (50%) of all
patients receiving BoNTA and 86 of 178 (48.3%) of pa-
tients receiving placebo (Table 2). At baseline, 95.1%,
97.6%, 96.0%, and 96.1% of patients in the BoNTA 225 U,
150 U, 75 U, and placebo groups, respectively, were using
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BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHE
FIGURE 1. Mean change from baseline in the number of headache-free days per 30-day
period in placebo nonresponders. BoNTA = botulinum toxin type A.
0Day
30
Day
60
Day
90
Day
120
Day
150
Day
180
Day
210
Day
240
Day
270
1
2
3
4
5
6
No.ofheadache-freed
ays
(meanchangefrombas
eline)
7
8
9
10
BoNTA 225 U BoNTA 150 U BoNTA 75 U Placebo
medication for acute headache (eg, pain and antinausea
medications; P=.66). The mean number of days with medi-
cation for acute headache pain (eg, ergotamines, triptans,
simple analgesics, opioids, and combination medications
[ICHD-II section 8.2.1-8.2.5]) was 13.5, 12.6, 13.4, and
13.7 for the BoNTA 225 U, 150 U, 75 U, and placebo
groups, respectively (P=.49). According to the most re-
cently proposed definition ofmedication overuse (use for
15 days and 2 d/wk), about 42% of patients in all treat-
ment groups were overusing medication for acute headache
pain (ICHD-II, 2004), with no significant between-groupdifference (P=.92; Table 2).
ANALYSESOF EFFICACYMean Change From Baseline in the Frequency of
Headache-Free Days. In both the placebo nonresponders
and placebo responders, all treatment groups experienced
mean improvements from baseline in the number of head-
ache-free days per 30-day period.
At day 180, the primary end point, placebo nonre-
sponders treated with BoNTA at 225 U, 150 U, and 75 U
experienced mean changes from baseline of 6.0 (7.1), 7.9
(8.4), and 7.9 (7.8) headache-free days per 30-day pe-
riod, respectively, compared with a mean change frombaseline of 8.0 (8.8) headache-free days for placebo
patients treated in the same group (Figure 1). The among-
group difference was not statistically significant (P=.44);
therefore, the primary end point was not met. At day 30 in
the placebo nonresponder group, there was a mean in-
crease in the number of headache-free days from base-
line that was significantly greater for patients receiving
BoNTA at 75 U (5.06.5 headache-free days) compared
with the BoNTA 225 U, 150 U, and placebo groups
(3.16.0, 3.06.2, and 2.95.2 days, respectively; P=.01
for all).
In the placebo responder group, patients treated with
BoNTA at 225 U, 150 U, and 75 U experienced mean
changes from baseline at day 180 of 13.17.8, 11.47.5,
and 14.06.1 headache-free days, respectively, compared
with a mean change from baseline of 10.87.2 head-
ache-free days for placebo patients treated in the same
group. The among-group difference was not statistically
significant.Secondary Efficacy End Points. In the placebo non-
responder group at day 180, the percentages of patients
with a decrease from baseline of at least 50% in the
number of headache days per 30-day period were 25.4%,
35.1%, 30.9%, and 31.7% for the BoNTA 225 U, 150 U,
75 U, and placebo groups, respectively. The among-group
difference was not statistically significant. In contrast, in
the placebo responder group at day 60, a significantly
higher percentage of patients treated with BoNTA at 225
U (69.6% [32/46]) had at least a 50% decrease from
baseline in the number of headache days per 30-day pe-
riod compared with patients treated with BoNTA at 150 U
(44.4% [16/36]; P=.02) and placebo (37.1% [13/35];P=.004).
POOLED POPULATIONBecause of the nonstatistically significant treatment-by-
responder interaction, the placebo nonresponder and pla-
cebo responder groups were pooled and a post hoc analysis
was completed to compare BoNTA with placebo (pooled
population) for additional efficacy variables.
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BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHE
78
9
10
6
5
4
3
2
1
0
No
.ofheadaches(meandecreasefrombasel
ine)
*
Day30
Day60
Day90
Day120
Day150
Day180
Day210
Day240
Day270
BoNTA 225 U BoNTA 150 U BoNTA 75 U Placebo
FIGURE 2. Mean decrease from baseline in the number of headaches per 30-dayperiod. BoNTA = botulinum toxin type A.* P=.04, BoNTA at 225 U and at 75 U vs 150 U.P=.03, BoNTA at 225 U and at 150 U vs placebo.
In the following sections, analyses are presented only
for the pooled population.Number of Headaches. After correcting for differences
in the baseline frequency of headaches, an analysis of
results showed a statistically significant between-group
difference in the frequency of headaches favoring BoNTA
over placebo at multiple time points (Figure 1). Statisti-
cally significant differences existed overall among the
treatment groups in the least squares mean changes from
baseline in the number of headaches per 30-day period at
days 30 and 240 (P=.04 and P=.03, respectively) (Figure
2). At day 30, the least squares mean change was signifi-
cantly greater for the BoNTA 225 U group (4.5; P=.02
ANCOVA) and BoNTA 75 U group (4.5; P=.01
ANCOVA) compared with the BoNTA 150 U group(3.3). At day 240, the least squares mean changes were
significantly greater for the BoNTA 225 U group (8.4;
P=.04) and 150 U group (8.6; P=.02 ANCOVA) com-
pared with placebo (6.4). Although the among-group P
values were not statistically significant at day 210 (P=.08)
and day 270 (P=.08), there were some trends observed
regarding the BoNTA 225 U group and 150 U group vs
placebo. At day 210, the least squares mean change was
significantly greater for the BoNTA 225 U group vs pla-
cebo (P=.03). On day 270, the least squares mean changewas significantly greater for the BoNTA 150 U group vs
placebo (P=.03).
Number of Migraines or Probable Migraine Head-
aches. The mean number of migraines or probable mi-
graines during baseline for each treatment group was 10.8,
10.0, 10.5, and 10.5 for the BoNTA 225 U, 150 U, 75 U,
and placebo groups, respectively. A covariate analysis of
variance was performed with baseline as the covariate.
Statistically significant among-group differences were ob-
served for the mean changefrom baseline in the number of
migraine or probable migraine headaches (per 30-day pe-
riod) compared with placebo at days 30, 90, and 150
(P=.02; P=.02; P=.03 ANCOVA, respectively) (Figure 3).At day 30, the least squares mean change in the number of
migraines or probable migraines was 3.9 in the BoNTA
225 U group compared with 2.7 in the BoNTA 150 U
group (P=.01 ANCOVA) and 2.8 in the placebo group
(P=.02 ANCOVA). At day 90, the least squares mean
change from baseline was 4.8 in the BoNTA 75 U group
compared with 3.5 in the BoNTA 150 U group and 3.4 in
the placebo group (P.01 ANCOVA). At day 150, the least
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BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHE
7
6
5
4
3
2
1
0
Day30
Day60
Day90
Day120
Day150
Day180
Day210
Day240
Day270
BoNTA 225 U BoNTA 150 U BoNTA 75 U Placebo
No.ofmigrainesorprobablemigrain
es
(meandecreasefrombaseline)
*
FIGURE 3. Mean decrease from baseline in the number of migraine or probablemigraine headaches per 30-day period. BoNTA = botulinum toxin type A.* P=.02 for BoNTA at 225 U vs BoNTA at 150 U and placebo.P=.02 for BoNTA at 75 U vs BoNTA at 150 U and placebo.P=.03 for BoNTA at 75 U vs placebo.P=.003 for BoNTA at 225 U and at 75 U vs placebo.P=.006 for BoNTA at 225 U, at 150 U, and at 75 U vs placebo.P=.01 for BoNTA at 150 U and at 75 U vs placebo.
squares mean change from baseline was 5.8 in the 75 U
group compared with 3.8 in the placebo group(P=.002ANCOVA).
Percentage of Patients Using and Overusing Acute
Headache Pain Medications. At day 30, acute headache
pain medications were used by a significantly lower per-
centage of patients in the BoNTA 225 U group (83.2%)
compared with the BoNTA 150 U group (93.4%; P=.003)
and placebo group (91.0%; P=.03). At day 90, pain medi-
cations for acute headache were used by a significantly
lower percentage of patients in the BoNTA 225 U group
(79.1%) compared with the BoNTA 150 U group (90.3%;
P=.006).
Although no statistically significant among-group dif-
ferences were observed from day 120 to day 270 (exceptfor the day 180 visit), a greater percentage of placebo
patients were using pain medication for acute head-
ache compared with all 3 of the BoNTA groups. Simi-
larly, for medication overuse, from day 30 to day 270,
a greater percentage of patients in the placebo group
were overusing pain medication for acute headache com-
pared with all 3 of the BoNTA groups (except at days 60
and 90 in the 225 U group) (Figure 4). A statistically sig-
nificant among-group difference was observed at day 210
(P=.05).
HEALTH OUTCOME MEASURESOccasional statistically significant improvements were ob-
served in headache-related disability, primarily in the pla-
cebo responder group, as measured by MIDAS. Further
exploration of treatment group differences with the SF-36
Health Survey may be worthwhile in future studies because
many of the domains in the pooled population exhibited
greater improvement with BoNTA treatment compared
with placebo including bodily pain, general health, vitality,
social functioning, and health transition (data not shown).
SAFETYAND TOLERABILITYOne or more adverse events, regardless of causality, were
reported for 80.2% of patients (146/182) treated with
BoNTA at 225 U, 79.2% (133/168) treated with BoNTA at
150 U, 81.6% (142/174) treated with BoNTA at 75 U, and
68.0% (121/178) treated with placebo.The overall inci-
dence of adverse events was greater in each BoNTA group
than in the placebo group (P.02).Most of the adverse
events were transient and mild or moderate in severity.
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BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHE
TABLE 3. Treatment-Related Adverse Events Reported by at Least 3% of Patientsin any Treatment Group (Pooled Population)*
BoNTA (U)225 150 75 Placebo
Adverse event (n=182) (n=168) (n=174) (n=178) P value
Any 119 (65.4) 92 (54.8) 97 (55.7) 38 (21.3)
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BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHE
Only 27 of 702 patients (3.8%) discontinued the study
due to adverse events (9 receiving BoNTA at 225 U, 13
receiving BoNTA at 150 U, 3 receiving BoNTA at 75 U,
and 2 placebo patients). Thirty-four patients experienced
39 serious adverse events, all of which the investigator
considered to be unrelated to study treatment.
DISCUSSION
Most patients with CDH who seek treatment in headache
clinics have transformed migraine. These patients head-
aches tend to be severe and disabling.2,12,33 The dominant
population enrolled in this study included patients with
moderate to severe transformed migraine, many of whom
were overusing pain medications for acute headache. These
patients had an average of more than 20 days of headaches
per month and severe disability at baseline. There is clearly
an unmet therapeutic need in this patient population for
effective and tolerable preventive headache treatment.
In this study, the response in the placebo group was
greater than expected. A high placebo response has been
reported to be a confounder in evaluating treatment of
painful conditions, including headache.34 According to
Linde et al,35 the more uneven the randomization, the
greater the placebo response. An additional and perhaps
more influential confounding factor was the use of pain
medication for acute headache. For ethical reasons, pa-
tients were allowed to take pain medications for acute
headache on an as-needed basis. This could have con-
founded the data in this study in 2 ways. First, the charac-
teristics of the headaches may have been modified. Forexample, without medication, patients would have experi-
enced all the symptoms necessary to classify a headache as
a migraine that meets the criteria of the International Head-
ache Society for migraine 1.1. However, because of short-
term medication use, the headaches did not meet the crite-
ria for even a probable migraine. Therefore, for future
studies, headache frequency may be a more appropriate
variable of interest rather than the frequency of headache-
free days. Second, a trend was observed in which a larger
percentage of patients in the placebo group were using (and
overusing) pain medications for acute headache compared
with all the BoNTA groups. This could be an important
confounding factor because to be significantly different,the BoNTA group needed to show efficacy statistically
greater than the placebo group in which more patients were
using (and overusing) acute headache pain medications to
treat their headaches.
Although the primary efficacy outcome was not met in
this trial, the results indicate that BoNTA, injected for up to
3 treatment cycles (at fixed total doses of 225 U, 150 U, or
75 U) and placebo profoundly increased the frequency of
headache-free days at all post-placebo run-in time points.
A statistically significant among-group difference was ob-
served at day 30. In the placebo nonresponder group, the
mean increase in the number of headache-free days from
baseline was significantly greater for the BoNTA 75 U
group compared with the other treatment groups. In the apriori analysis of pooled data (placebo responders and pla-
cebo nonresponders), those receiving BoNTA at 225 U or
150 U had statistically significant mean reductions from
baseline in headache frequency in a 30-day period com-
pared with placebo at day 240.
For other variables, in both the placebo nonresponders
and placebo responders group efficacy analyses, there
were some differences among treatment groups that
reached significance. These differences always favored
BoNTA, but no specific BoNTA group was consistently
better than placebo. On the basis of data for headache-free
days and the reduction of migraine and probable migraine
headaches in the pooled population, BoNTA revealed an
initial onset of action within 30 days of the first active
treatment.
Results were published recently from a large random-
ized, placebo-controlled trial, conducted by Mathew et al,29
of multiple treatments of BoNTA as prophylactic treatment
of CDH by using a modified follow-the-pain dosing
regimen. In that trial, patients who received a mean
BoNTA dose of 190 U had statistically significant reduc-
tions in headache frequency, 40% had at least a 50% reduc-
tion in headache days, and there was at least a 50% reduc-
tion in the mean number of headaches in a 30-day period.
These results suggest that an effective BoNTA dosagerange may be 150 to 225 U.
This study adopted a fixed-site approach, whereby the
injection sites and doses delivered to these sites were un-
changed by pain location reported by individual patients.
This approach was designed to cover a broad distribution
of the trigeminal nerve affecting sensory nerves innervat-
ing the trigeminal nerve receptive fields, as well as the
receptive fields innervated by the upper cervical sensory
afferent nerves. Similar approaches have yielded some
clinically important and statistically significant effects of
BoNTA treatment in patients with migraine.14,28 More re-
cently, follow-the-pain approaches, in which injection sites
and dose distribution are dictated by pain distribution, havebeen advocated.36 The study conducted by Mathew et al29
cited previously identified significant treatment responses
in a similar patient population using a follow-the-pain ap-
proach. The results from this trial do not necessarily sup-
port abandonment of the fixed-site approach. Patients in all
treatment groups had a robust response to treatment, but the
outcome appears to have been confounded by the greater
use of acute headache pain medications in the placebo
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BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHE
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and affects the generation of migraine is needed to stimu-
late informed discussion about the dose-response relation-
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The results of this trial showed that BoNTA treat-
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similar to those reported previously with BoNTA us-
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risk.
Dosing and results reported in this study are specific to
the formulation of botulinum toxin type A manufactured by
Allergan, Inc (Irvine, Calif). The Allergan, Inc, formula-
tion is not interchangeable with other botulinum toxin
products and cannot be converted by using a dose ratio.
CONCLUSIONSAlthough the primary efficacy end point was not met,
BoNTA treatment in this trial showed a significant differ-
ence from placebo in some analyses. At day 240, the de-
crease in headache frequency was significantly greater for
the BoNTA 225 U and 150 U groups compared with pla-
cebo; however, the placebo response was higher than ex-
pected. A greater percentage of patients in the placebo
group used pain medications for acute headache through-
out the study, thereby confounding the results. BoNTA
treatment was safe and well tolerated over multiple treat-
ment cycles. Thus, we believe that BoNTA prophylactic
treatment of migraine should be evaluated further in ran-domized, placebo-controlled trials with fewer treatment
arms to reduce the possibility of a placebo effect obscuring
genuine clinical phenomena. This approach may shed fur-
ther light on the appropriate treatment paradigm in the use
of BoNTA in migraine treatment.
Participants of theBoNTA-039 Study Group. Jeffrey Adel-
glass, MD (Skintastic, Dallas, Tex); Zahid H. Bajwa, MD (Beth
Israel Deaconess Medical Center, Boston, Mass); Peter J.
Barbour, MD (Lehigh Valley Hospital, Allentown, Pa); Werner
Becker, MD (Foothills Medical Center, Calgary, Alberta); David
Biondi, DO (Spaulding Rehabilitation Hospital, Boston, Mass);
Suzanne N. Christie, MD (Ottawa Headache Centre, Ottawa,
Ontario); David Dodick, MD (Mayo Clinic, Scottsdale, Ariz);
Ronald E. DeGryse, MS, MA (Allergan, Inc, Irvine, Calif);
Michael Elliott, MD (Virginia Mason Medical Center, Seattle,
Wash); Frederick Freitag, DO (Diamond Headache Clinic, Chi-
cago, Ill); Mark Forrest Gordon, MD (Long Island Jewish Med-
ical Center, New Hyde Park, NY); Matthews Gwynn, MD
(Neurotrials Research, Inc, Atlanta, Ga); Pan-Yu Lai, PhD
(Allergan, Inc, Irvine, Calif); Paul Later, MD (Fort Wayne Neuro-
logical Center, Fort Wayne, Ind); Kenneth A. Levin, MD (Neu-
rology Group of Bergen County, Ridgewood, NJ); Sylvia M.
Lucas, MD, PhD (University of Washington Medical Center,
Seattle); Joseph Nicolas, MD (University Neurology Inc, Cincin-
nati, Ohio); C. Phillip OCarroll, MD (Newport Beach Neurolo-
gists, Newport Beach, Calif); James Patton, MD (Mountain Neu-
rological Center, PA, Asheville, NC); Joel Saper, MD (MichiganHead Pain and Neurology Institute, Ann Arbor); Fred Sheftell,
MD (The New England Center for Headache, PC, Stamford,
Conn); Stephen D. Silberstein, MD (Jefferson Headache Center,
Philadelphia, Pa); Richard Singer, MD (Neurology Clinical Re-
search, Inc, Plantation, Fla); Robin Smith, RN, BSN (Allergan,
Inc, Irvine, Calif); Timothy Smith, MD (Mercy Health Research,
St Louis, Mo); Egilius Spierings, MD (MedTrial Boston Inc,
Wellesley, Mass); Stuart R. Stark, MD (The Neurology & Head-
ache Treatment Center, Alexandria, Va); Gabriel Tatarian, DO
(Jefferson Medical College of Thomas Jefferson University,
Philadelphia, Pa); Catherine C. Turkel (Allergan, Inc, Irvine,
Calif); Amanda M. VanDenburgh, PhD (Allergan, Inc, Irvine,
Calif); Thomas Ward, MD (Dartmouth Hitchcock Medical Cen-ter, Lebanon, NH); Kerri Wilks, MD (Baumel-Eisner Neuromed
Institute, Ft Lauderdale, Md).
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