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

Department of Neurology, Mayo Clinic Arizona, Phoenix, AZ, USA.
Headache The Journal of Head and Face Pain (Impact Factor: 3.19). 06/2010; 50(6):921-36. DOI: 10.1111/j.1526-4610.2010.01678.x
Source: PubMed

ABSTRACT To assess the efficacy, safety, and tolerability of onabotulinumtoxinA (BOTOX) as headache prophylaxis in adults with chronic migraine.
Chronic migraine is a prevalent, disabling, and undertreated neurological disorder. Few preventive treatments have been investigated and none is specifically indicated for chronic migraine.
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 ( 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 (> or =60) Headache Impact Test-6 score at week 24. Results of the pooled analyses of the 2 PREEMPT double-blind phases are presented.
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.
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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Available from: Richard Lipton, Aug 26, 2015
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    • "Few drugs have been tested for the preventive treatment of chronic migraine. Onabotulinum toxin-A [6] [7] and topiramate [8] [9] [10] have class I studies and evidence level A, and sodium valproate [11], class I study and level evidence B. The duration of preventive treatment for chronic migraine has not been established yet, but there are data demonstrating substantial rate of recurrence in patients treated for one year or less with early suspension of treatment [10] [12]. "
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    ABSTRACT: To determine the minimum duration of migraine prophylaxis, after patients become pain-free. Migraine patients diagnosed according to criteria of International Classification of Headache Disorders-2 were treated prophylactically. After becoming pain-free, they were divided into two equal groups: in group 1, prophylaxis was maintained for another 12months and in group 2, for 24months. Each group was followed for more three years after prophylaxis period. Of the 50 patients, 39 (78%) were female and 11 (22%) were male. The age ranged from 18 to 50years. Before treatment, the attack frequency for groups 1 and 2 was, respectively, 16.3±12.8 and 16.4±11.8days per month (p=0.769). Patients in groups 1 and 2 have become pain-free, respectively, with 21.4±11.2 and 16.8±9.9months (p=0.161). During three years without treatment, groups 1 and 2 maintained an annual frequency of respectively 3.2 and 0.5 headache days. Of the patients in group 2, 76.0% (19/25) remained pain-free during follow-up, versus 44.0% (11/25) of group 1, with a significant difference (p=0.001). The best results were obtained when migraine prophylaxis was maintained for 24months after patients became pain-free.
    Journal of the neurological sciences 11/2013; 337(1-2). DOI:10.1016/j.jns.2013.11.013 · 2.26 Impact Factor
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    • "between 30% and 50% (Dodick et al. 2010). The main disadvantage are the high costs of one Botox® treatment that are mostly not reimbursed. "
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    ABSTRACT: To evaluate if white matter lesions (WML) on MRI can be a potential marker for onabotulinum toxin A (Botox®) treatment success in migraine, given the limited response rate and high costs per treatment. Retrospective data base and MRI analysis of 529 migraineurs who received Botox® between 2002 and 2009. Responders were defined as patients who underwent three or more treatments, whereas non-responders had only one or two treatments. MRIs were analysed on axial T2 and coronar FLAIR (fluid attenuated inversion recovery) sequences for the presence of WML. Statistical analysis was done with the Chi-Square-Test and the Mann-Whitney-U-Test. Of 529 Botox® treated migraineurs, 111 patients had a MRI. Of these 111 patients, 47 were responders, 64 non-responders to Botox®. Response rate to Botox® in migraineurs with WML was 55.3%, in migraineurs without WML 44.7%. In the investigated items "age", "age at onset", "gender", "attack duration", "frequency", "aura", "WML", "size of WML", we found no statistical significant difference between the two groups. 55% of the responders and 50% of the non-responders showed WML. All WML were located supratentorially, anteriorly, mostly of small size (3-5 mm). WML on MRIs cannot serve as a marker to predict a positive response to Botox®.
    SpringerPlus 08/2013; 2:377. DOI:10.1186/2193-1801-2-377
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    • "The primary efficacy variable for all subgroup analyses, including CM + MO, was the same as the primary efficacy variable for the intent-to-treat (ITT) primary analyses of the pooled PREEMPT studies [19] "
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    ABSTRACT: Acute headache medication overuse (MO) is common in patients with chronic migraine (CM). We evaluated safety and efficacy of onabotulinumtoxinA as preventive treatment of headache in CM patients with baseline MO (CM+MO) in a planned secondary analysis from two similarly designed, randomized, placebo-controlled, parallel, Phase III trials. Patients were randomized to treatment groups (155-195U of onabotulinumtoxinA or placebo) using MO (patient-reported and diary-captured frequency of intake) as a stratifying variable. Of 1384 patients, 65.3% (n=904) met MO criteria (onabotulinumtoxinA: n=445, placebo: n=459). For the CM+MO subgroup at Week 24, statistically significant between-treatment group mean changes from baseline favoring onabotulinumtoxinA versus placebo were observed for headache days (primary endpoint: -8.2 vs. -6.2; p<0.001) and other secondary endpoints: frequencies of migraine days (p<0.001), moderate/severe headache days (p<0.001), cumulative headache hours on headache days (p<0.001), headache episodes (p=0.028), and migraine episodes (p=0.018) and the percentage of patients with severe Headache Impact Test-6 category (p<0.001). At Week 24, change from baseline in frequency of acute headache medication intakes (secondary endpoint) was not statistically significant (p=0.210) between groups, except for triptan intakes (p<0.001), where the onabotulinumtoxinA-treated group was favored. OnabotulinumtoxinA was effective and well tolerated as headache prophylaxis in CM+MO patients.
    Journal of the neurological sciences 06/2013; 331(1-2). DOI:10.1016/j.jns.2013.05.003 · 2.26 Impact Factor
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