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.