Abstract
Objective: To evaluate the safety and efficacy of oxcarbazepine (OXC) 2,400 mg/day versus OXC 300 mg/day monotherapy in patients with medically refractory partial epilepsy.
Background: OXC is primarily metabolized by reductase enzymes and, consequently, has a low propensity to inhibit or induce oxidative enzymes and a minimal potential for drug–drug interactions. The efficacy of OXC as monotherapy was shown in several comparative trials in patients with newly diagnosed epilepsy and in hospitalized patients undergoing evaluation for epilepsy surgery.
Methods: A multicenter, double-blind, randomized, parallel-group trial design was chosen to assess the antiepileptic efficacy of OXC as monotherapy in a refractory epilepsy patient population. Outpatients aged 12 years or older with inadequately controlled partial seizures, with or without secondarily generalized seizures, were enrolled. Patients finished the trial by completing the double-blind phase or by meeting one of four predefined exit criteria: a twofold increase in partial seizure frequency in any 28-day period relative to baseline; a twofold increase in the highest consecutive 2-day partial seizure frequency relative to baseline; occurrence of a single generalized seizure if none occurred during the 6 months prior to randomization; or prolongation or worsening of generalized seizure duration or frequency requiring intervention. Adverse events (AEs), vital signs, and clinical laboratory tests were evaluated.
Results: The percentage of patients meeting one of the exit criteria was significantly lower (p < 0.0001) for the OXC 2400 mg/day group (14/34; 41%) than the OXC 300 mg/day group (42/45; 93%). In addition, there was a significant difference in time to exit in favor of the OXC 2400 mg/day group (p = 0.0001). In the intent-to-treat analysis, 12% of patients in the OXC 2400 mg/day group were seizure-free compared with none in the 300 mg/day group. OXC was well-tolerated, with dizziness, fatigue, somnolence, and nausea being the most frequent AEs. Most of these AEs were transient and rated as mild to moderate in intensity.
Conclusion: OXC is safe and effective in the treatment of patients with partial epilepsy previously receiving treatment with other antiepileptic drugs. The results of this trial are consistent with previous monotherapy trials with OXC.
Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]-azepine-5-carboxamide; GP 47680; Trileptal [Norvartis Pharma AG, Basle, Switzerland]; [OXC]) is an antiepileptic drug (AED) that is approved in more than 50 countries as monotherapy and adjunctive therapy for the treatment of partial seizures with or without secondarily generalized seizures, and generalized tonic-clonic seizures.
OXC is structurally related to carbamazepine with a similar spectrum of activity and anticonvulsant efficacy in animal models of seizures.1 However, unlike carbamazepine, phenytoin, and valproic acid, which undergo oxidative metabolism, OXC is extensively and rapidly metabolized by reduction to MHD (10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide; GP 47779), which is likely to be the major active component responsible for the pharmacologic effect of OXC.2 As a result, OXC has a low potential for induction of hepatic enzymes,3 and a low propensity for drug–drug interactions. The anticonvulsant properties of OXC are possibly mediated through effects on neuronal ion fluxes and specifically by blocking voltage-dependent sodium channels.4
Previous comparative monotherapy trials in patients with newly diagnosed epilepsy have shown that the efficacy of OXC was not different from that of phenytoin,5,6 valproic acid,7 and carbamazepine,8 with some advantages in tolerability over phenytoin and carbamazepine. The primary objective of this trial was to evaluate the safety and efficacy of OXC as monotherapy in patients with medically refractory partial epilepsy.
Methods.
Patients.
Patients at least 12 years of age and weighing at least 41 kg (90 pounds) with inadequately controlled partial seizures, which include the seizure subtypes of simple, complex, and partial seizures evolving to secondarily generalized seizures, maintained on one or two standard AEDs, were eligible for the trial. Plasma concentration of one of the AEDs (primary) had to be in the upper 50% of the therapeutic range or, if no therapeutic range was defined, the patient had to take a dosage above the recommended minimum effective dosage. If the patient was receiving a secondary AED, it had to be at less than 50% of the therapeutic range or recommended minimum effective dosage. Other requirements included an EEG consistent with localization-related epilepsy, a head CT scan or brain MRI exam confirming the absence of a progressive lesion, an EKG without clinically significant findings, and a serum sodium level ≥130 mmol/L. Pregnant or lactating women and women of childbearing potential not practicing adequate birth control were excluded from the trial.
Patients were also excluded from the study for the following reasons: a history of status epilepticus in the 3 months preceding randomization; intake of benzodiazepines on more than an occasional basis; intake of barbiturates at a dose of 15 mg/kg or greater; significant medical, psychiatric, or neurologic illness; nonepileptic seizures; simple partial seizures only; suspected substance or alcohol abuse within 12 months of randomization; participation in another investigational drug trial within 60 days of randomization; use of dihydropyridine calcium channel blockers or monoamine oxidase inhibitors; hypersensitivity to OXC or its metabolites; treatment with felbamate within 30 days prior to the Baseline Phase; history of OXC therapy; and history of noncompliance. The trial was conducted in accordance with the Declaration of Helsinki at nine centers in the United States between September 11, 1996 and October 1, 1997. The study protocol was approved by the institutional review board at each site, and each patient or the patient’s legal guardian provided written informed consent.
Study design.
This was a multicenter, randomized, double-blind, dosage-controlled, parallel-group trial comparing the efficacy and safety of two doses of OXC (300 mg/day and 2400 mg/day) administered as monotherapy. Randomization was on an individual basis from a computer-generated schedule. Allocation was made sequentially following a call to the central office. Patients were randomized to OXC 2400 mg/day or OXC 300 mg/day in a 1:1 ratio within each center and a block size of 4 was used. The study drug and placebo were supplied as tablets or matching placebo in blister cards. The investigator, site personnel, and sponsor personnel involved in the monitoring or conducting of the trial were blinded to the identity of the trial drug codes. Trial drug codes were not available to the above personnel until completion of the core trial and a clinical database lock was declared. Stopping rules were defined prospectively. They included the following: 1) pregnancy; 2) whenever the patient or the investigator decided that it was in the patient’s best interest; 3) intolerable adverse experiences; 4) development of any exclusion criteria; or 5) any major violation of the trial protocol.
The study included a 56-day baseline phase, followed by a 126-day double-blind treatment phase, which comprised a 14-day titration period and a 112-day maintenance period (figure 1). During the baseline phase, patients were maintained on a constant dosage of one or two AEDs. Patients were required to keep a seizure diary throughout the duration of the trial and to document the dates, times, and descriptions of their seizures. Seizures were classified according to the International League Against Epilepsy Commission on Classification.9 At each follow-up visit, patients were queried about adverse events (AEs). To qualify for advancement into the double-blind treatment phase, patients had to experience two to 40 seizures per 28-day period during the 56-day baseline phase. At the end of the baseline phase, qualifying patients were randomized to receive OXC 300 mg/day (150 mg twice/day) or 2400 mg/day (1200 mg twice/day) administered in two equally divided doses. Study medication was formulated as identical blinded capsules. Patients randomized to the OXC 300 mg/day group received a dosage of 300 mg/day throughout the double-blind treatment phase, beginning on day 1. Patients randomized to the OXC 2400 mg/day group received 1200 mg/day on days 1 through 7, 1800 mg/day on days 8 through 14, and 2400 mg/day on days 15 through 126. Patients were tapered and discontinued from their AED regimens over a 6-week period, beginning on day 1. On days 1, 8, and 15, the primary AED dosage was reduced by 25%. The primary AED dosage was maintained at 25% of the initial dosage between Days 15 and 42 and discontinued on day 43. For patients on two AEDs, the secondary AED was discontinued on day 1.
Figure 1. Trial design. OXC = oxcarbazepine; AEDs = antiepileptic drugs.
Patients unable to tolerate OXC at 2400 mg/day could have their dosage adjusted in a blinded fashion to 2100 mg/day or 1800 mg/day. No further downward dosage adjustment was permitted.
Exit criteria.
During the double-blind treatment phase, patients were required to exit the study if they experienced any of the following protocol-defined exit events: 1) a twofold increase in partial seizure frequency in any 28-day period compared to baseline; 2) a twofold increase in the highest consecutive 2-day seizure frequency that occurred during the baseline phase (patients with a single seizure as the highest 2-day baseline phase seizure frequency exited the trial if three or more seizures occurred during any 2-day period in the double-blind treatment phase); 3) occurrence of a single generalized seizure if none had occurred in the 6 months prior to randomization; or 4) a prolongation or worsening of seizure duration or frequency considered by the investigator to require intervention. Discontinuations for any other reason, including AEs, were considered premature discontinuations. Patients who completed the double-blind treatment phase or who met one of the protocol-defined exit criteria could participate in the open-label extension phase.
Efficacy variables.
The primary efficacy variable was the percentage of patients meeting one of the exit criteria. The secondary efficacy variable was the time to meeting one of the exit criteria.
Safety.
Safety was assessed on the basis of AEs, physical and neurologic examinations, vital signs, and clinical laboratory tests. AEs were rated as mild, moderate, or severe, and their relationship to OXC was assessed by the investigator. The International Medical Nomenclature/International Therapy Dictionary was used to categorize AEs.
Statistical analysis.
A sample size of 42 patients per treatment group was calculated to achieve 90% power to detect a 40% difference between the 2400 mg/day and 300 mg/day OXC treatment groups with a two-sided t-test at a significance level of 0.05. All randomized patients who received at least one dose of the trial medication were included in the efficacy analysis. The primary statistical analysis for the percentage of patients meeting one of the exit criteria was based on a Cochran-Mantel-Haenzel test controlling for center. The statistical analysis for time to meeting one of the exit criteria was based on the log-rank test, and Kaplan-Meier estimates were computed. In the analysis of the time to meeting one of the exit criteria for patients who discontinued prematurely due to adverse events (n = 6) or laboratory abnormalities (n = 1), the censoring time was imputed as the date of the last dose of double-blind trial medication. Therefore the time of withdrawal used in the analysis for those patients was calculated as (date of last dose of trial medication − date of first dose of trial medication) + 1.
Results.
Patient characteristics.
A total of 87 patients were randomized to double-blind treatment (46 to OXC 300 mg/day; 41 to OXC 2400 mg/day) (figure 2). The baseline characteristics for all randomized patients are shown in table 1. Comparison of patient characteristics between the two dosage groups showed no significant differences. There was no significant difference in baseline partial seizure frequency between the two treatment groups (Wilcoxon’s rank sum test; p = 0.217). During the 6 months prior to randomization, 28 (32%) of the patients experienced secondarily generalized seizures. No patient was discontinued from the trial due to protocol violations.
Figure 2. Discontinuation/completion summary. If the highest consecutive 2-day seizure frequency was during the baseline phase, three or more seizures were required to occur in the highest 2-day consecutive period during the double-blind treatment phase. OXC = oxcarbazepine.
Baseline characteristics for all randomized patients
Efficacy variables.
All 87 randomized patients were included in the intent-to-treat analysis for the efficacy analyses. However, eight patients who prematurely discontinued the study medication were excluded from the frequency distribution. The primary efficacy variable—the percentage of patients meeting one of the exit criteria—was significantly lower (p < 0.0001) for the OXC 2400 mg/day treatment group 14/34 (41.2%) relative to the OXC 300 mg/day treatment group 42/45 (93.3%) (figure 3). The reasons for study exit for each dosage group are summarized in figure 2. A worst-case analysis, in which all patients in the 2400 mg/day group who prematurely discontinued were considered to have met exit criteria and in which all patients in the 300 mg/day group who prematurely discontinued were considered to have successfully completed the trial, was still significantly in favor of the 2400 mg/day group (p < 0.0001).
Figure 3. Between-treatment comparison for the percentage of patients meeting one of the exit criteria. OXC = oxcarbazepine.
The secondary efficacy variable, the time to meeting one of the exit criteria, was also significantly in favor of the OXC 2400 mg/day group (p = 0.0001). In the OXC 2400 mg/day group, because fewer than 50% of the patients met one of the exit criteria, the median time to exit could not be computed. In comparison, the median time to meeting one of the exit criteria was 26 days for the OXC 300 mg/day group (figure 4). In addition, a Cox’s proportional hazards regression model was fitted to analyze time to meeting one of the exit criteria using center, sex, age, and baseline partial seizure frequency per 28 days as covariates. The treatment effect was still highly significant in this model (χ2 = 33.135 and p < 0.0001). Baseline partial seizure frequency was not significant in this model (p = 0.1273).
Figure 4. Between-treatment comparison for time to meeting one of the exit criteria (intent-to-treat patients). OXC = oxcarbazepine.
In the intent-to-treat analysis for the OXC 2400 mg/day group, 42% of patients had at least a 50% reduction in seizures and 12% were seizure-free, compared with 7% and 0% respectively, for the 300 mg/day group.
Safety.
Data from all 87 patients randomized to the double-blind treatment phase were included in the safety analyses. The frequency of AEs related to the study drug and reported by at least 10% of the patients during the double-blind treatment phase are shown in table 2. Most of these AEs were rated as mild to moderate in intensity and were typically transient.
Most frequent (≥10%) treatment-related adverse events
The most common treatment-limiting AEs were in the nervous system (dizziness, headache, and somnolence) and digestive system (nausea and vomiting). Six patients in the OXC 2400 mg/day group (6/41; 14.6%) and one patient in the OXC 300 mg/day group (1/46; 2.2%) were discontinued prematurely due to AEs during the double-blind treatment phase. All of these discontinuations occurred prior to reaching OXC monotherapy during the tapering of baseline AEDs.
Three patients (3/46; 6.5%) in the OXC 300 mg/day group and two patients (2/41; 4.9%) in the OXC 2400 mg/day group experienced serious AEs during the double-blind treatment phase. For two patients in the OXC 300 mg/day group, the serious AEs consisted of hospitalization for increased seizures; the third patient experienced postictal psychosis. In the OXC 2400 mg/day group, one patient (1/41; 2.4%) experienced angina and an exacerbation of congestive heart failure accompanied by hyponatremia and ataxia. The other patient in this group experienced a rib fracture and hemothorax after a fall. The postictal psychosis and ataxia were the only serious AEs considered trial–drug-related.
With one exception, clinically relevant laboratory abnormalities were not observed in either dosage group during the double-blind treatment phase. The mean serum sodium levels at the termination visit were 138.7 mmol/L in the high OXC dosage group and 139.8 mmol/L in the low OXC dosage group. The mean changes in sodium levels between baseline and termination were −1.9 mmol/L in the high OXC dosage group and 0.1 mmol/L in the low OXC dosage group. One patient (1/41; 2.4%) in the OXC 2400 mg/day group also receiving carbamazepine was discontinued from the study after 10 days of double-blind therapy. At baseline, the sodium level in this patient was 137 mmol/L. On day 10 of therapy, the sodium level was reduced to 121 mmol/L and the patient was discontinued from OXC treatment. Four days later, the serum sodium was 131 mmol/L. There were no deaths reported during the baseline phase or double-blind treatment phase of this trial.
Discussion.
The results of this double-blind, randomized clinical trial clearly demonstrate the anticonvulsant properties of OXC as monotherapy for the treatment of partial seizures. Fifty-nine percent of patients randomized to the OXC 2400 mg/day group completed the trial without meeting exit criteria, compared to 7% of those randomized to the OXC 300 mg/day group. The efficacy results remained significant even when assuming a worst-case analysis, in which all premature discontinuations in the 2400 mg/day group were considered to have met exit criteria and all patients in the 300 mg/day group who prematurely discontinued were considered to have successfully completed the trial. The results of time to exit were concordant with a significant difference favoring patients randomized to the 2400 mg/day group. Although previous comparative trials have shown that the efficacy of OXC is not different from that of standard AEDs for patients with newly diagnosed epilepsy, these equivalency trials do not satisfy U.S. regulatory requirements for efficacy.10 In this trial, the efficacy of OXC was demonstrated using a dosage-controlled trial, which incorporated protocol-defined exit criteria to maintain patient safety. At the time this study was designed, there was no available information on the minimum effective dosage of OXC as monotherapy. However, results from an add-on clinical trial with OXC in patients with medically refractory partial epilepsy (OT/PE1 study) demonstrated that 600 mg/day was the minimum effective dosage as adjunctive therapy.11 Because the clearance of OXC is known to increase by up to 40% in the presence of drugs such as carbamazepine and phenytoin, it was expected that the plasma levels attained with 300 mg OXC as monotherapy would be comparable to those achieved with 600 mg as adjunctive therapy. This was essentially the case, as the mean plasma level of the 300 mg/day OXC group in our trial (18.2 mol/L) was similar to the mean of 18.4 mol/L obtained in the 600 mg/day group of the OT/PE1 study.11,12
The design of monotherapy trials in evaluating the potential efficacy of a new AED for the treatment of patients with epilepsy has become a contentious issue, as evidenced by the recent editorial about this subject.15 Proponents of active control trials, in which the efficacy of a study drug is compared to that of a standard AED, use as their primary argument the declaration of Helsinki, which states that “In any medical study, every patient—including those of a control group, if any—should be assured of the best proven diagnosis and therapeutic method.” Conversely, supporters of therapeutic failure designs correctly point out that equivalency results are open to a number of interpretations, and that the only way to unequivocally establish the efficacy of a study drug is by demonstrating its statistical superiority against an internal control. A number of arguments and counter arguments can be made for both positions, ranging from ethical and safety issues to the scientific validity of the trial designs. Although some of those have been recently addressed,13-15 the complexity of this issue requires a fuller discussion in an editorial format. The shortcomings of the declaration of Helsinki, including its provisions regarding the control group in clinical trials and its need for revisions have been recently discussed.16 This has led to a number of proposed amendments of the declaration, including one in which the aforementioned wording has been changed to “patients should not be denied access to care that would otherwise be available to them.”17 Aside from the declaration of Helsinki, the design of monotherapy trials in the United States is in very large part dictated by the requirement of the Food and Drug Administration. This regulatory agency has made it clear that the only acceptable evidence of efficacy of a study drug is the proof of its statistical superiority over an internal control.10 Previous monotherapy trials planned for regulatory approval were all therapeutic failure designs18 with incorporated strict individualized exit criteria in order to protect patients and minimize morbidity.19-28 It is also important to note that patients who participated in this trial were highly refractory to medical treatment and have previously failed treatment with the available AEDs, as monotherapy or in combination.
The safety and efficacy of OXC was previously evaluated in four comparative, multicenter, randomized clinical trials versus phenytoin,5,6 valproic acid,7 and carbamazepine,8 in patients with newly diagnosed epilepsy. The trials consisted of an 8-week titration period followed by a 48-week maintenance period. Efficacy variables consisted of mean seizure frequency per week and percentage of seizure-free patients during the Maintenance Period. OXC was found not to differ in efficacy to phenytoin in children, adolescents, and adults,5,6 and was found not to differ in efficacy to valproic acid7 and carbamazepine8 in adults. OXC was, however, significantly better tolerated than either phenytoin5,6 or carbamazepine.8 The average daily OXC dosage in those trials averaged approximately 1000 mg, which is lower than the daily dosage of 2400 mg in the current trial, and which reflects the different patient populations under evaluation. The patients who were randomized in the current trial had medically refractory partial epilepsy with a median seizure frequency of 8 per 28 days despite treatment with one or two AEDs.
The short-term efficacy of OXC as monotherapy in patients with refractory partial epilepsy was demonstrated in a multicenter, double-blind, randomized, placebo-controlled inpatient trial in patients undergoing evaluation for epilepsy surgery.12 Eligible patients were randomized to treatment with OXC (1200 mg twice/day) or placebo, and remained in the trial for a total duration of 10 days or until they experienced protocol-defined exit criteria. A total of 102 patients were randomized in this trial. The time to meeting an exit criteria and the percentage of patients meeting an exit criteria were both significantly in favor of OXC.
The results of this trial showed that OXC was well-tolerated and that it can be rapidly titrated to 2400 mg over 14 days without compromising safety. The most common AEs in the 2400 mg/day group were dizziness, fatigue, headache, somnolence, nausea, and vomiting. Most of these AEs were rated as mild to moderate in severity and were transient in nature, with tolerance developing in the majority of patients. Although six patients in the 2400 mg/day withdrew because of AEs, this could have been due partly to AED load or pharmacodynamic interactions, as all these patients withdrew during the conversion period, when they were still being tapered from their baseline AEDs. No patient withdrew from the trial during monotherapy treatment with OXC.
No patient met the criteria for having a lowered plasma sodium level of clinical relevance (i.e., <125 mmol/L) on consecutive visits during the double-blind treatment phase. However, one patient in the 2400 mg/day group discontinued double-blind treatment because of a serum sodium of 121 mmol/L on a single determination. Lowered plasma levels of sodium have been previously reported in a small number of patients receiving OXC treatment. In all reported cases, serum sodium levels returned toward normal with dosage adjustment or discontinuation. Although hyponatremia has been reported, it is only in very rare cases accompanied by clinical symptomatology. Experience from clinical trials has shown that the incidence of two or more consecutive serum values less than 125 mmol/L was 0.41%. Serum sodium levels returned to normal when the OXC dosage was reduced, discontinued, or the patient’s fluid intake was restricted.13
Acknowledgments
Supported by a grant from Novartis Pharmaceutical Corporation, East Hanover, NJ.
Appendix. Additional investigators in this trial included the following: J. Hulihan, MD, Department of Neurology, Temple University Hospital, Philadelphia, PA; C. Lai, MD, Department of Neurology, University of Kansas Medical Center, Kansas City, KS; D. Nathanson, MD, Sacred Heart Hospital, Allentown, PA; M.D. Privitera, MD, Department of Neurology, University of Cincinnati Medical Center, Cincinnati, OH; M. Sperling, MD, Jefferson Epilepsy Center, Thomas Jefferson University Hospital, Philadelphia, PA; and D. Bennett, PhD, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Footnotes
-
See also page 2237
- Received June 7, 1999.
- Accepted March 13, 2000.
References
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