OnabotulinumtoxinA (Botox, Allergan) treatment is more effective, is better tolerated, and has greater functional improvement in the prevention of chronic migraine compared with the anticonvulsant topiramate, new research suggests.
In a 36-week head-to-head, prospective, open-label study, investigators found a greater proportion of patients in the onabotulinumtoxinA group (40%) achieved the primary outcome of a 50% or greater reduction in headache days from baseline compared with those in topiramate group (12%).
«The reason we did this trial is if we look at what happens in the community vs published data, there is a bit of a disconnect. In clinical practice, topiramate tends to be a first-line preventive treatment,» said study investigator Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad.
The findings were presented here at the American Headache Society (AHS) Annual Meeting 2018.
The Efficacy and Safety Study of BOTOX® Compared to Topiramate for the Prevention of Chronic Migraine in Adults» (FORWARD) study is not the first to look at the onabotulinumtoxinA for migraine relief.
Some of the earlier research was less convincing, including a 2011 review of two randomized, placebo-controlled trials that investigators said pointed to a «slight reduction» in chronic migraine with onabotulinumtoxinA. A meta-analysis of available evidence published the following year in JAMA pointed to a «small to modest benefit» for the toxin compared to placebo in treating chronic migraine.
In 2016, when the American Academy of Neurology updated its guideline on botulinum neurotoxins in neurologic disease, it reviewed evidence for treatment of headaches.
The AAN guidelines state:
- OnabotulinumtoxinA is established as effective and should be offered to increase headache-free days (Level A evidence) and is probably effective and should be considered to improve health-related quality of life (Level B) in chronic migraine.
- OnabotulinumtoxinA is established as ineffective and should not be offered for episodic migraine (Level A) and is probably ineffective for chronic tension-type headaches (Level B).
Postmarketing data support onabotulinumtoxinA as effective prophylaxis for chronic migraine, according to research presented at the European Academy of Neurology conference last year and reported by Medscape Medical News at that time.
Investigators reported no new safety signals and that about two thirds of patients were satisfied. The Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) studies offered a «real-world» look at safety and use of the agent.
In the current study, patients received onabotulinumtoxinA injection of 155 U in three cycles 12 weeks apart or topiramate titrated up to the approved dose over the first 12 weeks, and then maintained at 50 to 100 mg/day up to week 36. This was also a «real-world study design,» Blumenfeld said.
In a comparison against baseline scores on the 9-Item Patient Health Questionnaire (PHQ-9), onabotulinumtoxinA treatment was associated with significant improvements in depression symptoms compared with topiramate at week 36. Mean scores were 4.4 in the toxin group vs 7.1 in the topiramate group (P < .001).
The investigators also compared cognition using Controlled Oral Word Association Test (COWAT) performance. They found toxin therapy associated with a small increase in COWAT scores, suggesting better cognition/verbal fluency, from a mean of 1.2 at week 12 to 2.8 at week 36. In contrast, COWAT scores decreased by 2.8 points in the topiramate group as early as week 12 «suggesting cognitive changes occurred early in treatment with topiramate.»
It was important to compare effectiveness instead of efficacy, Blumenfeld noted. «Effectiveness implies efficacy and good tolerability that allow you to stay longer on the medication,» he said. This measure is relevant because «many patients in the topiramate arm discontinued from side effect issues or a lack of efficacy.»
Only 19% of the topiramate group completed 36 weeks vs 82% of the onabotulinumtoxinA group. The high discontinuation rate in the topiramate group precluded a comparison of COWAT scores at week 36. The researchers used a baseline-observation-carried-forward statistical approach to compensate for the noncompleters.
Main reasons for study withdrawal included ineffectiveness, reported in 5% of the onabotulinumtoxinA group and 19% of the topiramate group. The rate of discontinuations due to adverse events also was lower in the toxin group than in the topiramate group, at 4% vs 51%.
However, participants who were able to remain on topiramate tended to do well, he said. Of the 25 completers in the topiramate group, 17 experienced at least a 50% reduction in headache days.
«This is what we see in clinical practice. The problem with the topiramate-treated patients, especially those with chronic migraine, is they have difficulty staying on medication long enough to see an effect.»
The proportion of toxin-treated patients reporting one or more adverse events was 45%, compared with 77% of the topiramate group. The researchers reported treatment-related adverse events in 17% and 69% of the cohorts, respectively.
A meeting attendee asked Blumenfeld whether he considered a double-blind study design.
«We would have needed to have a greater ‘N,’ and we had a difficult time enrolling these patients,» he said. «Enrollment was done at the same time the monoclonal antibody trials were being done, and we ended up with fewer enrolled participants than we wanted.»
Nevertheless, «onabotulinumtoxinA showed a superior tolerability profile vs topiramate based on treatment-related adverse events and the overall discontinuation rate,» Blumenfeldsaid.
Large Placebo Effect «Problematic»
Commenting on the findings for Medscape Medical News was Jeffrey L. Jackson, MD, MPH, professor of medicine at the Center for Advancing Population Science at the Medical College of Wisconsin in Milwaukee.
«This is a multicenter trial comparing Botox to topiramate for chronic migraine headaches. It is important to note that the trial was sponsored by Allergan, the company that manufactures botulinum.»
«They found that Botox was more likely to reduce headache frequency by more than 50%, compared to baseline than topiramate (40% vs 12%). Among the 142 patients randomized to topiramate, 80% dropped out. The authors used an intention-to-treat analysis based on baseline observation carried forward. Many researchers believe this is an inappropriate method of imputing missing data,» Jackson said.
«It’s particularly problematic in headache trials, in which there is usually a very large placebo effect. Bringing forward the baseline data for 80% of the topiramate group would almost inevitably lead to the conclusion that Botox was better than topiramate. This is a subtle but obvious bias in how this study was reported.
When given an opportunity to respond, Blumenfeld said, «Dr Jackson missed the key message, which is that this study measures effectiveness, not efficacy. Effectiveness requires that you remain on the drug in order to see the efficacy, and the best method to measure this is to use baseline observation carried forward.»
«Better would have been to use survival analytic methods to use the data that they had, for whatever period of time they had, rather than using a population that was used to impute missing values at primary time points. It would be very interesting to see the data on those who stayed in the trial. Another method to deal with missing data is to use the last data collected moved forward. That would have the advantage of preserving whatever benefit one had from the treatment.
«Topiramate is a difficult drug to take and has many side effects, dropouts are common in trials using this drug, but 80% dropout is quite excessive — usually dropouts are in the 60% range.»
In this trial, many patients could not remain on topiramate through week 36, the primary endpoint, Blumenfeld said. However, he disagreed with Jackson’s 60% estimate, saying «there is absolutely no published data to support this claim.»
Allergan funded the study. Blumenfeld reports he is a consultant for and receives honoraria for speaking and teaching from Allergan. Jackson has disclosed no relevant financial relationships.
American Headache Society (AHS) Annual Meeting 2018. Abstract IOR06. Presented June 30, 2018.
A Product Manager with expertise in pharma marketing and sales operations