OnabotulinumtoxinA improves quality of life and ...

OnabotulinumtoxinA improves quality of life and reduces impact of chronic migraine

R.B. Lipton, MD S.F. Varon, PhD B. Grosberg, MD P.J. McAllister, MD F. Freitag, DO S.K. Aurora, MD D.W. Dodick, MD S.D. Silberstein, MD H.C. Diener, MD R.E. DeGryse, MS M.E. Nolan, PhD C.C. Turkel, PharmD, MBA, PhD

Address correspondence and reprint requests to Dr. Richard B. Lipton, Albert Einstein College of Medicine, 1165 Morris Park Avenue, Rousso Building, Room 332, Bronx, NY 10461 [email protected]

ABSTRACT

Objective: To assess the effects of treatment with onabotulinumtoxinA (Botox, Allergan, Inc., Irvine, CA) on health-related quality of life (HRQoL) and headache impact in adults with chronic migraine (CM).

Methods: The Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program (PREEMPT 1 and 2) included a 24-week, double-blind phase (2 12-week cycles) followed by a 32-week, open-label phase (3 cycles). Thirty-one injections of 5U each (155 U of onabotulinumtoxinA or placebo) were administered to fixed sites. An additional 40 U could be administered “following the pain.” Prespecified analysis of headache impact (Headache Impact Test [HIT]–6) and HRQoL (Migraine-Specific Quality of Life Questionnaire v2.1 [MSQ]) assessments were performed. Because the studies were similar in design and did not notably differ in outcome, pooled results are presented here.

Results: A total of 1,384 subjects were included in the pooled analyses (onabotulinumtoxinA, n ⫽ 688; placebo, n ⫽ 696). Baseline mean total HIT-6 and MSQ v2.1 scores were comparable between groups; 93.1% were severely impacted based on HIT-6 scores ⱖ60. At 24 weeks, in comparison with placebo, onabotulinumtoxinA treatment significantly reduced HIT-6 scores and the proportion of patients with HIT-6 scores in the severe range at all timepoints including week 24 (p ⬍ 0.001). OnabotulinumtoxinA treatment significantly improved all domains of the MSQ v2.1 at 24 weeks (p ⬍ 0.001). Conclusions: Treatment of CM with onabotulinumtoxinA is associated with significant and clinically meaningful reductions in headache impact and improvements in HRQoL.

Classification of evidence: This study provides Class 1A evidence that onabotulinumtoxinA treatment reduces headache impact and improves HRQoL. Neurology® 2011;77:1465–1472 GLOSSARY CM ⫽ chronic migraine; DB ⫽ double-blind phase; EF ⫽ emotional functioning; EM ⫽ episodic migraine; HIT ⫽ Headache Impact Test; HRQoL ⫽ health-related quality of life; ICHD-2 ⫽ International Classification of Headache Disorders, 2nd edition; MID ⫽ minimal important difference; MSQ ⫽ Migraine-Specific Quality of Life Questionnaire v2.1; PREEMPT ⫽ Phase III Research Evaluating Migraine Prophylaxis Therapy; RP ⫽ role preventive; RR ⫽ role restrictive.

Chronic migraine (CM) is a common, debilitating neurologic disorder affecting ⬃2.0% of the population.1,2 CM is characterized by ⱖ15 headache days/month for ⱖ3 months.3,4 Persons with CM have reduced health-related quality of life (HRQoL), more severe disability, and greater economic burden than patients with episodic migraine (EM).5–9 HRQoL has increasingly been recognized as an important complementary measure critical to understanding the burden of a condition; improving HRQoL has emerged as a crucial measure of treatment benefit.6,10,11 There are few well-designed clinical trials evaluating preventive treatments for CM.12 Given that CM is common and disruptive to HRQoL, effective, safe, evidence-based treatments for CME

From the Albert Einstein College of Medicine (R.B.L., B.G.), Bronx; Montefiore Headache Center (R.B.L., B.G.), Bronx, NY; Allergan, Inc. (S.F.V., R.E.D., C.C.T.), Irvine, CA; Associated Neurologists of Southern Connecticut (P.J.M.), Fairfield, CT; Baylor University Medical Center (F.F.), Dallas, TX; Swedish Neuroscience Institute (S.K.A.), Seattle, WA; Mayo Clinic Arizona (D.W.D.), Phoenix; Thomas Jefferson University (S.D.S.), Philadelphia, PA; University of Essen (H.C.D.), Essen, Germany; and Imprint Publication Science (M.E.N.), New York, NY. Study funding: PREEMPT was sponsored by Allergan, Inc., Irvine, CA. Disclosure: Author disclosures are provided at the end of the article. Copyright © 2011 by AAN Enterprises, Inc.

1465

prevention of CM are needed. OnabotulinumtoxinA (Botox, Allergan, Inc., Irvine, CA) has demonstrated efficacy in CM as supported by the Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials. In this program (2 large, double-blind studies), onabotulinumtoxinA compared with placebo was associated with significant improvements in multiple efficacy variables, including the primary endpoint of change in frequency of headache days at week 24, in both PREEMPT 2 and the pooled analysis.13,14 PREEMPT 1 did not demonstrate significant differences for its primary endpoint, change in frequency of headache episodes at week 24, but showed significant differences in improvement in number of headache days and many other endpoints.13,15 The studies also showed that onabotulinumtoxinA was safe and welltolerated in patients with CM.13 Herein, we examine results from the pooled PREEMPT studies regarding headache impact and HRQoL outcomes for onabotulinumtoxinA in patients with CM. METHODS Study design. The PREEMPT clinical program included 2 parallel-group, placebo-controlled, class 1A studies conducted from 2006 to 2008 at 122 sites (106 North American; 16 European). Both studies had a 28-day screening period (baseline) and a 24-week, double-blind phase (DB), followed by a 32-week, open-label phase. The studies, both phase 3 registration trials, were similarly designed with the exception of the designation of the primary endpoints: mean change from baseline in frequency of headache episodes in PREEMPT 1 and mean change from baseline in frequency of headache days in PREEMPT 2. Primary and secondary endpoint data from individual PREEMPT studies at week 24 have been reported.13–15 All prespecified primary and secondary efficacy endpoints were evaluated in pooled analyses in addition to prespecified assessments of headache impact and HRQoL. Predefined pooling of both studies was performed to present a complete summary of the clinical program.13

Standard protocol approvals, registrations, and patient consents. PREEMPT was conducted in accordance with the Declaration of Helsinki ethical principles and Good Clinical Practices. The study was approved at each site by an Independent Ethics Committee or a local Institutional Review Board. Clinical Trial Registration Numbers are NCT00156910 and NCT00168428 (ClinicalTrials.gov). Written informed consent was obtained from each randomized patient.

Study participants. Inclusion and exclusion criteria have been described previously.14,15 In brief, eligible subjects were men or women aged 18 – 65 years with a history of International Classification of Headache Disorders, 2nd edition (ICHD-2)– defined migraine.3 Subjects had to complete a baseline telephone diary and provide data for ⱖ20 of 28 days. Eligible subjects had ⱖ15 headache days/28 days (where each day had ⱖ4 hours of 1466

Neurology 77

October 11, 2011

continuous headache) with at least half meeting criteria for migraine or probable migraine (referred to hereafter as migraine days). They also needed ⱖ4 distinct headache episodes, each lasting ⱖ4 hours. Subjects who were taking a concurrent headache prophylaxis within 4 weeks of the start of baseline or had previously received any type of botulinum toxin treatment were not eligible.

Study treatment. Qualified subjects were randomized (1:1) to onabotulinumtoxinA or placebo. OnabotulinumtoxinA 155 U or placebo was administered as 31 fixed-site, fixed-dose, IM injections across 7 specific head/neck muscle areas every 12 weeks over 24 weeks (2 cycles). At the investigator’s discretion, an additional 40 U (maximum total dose 195 U) of onabotulinumtoxinA could be administered using a protocol-defined, followthe-pain strategy. Details of injection doses and location have been previously described.16

Headache impact measure. The Headache Impact Test (HIT)– 6 is a validated 6-item questionnaire covering content categories in pain, role functioning, social functioning, vitality, cognitive functioning, and psychological distress. Developed for episodic migraine, it is reliable and valid for use in the CM population.17,18 Responses to each HIT-6 item reflect the frequency of headache-related interruptions in 6 domains scored as never ⫽ 6, rarely ⫽ 8, sometimes ⫽ 10, very often ⫽ 11, and always ⫽ 13. Response scores for all 6 questions are summed to give a total HIT-6 score, with scores ranging from 36 to 78. Higher total scores reflect greater adverse impact. A total score of ⱕ49 indicates little or no impact, 50 –55 indicates some impact, 56 –59 indicates substantial impact, and ⱖ60 reflects severe impact.19 In PREEMPT, HIT-6 scores were obtained at baseline and every 4 weeks; in terms of change in total HIT-6 score relative to baseline, a negative value reflects reduced headache impact and an improvement in the patient’s functionality. The proportion of patients with a severe HIT-6 (ⱖ60) score was a secondary endpoint in PREEMPT 2 and the pooled analysis.13,20 The between-group minimal important difference (MID) in the reduction in total HIT-6 scores has been previously defined as ⱖ2.3.21 A clinically meaningful change for an individual patient has been defined by the user guide for the HIT-6 scale as a ⱖ5-point decrease.20 HRQoL measure. HRQoL was measured by the MigraineSpecific Quality of Life Questionnaire (MSQ) v2.1,22,23 a 14item questionnaire designed to measure how migraines affect or limit patients’ daily performance over the preceding 4 weeks across 3 domains: role restrictive (RR), role preventive (RP), and emotional functioning (EF). Specifically, RR assesses how migraines limit a sufferer’s daily social- and work-related activities, RP measures how migraines prevent such activities, and EF gauges the emotions associated with migraine. The scores from each domain were totaled to give a raw score, which was then transformed to a 0 (poor HRQoL) to 100 (good HRQoL) scale.23 The MSQ v2.1 score was obtained at baseline and every 12 weeks. A positive change in MSQ v2.1 scores reflects improvement in HRQoL during the PREEMPT study. MIDs (between-group) for all domains of MSQ v2.1 have been established (3.2, 4.6, and 7.5 for RR, RP, and EF, respectively).24 Similarly, MIDs from baseline (within-group) have been established for MSQ v2.1 scale scores (⫹10.9, ⫹8.3, and ⫹12.2 for RR, RP, and EF, respectively).25 Statistical analysis. All efficacy analyses used the intent-totreat population, which included all randomized patients. The baseline and change from baseline for ordinal and continuous

OnabotulinumtoxinA (n ⴝ 688)

Placebo (n ⴝ 696)

p Value

Mean age, y

41.1

41.5

0.579

Mean years since onset of chronic migraine

19.4

19.0

0.488

Female, %

87.6

85.2

0.185

from previous studies for the primary efficacy measures evaluated and were calculated to detect, with at least 80% power, meaningful between-group differences of 1.5 headache episodes for PREEMPT 1 and 1.5 headache days for PREEMPT 2. Pooling of the PREEMPT 1 and 2 studies was performed for regulatory submissions and because the studies were of essentially the same design and were run almost simultaneously. Also, pooling provided additional statistical power to identify safety and tolerability results that could be missed if each study were only reported individually.13

Classification of evidence. The study provides class 1A evi-

Table 1

Baseline demographics and characteristics: Pooled data Pooled data

Caucasian, %

89.7

90.5

0.602

Mean HIT-6 scorea

65.5

65.4

0.638

% Patients with severe (>60) HIT-6 scorea

93.5

92.7

0.565

Role restrictive

38.5

38.7

0.974

Role preventive

56.0

56.1

0.825

Emotional functioning

42.1

42.4

0.806

MSQ v2.1b

dence on the effects of treatment with onabotulinumtoxinA (155 to 195 U) on headache impact and HRQoL in adults with CM. OnabotulinumtoxinA treatment is associated with significant and clinically meaningful reductions at week 24 in headache impact (HIT-6 score: ⫺4.8 onabotulinumtoxinA [SD ⫽ 7.04] vs ⫺2.4 placebo [SD ⫽ 6.09]; p ⬍ 0.001) and improvements in HRQoL (group for all 3 domains of the MSQ v2.1 [ p ⬍ 0.001]). RESULTS Demographic and baseline characteristics.

Abbreviations: HIT ⫽ Headache Impact Test; MSQ ⫽ Migraine-Specific Quality of Life Questionnaire. a HIT-6 scores of 36–49 indicate little or no impact; 50–55, some impact; 56–59, substantial impact; 60–78, severe impact. b MSQ v2.1 scores range from 0 (poor health-related quality of life) to 100 (good healthrelated quality of life).

variables for HIT-6 and MSQ v2.1 were compared between treatment groups by the Wilcoxon rank sum test. MSQ v2.1 used observed data (without imputation), and missing data for HIT-6 were imputed using a prespecified modified last observation carried forward methodology, because of inclusion of severe HIT-6 as a secondary variable, as previously described.13,14 Briefly, missing data were imputed for a 28-day period by multiplying a patient’s score for the previous 28-day period by the average percent change across all patients from that previous 28day period to that 28-day period of imputation. A p value ⱕ0.05 was considered to be significant. Sample sizes specified in the study protocols were based on population standard deviations

Figure 1

Mean change from baseline in total Headache Impact Test (HIT)–6 score

*Significant between-group difference favoring onabotulinumtoxinA. **Clinically meaningful between-group difference. Data are mean ⫾ SE.

A total of 1,384 subjects were included in the pooled analyses (n ⫽ 688, onabotulinumtoxinA; n ⫽ 696, placebo). Baseline demographics were similar in both groups. The majority of subjects were female (86.4%) and Caucasian (90.1%). The mean age of the subjects was 41.3 years, with a mean of 19.2 years since the onset of CM. Baseline mean total HIT-6 scores for both treatment groups were ⱖ60 (65.5 onabotulinumtoxinA [SD ⫽ 4.05] vs 65.4 placebo [SD ⫽ 4.32]; p ⫽ 0.638), reflecting how severely CM affects this patient population. The baseline proportion of patients with severe (ⱖ60) HIT-6 score was comparable between the onabotulinumtoxinA group (93.5%) and the placebo group (92.7%; p ⫽ 0.565). Baseline mean MSQ v2.1 scores for all 3 domains, RR, RP, and EF, were low (indicating poor HRQoL) and similar between the 2 treatment groups ( p ⫽ 0.974, p ⫽ 0.825, and p ⫽ 0.806, respectively) (table 1). HIT-6. The proportion of patients with a severe (ⱖ60) HIT-6 score notably decreased from baseline in both the placebo- and onabotulinumtoxinAtreated groups; however, significantly fewer patients in the onabotulinumtoxinA-treated group had a severe (ⱖ60) HIT-6 score at all weeks during the DB phase ( p ⱕ 0.014), including week 24 (67.6% onabotulinumtoxinA vs 78.2% placebo; p ⬍ 0.001).13 Both treatment groups showed a decrease in headache impact at week 24; significant reductions in headache impact favoring onabotulinumtoxinA were observed at weeks 4, 8, 12, 16, 20, and 24, as measured by total HIT-6 score at the end of each 28-day period ( p ⬍ 0.001) (figure 1). The betweengroup difference was 2.4 at 24 weeks (⫺4.8 onabotulinumtoxinA [SD ⫽ 7.04] vs ⫺2.4 placebo [SD ⫽ 6.09]; p ⬍ 0.001) (figure 1, table 2). Table 2 also includes Cohen d as an estimate of effect size. In general, paNeurology 77

October 11, 2011

1467

Table 2

Change in HIT-6 and MSQ v2.1 scores from baseline to weeks 12 and 24

OnabotulinumtoxinA (n ⴝ 688)

Placebo (n ⴝ 696)

Mean intergroup difference

65.5

65.4

—

p Value

Effect size (Cohen d)

Total HIT-6 scorea Baseline, mean

0.638

—

Change from baseline, week 12

⫺4.7

⫺2.6

⫺2.1

⬍0.001

0.33


⫺4.8

⫺2.4

⫺2.4

⬍0.001

0.36

Baseline, mean

38.5

38.7

—


16.2

9.9

6.3

⬍0.001

0.32


17.0

8.6

8.4

⬍0.001

0.39

Baseline, mean

56.0

56.1


13.0

8.0

5.0

⬍0.001

0.25


13.1

6.4

6.7

⬍0.001

0.32

Baseline, mean

42.1

42.4


18.3

11.0

7.3

⬍0.001

0.30


17.9

9.5

8.4

⬍0.001

0.32

MSQ role restrictiveb

MSQ role preventive

0.974

—

b

MSQ emotional functioning

—

0.825

—

b

—

0.806

—

Abbreviations: HIT ⫽ Headache Impact Test; MSQ ⫽ Migraine-Specific Quality of Life Questionnaire. a HIT-6 scores of 36–49 indicate little or no impact; 50–55, some impact; 56–59, substantial impact; 60–78, severe impact. Note that lower HIT-6 scores reflect improvement in functional status (less impact). b MSQ v2.1 scores range from 0 (poor health-related quality of life) to 100 (good health-related quality of life). Note that higher MSQ scores reflect improvement in quality of life.

tients treated with onabotulinumtoxinA have an effect size of about one-quarter to one-third of a SD unit relative to patients treated with placebo. Although both treatment groups showed a decrease in headache impact, the proportion of patients with a ⱖ5-point change in total HIT-6 score was greater in the onabotulinumtoxinA group than in the placebo group at 24 weeks (40.8% onabotulinumtoxinA [SE ⫽ 1.9] vs 25.3% placebo [SE ⫽ 1.7]) and at each assessment during the DB phase ( p ⬍ 0.001) (figure 2A). Additionally, the between-group differences were significant for patients who had a ⱖ5-point change in total HIT-6 score and a clinically meaningful reduction in number of headache days (ⱖ50%) from baseline at weeks 4, 8, 12, 16, 20, and 24 ( p ⱕ 0.025) (figure 2B). Figure 2C shows the percent of onabotulinumtoxinA-treated patients who had a ⱖ50% reduction from baseline in headache days13 on the same graph as those who had a ⱖ5point change in total HIT-6 score, as well as those onabotulinumtoxinA-treated patients who had both clinically meaningful response rates. MSQ v2.1. Significantly greater improvements were found in the onabotulinumtoxinA group for all 3 domains of the MSQ v2.1 ( p ⬍ 0.001) at weeks 12 and 24 (table 2). The mean between-group differences at week 24 were 8.4 (RR), 6.7 (RP), and 8.4 (EF) (table 2). 1468

Neurology 77

October 11, 2011

These analyses demonstrate that, compared with placebo, onabotulinumtoxinA is effective in the treatment of CM as measured by assessments of headache impact (HIT-6) and HRQoL (MSQ v2.1). These data support the original findings from the primary and secondary efficacy endpoints in the PREEMPT clinical program,13 displaying the time-effect curves in reduction of headache impact observed with onabotulinumtoxinA treatment over the 24-week period. PREEMPT studies show significant between-group differences favoring onabotulinumtoxinA in reduction from baseline in frequency of headache days and in 6 of the 7 secondary efficacy variables.13 Treatment with 155–195 U of onabotulinumtoxinA every 12 weeks was safe and well-tolerated, with individual adverse events reported in ⬍10% of patients.13 At baseline, the mean total HIT-6 score for all patients was 65, which reflects how severely these patients are affected by CM (table 1) and is similar to findings in prior CM studies.21 Much of the reduction in headache impact occurred over the first 4 weeks. The treatment groups quickly separated and the benefit of active treatment was maintained throughout the 24week DB phase (figure 1, figure 2A). The time course of improvement in headache impact and HRQoL parallels the findings from studies using more traditional measures to assess the benefits DISCUSSION

Figure 2

Percent of patients with a clinically meaningful change in Headache Impact Test (HIT)–6 (>5 points)

(A) Proportion of patients with a clinically meaningful change (ⱖ5) in HIT-6 score. (B) Percent of patients who were responders (ⱖ50% decrease in number of headache days from baseline) and had a clinically meaningful change in HIT-6 score (ⱖ5 points). (C) Percent of onabotulinumtoxinA-treated patients who had a ⱖ50% decrease in number of headache days from baseline, a clinically meaningful change in HIT-6 score (ⱖ5 points), and who had both a ⱖ50% decrease in number of headache days and a clinically meaningful change in HIT-6 score. *Significant between-group difference favoring onabotulinumtoxinA. Data are mean ⫾ SE.

of preventive treatment.25,26 This convergence of results supports the validity of the findings and of the various methods of measurement. For example, total HIT-6 scores decreased for onabotulinumtoxinA treatment during the first 8 weeks and stayed relatively constant through the DB period. The decrease in headache impact aligns with the reduction in frequency of headache days with onabotulinumtoxinA treatment during the DB period (week 24: ⫺8.5 days).13 This association of headache days with impact and HRQoL has been previously demonstrated.10,26 It is important to note that a high placebo response was observed over the entire 24-week DB phase; this is consistent with what has been observed in other migraine studies.27 The placebo effect in pain trials may be attributed to the degree of expectation, Pavlovian conditioning, and reduction of anxiety.27 Parenteral pain treatments are known to have higher placebo rates than oral placebo due to heightened expectations.28 Although a high placebo response was observed during the DB phase, there was a lack of a parallel “nocebo” effect among placebo-treated patients. Furthermore, despite the high placebo response, significance always favoring onabotulinumtoxinA vs placebo was achieved in all HRQoL measures. Addressing clinically meaningful change in a particular measure is challenging, and no single method can be regarded as fully reliable. The approaches for establishing MIDs are evolving and each method has limitations.29 However, we can use the current understanding and published methods to assess the clinical relevance of these analyses. Clinically meaningful change can be addressed both for groups and for individuals. A previous report addressed clinically meaningful group-level changes in HIT-6 for CM.21 The study showed that the relationship between changes in HIT-6 scores and patient-perceived clinical change was approximately linear, and that the estimates generated by each method were similar. HIT-6 scores differed by 2.3 points among patients who reported feeling “somewhat better” when compared with those who reported no change. Therefore in CM, a change in HIT-6 score of ⱖ2.3 was considered evidence of clinically meaningful improvement.21 This threshold was exceeded in the current report from week 16 through week 24 (figure 1). Similarly, the between-group MIDs for all 3 domains of the MSQv2.124 were exceeded by the onabotulinumtoxinA group vs the placebo group. For example, the MID for the mean RR values at 12 weeks were 16.2 for onabotulinumtoxinA and 9.9 for placebo. MIDs were also exceeded for both the RP and EF domains (table 2). One can also evaluate MID for individuals. The previously defined ⱖ5-point decrease is considered a Neurology 77

October 11, 2011

1469

clinically meaningful change for an individual patient.20 The between-group differences were significant at all weeks during the DB phase for the percentage of subjects with a clinically meaningful change (ⱖ5) in their individual HIT-6 score (figure 2A). A clinically meaningful reduction in frequency of headache days was previously determined to be ⱖ50% from baseline,30 and 47.1% of onabotulinumtoxinA-treated patients achieved this reduction at week 24 (figure 2C).13 More than 25% of onabotulinumtoxinA-treated patients had both a clinically meaningful improvement in individual HIT-6 scores and ⱖ50% reduction in frequency of headache days (figure 2B). In other words, as headache frequency is decreased, headache impact is also reduced. This concordance (improvement in functionality as headache-day frequency is decreased) observed in our study is in agreement with a recent publication that demonstrated an additional day of headache was associated with significant reductions in HRQoL.26 There are several strengths and limitations to using the HIT-6 and MSQv2.1. While using generic health status measures such as the Short Form health surveys SF-12 or SF-36 allows for comparison across diseases states, the use of headache patient-reported outcomes allows for a more precise measurement of how patients are affected by CM and the benefits of treatment. Both the MSQv2.1 and HIT-6 are validated measures of the burden of CM.18,31 Because they were originally calibrated to measure the burden of episodic migraine, the effects of CM may be underestimated. In our study, 93% of patients with CM were in the severely impacted group at baseline. Therefore, it might be useful to define a very severe group of CM as patients with HIT-6 scores ⱖ65. Differences between episodic and chronic migraine could explain why a high proportion of patients remained in the severely impacted category at week 24 (67.6% onabotulinumtoxinA vs 78.3% placebo). Additionally, HIT-6 was adapted from a pool of 89 items to provide coverage for episodic migraine.17 Selecting different items might increase sensitivity to change. Guidelines for interpreting the clinical importance of group differences in chronic pain studies were recently published by the Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT).32 The recommendations suggest that the primary efficacy endpoint alone may not adequately describe the potential benefits of a treatment without additional consideration of secondary outcomes, safety and tolerability, and other factors, including, but not limited to, the proportion of treatment responders, onset and durability of treatment 1470

Neurology 77

October 11, 2011

benefit, and treatment benefit relative to other treatments.32 The PREEMPT clinical program evaluated multiple headache symptom measures consistent with these recommendations and demonstrated clinically meaningful results. OnabotulinumtoxinA treatment is associated with significant reductions in headache impact and improvements in HRQoL. Given the physical and emotional disability attributed to CM, measures of HRQoL and headache impact make a valuable contribution to the assessment of therapeutic interventions. The goal of the PREEMPT program was to assess efficacy and tolerability of a single treatment. Therefore, all other aspects of treatment were held constant. In clinical practice, multiple treatment modalities are used to improve CM.33 Although there are currently no formal recommendations for CM management, current practice combines behavioral interventions, acute treatments, preventative treatments, and management of triggers and exacerbating factors including medication overuse. For episodic migraine, studies have examined the aggregate benefits of a broad-based program of optimal care.34 This study suggests that prophylactic therapy with onabotulinumtoxinA is an option for this highly disabled patient population. Treatment with onabotulinumtoxinA was associated with reductions in headache days, episodes, and impact. Treated patients’ HRQoL improved. The magnitude of improvement in HRQoL is significant and reflects clinically meaningful improvements in functioning and vitality. In addition, onabotulinumtoxinA treatment is safe and well-tolerated. Future studies should examine the benefits of onabotulinumtoxinA as part of a comprehensive treatment program. AUTHOR CONTRIBUTIONS Dr. Lipton participated in the PREEMPT study design, was a PREEMPT investigator, interpreted data, and wrote and revised the manuscript for content and clarity. Dr. Varon interpreted data and wrote and revised the manuscript for content and clarity. Dr. Grosberg was a PREEMPT investigator and revised the manuscript for content and clarity. Dr. McAllister was a PREEMPT investigator and revised the manuscript for content and clarity. Dr. Freitag was a PREEMPT investigator and revised the manuscript for content and clarity. Dr. Aurora participated in the PREEMPT study design, was a PREEMPT investigator, interpreted data, and revised the manuscript for content and clarity. Dr. Dodick participated in the PREEMPT study design, was a PREEMPT investigator, interpreted data, and revised the manuscript for content and clarity. Dr. Silberstein participated in the PREEMPT study design, was a PREEMPT investigator, interpreted data, and revised the manuscript for content and clarity. Dr. Diener participated in the PREEMPT study design, was a PREEMPT investigator, interpreted data, and revised the manuscript for content and clarity. R.E. DeGryse participated in the PREEMPT study design, analyzed and interpreted data, and revised the manuscript for content and clarity. Dr. Nolan revised the manuscript for content and clarity. Dr. Turkel participated in the PREEMPT study design, interpreted data, and wrote and revised the manuscript for content and clarity.

ACKNOWLEDGMENT The authors thank Allergan, Inc., for funding Imprint Publication Science, New York, NY, for providing support in revising the manuscript, responding to the reviewer comments, and copyediting of this manuscript.

DISCLOSURE Dr. Lipton serves on scientific advisory boards for Allergan, Inc., Merck Serono, Neuralieve, Inc., and Pfizer Inc.; has received funding for travel from the American Headache Society, Cognimed, Diamond Headache Clinic Research, Market Force Communications, Merck Serono, Migraine Research Foundation, Scienta, and Talley Management; serves as Associate Editor of Cephalalgia and on the editorial boards of Neurology® and Headache; receives royalties from publishing Headache in Clinical Practice (Isis Medical Media, 2002), Headache in Primary Care (Isis Medical Media, 1999), Wolff ’s Headache (Oxford University Press, 2001, 2008), Managing Migraine: A Physician’s Guide (BC Decker, 2008), and Managing Migraine: A Patient’s Guide (BC Decker, 2008); has received speaker honoraria from the National Headache Foundation, the University of Oklahoma, the American Academy of Neurology, the Annenberg Foundation, Merck Serono, GlaxoSmithKline, and Coherex Medical; serves as a consultant for Allergan, Inc., Autonomic Technologies, MAP Pharmaceuticals, Inc., Neuralieve, Inc., and Novartis; receives/has received research support from AstraZeneca, Ortho-McNeil/Janssen, GlaxoSmithKline, Merck Serono, ProEthic Pharmaceutical, Inc., Advanced Bionics, the NIH/NIA, St. Jude Medical, the Migraine Research Foundation, and the National Headache Foundation; and holds stock options in Minster Pharmaceuticals plc. Dr. Varon is an employee of and holds stock in Allergan, Inc. Dr. Grosberg serves on a scientific advisory board for Kowa Pharmaceuticals America, Inc.; has received speaker honoraria from Merck Serono and GlaxoSmithKline; and receives research support from Allergan, Inc., Merck Serono, CAPNIA, Advanced Bionics, GlaxoSmithKline, Endo Pharmaceuticals, Boston Scientific, Minster Pharmaceuticals plc, and Neuralieve Inc. Dr. McAllister serves as a consultant for Allergan, Inc., GlaxoSmithKline, and Merck Serono; serves on speakers’ bureaus for Allergan, Inc., Ipsen, Merz Pharmaceuticals, LLC, GlaxoSmithKline, and Merck Serono; and receives research support from Allergan, Inc., GlaxoSmithKline, Merz Pharmaceuticals, LLC, and Merck Serono. Dr. Freitag serves on scientific advisory boards for Zogenix, Inc., Allergan, Inc., and Nautilus; has received funding for travel and speaker honoraria from GlaxoSmithKline, Zogenix, Inc., Merck Serono, and Nautilus; serves on speakers’ bureaus for GlaxoSmithKline, Zogenix, Inc., and Merck Serono; treats patients with chronic migraine headache and administers onabotulinumtoxinA in less than 1% of patients; and has received research support from Advanced Bionics, AstraZeneca, GlaxoSmithKline, Merck and Co., Ortho-McNeil/Janssen, Neurologics; and has served as consultant for Allergan, AstraZeneca, Capnia, Endo, Merck and Co., NuPathe, Ortho-McNeil/Janssen, Valeant Pharmaceuticals, Zogenix, Inc., and GlaxoSmithKline. Dr. Aurora serves on the editorial board of Headache; is listed as author on a patent re: Gastric stasis and improvement with onabotulinumtoxinA (Allergan, Inc.); has received research support from Advanced Bionics, Alexza Pharmaceuticals, AstraZeneca, Allergan, Inc., Boston Scientific, CAPNIA, GlaxoSmithKline, MAP Pharmaceuticals, Inc., Merck and Co, Ortho-McNeil/Janssen, Neuralieve Inc., NuPath Inc., Takeda Pharmaceutical Company Limited, Winston Pharmaceuticals, Inc., and the NIH; has served as a consultant for Astra Zeneca, Valeant Pharmaceuticals International, NMT Medical, Inc., Ortho-McNeil/Janssen, Pfizer Inc, Medtronic, Inc., Merck and Co., GlaxoSmithKline, Allergan, Inc., Neuralieve Inc., NuPath Inc.; and has received honoraria from Merck and Co., GlaxoSmithKline, Nautilius, NuPath Inc., and Zogenix, Inc. Dr. Dodick serves on scientific advisory boards and as a consultant for Allergan, Inc., Pfizer Inc., Novartis, Merck Serono, NuPath Inc., Nautilus, Coherex Medical, Boston Scientific, Medtronic, Inc., GlaxoSmithKline, CoLucid Pharmaceuticals, Autonomic Technologies, Eli Lilly and Company, Miller Medical, Neuralieve Inc., NeurAxon, Inc., St. Jude Medical, Inc., Zogenix, Inc., CogniMed Inc., MAP Pharmaceuticals, Inc., Lundbeck Inc., IMPAX Laboratories, Inc., and the NIH/NINDS; has received funding for travel or speaker honoraria from CogniMed Inc., Miller Medical, and Annenberg Center for Health Sciences; serves as Editor-in-Chief of Cephalalgia, Editor-in-Chief and on the

editorial boards of The Neurologist, Lancet Neurology, and Postgraduate Medicine; and has served as Editor-in-Chief of Headache Currents and as an Associate Editor of Headache; receives publishing royalties for Wolff ’s Headache, 8th edition (Oxford University Press, 2009) and Handbook of Headache (Cambridge University Press, 2010); and receives research support from Boston Scientific, Medtronic, Inc., Advanced Neurostimulation Systems, St. Jude Medical, Inc., and the NIH/NINDS. Dr. Silberstein serves on scientific advisory boards for AGA Medical Corporation, Allergan, Inc., Amgen, Boston Scientific, CAPNIA, Coherex Medical, CoLucid Pharmaceuticals, CyDex Pharmaceuticals, Inc., GlaxoSmithKline, Eli Lilly and Company, MAP Pharmaceuticals, Inc., Medtronic, Inc., Merck Serono, Minster Pharmaceuticals plc, Neuralieve Inc., the NIH/NINDS, NuPathe Inc., Pfizer Inc, St. Jude Medical, and Valeant Pharmaceuticals International; serves on the editorial boards of Cephalalgia and Current Pain and Headache Reports; serves on the speakers’ bureaus for Endo Pharmaceuticals, GlaxoSmithKline, and Merck; serves as a consultant for Amgen, Novartis, Opti-Nose, and Sepracor Inc.; his employer receives research support from AGA, Allergan, Boston Scientific, CAPNIA, Coherex, Endo, GlaxoSmithKline, Lilly, MAP, Medtronic, Merck, the NIH/NINDS, NuPathe, St. Jude Medical, Valeant, and Zogenix, Inc.; and receives research support from the American Headache Society and the International Headache Society. Dr. Diener has received honoraria for participation in clinical trials, contribution to advisory boards and/or oral presentations from Addex Pharma, Allergan, Almirall, AstraZeneca, Bayer Vital, Berlin Chemie, CoLucid, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Grunenthal, Janssen-Cilag, Lilly, La Roche, 3M Medica, Minster, MSD, Novartis, Johnson & Johnson, Pierre Fabre, Pfizer, Schaper and Brummer, SanofiAventis and Weber & Weber; and has also received financial support for research projects from Allergan, Almirall, AstraZeneca, Bayer, GlaxoSmithKline, Jannsen-Cilag and Pfizer. Headache research at the department of Neurology in Essen, where Dr. Diener is professor, is supported by the German Research Council (DFG), the German Ministry of Education and Research (BMBF) and the European Union. R.E. DeGryse is an employee of and holds stock in Allergan, Inc. Dr. Nolan is an employee of Imprint Publication Science, which was funded by Allergan, Inc. Dr. Turkel has patents pending re: Treatment of migraine and is an employee of and holds stock and stock options in Allergan, Inc.

Received November 18, 2010. Accepted in final form July 6, 2011.

REFERENCES 1. Bigal ME, Serrano D, Reed M, Lipton RB. Chronic migraine in the population: burden, diagnosis, and satisfaction with treatment. Neurology 2008;71:559 –566. 2. Natoli J, Manack A, Dean B, et al. Global prevalence of chronic migraine: a systematic review. Cephalalgia 2009; 30:599 – 609. 3. The International Classification of Headache Disorders, 2nd edition. Cephalalgia 2004;24(suppl 1):9 –160. 4. Olesen J, Bousser MG, Diener HC, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 2006;26:742–746. 5. Bigal ME, Rapoport AM, Lipton RB, Tepper SJ, Sheftell FD. Assessment of migraine disability using the migraine disability assessment (MIDAS) questionnaire: a comparison of chronic migraine with episodic migraine. Headache 2003;43:336 –342. 6. Meletiche DM, Lofland JH, Young WB. Quality-of-life differences between patients with episodic and transformed migraine. Headache 2001;41:573–578. 7. Munakata J, Hazard E, Serrano D, et al. Economic burden of transformed migraine: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache 2009;49:498 –508. 8. Blumenfeld A, Varon S, Wilcox TK, et al. Disability, HRQoL and resource use among chronic and episodic miNeurology 77

October 11, 2011

1471

graineurs: results from the International Burden of Migraine Study (IBMS). Cephalalgia 2011;31:301–315. 9. Stewart WF, Wood GC, Manack A, Varon SF, Buse DC, Lipton RB. Employment and work impact of chronic migraine and episodic migraine. J Occup Environ Med 2010; 52:8 –14. 10. Duru G, Auray JP, Gaudin AF, et al. Impact of headache on quality of life in a general population survey in France (GRIM2000 Study). Headache 2004;44:571–580. 11. Osterhaus JT, Townsend RJ, Gandek B, Ware JE Jr. Measuring the functional status and well-being of patients with migraine headache. Headache 1994;34:337–343. 12. Lovell BV, Marmura MJ. New therapeutic developments in chronic migraine. Curr Opin Neurol 2010;23:254 –258. 13. Dodick DW, Turkel CC, DeGryse R, et al. OnabotulinumtoxinA for treatment of chronic migraine: Pooled results from the double-blind, randomized, placebocontrolled phases of the PREEMPT clinical program. Headache 2010;50:921–936. 14. Diener HC, Dodick DW, Aurora SK, et al. OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia 2010;30:804 – 814. 15. Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia 2010;30:793– 803. 16. Blumenfeld A, Silberstein SD, Dodick DW, Aurora SK, Turkel CC, Binder WJ. Method of injection of onabotulinumtoxinA for chronic migraine: a safe, well-tolerated, and effective treatment paradigm based on the PREEMPT clinical program. Headache 2010;50:1406 –1418. 17. Kosinski M, Bayliss MS, Bjorner JB, et al. A six-item shortform survey for measuring headache impact: the HIT-6. Qual Life Res 2003;12:963–974. 18. Yang M, Rendas-Baum R, Varon SF, Kosinski M. Validation of the headache impact test (HIT-6TM) across episodic and chronic migraine. Cephalalgia 2011;31: 357–367. 19. Martin M, Blaisdell B, Kwong JW, Bjorner JB. The ShortForm Headache Impact Test (HIT-6) was psychometrically equivalent in nine languages. J Clin Epidemiol 2004; 57:1271–1278. 20. Bayliss MS, Batenhorst AS. The HIT-6™ A User’s Guide. Lincoln, RI: QualityMetric Incorporated; 2002. 21. Coeytaux RR, Kaufman JS, Chao R, Mann JD, Devellis RF. Four methods of estimating the minimal important

difference score were compared to establish a clinically significant change in Headache Impact Test. J Clin Epidemiol 2006;59:374 –380. 22. Cole JC, Lin P, Rupnow MF. Validation of the MigraineSpecific Quality of Life Questionnaire version 2.1 (MSQ v. 2.1) for patients undergoing prophylactic migraine treatment. Qual Life Res 2007;16:1231–1237. 23. Jhingran P, Davis SM, LaVange LM, Miller DW, Helms RW. MSQ: Migraine-Specific Quality-of-Life Questionnaire: further investigation of the factor structure. Pharmacoeconomics 1998;13:707–717. 24. Cole JC, Lin P, Rupnow MF. Minimal important differences in the Migraine-Specific Quality of Life Questionnaire (MSQ) version. Cephalalgia 2009;29:1180 –1187. 25. Dodick DW, Silberstein S, Saper J, et al. The impact of topiramate on health-related quality of life indicators in chronic migraine. Headache 2007;47:1398 –1408. 26. Silberstein SD, Marmura MJ, Shaw J, Yu S. Headache prophylaxis with BoNTA: patient characteristics. Headache 2010;50:63–70. 27. Diener HC, Schorn CF, Bingel U, Dodick DW. The importance of placebo in headache research. Cephalalgia 2008;28:1003–1011. 28. Aurora S. Botulinum toxin type A for the treatment of migraine. Expert Opin Pharmacother 2006;7:1085–1095. 29. Hays RD, Farivar SS, Liu H. Approaches and recommendations for estimating minimally important differences for health-related quality of life measures. COPD 2005;2:63– 67. 30. Silberstein S, Tfelt-Hansen P, Dodick DW, et al. Guidelines for controlled trials of prophylactic treatment of chronic migraine in adults. Cephalalgia 2008;28:484 – 495. 31. Elson CL, Maglinte GA, Rendas-Baum R, De Rosa M, Yang M, Varon SF. Validating use of the migraine-specific quality of life questionnaire version 2.1 (MSQ) across migraine disorders. Value Health 2010;13:A142. ISPOR abstract PND26. 32. Dworkin RH, Turk DC, McDermott MP, et al. Interpreting the clinical importance of group differences in chronic pain clinical trials: IMMPACT recommendations. Pain 2009;146:238 –244. 33. Dodick DW. Clinical practice: chronic daily headache. N Engl J Med 2006;354:158 –165. 34. Matchar DB, Harpole L, Samsa GP, et al. The headache management trial: a randomized study of coordinated care. Headache 2008;48:1294 –1310.

Neurology® Launches Subspecialty Alerts by E-mail! Customize your online journal experience by signing up for e-mail alerts related to your subspecialty or area of interest. Access this free service by visiting http://www.neurology.org/site/subscriptions/ etoc.xhtml or click on the “E-mail Alerts” link on the home page. An extensive list of subspecialties, methods, and study design choices will be available for you to choose from—allowing you priority alerts to cutting-edge research in your field!

1472

Neurology 77

October 11, 2011