Chronic Migraine: Study to Look at Long-Term Use of OnabotulinumtoxinA

A recently completed Phase III trial — called PREEMPT – established the efficacy and safety of onabotulinumtoxinA (marketed by Allergan under the brand name Botox^®) in treating chronic migraine. Following those results, a new long-term trial is currently underway to analyze some of the clinical questions raised but not answered in PREEMPT.

Chronic migraine (CM) is a severe neurological disorder with a global prevalence of approximately 2% of adults. Headaches are classified as CM if they persist 15 or more days per month for more than three months (at least eight days should meet criteria for migraine without aura or respond to migraine-specific treatment), according to the International Headache Society. OnabotulinumtoxinA is the only therapy specifically approved in the US for prophylaxis of headache in patients with CM. While less prevalent than episodic migraine, CM is more likely to be accompanied by severe disability and an inability to work; it is also more likely to come with psychiatric conditions such as depression and anxiety.

PREEMPT evaluated onabotulinumtoxinA versus placebo in treatment of CM over a 56-week period (24-week, double-blind period, followed by 32 weeks of open-label use). The data showed that onabotulinumtoxinA was more effective than placebo in reducing mean frequency of headache days from baseline at every visit from week 4 to the primary endpoint of week 24 (−8.4 onabotulinumtoxinA vs. -6.6 placebo; p&thinsp;<&thinsp;0.001).

The upcoming study, called COMPEL (Chronic Migraine OnabotulinumtoxinA Prolonged Efficacy open Label), will enroll 500 adult patients with chronic migraine at international sites and follow the patients over two years, following a four-week baseline period. Qualified subjects will receive onabotulinumtoxinA every 12 weeks for nine open-label cycles.

The primary endpoint will be mean change from baseline in frequency of headache days at 108 weeks. Other endpoints will include additional assessments of the efficacy and safety of onabotulinumtoxinA and its effect of quality-of-life measures, disability, and health economic outcomes. The study will also take a closer look at common chronic migraine comorbidities, including sleep disorders, fatigue, and anxiety.

One of the lingering questions from the PREEMPT trial that COMPEL will seek to answer is the long-term effect of onabotulinumtoxinA — specifically, whether there is a plateau established in the treatment cycle.

“By creating a large database and analyzing a variety of outcome measures over an extended time frame, the COMPEL study will seek to contribute substantially to the existing knowledge of the chronic migraine population and the long-term management of this debilitating disorder,” the authors noted.

While other botulinum toxins have been clinically studied for CM treatment, each formulation of is different, and therefore the units of activity are specific to each product and not interchangeable with those of any other botulinum toxins. Clinical trials to this point have been shorter in duration than the COMPEL trial will be.

According to the study authors, “To our knowledge, COMPEL will be the longest CM trial ever conducted and is expected to add significant knowledge to the literature about long-term use of prophylactic therapy in this patient population.”

One limitation of the study is that its open-label design with long-term follow up can be subject to multiple confounders such as unintentional bias, low persistency rates, and concomitant medication changes. Further, while COMPEL will examine many comorbidities, not all comorbidities will be captured; patients with severe depressive symptoms and suicidal ideation will be excluded.