By Chris Berrie
BRUSSELS, BELGIUM -- August 30, 2007 -- Topiramate, an anticonvulsant, provides prophylactic efficacy along with the expected safety profile for subjects who meet the International Headache Society (IHC) criteria as migraine sufferers, say researchers. Furthermore, the effective migraine prophylaxis achieved is largely maintained after termination of 6 months of prophylaxis.
The findings of this combination open-phase and randomised, double-blind trial were presented here on August 28 at the 11th Congress of the European Federation of Neurological Societies (EFNS) on behalf of the Prolonged Migraine Prevention with Topiramate (PROMPT) Study Group by Hans Christoph Diener, MD, PhD, Principal Investigator, Professor and Head, Department of Neurology, University Hospital of Essen, Essen, Germany.
Dr. Diener said, "Topiramate is approved for the prevention of migraine in most of the European countries, and as with all the preventive therapies, the label does not limit the duration of therapy of any of these preventive drugs." However, most of these countries have guidelines to limit topiramate use to 4 to 6 months. As there is no evidence from clinical studies to support the validity of this restriction, Dr. Diener explained that this was "why we set-up PROMPT, to address the issue of what happens when you terminate long-term preventive therapy."
The trial started with a 4- to 8-week prospective baseline phase with no preventive treatment for baseline migraine characteristics. This phase was followed by a 6-month open-label phase divided into month 1, up-titration (25 mg/day increments/week); months 2 to 5, flexible dosing (50-200 mg/day) for preferred doses; and month 6, fixed at the preferred dose.
Subjects were then randomised to placebo or topiramate in the double-blind phase, following the treatment profile determined for month 6. Finally, at week 52 (termination), there was a 1-week run-out phase.
The primary objective was to evaluate continued efficacy beyond 6 months of topiramate treatment in the prophylaxis of migraine, with secondary objectives of determining preferred topiramate doses and evaluation of use of acute medication.
The inclusion criteria required adults (18-80 years) who met IHC criteria for migraine to have a history of migraine for 1 year or longer. Subjects also had to have had 4 or more monthly migraine days in the previous 3 months and had to be capable of keeping records of their migraines. The exclusion criteria were based around recent prior use of various migraine prophylactics or other specific medications.
Of 818 subjects who entered the open-label phase (mean monthly migraine days, 8.9), 559 completed and 512 entered randomisation (mean monthly migraine days, 8.7) to either placebo (n = 258; mean age, 40.1 years; male, 11%; mean monthly migraine days, 4.6) or their previously decided topiramate dosing (n = 254; mean age, 40.1; male, 15%; mean monthly migraine days, 4.9). This double-blind phase was fully completed by 207 and 210 subjects, respectively.
The distribution of the modal daily topiramate dose established during the open-label phase showed a distinct preference for 100 mg/day (50%). As an intent-to-treat (ITT) analysis, topiramate saw a significant (P <.0001) -3.1 change in mean number of migraine days/4 weeks from baseline to the end of month 6.
For the primary efficacy parameter from the double-blind phase, the mean changes in number of migraine days in 4 weeks indicated significantly greater increments for topiramate withdrawal (from open-label topiramate to placebo) over continued topiramate treatment at most of the assessments. Also, there was no rebound effect seen on subjects randomised to placebo, whereby the number of migraine days in 4 weeks did not returned to baseline and remained similar to, and not significantly different from, those with continued active treatment.
At the primary endpoint for the last 4 weeks of the double-blind phase, the placebo group showed a continuing increase in the number of migraine days, which was not seen for those on active treatment (1.2 vs 0.1; P <.01). Of note, a "worry effect" was seen under continued topiramate use after randomisation, whereby there was a small increase in migraine days over the first assessments, probably provoked by patients' knowledge of the possibility of having their medication removed.
When acute medication intake was considered, the mean number of days in 4 weeks with any, triptan, or analgesic medications during both the open-label and double-blind phases paralleled closely the mean number of migraine days over the same periods, demonstrating a close link between migraine and use of acute medications. Again, there was a worry effect seen for those randomised to topiramate.
Consideration of safety data indicates that the overall prevalence of treatment-emergent adverse events (AEs) was similar across the changing treatment groups throughout this trial. These AEs were similar to those seen in previous topiramate studies, both in nature and frequency of occurrence.
Dr. Diener pointed out that progressive weight loss for all observed cases in the open-label phase that continued into the double-blind phase remained only for those on active treatment. The placebo group rapidly recovered lost weight, although they did not return to baseline within the duration of the trial.
Of note, Dr. Diener stressed that this first randomised trial investigating the effect of terminating migraine-preventive therapy has shown that "the bad news is, when you terminate prophylactic therapy, you get an increase in migraine frequency; the good news is, migraine frequency does not return to the original level, so you have a sustained treatment effect if you stop after 6 months."
This study was sponsored by Janssen-Cilag.
[Study Title: Prolonged Migraine Prevention With Topiramate (PROMPT). Abstract LBN105]
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