One-year results from the PREVAIL OLE extension trial discuss the safety and efficacy of topiramate for refractory partial onset seizures.
One-year results from the PREVAIL-OLE extension trial have shown that adjunctive treatment with extended release topiramate (USL255, Qudexy® XR, Upsher-Smith, Maple Grove, MN) is safe and effective in adults with refractory partial-onset seizures.
“These data suggest that once-daily USL255, Qudexy® XR (topiramate) extended-release capsules, may be a safe and beneficial treatment option for the long-term management of epilepsy in a variety of adult patients with POS [partial onset seizures],” wrote first author Steve Chung, MD, of Banner University Medical Center, (Phoenix, AZ), and colleagues.
“[T]he long-term evaluation of USL255 in an open-label setting, which allows for dosage adjustments to both USL255 and concomitant AEDs [antiepileptic drugs], provides safety and efficacy data that better reflect clinical practice,” they added.
Extended release formulations may reduce breakthrough seizures by decreasing dose frequency and maintaining more consistent drug blood levels. Extended release topiramate provides overall drug blood levels similar to immediate release topiramate, but with a more narrow maximum and minimum concentration window, according to background information in the article.
The study, called PREVAIL OLE, was an open-label one-year extension phase of the 11-week double-blind randomized placebo-controlled phase 3 PREVAIL trial, which took place from October 2010 to March 2014 at 54 study sites in 15 countries.
The extension phase included 97% of participants who completed PREVAIL. Participants had hard to treat seizures: 74% were on at least two concomitant antiepileptic drugs and the mean duration of epilepsy was 21 years. PREVAIL OLE consisted of a 3-week blinded conversion phase in which patients who had previously received placebo were switched to topiramate extended release, and a 52-week open-label phase. Participants received extended release topiramate 200 mg/day, titrated up as needed to a maximum dose of 400 mg/day.
Researchers evaluated improvement in seizure frequency (median percent reduction from baseline), responder rate, and seizure-free intervals. They also assessed provider-reported Global Impression of Changes (seizure frequency, severity, adverse events, and overall functioning) and patient reported Quality of Life in Epilepsy.
Key results for the 55-week extension period:
• 71% completion rate, with discontinuation mostly due to voluntary withdrawal (11%) and adverse effects (9.5%)
• Treatment emergent adverse events:
♦ Reported by 69.5% of participants, 90% of which were mild or moderate
♦ Most common adverse events were headache, weight decrease, somnolence, dizziness, aphasia, and fatigue
♦ Low individual neurocognitive treatment emergent adverse events: Reported by <3% of participants, aphasia reported by 5.2%
♦ No reports of metabolic acidosis, kidney stones, decreased sweating, or increased body temperature
♦ No suicidal behavior, though one patient reported suicidal ideation
• Sustained seizure reduction:
♦ 58% had at least 50% reduction in seizure frequency
♦ 5% had 100% response
♦ Relatively consistent seizure reduction across time, and for subgroups including those with highly drug-resistant seizures and older patients (≥50 years)
• Seizure-free intervals:
♦ 4 weeks: 51%
♦ 12 weeks: 19%
♦ 24 weeks: 11%
♦ 36 weeks: 7.2%
♦ 48 weeks: 2.4%
• Global impression of changes and quality of life scores also improved
Even though participants could increase their dosage to a maximum of 400 mg/day, most stayed below 300 mg/day, suggesting that the optimal maintenance adjunctive dose may be 200-275 mg/day, the authors noted.
They also pointed out that the study’s open label design could hinder evaluation of long-term efficacy and introduce bias from patients aware of which drug they received. Also, the study could not control for the effects of concomitant medications.
Nevertheless, they concluded: “Overall, the results of this 1-year PREVAIL OLE demonstrate that adjunctive treatment with up to 400 mg/day of USL255 has a favorable safety and tolerability profile in adults with refractory POS. USL255 led to reductions in seizure frequency that were similar at each phase of the year-long study suggestive of efficacy that is consistent and long-lasting.”
• The open-label year-long extension phase of the PREVAIL OLE trial of adjunctive treatment with extended release topiramate in adults with refractory partial-onset seizures found sustained seizure reduction across time, even in highly drug-resistant and older patients.
• Most treatment emergent adverse events were mild or moderate, and there was a low rate of individual neurocognitive treatment emergent adverse events.
• Results suggest that extended release topiramate may have consistent and long-lasting efficacy in patients with partial onset seizures.
Reference: Chung SS, et al. Long-term safety and sustained efficacy of USL255 (topiramate extended-release capsules) in patients with refractory partial-onset seizures. Epilepsy Behav. 2016 Apr 13;59:13-20.