A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind,published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other , which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.