Levetiracetam Is Not Better than Older Antiepileptic Drugs as Initial Monotherapy for Newly Diagnosed Epilepsy
Abstract & Commentary
By Elayna Rubens, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Rubens reports no financial relationships relevant to this field of study.
Synopsis: In patients with newly diagnosed epilepsy, levetiracetam monotherapy was not superior to monotherapy with controlled-release carbamazepine or extended-release sodium valproate.
Source: Trinka E, et al. KOMET: An unblinded, randomized, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy. J Neurol Neurosurg Psychiatry 2013;84:1138-1147.
The development of newer antiepileptic drugs (aeds) has resulted in many new treatment options for patients with epilepsy. Despite the increasing number of choices, however, there is limited information to guide clinical selection of an AED, particularly in the common scenario of selecting a drug for initial monotherapy. The limitations of existing clinical trials of newer AEDs (small sample size, short follow-up duration, dose variation, adjunctive treatments, and limited patient population) make their results difficult to apply to everyday clinical practice. While many studies have shown that newer AEDs are efficacious in the treatment of seizures, their effectiveness as monotherapy compared to older AEDs is not well established. KOMET (Keppra against Older Monotherapy in Epilepsy Trial) attempts to compare, head-to-head, the effectiveness of levetiracetam (LEV) to that of controlled-release carbamazepine (CBZ) and extended-release sodium valproate (VPA). The study was designed to evaluate whether initial monotherapy with LEV is superior to treatment with either CBZ or VPA with the primary outcome measure of time to withdrawal of treatment (a measure of effectiveness reflecting both efficacy and tolerability).
KOMET is an industry-sponsored (UCB), unblinded, randomized, parallel-group, 52-week follow-up study that was conducted between February 2005 and October 2007 in 269 centers in Europe and Australia. Patients were aged 16 years and older, had two or more unprovoked seizures in the previous 2 years, and had at least one seizure in the previous 6 months. Exclusion criteria were prior treatment with LEV, CBZ or VPA, or any AED in the past 6 months. At the initial screening, clinicians decided whether a given patient would receive VPA or CBZ as the standard first-line treatment. Within each stratum (VPA or CBZ), the patients were randomized to receive either the standard AED or LEV. Initially, patients entered a 2-week titration period during which they received LEV 500 mg/day, VPA 500 mg/day, or CBZ 200 mg/day at first with uptitration to initial target doses LEV 1000 mg/day, VPA 1000 mg/day, and CBZ 600 mg/day. Further dose increases were permitted up to a predetermined maximum dose at the clinician’s discretion. Patients underwent an evaluation period of 52 weeks during which time seizures and adverse events were tracked and quality of life and health status questionnaires were completed. The primary outcome measure, time to withdrawal from study medication, was calculated from the time of randomization. Secondary outcome measures were time to first seizure as well as treatment withdrawal and seizure freedom rates at 6 and 12 months.
A total of 1688 patients were included in the study. For the primary outcome measure, time to withdrawal from study medication, there was no significant difference between LEV and standard AEDs when treatment strata were combined or analyzed separately. The time to first seizure was significantly longer for patients receiving standard AEDs than in those receiving LEV (hazard ratio 1.2; 95% confidence interval, 1.03-1.39). Analysis of the time to first seizure within each treatment stratum also favored the older AEDs, but the differences were not statistically significant. Seizure freedom rates at 6 and 12 months showed no difference between LEV and the older AEDs. The authors conclude from these findings that LEV is non-superior to both VPA and CBZ for monotherapy in patients with newly diagnosed epilepsy.
Commentary
Clinical trials of most of the newer-generation AEDs are adjunctive therapy trials wherein the newer medications were shown, against placebo, to be effective when added to existing AED treatment. Thus, many of the second-generation AEDs, including LEV, are approved in the United States only as add-on therapy. LEV is approved for use in the United States as an adjunctive treatment for partial-onset seizures in adults and children, myoclonic seizures in adolescents and adults with juvenile myoclonic epilepsy, and primary generalized tonic-clonic seizures in adults and children with idiopathic generalized epilepsy. However, in clinical practice, LEV is increasingly being used as monotherapy. The increasing off-label use is due to accumulated clinical experience, broad-spectrum efficacy, ease of use, tolerability, availability in IV formulation, few drug-drug interactions, and successful marketing of the drug by the pharmaceutical industry to doctors and patients. It has been assumed that LEV, given its adjunctive efficacy, will also work as monotherapy. This assumption needs to be systematically examined in long-term clinical monotherapy trials. KOMET attempts to do so, but falls short of providing a definitive answer regarding the effectiveness of LEV in monotherapy compared to older AEDs.
In order for an AED to obtain an indication for monotherapy in the United States, the FDA requires that the drug is determined to be superior to a placebo control. The placebo can take the form of an inactive placebo, suboptimal drug dose (also known as a "pseudoplacebo"), or, in some cases, historical controls. However, in the treatment of epilepsy, the gold standard placebo-controlled trial is ethically unacceptable since one group of patients would receive no or suboptimal treatment. To circumvent this ethical dilemma, active-control (head-to-head) comparison trials (like KOMET) that compare a new drug to an accepted treatment have been used to establish non-inferiority or superiority of the new drug. In other words, non-inferiority trials are designed to establish that the new drug is at least not worse than the old one, while superiority trials aim to show that one drug is better than another. Non-inferiority trials are used to establish monotherapy indications by regulatory bodies in Europe, but are not acceptable to the FDA due to questions of validity of comparing two active drugs that could be equally ineffective. Prior head-to-head comparison studies of older and newer AEDs have not shown significant differences in efficacy and typically have shown equal or slightly better tolerability of the newer AEDs.1 One previous randomized, double-blind, non-inferiority trial of LEV compared to CBZ in adults with newly diagnosed epilepsy showed that LEV was non-inferior to CBZ.2 This trial resulted in a monotherapy indication for LEV in Europe and offered reassurance to doctors and patients using LEV as off-label monotherapy.
KOMET, however, was not designed as a non-inferiority trial. KOMET is an active-control superiority trial. This distinction is important when interpreting the results of KOMET. Because there was no significant difference between LEV and the older AEDs, in this study the results can only be used to make the claim that Keppra is not better than the old AEDs. One cannot, on the other hand, use the results of KOMET to claim that LEV is the same or equally as good as the older AEDs. This conclusion would require a different data analysis and larger sample size. Unfortunately, the misinterpretation of a nonsignificant superiority trial such as KOMET to mean evidence of no difference between treatments is common.3 If LEV is non-inferior to the older AEDs, KOMET does not prove it. Therefore, further long-term monotherapy trials of the newer AEDs, including LEV, are necessary to better define their use in the clinical scenario of choosing an initial monotherapy for newly diagnosed epilepsy.
References
- French JA, Gazzola DM. Antiepileptic drug treatment: New drugs and new strategies. Continuuum (Minneap Minn) 2013;19:643-655.
- Brodie MJ, et al. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007;68:402-408.
- Lesaffre E. Superiority, equivalence and non-inferiority trials. Bull NYU Hosp Jt Dis 2008;66:150-154.
