New drug works well as sole epilepsy therapy for difficult-to-treat patients

June 25, 2000

Research led by researchers at the University of Michigan suggests oxcarbazepine may provide new hope to those who have failed on other medications

ANN ARBOR, MI -- New results of a study led by a University of Michigan neurologist demonstrate that a drug called oxcarbazepine is safe and effective enough to be used alone in patients with partial epilepsy who do not respond to other anti-epileptic drugs.

The study, published in the current issue of the journal Neurology, looked at the safety and efficacy of the compound in trials at the U-M and several other sites. It compared the results of treatment with a dose of 300 milligrams per day with results from a dose of 2,400 mg/day.

"Patients participating in this study were averaging eight seizures a month despite treatment with other antiepileptic drugs," says Ahmad Beydoun, M.D., associate professor of neurology and director of the Comprehensive Epilepsy Center at the U-M Health System. "The results are particularly encouraging as this difficult-to-treat population responded well to Trileptal, with 12 percent of patients in the 2400 mg/day group remaining seizure-free during the four-month trial."

The research was sponsored by Novartis Pharmaceutical Corporation, which makes oxcarbazepine as Trileptal. The drug was approved in January by the Food and Drug Administration, partly on the basis of the findings of this trial.

More than 2.3 million American children and adults have some form of epilepsy, and approximately 181,000 new cases of the neurological disorder are diagnosed each year. Epilepsy costs the United States approximately $12.5 billion per year in direct (healthcare and related) and indirect (lost income) expenses.

One of its most common symptoms is the seizure, which occurs when certain brain cells release too much electrical energy and trigger a sudden loss of control over movement, thought or awareness. The most common type of seizure, occurring in up to 70 percent of seizure disorders, is a partial seizure, which begins in a localized area of the brain. Secondarily generalized seizures begin in one area of the brain and then spread throughout the brain. Drugs can often control epilepsy's symptoms, but as many as 20 percent do not respond to treatment.

Trial Design and Results

The multicenter, double-blind, randomized, dose-controlled, parallel-group trial led by the U-M compared the safety and efficacy of Trileptal administered as monotherapy, the only therapy patients received. It enrolled 87 outpatients as young as 12 with inadequately controlled partial seizures, whether or not they had secondarily generalized seizures.

The study included a 56-day baseline phase, during which patients were maintained on a constant dose of the one or two antiepileptic drugs they had been taking prior to enrollment. To qualify for advancement into the double-blind treatment phase, patients had to experience 2 to 40 seizures per 28-day period during the baseline evaluation. Qualifying patients were then tapered off of their existing drug regimen and treated only with either the 300 mg/day or 2,400 mg/day dose of oxcarbazepine.

Despite their failure to respond to other antiepileptic drugs, 42 percent of patients in the 2,400 mg/day group had at least a 50 percent reduction in seizures and 12 percent were seizure-free, compared with 7 percent and 0 percent respectively for the 300 mg/day group.

Patients in the higher-dose group were far less likely than those in the lower-dose group to leave the trial because their seizures increased in frequency or duration. Less than half of the patients receiving 2,400 mg/day met one of the defined "exit criteria", while more than 90 percent of patients on the lower dose left the trial before completing the double-blind phase, most often after receiving the lower dose for slightly less than a month.

Exit criteria during the double-blind treatment phase included: Safety & Tolerability

"In epilepsy drug therapy, tolerability and efficacy are often closely related," says Dr. Beydoun. "One of the challenges in treating this disorder are the side effects associated with the standard antiepileptic drugs - many patients have difficulty attaining seizure control with these medications simply because they cannot tolerate them at higher doses. The great majority of patients in this trial reached the highest recommended dose of Trileptal, which may partly explain the efficacy results and seizure-free rates observed during the trial."

Six of the 41 patients in the 2,400 mg/day treatment group and one of the 46 patients in the 300 mg/day treatment group discontinued prematurely due to side effects; however, all of these discontinuations occurred while patients were still taking tapered doses of their baseline antiepileptic drugs in addition to Trileptal.

The most common treatment-limiting side effects were in the nervous system (dizziness, headache, and somnolence) and digestive system (nausea and vomiting). One patient in the 2,400 mg/day treatment group also receiving carbamazepine was discontinued from the study after 10-days of double-blind treatment because of low serum sodium levels.

Most side effects observed during the double-blind treatment phase of the trial were mild to moderate in severity and transient.

The efficacy of Trileptal as monotherapy has also been demonstrated in patients with all levels of severity of seizures, including several comparative trials which ranged from patients newly diagnosed with epilepsy to hospitalized patients undergoing evaluation for epilepsy surgery.

The medication is indicated for the treatment of partial seizures as monotherapy in adults or adjunctive therapy (use in combination with other antiepileptic drugs) in adults and children as young as four years of age.
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The University of Michigan Health System, which served as the lead site for this trial, comprises the U-M Medical School, three hospitals and dozens of health centers, the M-CARE managed care organization, and numerous outpatient specialty clinics including the Comprehensive Epilepsy Center. Patients and physicians may find out more about the center at http://www.med.umich.edu/1libr/epilepsy/ or by calling 734-936-7310.




University of Michigan Health System

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