Efficacy and Safety of Topiramate for the Treatment of Chronic Migraine: A Randomized, Double-Blind, Placebo-Controlled Trial

Authors

  • Stephen D. Silberstein MD,

  • Richard B. Lipton MD,

  • David W. Dodick MD,

  • Frederick G. Freitag DO,

  • Nabih Ramadan MD,

  • Ninan Mathew MD,

  • Jan L. Brandes MD,

  • Marcelo Bigal MD,

  • Joel Saper MD,

  • Steven Ascher PhD,

  • Donna M. Jordan RN,

  • Steven J. Greenberg MD,

  • Joseph Hulihan MD,

  • on behalf of the Topiramate Chronic Migraine Study Group


  • From the Jefferson Headache Center, Philadelphia, PA, USA (Dr. Silberstein); Albert Einstein College of Medicine, Bronx, NY, USA (Drs. Lipton and Bigal); Mayo Clinic, Scottsdale, AZ, USA (Dr. Dodick); Diamond Headache Clinic, Chicago, IL, USA (Dr. Freitag); Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA (Dr. Ramadan); Houston Headache Clinic, Houston TX, USA (Dr. Mathew); Nashville Neuroscience Group, Nashville, TN, USA (Dr. Brandes); Michigan Head Pain and Neurological Institute, Ann Arbor, MI, USA (Dr. Saper); Ortho-McNeil Janssen Scientific Affairs, LLC, Titusville, NJ, USA (Dr. Ascher); PriCara, Unit of Ortho-McNeil, Inc., Raritan, NJ, USA (Ms. Jordan); Ortho-McNeil Neurologics, Titusville, NJ, USA (Drs. Greenberg and Hulihan);

  • Topiramate Chronic Migraine Study Group Investigators (listed alphabetically with the location of their trial sites): James Adelman, MD (Greensboro, NC, USA); James Banks, MD (Roanoke, VA, USA); Frank R. Berenson, MD (Atlanta, GA, USA); Tanya R. Bilchik, MD (Hartford, CT, USA); Harvey Blumenthal, MD (Tulsa, OK, USA); Bradley S. Boop, MD (Little Rock, AR, USA); Jan L. Brandes, MD (Nashville, TN, USA); Roger Cady, MD (Springfield, MO, USA); John E. Castaldo, MD (Allentown, PA, USA); John Cochran, MD (Alexandria, VA, USA); James Couch, MD (Oklahoma City, OK, USA); F. Michael Cutrer, MD (Rochester, MN, USA); Kathleen Digre, MD (Salt Lake City, UT, USA); David W. Dodick, MD (Scottsdale, AZ, USA); Robert A. Duarte, MD (Manhasset, NY, USA); Grace Forde, MD (Valley Stream, NY, USA); Frederick Freitag, DO (Chicago, IL, USA); Gerard Gary, MD (Toledo, OH, USA); Gordon Gibson, MD (Little Rock, AR, USA); Richard Hull, MD (Huntsville, AL, USA); Nancy Juopperi, DO (Madison Heights, MI, USA); Simmons L. Keith, DO (Tulsa, OK, USA); John R. Kirchner, MD (Omaha, NE, USA); David Kudrow, MD (Santa Monica, CA, USA); Howard LaRoche, MD (Lake Jackson, TX, USA); Hubert A. Leonard, MD (Portland, OR, USA); Robert S. Lipetz, DO (Spring Valley, CA, USA); Elizabeth W. Loder, MD (Boston, MA, USA); Morris Maizels, MD (Woodland Hills, CA, USA); Lisa Mannix, MD (West Chester, OH, USA); Herbert Markley, MD (Worcester, MA, USA); Ninan Mathew, MD (Houston, TX, USA); Peter McAllister, MD (Fairfield, CT, USA); Laszlo Mechtler, MD (Amherst, NY, USA); Marshall Nash, MD (Decatur, GA, USA); William Noran, MD (Jacksonville, FL, USA); James Patton, MD (Asheville, NC, USA); Eric Pearlman, MD, PhD (Savannah, GA, USA); Nabih Ramadan, MD (North Chicago, IL, USA); Alan Rapoport, MD (Stamford, CT, USA); John Rothrock, MD (Mobile, AL, USA); Todd Rozen, MD (Ann Arbor, MI, USA); Aurora Sheena, MD (Seattle, WA, USA); Stephen Silberstein, MD (Philadelphia, PA, USA); Richard P. Singer, MD (Plantation, FL, USA); Timothy Smith, MD (St. Louis, MO, USA); Kenneth Sokolski, MD (Santa Ana, CA, USA); Egilius Spierings, MD, PhD (Wellesley Hill, MA, USA); Alexandre Todorov, MD (Northport, AL, USA); Steve Wheeler, MD (Hialeah, FL, USA); Paul Winner, DO (West Palm Beach, FL, USA).

Address all correspondence to Dr. Stephen Silberstein, Jefferson Headache Center, 111 South 11th Street, Suite 8130 Gibbon, Philadelphia, PA 19107, USA.

Abstract

Objective.—To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine.

Methods.—This was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events.

Results.—The intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8% of the topiramate group and 55.2% on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate −6.4 vs placebo −4.7, P= .010) and migraine headache days relative to baseline (topiramate −5.6 vs placebo −4.1, P= .032). Treatment-emergent adverse events occurred in 132 (82.5%) and 113 (70.2%) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8%), upper respiratory tract infection (n = 22, 13.8%), and fatigue (n = 19, 11.9%). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4%), fatigue (n = 16, 9.9%), and nausea (n = 13, 8.1%). Discontinuations due to adverse events occurred in 18 (10.9%) topiramate subjects and 10 (6.1%) placebo subjects. There were no serious adverse events or deaths.

Conclusions.—Topiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.

Chronic daily headache (CDH) comprises a group of heterogeneous disorders characterized by the occurrence of headaches on at least 15 days per month.1–3 In subspecialty care, most subjects with CDH have a form of the disorder linked to migraine.1,4,5 Terminology and diagnostic criteria for these disorders continue to evolve. Transformed migraine has been proposed to be a subtype of CDH; the term is widely used to describe patients who have a history of episodic migraine in which the frequency of headache episodes increases until the patients experience daily or near-daily migrainous and nonmigrainous headaches.4–6

In the International Classification of Headache Disorders-2 (ICHD-2), chronic migraine was defined by the presence of migraine without aura 15 or more days per month.2 More recently, a revision was proposed requiring 15 or more headache days per month with migraine or response to triptans or ergots on at least 8 days.3 For the purposes of this study, chronic migraine was defined as the presence of at least 15 headache days per 28 days, of which at least half were migraine (International Headache Society; IHS 1.1 or 1.2) or migrainous headache. The criteria for this protocol were determined at the same time as the ICHD-2 criteria for chronic migraine were being discussed. Although migraine terminology has continued to evolve, evidence suggests a very high degree of overlap using various definitions for chronic migraine based on different criteria.7 In addition, although the term probable migraine was discussed as being more descriptive of headaches that did not meet all criteria for migraine headache, the term migrainous headache was still widely used at the time.

CDH and its subtypes are an important public health priority associated with a high degree of disability that exceeds episodic migraine;8 CDH has been linked to overuse of acute headache pain medicines.9,10 Also, patients with CDH often have been considered to be refractory to preventive medications, especially when acute “symptomatic” medications for acute headache are being overused.11 Preventive treatments for patients with frequent or severe episodic migraine are widely used in clinical practice for preventive treatment of chronic migraine, typically in the absence of evidence from controlled trials that would support such a practice.12,13 Accordingly, chronic migraine is a disease state characterized by severe disability, important unmet treatment needs, and lack of rigorous evidence to support therapies currently employed.

Topiramate is approved for use in adults for migraine prevention. In several randomized, double-blind, placebo-controlled, dose-ranging trials involving adult patients with episodic migraine, topiramate treatment resulted in significant benefit compared with placebo, with efficacy observed within the first month of treatment.14–16 The results from these trials confirmed topiramate 100 mg/day to be an effective, safe, and generally well-tolerated preventive treatment for migraine.14–17

In 2 separate small, single-center, randomized, double-blind, placebo-controlled, or active-comparator-controlled pilot trials, topiramate significantly lowered the mean monthly headache frequency in patients with chronic migraine.18,19 To confirm these data, we designed the current large, multicenter study to evaluate the efficacy and safety of topiramate 100 mg/day for the treatment of chronic migraine.

METHODS

This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial (46 U.S. sites) conducted in accordance with the Declaration of Helsinki from September 2003 to March 2005. Written informed consent was obtained from all participants before they underwent any study-related procedure, and approval for the study was provided at each site by an Independent Ethics Committee or Institutional Review Board.

The study consisted of a pretreatment phase lasting up to 56 days, a double-blind treatment phase lasting 16 weeks, and a taper/exit period that lasted up to 2 weeks (Fig. 1). The pretreatment phase consisted of 2 study periods: a screening and washout period (day −56 to day −29), and a prospective baseline period (day −28 to day 0). The screening and washout period commenced at visit 1 and occurred within 28 days of the start of the prospective baseline period (visit 2). Patients were instructed to discontinue all preventive migraine medications for 14 to 28 days prior to visit 2 and for the duration of the study.

Figure 1.—.

Study design.

The prospective baseline period began on day −28 (visit 2), as soon as the patient completed the screening and washout period. Subjects were required to maintain a daily headache record during this period. Subjects who completed the prospective baseline period and met the prespecified entry criteria were randomized 1:1 to topiramate or placebo.

The double-blind treatment phase consisted of a 4-week titration period and a 12-week maintenance period. During the titration period, subjects were given topiramate (or matching placebo) 25 mg/day once daily for 7 days, followed by weekly increases of 25 mg until either 100 mg/day of topiramate (or matching placebo) or a maximum tolerated dose was reached. All subjects were required to follow the same titration schedule. Starting in week 2, study medication was given twice daily. During the maintenance period, a stable topiramate dose of at least 50 mg/day was required. For all subjects exiting the study (completers or those who discontinued the study drug), a dose taper period of up to 2 weeks was recommended. The investigator determined the duration of the taper, which was based on the maximum dose achieved during the maintenance period.

Study Participants.—

Inclusion Criteria.— During the screening period, eligibility for participation in the study was determined. Adult subjects with a diagnosis of chronic migraine, defined according to Silberstein/Lipton criteria for transformed migraine,20 were identified. Subjects who met these criteria for chronic migraine during the screening period were required to meet additional criteria to proceed to randomization. Subjects were required to have at least 15 headache days per 28 days, defined as a calendar day during which they experienced head pain for at least 30 minutes. On at least half of these days, subjects were required to have experienced migraine with or without aura (IHS 1.1 or 1.2)21 or migrainous headache. Migrainous headache was defined as moderate to severe headache with 1 or more of the following migraine features: unilateral pain or pain worse on 1 side of the head, pulsatile pain, photophobia and/or phonophobia, nausea and/or vomiting, or pain made worse by physical activity. Eligible subjects also were required to have a Migraine Disability Assessment (MIDAS)22 score of at least 11 at visit 1.

Exclusion Criteria.— Subjects were excluded from study participation if they met any of the following criteria:

  • • Previously failed more than 2 adequate trials of migraine preventive medications (adequate was defined as a trial of at least 3 months' duration at the recommended dose)
  • • Previously failed an adequate trial of topiramate therapy due to lack of efficacy or adverse events
  • • History of cluster headache or basilar, ophthalmoplegic, or hemiplegic migraines
  • • Migraine onset after age 50
  • • Overuse of acute migraine medication (defined in this trial as use in excess of 4 days per week during the prospective baseline period)
  • • History of hepatic disorder or nephrolithiasis
  • • Progressive neurologic disorder other than migraine
  • • Pregnant or nursing

Concomitant Headache Medications.— All preventive migraine treatments were discontinued at least 14 to 28 days prior to the prospective baseline period and for the duration of the study. Use of acute headache pain medications such as analgesics, nonsteroidal anti-inflammatory drugs, triptans, opioids, and ergot derivatives was permitted for symptomatic relief of headache but could not exceed 4 days per week during the maintenance period. The specific acute headache pain medications used were recorded in the daily headache record along with migraine episode information. As much as possible, subjects were to utilize the same acute medications throughout the study as those they had employed prior to enrollment.

Randomization and Blinding.— At visit 1, subjects were assigned a 5-digit number that was retained for the duration of the study. Computer-generated random medication code numbers were prepared and preprinted on the study medication labels. Eligible subjects were randomized and assigned sequentially 1:1 to either topiramate or placebo at the end of the prospective baseline period (day 1). The investigators entered the qualified patient's identifier in numerical order. The randomization was performed using permuted blocks.

Efficacy Measures.— The primary endpoint was the change from baseline in the mean monthly (28 day) number of migraine/migrainous days. The change from baseline in the mean monthly number of migraine days also was analyzed in addition to the percent change from baseline for these 2 efficacy parameters.

Secondary prespecified efficacy measures that were derived but will be detailed in a subsequent publication include:

  • • Categorical responder rates in the percent change from baseline in mean monthly number of migraine/migrainous, migraine, and total headache days
  • • Change in the mean monthly rate of headache days
  • • Change in monthly headache-free days
  • • Reduction from baseline in the use of acute headache medications
  • • Occurrence of associated symptoms of photophobia, phonophobia, and nausea
  • • Absolute change in a Headache Index (which was defined as the sum of the product of daily average severity multiplied by headache duration for the day, divided by the number of days in the specified period. Severity was based on 5 categories: 1 = mild headache, easily ignored; 2 = mild bothersome discomfort; 3 = moderate, painful; 4 = moderate, very painful; and 5 = severe, intensely painful) during the last 4 weeks of double-blind treatment compared with the prospective baseline period.

Effects of study drug on MIDAS,22 Physician's Global Impression of Change, Subject's Global Impression of Change, and the Migraine-Specific Quality-of-Life Questionnaire were evaluated.

Safety and Tolerability Measures.— Safety measures included measurement of vital signs, serial physical and brief neurologic examinations, and clinical laboratory parameters (hematology, chemistry, and urinalysis). Women of childbearing potential had urine pregnancy tests. Spontaneously reported adverse events were collected and recorded at each visit. Treatment-emergent adverse events (TEAEs) were defined as those that were new in onset or aggravated in severity or frequency between the prospective baseline period and the conclusion of the double-blind treatment phase. The investigators recorded the date of onset, severity, and outcome of each adverse event, evaluated the possible relationship to treatment and recorded any action taken.

Statistical Analysis.— Analyses of treatment effectiveness were performed on the intent-to-treat population (full analysis set), which consisted of all randomized subjects who received at least 1 dose of study medication and provided at least 1 postrandomization efficacy evaluation. Safety analyses were performed on all randomized subjects who received at least 1 dose of study medication and for whom at least 1 posttreatment safety measurement was available.

The mean monthly rate of migraine/migrainous headache days and migraine headache days were analyzed with analysis of covariance models using a fixed-sequence (ie, a gatekeeper approach)23 to control the overall Type I error rate at the 2-sided 5% level. Treatment and treatment center were qualitative design factors, with baseline rate as a covariate. The first step involved an assessment of the change relative to baseline in the mean number of days per month with migraine/migrainous headache at the 2-sided 0.05 level of significance. If statistical significance was achieved, then the change in the mean monthly rate of migraine days could also be tested at the 2-sided 0.05 level. If significance again was achieved, then statistical significance would be declared at the 2-sided 0.05 level for both measures. If significance on the migraine/migrainous parameter was not achieved, then the formal testing procedure ended. Analyses of additional efficacy variables were not adjusted for multiplicity.

RESULTS

Demographic and Baseline Headache Characteristics.— A total of 686 subjects were screened, and 328 subjects were enrolled and randomized in the trial (topiramate: n = 165; placebo: n = 163). A total of 358 subjects were not included in the trial for the following reasons: 196 subjects did not meet inclusion/exclusion criteria; 73 subjects declined participation; 23 subjects were lost to follow-up; 8 subjects were not enrolled for reasons listed as unknown; 6 subjects were listed as having adverse events; and 52 subjects were not enrolled due to other reasons. The intent-to-treat population consisted of 306 subjects (topiramate: n = 153; placebo: n = 153) with a mean (±SD) age of 38.2 (±12.1) years (range, 18–74 years). The safety population consisted of 321 subjects (topiramate: n = 160; placebo: n = 161). Demographic and baseline headache characteristics of both groups were similar (Tables 1 and 2).

Table 1.—.  Demographic and Baseline Characteristics (Intent-to-Treat Subjects)
VariableTopiramate (n = 153)Placebo (n = 153)Total (N = 306)
  1. SD = standard deviation; Min = minimum; Max = maximum; BMI (kg/m2) = weight (kg)/height (m)2.

Age, years
 n 153 153  306
 Mean 37.8 38.6  38.2
 SD 12.38 11.80  12.08
 Median 37.0 40.0  39.0
 Min, Max 18, 64 18, 74  18, 74
Sex, n (%)
 Male 25 (16.3) 20 (13.1)   45 (14.7)
 Female128 (83.7) 133 (86.9)  261 (85.3)
Race, n (%)
 White126 (82.4) 120 (78.4)  246 (80.4)
 Black 19 (12.4) 26 (17.0)   45 (14.7)
 Asian  1 (0.7)  2 (1.3)    3 (1.0)
 Other  7 (4.6)  5 (3.3)   12 (3.9)
Weight (kg)
 n  153  152  305
 Mean 80.00 76.84  78.43
 SD 20.276 22.221  21.292
 Median 76.64 72.79  74.38
 Min, Max 39.9, 154.2 46.3, 190.5  39.9, 190.5
Body mass index (kg/m2)
   n  152  150  302
   Mean 29.161 27.965  28.567
   SD  6.9659  7.2853  7.1396
   Median 28.007 26.614  27.427
   Min, Max 15.69, 54.87 16.60, 57.5715.69, 57.57
Table 2.—.  Baseline Headache Characteristics: Intent-to-Treat Population
Variable, mean ± SDTopiramate (n = 153)Placebo (n = 153)
  1. SD = standard deviation.

Age at migraine onset, years19.0 ± 10.120.4 ± 10.5
Duration of chronic migraine, years 9.3 ± 10.5 9.1 ± 10.6
Baseline monthly rate of migraine or migrainous days17.1 ± 5.417.0 ± 5.0
Baseline monthly rate of migraine days15.2 ± 6.415.1 ± 5.8
Baseline monthly rate of total headache days20.4 ± 4.820.8 ± 4.6
Baseline number of days per month of acute medication use11.9 ± 7.011.4 ± 6.6

Patient Disposition.— A total of 92 subjects (55.8%) in the topiramate group and 90 subjects (55.2%) in the placebo group completed the double-blind phase of treatment (Table 3, Fig. 2). Seventy-three subjects (44.2%) in the topiramate group and 73 subjects (44.8%) in the placebo group discontinued the double-blind phase prematurely. In the topiramate group, 38 of the 73 subjects (52.1%) who discontinued did so during the first 56 days of treatment, compared with 37 subjects (50.7%) in the placebo group. The most common reason for discontinuation of treatment was inadequate efficacy (topiramate subjects 12.7%; placebo subjects 18.4%). Eighteen topiramate-treated subjects (10.9%) and 10 subjects on placebo (6.1%) discontinued therapy due to adverse events.

Table 3.—.  Patient Disposition
StatusTopiramate (n = 165)Placebo (n = 163)
Completed double-blind phase, n (%)92 (55.8)90 (55.2)
Reasons for discontinuation, n (%)
 Lack of efficacy21 (12.7)30 (18.4)
 Subject choice13 (7.9)10 (6.1)
 Protocol violation 5 (3.0) 6 (3.7)
 Limiting adverse events18 (10.9)10 (6.1)
 Lost to follow-up15 (9.1)16 (9.8)
 Other 1 (0.6) 1 (0.6)
Figure 2.—.

Patient disposition: intent-to-treat population and patients evaluable for safety.

Treatment Exposure.— The mean (±SD) dose of study medication used during the double-blind phase and maintenance period was 74.6 (±17.7) mg/day and 88.2 (±16.7) mg/day, respectively, for the topiramate group and 75.5 (±18.5) mg/day and 89.6 (±17.1) mg/day equivalents, respectively, for the placebo group. The mean (±SD) final maintenance dose of study medication was 86.0 (±29.7) mg/day for the topiramate group and 88.9 (±28.8) mg/day equivalent for the placebo group. At the last study visit during the double-blind phase, 72.5% of topiramate-treated subjects and 80.4% of placebo subjects had received study medication at the 100 mg/day level.

The majority of the intent-to-treat population received study medication for at least 85 days, including 103 topiramate subjects (67.3%) and 98 placebo subjects (64.0%). The mean (±SD) duration of therapy was 91.7 (±34.7) days for the topiramate group and 90.6 (±34.8) days for the placebo group.

Efficacy Measures.—

Primary: Change From Baseline in Mean Monthly Rate of Migraine/Migrainous Days.— During the prospective baseline period, subjects in the topiramate and placebo groups had a mean (±SD) monthly rate of 17.1 (±5.4) and 17.0 (±5.0) migraine/migrainous days, respectively. During the double-blind phase, topiramate treatment resulted in a mean (±SD) reduction from baseline of 6.4 (±5.8) migraine/migrainous days per month compared with 4.7 (±6.1) for the placebo group (P= .010) (Fig. 3). Topiramate treatment also resulted in a significantly greater mean (±SD) percentage reduction in the mean number of migraine/migrainous days from baseline compared with placebo (37.1%± 34.8 vs 26.0%± 40.8, P= .012).

Figure 3.—.

Change from baseline in monthly (28-day) rate of migraine/migrainous and migraine days. N = 153 for topiramate and placebo groups. P value based on analysis of covariance models including treatment and center as main effect and baseline monthly migraine/migrainous or migraine days as covariates.

Change From Baseline in Mean Monthly Rate of Migraine Days.— Subjects in the topiramate and placebo groups had a mean (±SD) monthly rate at baseline of 15.2 (±6.4) and 15.1 (±5.8) migraine days, respectively. During the double-blind phase, topiramate treatment resulted in a mean (±SD) reduction from baseline of 5.6 (±6.0) migraine days per month compared with 4.1 (±6.1) for the placebo group (P= .032; Fig. 3). Hence, as per the gatekeeper approach, both reduction from baseline in mean monthly migraine/migrainous days and migraine days were declared statistically significant. Also, topiramate treatment resulted in a greater mean (±SD) percentage reduction in the mean number of migraine days from baseline that was not statistically significant (P= .152) compared with placebo (32.9%± 48.8 vs 25.2%± 45.4).

Safety and Tolerability.— No clinically relevant changes in mean laboratory test values were observed for either treatment group. No deaths or serious adverse events were reported during the study. Subjects treated with topiramate experienced a mean weight reduction of 2.3 ± 2.9 kg during the trial, while subjects on placebo gained a mean of 0.1 ± 3.1 kg.

TEAEs occurred in 132 (82.5%) topiramate-treated subjects and in 113 (70.2%) of those on placebo (Table 4). The most commonly reported TEAEs reported in the topiramate group were paresthesia (28.8% vs. placebo 7.5%), upper respiratory tract infection (13.8% vs placebo 12.4%), and fatigue (11.9% vs. placebo 9.9%). In addition to upper respiratory infection and fatigue, the most commonly reported TEAE in the placebo group was nausea (8.1% vs topiramate 8.8%).

Table 4.—.  Incidence of Most Common Treatment-Emergent Adverse Events*
 Topiramate (n = 160)Placebo (n = 161)
  1. *Adverse events reported by at least 5% of subjects in any treatment group.

Subjects with any adverse event, %82.570.2
Paresthesia28.8 7.5
Upper respiratory tract infection13.812.4
Fatigue11.9 9.9
Hypoesthesia 9.4 0
Dry mouth 9.4 3.1
Difficulty with concentration/attention 9.4 2.5
Taste perversion 9.4 2.5
Nausea 8.8 8.1
Difficulty with memory, not otherwise specified 6.9 6.2
Somnolence 5.6 4.3
Injury 5.0 1.2
Anorexia 5.0 5.6
Sinusitis 4.4 5.0
Dizziness 3.8 7.5

Treatment-related adverse events (TRAEs) were reported by 104 subjects (65.0%) in the topiramate group and 69 subjects (42.9%) in the placebo group. The most commonly reported TRAEs in the topiramate group were paresthesia (28.8% vs. placebo 7.5%), fatigue (10.6% vs placebo 9.3%), difficulty with concentration (9.4% vs placebo 2.5%), and dry mouth and nausea (8.1% for both events vs placebo 2.5% and 5.6%, respectively). In addition to fatigue and paresthesia, the most commonly reported TRAEs in the placebo group were dizziness and difficulty with memory (6.2% for both events vs topiramate 2.5% and 6.3%, respectively).

Adverse events that were mild or moderate in severity accounted for the majority of TEAEs in both treatment groups. In the topiramate group, 47 subjects (29.4%) experienced only mild adverse events, 59 subjects (36.9%) experienced an adverse event that was no more than moderate in severity and 26 subjects (16.3%) experienced marked adverse events. In the placebo group, the most severe event was reported as mild in 49 subjects (30.4%), as moderate in 46 subjects (28.6%), and as marked in 18 subjects (11.2%).

DISCUSSION

In this study, topiramate administered to subjects with chronic migraine defined according to revised Silberstein/Lipton criteria as those who experienced at least 15 headache days/month, at least half of which were migraine or migrainous, resulted in significant reductions in the mean monthly number of migraine/migrainous days and the mean number of migraine days.

A maximum target daily dose of topiramate 100 mg was chosen, and there were several factors supporting that choice. First, pooled data from 3 large, randomized, double-blind, placebo-controlled, dose-ranging trials evaluating topiramate for prophylaxis of episodic migraine suggested that topiramate 100 mg/day possessed the most favorable efficacy and tolerability profile.17 Second, restricting the topiramate dose to 100 mg/day allowed evaluation of the drug taken at the dose recommended according to approved U.S. prescribing information. Third, in any study of this type, fixing the upper level of dosage of active drug limits the potential for variable results that likely would accompany a flexible-dose protocol.

Topiramate treatment was safe and well tolerated in this trial. Serious adverse events or deaths did not occur. For the vast majority of subjects who experienced any adverse events, TEAEs were limited to mild or moderate severity (80% and 84% in the topiramate and placebo groups, respectively). Also, withdrawal from the study due to adverse events occurred in a more limited proportion of subjects: 18 (10.9%) treated with topiramate and 10 (6.1%) treated with placebo.

The adverse-event profile of topiramate observed in this trial was similar to that observed in the topiramate pivotal migraine trials.24 An examination of the more commonly reported TEAEs in this trial and the 100 mg/day treatment arms of the topiramate pivotal migraine trials (N = 386)24 showed that the following percentages of subjects experienced: paresthesia (28.8% vs 51.0%); upper respiratory tract infection (13.8% vs 14.0%); fatigue (11.9% vs 15.0%); hypoesthesia (9.4% vs 7.0%); dry mouth (9.4% vs 3.0%); difficulty with concentration (9.4% vs 6.0%); taste perversion (9.4% vs 8.0%); nausea (8.8% vs 13.0%); difficulty with memory (not otherwise specified) (6.9% vs 7.0%); somnolence (5.6% vs 7.0%); injury (5.0% vs 6.0%); anorexia (5.0% vs 15.0%); sinusitis (4.4% vs 6.0%); and dizziness (3.8% vs 9.0%), respectively.

The results of this trial support the evidence from previous trials that demonstrated the efficacy of topiramate at a dose of 100 mg/day for treatment of migraine of varying frequencies.14–16,18,19 However, comparisons made between clinical trials are difficult due to different inclusion criteria and the distinct patient characteristics of the patient population (ie, episodic vs chronic disease, allowance of preventive migraine medications, different outcome measures).

Considerable effort has been made over the last decade to identify the clinical features of the subgroup of migraineurs who experience chronic migraine.2,3,7,20,25 Although work to reach a consensus on the definition of chronic migraine is ongoing, efforts to establish diagnostic criteria for these subjects can only assist the identification of appropriate candidates for preventive treatment, and, it is hoped, alleviate the suffering and considerable burden experienced by chronic migraineurs.

The definition of chronic migraine utilized in this trial differs in some aspects from the current IHS definitions. In addition, some of the subjects in this trial could be classified as having medication overuse headache via the current IHS definition.2 Although the criteria used in this study are not identical to those recently adopted by the IHS, they are quite similar and do reflect what was under discussion by the IHS classification committee at the study's inception. In addition, a recent study comparing the various definitions for transformed migraine and chronic migraine showed considerable agreement in diagnosis.7 Finally, the condition identified as “migrainous headache” was in use at the time the protocol for this study was developed; the term has been replaced by “probable migraine.” We plan post hoc analyses of subpopulations of subjects in this trial to identify any variation in results related to diagnostic reclassification.

Few of the preventive agents commonly used for migraine prevention have been evaluated for their efficacy in treating chronic migraine. Frequently used agents for migraine prevention include β-blockers, anticonvulsants (for example valproic acid, divalproex sodium, gabapentin), calcium channel blockers (verapamil), or tricyclic antidepressants (amitriptyline).12,26,27 Again, the efficacy of these agents for the preventive treatment of chronic migraine has not been evaluated in large, multicenter, controlled clinical trials.

This trial demonstrates that topiramate 100 mg/day significantly reduced mean monthly migraine/migrainous days and migraine days compared with placebo and was a safe and well-tolerated preventive therapy in this group of subjects with chronic migraine, a therapeutic area in which profound clinical needs exist. These results add to the existing evidence supporting the consistent therapeutic efficacy of topiramate in subjects with migraine.

Acknowledgments

Acknowledgment: This study was supported by Ortho-McNeil Neurologics, Titusville, New Jersey.

Conflict of Interest: Dr. Silberstein has received personal compensation for activities with: GlaxoSmithKline, Inc., Johnson & Johnson, Merck & Co., Inc., UCB Pharma, AstraZeneca Pharmaceuticals, Inc., Pfizer, Inc., Allergan, Inc., Pozen, Inc., Abbott Laboratories, Inc., Eli Lilly & Company, NPS, and Xcel Pharmaceuticals; has received personal compensation in an editorial capacity for Current Pain and Headache; and has received financial support for scholarly activities from GlaxoSmithKline, Inc., Johnson & Johnson, Merck & Co., Inc., Pfizer, Inc., Allergan, Inc., and Abbott Laboratories, Inc.

Dr. Lipton has consulted for, conducted studies funded by, or received lecture honoraria from Allergan, Inc., Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck, Ortho-McNeil, Pfizer, Pozen, among other companies.

Dr. Dodick has received personal compensation for activities with Allergan, Inc., GlaxoSmithKline, Inc., Pfizer, Inc., Endo Pharmaceuticals, Ortho-McNeil Pharmaceutical, Inc., Merck & Co., Inc., Medtronic, Neuralieve; has received personal compensation in an editorial capacity for Headache Currents; and has received research support from St. Jude, Allergan, Inc., Medtronic, Inc., National Institutes of Health, Mayo Clinic College of Medicine, and Advanced Bionics.

Dr. Freitag has received personal compensation for activities with Allergan, Inc., AstraZeneca Pharmaceuticals, Inc., Merck & Co., Inc., Ortho-McNeil Pharmaceuticals, Inc., Valeant Pharmaceuticals International, Pfizer, Inc., and GlaxoSmithKline, Inc., and has received research support from Alzyer, AstraZeneca Pharmaceuticals, Inc., GlaxoSmithKline, Inc., Merck & Co., Inc., Ortho-McNeil Pharmaceuticals, Inc., Precision, Division of Boston Scientific, Solvay S.A., and Vernalis.

Dr. Ramadan has received personal compensation for activities with GlaxoSmithKline, Inc., Ortho-McNeil Neurologics, Inc., Eli Lilly & Company, Eisai, Inc., AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Company, Pfizer, Inc., Merck & Co., Inc., Aradign Corp., Boehringer Ingelheim Pharmaceuticals, and Map Pharmaceuticals; has received personal compensation in an editorial capacity for Web Alert; and has received research support from Ortho-McNeil Neurologics, Eli Lilly & Company, Pfizer, Inc., and the National Headache Ambassador Program.

Dr. Mathew has received personal compensation for activities with Eisai.

Dr. Brandes has received grants or research support from Merck, GlaxoSmithKline, UCB Pharma, Allergan, Johnson & Johnson, AstraZeneca, Pfizer, Bristol-Myers Squibb, Winston Laboratories, Sanofi-Aventis, Elan Pharmaceuticals, Novartis, Endo, Pozen, Inc., Vernalis, Ortho-McNeil, Advanced Bionics; has served on the speakers bureau for GlaxoSmithKline, AstraZeneca, Pfizer, Merck, Ortho-McNeil, Allergan, MedPointe Pharmaceuticals, Endo, UCB Pharma; has served as a consultant to Merck, GlaxoSmithKline, Pfizer, AstraZeneca, Allergan, Ortho-McNeil, Aradigm Corporation; and has received educational funding from GlaxoSmithKline.

Dr. Bigal has received personal compensation for activities from Allergan, Boehringer Ingelheim, GlaxoSmithKline, Merck, Ortho-McNeil, UCB, AstraZeneca, Pfizer, Inc., and Advance PCS and has received research support from Allergan, Boehringer Ingelheim, GlaxoSmithKline, Merck, Ortho-McNeil, Pfizer, UCB, AstraZeneca, and Advance PCS.

Dr. Saper has received honoraria for speaking from GlaxoSmithKline, Merck & Co., Inc., Abbott Laboratories, Inc., Elan Corporation, AstraZeneca Pharmaceuticals, Pfizer, Inc., Ortho-McNeil Pharmaceuticals, Bristol-Myers Squibb, Medtronic, Inc., Endo Pharmaceuticals, Advanced Bionics, Pozen, Inc., and Penwest Pharmaceuticals Co; has received personal compensation in an editorial capacity for Pain Watch and Migraine Monitor; holds stock in Pozen, Inc.; and has received research support from Novartis, Ortho-McNeil Pharmaceuticals, Merck & Co., Inc., GlaxoSmithKline, Allergan, Inc., Eisai, Inc., AstraZeneca Pharmaceuticals, Abbott, Advanced Bionics, Medtronic, Renovis, and Pozen, Inc.

Dr. Ascher is an employee of Ortho-McNeil Janssen Scientific Affairs, LLC.

Dr. Jordan is an employee of PriCara, a Unit of Ortho-McNeil, Inc.

Drs. Greenberg and Joseph Hulihan are employees of Ortho-McNeil Neurologics.

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