OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Results From the Double-Blind, Randomized, Placebo-Controlled Phases of the PREEMPT Clinical Program

Authors

  • David W. Dodick MD,

    1. From the Mayo Clinic Arizona, Phoenix, AZ, USA (D.W. Dodick); Allergan, Inc., Irvine, CA, USA (C.C. Turkel, R.E. DeGryse, and M.F. Brin); Swedish Neuroscience Institute, Seattle, WA, USA (S.K. Aurora); Thomas Jefferson University, Philadelphia, PA, USA (S.D. Silberstein); Albert Einstein College of Medicine, Bronx, NY, USA (R.B. Lipton); Department of Neurology, University of Essen, Germany (H.-C. Diener); Department of Neurology, University of California, Irvine, CA, USA (M.F. Brin).
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  • Catherine C. Turkel PharmD, PhD,

    1. From the Mayo Clinic Arizona, Phoenix, AZ, USA (D.W. Dodick); Allergan, Inc., Irvine, CA, USA (C.C. Turkel, R.E. DeGryse, and M.F. Brin); Swedish Neuroscience Institute, Seattle, WA, USA (S.K. Aurora); Thomas Jefferson University, Philadelphia, PA, USA (S.D. Silberstein); Albert Einstein College of Medicine, Bronx, NY, USA (R.B. Lipton); Department of Neurology, University of Essen, Germany (H.-C. Diener); Department of Neurology, University of California, Irvine, CA, USA (M.F. Brin).
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  • Ronald E. DeGryse MS,

    1. From the Mayo Clinic Arizona, Phoenix, AZ, USA (D.W. Dodick); Allergan, Inc., Irvine, CA, USA (C.C. Turkel, R.E. DeGryse, and M.F. Brin); Swedish Neuroscience Institute, Seattle, WA, USA (S.K. Aurora); Thomas Jefferson University, Philadelphia, PA, USA (S.D. Silberstein); Albert Einstein College of Medicine, Bronx, NY, USA (R.B. Lipton); Department of Neurology, University of Essen, Germany (H.-C. Diener); Department of Neurology, University of California, Irvine, CA, USA (M.F. Brin).
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  • Sheena K. Aurora MD,

    1. From the Mayo Clinic Arizona, Phoenix, AZ, USA (D.W. Dodick); Allergan, Inc., Irvine, CA, USA (C.C. Turkel, R.E. DeGryse, and M.F. Brin); Swedish Neuroscience Institute, Seattle, WA, USA (S.K. Aurora); Thomas Jefferson University, Philadelphia, PA, USA (S.D. Silberstein); Albert Einstein College of Medicine, Bronx, NY, USA (R.B. Lipton); Department of Neurology, University of Essen, Germany (H.-C. Diener); Department of Neurology, University of California, Irvine, CA, USA (M.F. Brin).
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  • Stephen D. Silberstein MD,

    1. From the Mayo Clinic Arizona, Phoenix, AZ, USA (D.W. Dodick); Allergan, Inc., Irvine, CA, USA (C.C. Turkel, R.E. DeGryse, and M.F. Brin); Swedish Neuroscience Institute, Seattle, WA, USA (S.K. Aurora); Thomas Jefferson University, Philadelphia, PA, USA (S.D. Silberstein); Albert Einstein College of Medicine, Bronx, NY, USA (R.B. Lipton); Department of Neurology, University of Essen, Germany (H.-C. Diener); Department of Neurology, University of California, Irvine, CA, USA (M.F. Brin).
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  • Richard B. Lipton MD,

    1. From the Mayo Clinic Arizona, Phoenix, AZ, USA (D.W. Dodick); Allergan, Inc., Irvine, CA, USA (C.C. Turkel, R.E. DeGryse, and M.F. Brin); Swedish Neuroscience Institute, Seattle, WA, USA (S.K. Aurora); Thomas Jefferson University, Philadelphia, PA, USA (S.D. Silberstein); Albert Einstein College of Medicine, Bronx, NY, USA (R.B. Lipton); Department of Neurology, University of Essen, Germany (H.-C. Diener); Department of Neurology, University of California, Irvine, CA, USA (M.F. Brin).
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  • Hans-Christoph Diener MD,

    1. From the Mayo Clinic Arizona, Phoenix, AZ, USA (D.W. Dodick); Allergan, Inc., Irvine, CA, USA (C.C. Turkel, R.E. DeGryse, and M.F. Brin); Swedish Neuroscience Institute, Seattle, WA, USA (S.K. Aurora); Thomas Jefferson University, Philadelphia, PA, USA (S.D. Silberstein); Albert Einstein College of Medicine, Bronx, NY, USA (R.B. Lipton); Department of Neurology, University of Essen, Germany (H.-C. Diener); Department of Neurology, University of California, Irvine, CA, USA (M.F. Brin).
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  • Mitchell F. Brin MD

    1. From the Mayo Clinic Arizona, Phoenix, AZ, USA (D.W. Dodick); Allergan, Inc., Irvine, CA, USA (C.C. Turkel, R.E. DeGryse, and M.F. Brin); Swedish Neuroscience Institute, Seattle, WA, USA (S.K. Aurora); Thomas Jefferson University, Philadelphia, PA, USA (S.D. Silberstein); Albert Einstein College of Medicine, Bronx, NY, USA (R.B. Lipton); Department of Neurology, University of Essen, Germany (H.-C. Diener); Department of Neurology, University of California, Irvine, CA, USA (M.F. Brin).
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  • Funding: Allergan, Inc.

  • ClinicalTrials.gov identifiers: NCT00156910, NCT00168428.

  • Conflict of Interest: D.W.D. has received honoraria from Allergan, Merck, Neuralieve, Coherex, Kowa, Minster, NeurAxon, H Lundbeck, Endo, Pfizer, Nupathe, and MAP Pharmaceuticals, in addition to being a consultant to and on the advisory board of these pharmaceutical companies. He has also received funding from Advanced Neurostimulation Systems, St. Jude Medical Center, and Medtronic. S.K.A. received, within the last 2 years, grants and research support from Advanced Bionics, Alexza, Allergan, Capnia, GlaxoSmithKline, MAP Pharmaceuticals, Merck and Co., Ortho-McNeil, Neuralieve, NuPathe, and Takeda. She is a consultant for Ortho-McNeil, Merck and Co., GlaxoSmithKline, Allergan, Neuralieve, NuPathe, and MAP Pharmaceuticals. She has also received honoraria from Merck and Co., GlaxoSmithKline, Kowa, NuPathe, and Ortho-McNeil. C.C.T., R.E.D., and M.F.B. are employees of Allergan, Inc., and own stock in the company. S.D.S. and R.B.L. have received honoraria and research funding from Allergan, Inc., in addition to being consultants to and on the advisory board of Allergan. H.C.D. received honoraria for participation in clinical trials, contribution to advisory boards, 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, Sanofi-Aventis, Weber & Weber. He also received financial support for research projects from Allergan, Almirall, AstraZeneca, Bayer, GlaxoSmithKline, Janssen-Cilag, and Pfizer. Headache research at the Department of Neurology in Essen, where H.C.D. is Professor, is supported by the German Research Council (DFG), the German Ministry of Education and Research (BMBF), and the European Union.

D.W. Dodick, Mayo Clinic, Scottsdale – Neurology, Department of Neurology, 13400 East Shea Blvd, Scottsdale, AZ 85259, USA.

Abstract

(Headache 2010;50:921-936)

Objective.— To assess the efficacy, safety, and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine.

Background.— Chronic migraine is a prevalent, disabling, and undertreated neurological disorder. Few preventive treatments have been investigated and none is specifically indicated for chronic migraine.

Methods.— The 2 multicenter, pivotal trials in the PREEMPT: Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy clinical program each included a 24-week randomized, double-blind phase followed by a 32-week open-label phase (ClinicalTrials.gov identifiers NCT00156910, NCT00168428). Qualified patients were randomized (1:1) to onabotulinumtoxinA (155-195 U) or placebo injections every 12 weeks. Study visits occurred every 4 weeks. These studies were identical in design (eg, inclusion/exclusion criteria, randomization, visits, double-blind phase, open-label phase, safety assessments, treatment), with the only exception being the designation of the primary and secondary endpoints. Therefore, the predefined pooling of the results was justified and performed to provide a complete overview of between-group differences in efficacy, safety, and tolerability that may not have been evident in individual studies. The primary endpoint for the pooled analysis was mean change from baseline in frequency of headache days at 24 weeks. Secondary endpoints were mean change from baseline to week 24 in frequency of migraine/probable migraine days, frequency of moderate/severe headache days, total cumulative hours of headache on headache days, frequency of headache episodes, frequency of migraine/probable migraine episodes, frequency of acute headache pain medication intakes, and the proportion of patients with severe (≥60) Headache Impact Test-6 score at week 24. Results of the pooled analyses of the 2 PREEMPT double-blind phases are presented.

Results.— A total of 1384 adults were randomized to onabotulinumtoxinA (n = 688) or placebo (n = 696). Pooled analyses demonstrated a large mean decrease from baseline in frequency of headache days, with statistically significant between-group differences favoring onabotulinumtoxinA over placebo at week 24 (−8.4 vs −6.6; P < .001) and at all other time points. Significant differences favoring onabotulinumtoxinA were also observed for all secondary efficacy variables at all time points, with the exception of frequency of acute headache pain medication intakes. Adverse events occurred in 62.4% of onabotulinumtoxinA patients and 51.7% of placebo patients. Most patients reported adverse events that were mild to moderate in severity and few discontinued (onabotulinumtoxinA, 3.8%; placebo, 1.2%) due to adverse events. No unexpected treatment-related adverse events were identified.

Conclusions.— The pooled PREEMPT results demonstrate that onabotulinumtoxinA is an effective prophylactic treatment for chronic migraine. OnabotulinumtoxinA resulted in significant improvements compared with placebo in multiple headache symptom measures, and significantly reduced headache-related disability and improved functioning, vitality, and overall health-related quality of life. Repeat treatments with onabotulinumtoxinA were safe and well tolerated.

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