PHILADELPHIA—Patients with chronic migraine who were treated with onabotulinumtoxin A (Botox) showed significant reduction in frequency of headache days, compared with patients who received placebo, according to data presented at the 14th Congress of the International Headache Society.

Pooled results from the double-blind, randomized, placebo-controlled phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) 1 and 2 trials were reported by David Dodick, MD, Professor of Neurology at the Mayo Clinic in Phoenix, and colleagues. “Based on data from a previous phase II trial of onabotulinumtoxin A, the PREEMPT clinical program (PREEMPT 1 and 2) was conducted to evaluate the safety and efficacy of onabotulinumtoxin A in adults with chronic migraine,” said Dr. Dodick.

PREEMPT Design

Participants included men and women ages 18 to 65 (mean age, 41) with history of migraine that met diagnostic criteria listed in the International Classification of Headache Disorders-II, did not use other prophylactic medications four weeks prior to baseline, and did not have previous exposure to any other botulinum toxin serotype. All patients also had 15 or more headache days per month, at least four distinct headache episodes that lasted four hours or more, and at least 50% of baseline headache days that were migraine or probable migraine. “We were very clear about what constituted a headache day,” Dr. Dodick said.

Subjects were randomized to onabotulinumtoxin A (n = 688) or placebo (n = 696), administered as 31 fixed-site, fixed dose IM injections across seven specific head and neck muscle areas, every 12 weeks throughout 24 weeks. “An additional 40 U onabotulinumtoxin A could have been injected among three muscle groups (occipitalis, temporalis, or trapezius; total of eight sites) using a protocol-defined follow-the-pain paradigm,” Dr. Dodick and colleagues stated. The maximum dose was 195 U at 39 sites. Randomization was stratified according to acute headache medication overuse. Change from baseline to 28 days ending with week 24 was the basis for all efficacy analyses. PREEMPT was conducted in 122 centers across North America and Europe. During the four-week baseline phase, patients recorded their headaches and associated symptoms in electronic diaries. The mean baseline patient diary-day compliance rate was 99% and remained high (greater than 93%) in both treatment groups during the 24-week phase.

Pooled Analyses Reveal Positive Findings

Mean frequency of headache days decreased more significantly among patients treated with onabotulinumtoxin A (-8.4) than with placebo (-6.6) at week 24, and at all other time points. Mean change from baseline for frequency of headache episodes also favored onabotulinumtoxin A at all time points, including week 24 (-5.2), compared with placebo (-4.9). Secondary efficacy variables included frequencies of migraine episodes, migraine days, moderate/severe headache days, total cumulative headache hours on headache days, headache episodes, acute medication use, and the proportion of patients with severe (greater than 60) Headache Impact Test (HIT)-6 score. Significant differences favoring onabotulinumtoxin A were found for all secondary variables in all time points, with the exception of acute medication use.

“We have seen that in previous comparative studies,” Dr. Dodick commented. “The only other two randomized controlled studies to be done in this population also failed to show a significant decrease in the consumption of acute headache medications when compared to the placebo group.However, when we went back and looked at the frequency of triptan use, we showed that both in PREEMPT 1 and PREEMPT 2, there was a statistically significant reduction in the consumption of triptans in the onabotulinumtoxin A group, compared to placebo, but not in other analgesics or pain medications.”

Impact on disability in functioning and vitality, psychologic distress, and health-related quality of life were also assessed by mean change in baseline with total HIT-6 score and with the Migraine-Specific Quality of Life Questionnaire, in the restrictive, preventive, and emotional domains. “Patients treated with onabotulinumtoxin A achieved significant improvements in all of these areas, which I think is an important end point in this population,” Dr. Dodick stated.

Adverse events occurred in 62.4% of the onabotulinumtoxin A group, compared with 51.7% in the placebo group. “Most adverse events reported by patients were mild or moderate in severity, and adverse events resolved without sequelae,” Dr. Dodick and investigators stated. Discontinuation occurred in 2.8% of participants in the onabotulinumtoxin A group, and 0.7% of those in the placebo group. In the onabotulinumtoxin A group, 8.7% of patients experienced neck pain. In the placebo group, 5.3% of patients experienced upper respiratory tract infection. These were the only adverse events to occur at a rate greater than 5%. “Treatment-related adverse events were consistent with the known tolerability profile of onabotulinumtoxin A, and no newly emerged safety findings were observed,” Dr. Dodick’s group noted.

PREEMPT 1 Versus PREEMPT 2

Although pooled analyses from the two studies showed overall positive results, the findings differed regarding primary end points between PREEMPT 1 and PREEMPT 2.

In PREEMPT 1, onabotulinumtoxin A was not more effective than placebo regarding change from baseline frequency of headache episodes to headache frequency at week 24. There was a significant imbalance at baseline in the frequency of headache episodes between the onabotulinumtoxin A and placebo groups. In a post-hoc analysis of headache episode frequency during the first 14 days of baseline, no significant between-group differences were shown. When this baseline was used, significant between-group differences favoring onabotulinumtoxin A were observed at weeks four, eight, 20, and 24. At week 24, statistically significant mean improvements were also observed for frequencies of headache days (-7.8, onabotulinumtoxin A; -6.4, placebo) and migraine days (-7.6, onabotulinumtoxin A; -6.1, placebo).

PREEMPT 1 included 341 patients randomized to onabotulinumtoxin A, and 338 to placebo. A total of 18 (5.3%) of patients receiving onabotulinumtoxin A reported serious adverse events, compared with eight (2.4%) receiving placebo. Neck pain (8.2%) and muscular weakness (5.9%) were reported by patients receiving onabotulinumtoxin A, while upper respiratory tract infection and sinusitis were experienced by 6.0% and 5.1%, respectively, of the placebo group.

For PREEMPT 2, however, Dr. Dodick and colleagues found that onabotulinumtoxin A was significantly more effective than placebo (n = 358) in achieving its primary end point—reduction in frequency of headache days. Patients who received onabotulinumtoxin A (n = 347) also had significant improvement compared with those who received placebo regarding all secondary end points, including frequency of migraine days, frequency of moderate/severe headache days, monthly cumulative headache hours on headache days, proportion of patients with severe HIT-6 score, and frequency of headache episodes.

Overall, 15 (4.3%) of onabotulinumtoxin A patients in PREEMPT 2 reported serious adverse events, compared with eight (2.2%) placebo patients. Neck pain and muscular weakness were reported by 9.8% and 5.2%, respectively, of patients using onabotulinumtoxin A.

The Future of Migraine Treatment?

“Onabotulinumtoxin A is shown to be an effective, safe, and well-tolerated treatment for the prophylaxis of chronic migraine,” Dr. Dodick said. In addition, multiple IM treatments of onabotulinumtoxin A, from 155 U to 195 U per treatment cycle, were safe and well tolerated. “Pooled analyses from the PREEMPT 1 and 2 trials demonstrate that treatment with onabotulinumtoxin A resulted in highly significant improvements in onabotulinumtoxin A–treated patients versus placebo-treated patients in frequency of headache days in patients suffering from chronic migraine,” Dr. Dodick’s group reported.”

—Laura Sassano

Suggested Reading
Lima MM, Padula NA. Santos LC, et al. Critical analysis of the international classification of headache disorders diagnostic criteria (ICHD I-1988) and (ICHD II-2004), for migraine in children and adolescents. Cephalalgia. 2005;25(11): 1042-1047.

Petri S, Tölle T, Straube A, et al. Botulinum toxin as preventive treatment for migraine: a randomized double-blind study. Eur Neurol. 2009;62(4):204-211.

Sidebar: Patients Treated With Botox Have Reduced MIDAS Scores

PHILADELPHIA—Sustained reduction in migraine-related disability, headache days, and acute medication use were observed in patients treated with onabotulinumtoxin A, according to data presented at the 14th Congress of the International Headache Society.

Ira M. Turner, MD, of the Center for Headache Care and Research at Island Neurological Associates, PC, in Plainview, New York, and colleagues, retrospectively reviewed 40 patients treated with onabotulinumtoxin A for chronic migraine (15 or more headache days per month) or high frequency migraine (eight to 14 headache days per month) in three consecutive monthly treatment cycles. The primary end point was a reduction in Migraine Disability Assessment (MIDAS) scores. Reduced headache days and acute medication use were secondary end points.

“The average MIDAS score at baseline was 62.8,” Dr. Turner and investigators stated. “Over the next three cycles, these scores were reduced to 29.2, 31.1, and 24.8.” A reduction in headache days was also seen. “These were reduced from a baseline of 20.7 headache days to 11.6, 9.8, and 9.6 days over successive cycles.” A similar sustained decrease for acute medication intake was also noted, from a baseline average of 51.5 doses per month to 27.9, 24.4, and 21.4 monthly doses.

“This retrospective data review of our community-based experience with chronic migraine and high frequency migraine suggests a sustained response to regular onabotulinumtoxin A treatments at roughly three-month intervals in regard to migraine-related disability,” Dr. Turner’s group concluded. A concomitant persisting decrease in headache days and acute medication usage was also shown. “In combination, these have resulted in much less time lost from work and social and family activities, as well as pharmaco-economic savings in terms of reduced acute medication, primarily triptan, usage.”

—Laura Sassano

Botox Is Safe and Effective as Preventive Treatment for Chronic Migraine