Twenty-five percent of chronic migraine patients experience at least a 75% reduction in headache days per month after 6 months of treatment with onabotulinumtoxinA, according to a new analysis of data from the landmark PREEMPT trials.

“That’s what I tell my patients to expect: If they go on Botox [onabotulinumtoxinA], they have a 1 in 4 chance of a 75% or greater reduction in headache symptoms over 6 months of therapy,” Dr. David W. Dodick said at the European Headache and Migraine Trust International Congress.

David Dodick

PREEMPT (Phase III Research Evaluating Migraine Prophylaxis Therapy) consisted of two pivotal trials that resulted in Food and Drug Administration licensure of Botox as the only approved treatment for chronic migraine, an often-disabling disorder that affects 1%-2% of the U.S. adult population.

PREEMPT involved 1,384 adults with chronic migraine as defined by the International Classification of Headache Disorders, 2nd edition, criteria – basically, an average of at least 15 days of headache per month – at 122 U.S. and European sites. Participants were randomized double-blind to Botox or placebo injections at baseline, 12, and 24 weeks. Then the placebo group was crossed over to open-label Botox, which all subjects received at weeks 36 and 48.

The previously reported primary end point was the change in frequency of headache days per month between baseline and 6 months. Botox significantly outperformed placebo, achieving a mean 8.4-day decrease in headache days per month from the pretreatment baseline of 19.9 days, compared with a 6.6-day drop with placebo (Cephalalgia 2010;30:793-803 and 804-14).

Dr. Dodick’s report on the proportion of patients achieving at least a 75% reduction in headache days per month was just one of several secondary end points in PREEMPT presented at the congress for the first time. Some PREEMPT investigators indicated they found these secondary outcome measures more clinically relevant than the primary study end point.

John F. Rothrock

“The primary end point was perhaps one I wouldn’t have chosen myself,” said Dr. John F. Rothrock, professor and chief of neurosciences at the University of Nevada, Reno, and editor-in-chief of the journal Headache. “The fact that you lose 1.8 headache days per month if you treat your patient with Botox is not really very exciting to me. It doesn’t lead me to be very enthusiastic about implementing a therapy that costs as much as Botox.”

“A far more interesting end point to me – and one that was a secondary assessment in PREEMPT – was in how many patients do you achieve remission from chronic migraine back to episodic migraine with implementation of Botox therapy? Because that’s really what we’re after as clinicians: not just lopping off a couple of headache days per month, but how often can I wipe the slate clean and take that patient who has headache on more days than not – and in some cases, daily – and give them a headache-free or nearly headache-free existence off prophylactic medications and only occasionally using abortive therapy?” he continued.

The good news is that at the study’s end at week 56, roughly 70% of patients had achieved a 50% or greater reduction in headache days per month, compared with baseline. The divergence between active treatment and placebo in this secondary outcome measure was already significant at the first assessment, just 4 weeks after the first treatment session. The divergence grew through the first 6 months, then diminished once the former placebo group went on Botox, Dr. Rothrock noted.

The one potentially treatment-related serious adverse event seen in the study was status migrainosus requiring hospitalization. The incidence was 0.1% in the Botox arm and zero in the placebo group.

“I’ve now treated just short of 1,000 patients with Botox using the PREEMPT protocol, and it’s really unusual to run into a clinically significant side effect. The most common side effect in the PREEMPT trials was neck pain and stiffness. Patients talk about a wobbly neck or bobble head, a weakness in the neck. Other than that, it’s a very clean therapy, especially compared to other things that we use to try to suppress chronic migraine and get it to remit to episodic migraine,” the neurologist observed.

Dr. Dodick agreed that the primary end point in PREEMPT doesn’t come close to capturing the whole story regarding Botox therapy.

“My own clinical experience using it for the last 12 years is that some patients have a significant reduction in headache days, while others who’ve had one continuous headache continue to do so with zero days reduction, but the severity is dramatically reduced. Their consumption of acute medications decreases and their response to medications is enhanced. So if you look at just one clinical end point – headache days per month – you may miss a dramatic improvement that occurs with no reduction in days,” said Dr. Dodick, professor of neurology at the Mayo Clinic, Phoenix, and a past president of the American Headache Society.

Another newly analyzed secondary end point was the response rate per treatment cycle in PREEMPT. Dr. Dodick reported that 49% of participants responded to the first Botox injection with at 50% or greater reduction in their frequency of headache days per month. An additional 11% achieved this benchmark only after the second treatment cycle, and another 10% did so after the third.

“Just because a patient doesn’t respond to one injection doesn’t mean we shouldn’t try a second. I generally don’t go beyond two nonresponding injections. But don’t stop after one,” he urged.

That advice is consistent with the results of an appraisal by the U.K. National Institute for Health and Clinical Excellence (NICE), which deemed Botox for chronic migraine “an appropriate use of NHS [National Health Service] resources,” with the proviso that the treatment be stopped if it hasn’t achieved a 30% reduction in the number of headache days per month after two cycles.

THE PREEMPT trials and the new secondary analyses were sponsored by Allergan. Both Dr. Dodick and Dr. Rothrock reported receiving research funds from and consulting for the company.