SEARCH

SEARCH BY CITATION

Keywords:

  • Adjunctive;
  • Antiepileptic;
  • Carisbamate;
  • Partial-onset seizures;
  • Uridine diphosphate glucuronosyltransferase

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Purpose: To assess the efficacy, safety, and tolerability of the investigational drug carisbamate as adjunctive treatment for partial-onset seizures (POS).

Methods: Two identical, randomized, placebo-controlled, double-blind studies were conducted in adults with POS uncontrolled for ≥1 year. Therapy-refractory epilepsy patients (≥16 years) remained on stable doses of prescribed antiepileptic drugs (≤2) for an 8-week prospective baseline phase and were then randomized (1:1:1) to carisbamate 200 mg/day, carisbamate 400 mg/day, or placebo, for a 12-week double-blind phase. Primary efficacy end points were percent reduction in seizure frequency and responder rate (patients with ≥50% reduction in POS frequency) during the double-blind phase compared with the prospective baseline phase.

Results: Of the 565 patients randomized in study 1, 93% completed the study; of the 562 randomized in study 2, 94% completed the study. Patient characteristics were similar across both studies and treatment arms: mean age, 35 years (study 1, range 16–75 years) and 36 years (study 2, range 16–74 years); approximately 50% were men. Treatment with carisbamate 400 mg/day resulted in significant improvement (p < 0.01) in both efficacy measures compared with placebo in study 1 but not in study 2. Carisbamate 200 mg/day did not differ statistically from placebo in either study. Among the most common treatment-emergent adverse events (≥5% in any group), those with an incidence exceeding placebo (≥3%) were dizziness (400 mg/day group) and somnolence.

Conclusions: Carisbamate 400 mg/day was effective in patients with refractory partial-onset seizures in one of these global studies. More than 200 mg/day of carisbamate is required for efficacy. Carisbamate was well-tolerated in both studies.

Because the addition of new antiepileptic drugs (AEDs) to the therapeutic armamentarium in the last decade has not significantly increased the proportion of patients whose seizures are well-controlled by medication, new treatments are needed (Brodie, 2001; Onat & Ozkara, 2004; Stacey & Litt, 2008). Carisbamate (S-2-O-carbamoyl-1-o-chlorophenyl-ethanol) is an investigational agent that displays highly potent anticonvulsant activity against a variety of seizure types in animal models (Francois et al., 2008; Grabenstatter & Dudek, 2008). It showed dose-dependent antiepileptogenic and neuroprotective properties in rodent models of amygdala kindling as well as a spontaneous seizure model after status epilepticus (Bialer et al., 2009). Although carisbamate has been reported to block voltage-gated sodium channels in preclinical models, additional mechanisms or targets may be contributing to the antiepileptic activity of carisbamate (Liu et al., 2009). Carisbamate has several characteristics that are sought in an AED; it is quickly absorbed, is only moderately bound to plasma proteins (approximately 40%), and has a half-life of approximately 12 h (in patients coadministered enzyme noninducing AEDs) (Yao et al., 2006). The pharmacokinetics of carisbamate together with its immediate-release formulation makes it suitable for twice-daily dosing (Yao et al., 2006). It is metabolized by uridine diphosphate glucuronosyltransferase (glucuronidation) and exhibits minimal first-pass hepatic metabolism (Yao et al., 2006). It does not appear to significantly alter serum concentrations of other AEDs, including lamotrigine, carbamazepine, and valproate (Chien et al., 2006, 2007). However, drug metabolism enzyme-inducing AEDs [phenytoin (54%), carbamazepine (49%), phenobarbital, or primidone (20%)] increase carisbamate clearance, resulting in shortened half-life of carisbamate (by approximately 3 h), thereby lowering carisbamate plasma concentrations (Novak et al., 2008; Chien et al., 2006).

A dose-ranging study conducted in more than 500 patients found that adjunctive carisbamate, in doses of 300, 800, and 1,600 mg/day, reduced seizure frequency compared with placebo (Faught et al., 2008). Carisbamate was well-tolerated, with modest increases in somnolence, dizziness, and nausea without adverse cognitive, behavioral, or psychiatric adverse effects, compared with placebo (Faught et al., 2008). Because significant efficacy was observed at 300 mg/day in this study, the present studies evaluated doses of either 200 or 400 mg daily with placebo in an effort to ascertain the minimum effective dose and to confirm efficacy in this dose range. We report here the findings from two identical pivotal phase 3 studies that were conducted to assess the efficacy, safety, and tolerability of carisbamate as adjunctive treatment for refractory partial epilepsy.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Patients

Men and women aged 16 years or older, weighing at least 35 kg, were eligible if they had a history of partial seizures for at least 1 year [using the International League Against Epilepsy (ILAE) criteria] that included simple partial seizures (SPS) with a motor component, complex partial seizures (CPS), or secondarily generalized seizures; had inadequate response to treatment with at least one AED (given at appropriate dosage) for a sufficient treatment period; and were receiving concomitant treatment with at least one and no more than two AEDs at stable doses, for at least 1 month prior to screening (and no new AEDs added for the previous 2 months).

Exclusion criteria were a history of: status epilepticus within the previous 6 months; generalized epileptic syndromes, including Lennox-Gastaut syndrome; patients whose only partial-onset seizure (POS) types were simple partial sensory, psychic, or other simple partial nonmotor seizures; history of nonepileptic seizures; seizures that could not be counted accurately; serious systemic disease, major psychiatric disease, or drug or alcohol abuse within 1 year of screening; felbamate treatment within 90 days; current vigabatrin treatment; or current treatment with vagal nerve stimulation for <12 months or discontinuation of vagal nerve stimulation within the preceding 3 months. Patients with progressive neurologic disorder, active central nervous system (CNS) infection, major psychotic disorders in the preceding 1 year, and exacerbation of major depression in the previous 6 months, were also excluded. Women were excluded if pregnant, nursing, or planning to become pregnant.

These studies were conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. All patients or their legally acceptable representatives provided written informed consent before entering the studies.

Study design, randomization, and blinding

These two identically designed, randomized, double-blind, placebo-controlled, parallel-group phase 3 studies (study 1 and study 2) were conducted from September 2006 through October 2007 (at 91 centers in 13 countries for study 1 and at 83 centers in 12 countries for study 2), in the United States, South America, Europe, and Asia.

The studies each consisted of three phases: pretreatment, double-blind treatment, and posttreatment phase. The pretreatment phase consisted of a screening period and an 8-week prospective baseline period. Patients with an occurrence of at least six POS, and no seizure-free intervals for more than 3 weeks during the 8-week baseline period, were randomized 1:1:1 to 12 weeks of double-blind treatment with placebo, carisbamate 200 mg/day, or carisbamate 400 mg/day (administered in two equally divided doses). Randomization was via a computer-generated scheme, balanced using permuted blocks across treatment groups, stratified by country, and implemented using an interactive voice-response system. After completing the 12-week double-blind treatment phase, patients either enrolled in an open-label extension study, or had a 2-week blinded-withdrawal taper from study drug followed by a posttreatment assessment 7 days after the last dose. The results through the double-blind treatment period for each study are reported here.

The assigned treatments were given without titration. During the first month of the treatment phase, investigators were permitted to implement a one-time dose reduction (to 200 mg/day) for patients in the carisbamate 400 mg/day group who experienced adverse effects. The treatment assignment remained blinded; patients receiving 200 mg/day or placebo remained on their originally assigned dosage. Carisbamate was formulated in tablets of 100 and 200 mg, with identical-appearing placebo comparators for each tablet size. Patients received two tablets of different sizes, twice daily. If the reduced dosage was not tolerated, the patient discontinued the study. Dosage reduction of concomitant AEDs because of elevated plasma levels of the AED or adverse effects was allowed no more than twice, once during the pretreatment phase and once during the double-blind treatment phase, based on the judgment of the investigator.

Criteria for evaluation

Efficacy assessments

The primary efficacy end points were the percent reduction in seizure frequency and the responder rate. The percent reduction in POS seizure frequency was the average monthly seizure rate per 28 days of all SPS motor, CPS, or secondarily generalized seizures during the double-blind treatment phase relative to the pretreatment baseline. The responder rate was calculated as the proportion of patients with ≥50% reduction from the pretreatment baseline in seizure frequency. Efficacy was evaluated based on seizure counts (assessed from patient diaries) obtained during the baseline period and during the double-blind treatment period.

Secondary efficacy end points were the percent reductions in frequency of the three partial-onset seizure types (SPS, CPS, or secondarily generalized seizures). Seizure freedom rates were also summarized.

Predefined subgroup analyses

The non–P450 enzyme uridine diphosphate glucuronosyltransferase can be induced by several AEDs, thus leading to an increased clearance of carisbamate. As a result, lower than expected plasma carisbamate concentrations may occur. To assess this potential effect, a predefined subgroup analysis by AED enzyme induction status was performed. Patients were categorized into two groups: (1) those receiving at least one of the “inducing” AEDs (carbamazepine, phenytoin, primidone, or phenobarbital) during the baseline phase (enzyme-inducing subgroup), and (2) all other patients (enzyme noninducing subgroup).

Safety and tolerability measures

Safety was evaluated by an assessment of treatment-emergent adverse events (TEAEs), laboratory tests, vital sign measurements, physical and neurologic examinations, and 12-lead electrocardiography.

Pharmacokinetic evaluations

The steady-state concentrations of carisbamate in plasma were determined from blood samples taken on days 15, 43, 57, and 85. The concentrations over the 12-h dosing interval were summarized using descriptive statistical analyses. On day 43, after completing half the double-blind treatment period (of 85 days), two blood samples were collected for determination of plasma concentrations of carisbamate; one was predose (trough) and other was postdose, approximately 2 h after study drug administration (peak). Trough plasma concentrations of each concomitant AED obtained during treatment (on day 43) were compared with those at baseline for the active and placebo treatment groups to assess the effect of carisbamate on these AEDs. Plasma levels of these AEDs were determined using a validated liquid chromatography–mass spectrometry/mass spectrometry method (PPD, Madison Laboratory, Madison, WI, U.S.A.). Plasma concentrations of carisbamate were determined using a validated liquid chromatography–mass spectrometry/mass spectrometry method (Global Preclinical Development, Beerse, Belgium).

Sample size calculations

It was estimated that 170 randomized patients per treatment group would provide 90% power to detect an 18% difference in reduction of seizure frequency between an active treatment group and placebo at a two-sided significance level of 0.05, assuming a standard deviation of 50%. For the responder rate, the estimated sample size provided 90% power to detect a 14% difference between an active dosage group and the placebo group at a two-sided significance level of 0.05, assuming a 10% responder rate in the placebo group.

Statistical analysis

The Wilcoxon rank sum test, stratified by country, was used to compare the treatment groups with placebo for the reduction in seizure frequency of all SPS, CPS, or secondarily generalized seizures, and the Cochran-Mantel-Haenszel test for nonzero correlation stratified by pooled country was used to compare the responder rates of all SPS, CPS, or secondarily generalized seizures. Both analyses followed a step-down procedure to ensure the type I error rate due to multiple treatment comparisons was controlled at the 5% level. Countries with zero responders or zero nonresponders in any of the treatment comparisons for the 50% responder rate were “pooled” along with another country with the most comparable median baseline POS frequency according to the prespecified pooling strategy. Percent reduction and responder rate were summarized for predefined subgroups based on enzyme induction status using summary statistics (n, median, range, and percentages). A post hoc analysis of the same data was used to determine p-values. For the secondary efficacy end points of percent reduction from the pretreatment baseline to the end of the double-blind phase in each of the POS types (SPS, CPS, and partial evolving to secondarily generalized seizures), the Wilcoxon rank-sum test (not stratified by country) was used to compare each treatment group and was compared with the placebo group at a two-sided 0.05 level. All statistical analyses were performed using the SAS version 9.2 (SAS Institute, Inc., Cary, NC, U.S.A.). Safety analyses were descriptive; no statistical analyses were prespecified or performed. There were no comparative analyses of results obtained for study 1 versus study 2.

Populations assessed

The intent-to-treat (ITT) population was the primary efficacy population, and included all randomized patients who had completed the seizure diary during both the baseline treatment phase and for at least one assessment during the double-blind treatment phase. The safety population consisted of all patients who had taken at least one dose of study medication.

Patients who were randomized but dropped out early without having provided the seizure diary during the double-blind phase were not included in the ITT population. There were four such patients in study 1, and seven in study 2. No imputations, such as the last observation carried forward approach, were applied to these patients; they were excluded from the analysis. Each ITT patient (including those lost to follow-up and other withdrawals) had a 28-day rate of seizures calculated for the entire double-blind phase.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Patient characteristics and disposition

In study 1, of the 713 patients screened, 565 (79%) were randomized, of whom 527 (93%) completed the study (Fig. 1A). In study 2, of the 721 patients screened, 562 (78%) were randomized, of whom 528 (94%) completed the study (Fig. 1B). In study 1, adverse events (AEs) were the main reason for study medication discontinuation in the carisbamate 400 mg/day (9 of 12 withdrawals), and placebo (seven of 15 withdrawals) groups, whereas withdrawal of consent was the main reason in the carisbamate 200 mg/day (5 of 11 withdrawals) group. For study 2, withdrawal of consent was the main reason for study medication discontinuation in the carisbamate 200 mg/day (5 of 12 withdrawals) and placebo groups (5 of 11 withdrawals), whereas AEs were the main reason in the carisbamate 400 mg/day group (6 of 11 withdrawals).

image

Figure 1.   (A) Study design and patient disposition for study 1 (all assessed patients set). All assessed patients set: includes all 713 patients who met entrance criteria and had completed the visit 1 assessments at day-56. *An additional two placebo patients had a premature discontinuation due to adverse events (AEs) and are included in the assessment of AEs leading to study discontinuation. **Other includes pregnancy, noncompliance with medication, noncompliance with study procedures, and episode of status epilepticus. (B) Study design and patient disposition for study 2 (All assessed patients set). All assessed patients set: Includes all 721 patients who met entrance criteria and had completed the visit 1 assessments at day-56. *An additional placebo patient had a premature discontinuation due to AEs and is included in the assessment of AEs leading to study discontinuation. **Other includes noncompliance with medication, noncompliance with study procedures, and episode of status epilepticus. CRS, carisbamate.

Download figure to PowerPoint

The demographic characteristics, background characteristics, and baseline epilepsy characteristics were comparable across treatment groups in both studies (Table 1). The patients had a mean age of 35 years (range 16–75 years) in study 1, and 36 years (range 16–74 years) in study 2. Most patients were either white (61% study 1, 53% study 2) or Asian (36% study 1, 46% study 2). At study entry, a majority of patients (69–77%) were receiving two concomitant AEDs and more than half of all patients were receiving enzyme-inducing AEDs (56% study 1, 61% study 2). In both studies, the concomitant enzyme-inducing AED most commonly used was carbamazepine (45%). The concomitant enzyme noninducing AEDs most commonly used were valproic acid (32%), lamotrigine (19%), and topiramate (16%).

Table 1.   Demographic and baseline characteristics for both the studies (intent-to-treat analysis set)
 PlaceboCRS 200 mgCRS 400 mg
Study 1Study 2Study 1Study 2Study 1Study 2
(N = 183)(N = 188)(N = 187)(N = 186)(N = 191)(N = 181)
  1. AED, antiepileptic drug; CRS, carisbamate; POS, partial-onset seizures; SD, standard deviation.

  2. aN = 186 in CRS 200 mg group – study 1, N = 187 in Placebo group – study 2.

  3. bN = 190 in CRS 400 mg group – study 1.

  4. cThree patients (one in CRS 200 mg group and two in CRS 400 mg group) received more than two concomitant AEDs in study 1.

Sex, n (%)
 Men85 (46)79 (42)92 (49)94 (51)105 (55)94 (52)
 Women98 (54)109 (58)95 (51)92 (49)86 (45)87 (48)
Race, n (%)a
 White109 (60)99 (53)117 (63)101 (54)117 (61)96 (53)
 Black or African American4 (2)01 (1)02 (1)2 (1)
 Asian65 (36)87 (47)66 (35)84 (45)70 (37)83 (46)
 Other5 (3)1 (1)2 (1)1 (1)2 (1)0
Age (years)
 Mean (SD)36 (13.06)36 (12.21)35 (12.11)36 (11.70)35 (12.87)35 (13.94)
Weight (kg)
 Mean (SD)70.0 (17.85)66.3 (14.92)69.2 (16.65)68.3 (16.78)69.3 (19.22)68.4 (17.98)
Time since epilepsy diagnosis  (years)
 Median (range)19.0 (1–55)16.0 (1–50)20.0 (1–52)15.0 (1–58)18.0b (1–57)16.0 (1–62)
AED enzyme induction subgroup, n (%)
 Enzyme-inducing94 (51)117 (62)113 (60)116 (62)106 (55)107 (59)
 Without enzyme-inducing89 (49)71 (38)74 (40)70 (38)85 (45)74 (41)
Number of prior reported AEDs
 Median (range)5.0 (1–24)4.0 (1–17)5.0 (1–17)4.0 (1–14)5.0 (1–21)4.0 (1–14)
Baseline monthly POS seizure  rate
 Median (range)8.50 (2.0–218.9)6.75 (2.5–260.4)9.50 (2.5–519.0)7.00 (2.0–274.2)8.40 (2.3–613.5)7.50 (2.0–258.2)
Number of concomitant  AEDs, n (%)c
 Patients with one Co-AED46 (25)62 (33)43 (23)61 (33)38 (20)48 (27)
 Patients with two Co-AEDs137 (75)126 (67)143 (76)125 (67)151 (79)133 (73)

Reduction in dose of carisbamate (≤8 patients) and the concomitant AEDs (≤5 patients) during the first month of the double-blind treatment period was infrequent and occurred with similar frequency in all three treatment groups in both the studies.

Primary efficacy findings

The median percent reduction from baseline to the double-blind phase in POS frequency was study 1: placebo (15.21), carisbamate 200 mg/day (16.44), carisbamate 400 mg/day (27.27); study 2: placebo (15.11), carisbamate 200 mg/day (21.59), and 400 mg/day (21.03). Overall, in study 1, the carisbamate 400 mg/day group showed a significant median percent reduction in POS frequency (p = 0.009), whereas the 200 mg/day group was not statistically different (p = 0.68) compared with placebo (Fig. 2A). In study 2, neither the carisbamate 200 mg/day group nor the carisbamate 400 mg/day group showed significant median percent reductions in POS frequency compared with placebo (p > 0.2 for both groups) (Fig. 2B).

image

Figure 2.   Median percent reduction in seizure frequency by seizure type (intent-to-treat analysis set). (A) Study 1. POS (partial-onset seizure) analyses included simple partial motor, complex partial, or secondarily generalized seizures. *Indicates the pairwise comparison of carisbamate 400 mg/day group versus placebo; p = 0.009 based on preplanned analysis of data using the Wilcoxon rank sum test stratified by country. **Indicates the pairwise comparison of carisbamate 400 mg/day group versus placebo; p = 0.002 based on preplanned analysis of data using the Wilcoxon rank sum test. (B) Study 2. POS analyses included simple partial motor, complex partial, or secondarily generalized seizures. CRS, carisbamate; POS, partial-onset seizures; SPS, simple partial seizures; CPS, complex partial seizures; SGS, secondarily generalized seizures.

Download figure to PowerPoint

In study 1, the responder rate (≥50% reduction) was 25% in the 200 mg/day group, 33% in the carisbamate 400 mg/day group (p < 0.001 vs. placebo), and 18% in the placebo group. In study 2, the responder rate was 23% in the 200 mg/day group, 24% in the 400 mg/day group, and 21% in the placebo group (no significant difference for either carisbamate 200 or 400 mg/day groups vs. placebo). Similar proportions of patients showed 100% reduction in seizures (seizure free) in carisbamate and the placebo treatment groups in each of the studies (study 1, 1–2%; study 2, 2–3%).

Secondary efficacy findings

At baseline, CPS was the most common seizure type. The proportion of patients who had seizures of each type was similar across treatment groups: CPS (study 1, 80%; study 2, 79%), secondarily generalized seizures (study 1, 37%; study 2, 43%), and SPS (study 1, 25%; study 2, 23%). In the analyses of individual seizure types, a significantly greater median percent reduction (p = 0.002) was noted for secondarily generalized seizures with the carisbamate 400 mg/day group, compared with the placebo group, in study 1 only (Fig. 2A,B). In addition, there was a trend of greater median percent reduction in secondarily generalized seizures for the carisbamate 200 mg/day groups in both the studies, in CPS for both carisbamate treatment groups in study 1 and in SPS for carisbamate 200 mg/day in study 2 versus placebo (Fig. 2A,B). The numbers of patients who actually had seizures of a given type were unequal, and were in all cases less than the total number of patients randomized. In addition, the monthly frequency differed for each seizure type. Therefore, the relative contributions of each seizure type to total POS were not equivalent, and each type comprised a different subpopulation; these limited comparisons or conclusions about efficacy of carisbamate among different seizure types.

Primary efficacy parameters, post hoc analysis

Based on post hoc analysis, a greater median percent reduction in POS frequency from baseline was observed in each study in the subgroup of patients concomitantly using enzyme noninducing enzyme AEDs (Fig. 3). In contrast, patients in the placebo group demonstrated similar median percent reductions in POS (approximately 15%) from baseline in both subgroups and in both studies. The difference in median percent reduction in POS frequency between the carisbamate 400 mg/day group and the placebo group in the enzyme noninducing subgroup reached statistical significance in study 1 (p = 0.003) but not in study 2 (Fig. 3). Similarly, among patients taking enzyme noninducing AEDs, there was a significantly higher percentage of responders in the carisbamate 400 mg/day group compared with the placebo group (38% vs. 17%, p = 0.002) in study 1 (but not in study 2) (Fig. 4).

image

Figure 3.   Median percent reduction from baseline to end of double-blind treatment period in partial onset seizure frequency by antiepileptic drug (AED) enzyme induction status (intent-to-treat analysis set). *Indicates the pairwise comparison of carisbamate 400 mg/day group versus placebo; p = 0.003 based on post hoc analysis of data using the Wilcoxon rank-sum test. CRS, carisbamate.

Download figure to PowerPoint

image

Figure 4.   Responder rate in double-blind treatment period by antiepileptic drug (AED) enzyme induction status for both the studies (intent-to-treat analysis set). *Indicates the pairwise comparison of carisbamate 400 mg/day group versus placebo; p = 0.002 based on post hoc analysis of data using the generalized Cochran-Mantel-Haenszel test for nonzero correlation. CRS, carisbamate.

Download figure to PowerPoint

Safety and tolerability findings

In both the studies, the incidence of all TEAEs (one or more) was similar between the placebo and carisbamate treatment groups (52–59% patients). Headache was the most frequently reported TEAE (in 12–15% patients in all treatment groups) (Fig. 5). Somnolence was the only TEAE that occurred at a higher percentage (≥3% difference vs. placebo) for both carisbamate groups [study 1: placebo (1%), carisbamate 200 mg/day (4%), carisbamate 400 mg/day (5%); study 2: placebo (4%), carisbamate 200 and 400 mg/day (9%)]. Dizziness occurred at a higher percentage (≥3% difference vs. placebo) in the carisbamate 400 mg/day group in both the studies [study 1: placebo (7%), carisbamate 400 mg/day (12%); study 2: placebo (7%), carisbamate 400 mg/day (13%)]. In both studies, most of the TEAEs were generally mild or moderate in severity.

image

Figure 5.   Treatment-emergent adverse events (AEs) in at least 5% of patients in any treatment group (safety analysis set). (A) Study 1. aRepresents an identical incidence rate for the CRS 200 mg/day and the CRS 400 mg/day groups for the event of nasopharyngitis. (B) Study 2. aRepresents an identical incidence rate for the CRS 200 mg/day and the CRS 400 mg/day groups for the event of somnolence. bRepresents an identical incidence rate for placebo and the CRS 400 mg/day group for the event of headache. TEAEs are listed from top to bottom in order of decreasing frequency overall. Plots show that incidence rates for carisbamate doses were largely similar to placebo. Dizziness and somnolence were slightly higher in at least one of the carisbamate groups than placebo. CRS, carisbamate.

Download figure to PowerPoint

There were no deaths reported in either study. The incidence of serious TEAEs and TEAEs leading to discontinuation was low and similar for carisbamate and placebo groups (<5% patients in all treatment groups, both studies). The most frequently reported serious TEAEs were worsening of epilepsy (1–2%) and status epilepticus (1%) in study 1. The overall rate of serious TEAEs was also low (≤1%) for all treatment groups in study 2. Few patients (≤1%) experienced TEAEs related to cognition, memory, and disturbances of attention.

There were no clinically significant effects on electrocardiography (including QTc intervals), vital signs, or laboratory assessments, except for two patients who had an alanine aminotransferase elevation (≥3 × upper limit of normal); both were in the carisbamate 400 mg/day group, one in each study (including one with acute hepatitis B infection in study 2).

Pharmacokinetic findings

The changes (with carisbamate on day 43 vs. without carisbamate at baseline) in mean trough concentrations of the concomitant AEDs were minimal (<20%) except for a 25% decrease for phenytoin with 200 mg/day carisbamate in study 1 (Table 2A). These changes were not likely to be clinically significant for the concomitant AEDs in either of the studies. The mean plasma carisbamate levels obtained in patients after 10–12 h of their last dose (steady state) were lower in patients receiving enzyme-inducing concomitant AEDs in both carisbamate groups in both studies (Table 2B).

Table 2.   Pharmacokinetic findings (pharmacokinetic analysis set)
(A) Trough plasma concentrations of select coadministered AEDs at steady state (pharmacokinetic analysis set)
 Study 1Study 2
PlaceboCRS 200 mgCRS 400 mgPlaceboCRS 200 mgCRS 400 mg
Day 1Day 43Day 1Day 43Day 1Day 43Day 1Day 43Day 1Day 43Day 1Day 43
Enzyme-inducing AEDs
Carbamazepine (μg/ml)
 N565571727074777371747371
 Mean6.897.357.327.247.787.967.267.206.826.787.276.94
 SD2.732.902.372.442.892.753.113.473.283.523.203.13
Phenytoin
 N141614141716212213162120
 Mean8.689.699.777.329.678.3812.411.313.112.313.513.2
 SD5.987.418.425.087.325.718.756.7010.19.4010.47.84
Phenobarbital (μg/ml)
 N8911121113211817191717
 Mean20.216.217.820.022.418.318.120.019.722.019.320.4
 SD12.1011.76.518.357.419.088.078.4712.7016.511.3012.50
Enzyme noninducing AEDs
Lamotrigine (μg/ml)
 N383932262429243129272524
 Mean5.395.607.496.025.284.885.305.775.565.135.044.47
 SD4.534.264.894.434.173.634.984.813.973.254.294.33
Topiramate (μg/ml)
 N262638343033161814152122
 Mean4.674.235.635.905.855.835.154.665.494.387.076.33
 SD4.443.454.995.053.103.073.433.323.523.505.124.97
Valproic acid (μg/ml)
 N555962595652434638414445
 Mean50.252.951.951.252.950.862.863.550.852.752.945.9
 SD35.3035.2029.8030.1027.027.6034.4033.8028.8028.3028.5027.60
(B) Plasma concentrations of carisbamate at steady state over a dosing interval
 Time after dosing (h)
0–22.01–44.01–66.01–88.01–1010.01–12
Study 1
200 mg/day without enzyme-inducing AEDs
 N76541071244
 Mean3.253.373.282.342.032.07
 SD1.21.31.261.330.610.78
200 mg/day with enzyme-inducing AEDs
 N1016624142697
 Mean2.342.312.441.941.161.16
 SD0.820.790.630.560.480.47
400 mg/day without enzyme-inducing AEDs
 N83561314754
 Mean6.746.504.266.263.303.95
 SD3.393.081.592.710.731.76
400 mg/day with enzyme-inducing AEDs
 N1006414142484
 Mean4.534.904.243.862.972.40
 SD1.781.790.791.151.491.21
Study 2
200 mg/day without enzyme-inducing AEDs
 N7435721473
 Mean3.313.193.112.271.921.93
 SD1.501.140.410.100.790.87
200 mg/day with enzyme-inducing AEDs
 N906613710101
 Mean2.272.341.871.361.331.38
 SD1.080.790.420.480.360.87
400 mg/day without enzyme-inducing AEDs
 N66311011163
 Mean5.816.065.532.414.493.52
 SD2.232.061.651.421.32
400 mg/day with enzyme-inducing AEDs
 N7753127281
 Mean4.864.714.693.033.862.59
 SD2.081.921.551.550.1061.60

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Carisbamate is a novel therapeutic agent currently in development for epilepsy and the treatment of neuropathic pain. Its efficacy in treating refractory patients with POS was initially demonstrated across a wide dose range (300–1,600 mg) in a phase 2 trial (Faught et al., 2008). The present phase 3 studies extend those findings, with further evidence in study 1 for efficacy of the 400-mg dose of carisbamate, and lack of efficacy for the 200-mg dose. These studies assessed a relatively low dose range (200 mg and 400 mg) for carisbamate. The present findings, and those of the earlier phase 2 study, suggest that a dose higher than 200 mg/day is required for efficacy (Faught et al., 2008). Indeed, doses higher than 400 mg/day may be needed in some individuals, given the lack of consistent effect demonstrated in the present analysis. The safety and tolerability findings of carisbamate in the current studies were consistent with those observed in previous studies, with no emergence of any new safety signals (Novak et al., 2007; Faught et al., 2008).

A major consideration for AED therapy is the propensity for drug–drug interactions, which can limit their role in the treatment of epilepsy (Bialer, 2006). In the present studies, introduction of carisbamate as adjunctive treatment to other AEDs did not alter their plasma concentrations in a clinically relevant way, which is consistent with data from earlier studies (Novak et al., 2007). Therefore, dose-adjustment of other AEDs is not required when carisbamate is added. In contrast, carisbamate metabolism can be enhanced with the coadministration of enzyme-inducing AEDs, thus increasing its clearance and lowering its serum concentrations (Novak et al., 2008). In a previous phase 2 study (Faught et al., 2008), however, there was no consistent clinical effect of enzyme induction status on efficacy detected across the dose range, and, hence, stratification or dose adjustment was not incorporated into the phase 3 study designs. Nevertheless, in the present studies, the differences in efficacy between the enzyme-inducing and enzyme noninducing AEDs were nominally in favor of the latter. Future studies need to be suitably designed to assess enzyme induction as a possible factor influencing clinical response to the drug (Glauser et al., 2006). The placebo response was the same in both studies.

The low rates of study discontinuation (Levy et al., 2008), as well as the low rates of cognitive, behavioral, or psychiatric adverse effects observed in these studies, further confirm the favorable tolerability profile of carisbamate (Faught et al., 2008). This favorable tolerability profile suggests that treatment with carisbamate may encourage treatment adherence, which in turn has been shown to improve seizure control, minimize adverse effects, enhance quality of life, and assure long-term safety (Cramer, 1995). Additional trials are needed to determine if this good tolerability profile is maintained at higher doses.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

RWJ-333369 (S-2-O-carbamoyl-1-o-chlorophenyl-ethanol) is a novel therapeutic agent, initially developed by SK Biopharmaceuticals, under development for the treatment of epilepsy.

Dr. Madhavi Patil (SIRO Clinpharm Pvt. Ltd.) provided writing assistance and Dr. Wendy P. Battisti (Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) provided additional editorial support for this manuscript. We thank Dr. Peter Zannikos (Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) for his contributions in support of the pharmacokinetic data.

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

We thank the following investigators for their participation in this study: Argentina: Herrera, Gustavo, M.D.; Mesri, Jacobo, M.D.; Palacios Claudio, M.D.; and Thomson, Alfredo, M.D. Australia: Berkovic, Sam, M.B.B.S. F.R.A.C.P.; Bleasel, Andrew, M.B.B.S. F.R.A.C.P.; Cook, Mark, M.B.B.S. F.R.A.C.P.; Mclaughlin, Daniel, M.B.B.S. F.R.A.C.P.; O`brien, Terrence, M.B.B.S. F.R.A.C.P.; and Somerville, Ernest, M.B.B.S. F.R.A.C.P. Croatia: Hajnsek, Sanja, M.D., Ph.D. and Lusic, Ivo, M.D., Ph.D. Czech Republic: Hon, Petr, M.D.; Hovorka, Jiri, M.D., Ph.D.; Kalina, Miroslav, M.D.; Marusic, Petr, M.D., Ph.D.; Muzikova, Alena, M.D.; Rektor, Ivan, M.D., Ph.D.; Vysata, Oldrich, M.D.; and Vyskocilova, Dana, M.D. Finland: Kalviainen, Reeta, M.D.; Koivisto, Keijo, D.Med.Sc.; and Peltola, Jukka, D.Med.Sc. Germany: Elger, Christian, M.D.; Hagemann, Georg, M.D.; Hufnagel, Andreas, M.D.; Lerche, Holger, M.D.; Meencke, Heinz Joachim, M.D.; Schmitz, Bettina, M.D.; and Steinhoff, Bernhard, M.D. India: Jain, Satish, M.D.; Kulkarni, Rahul, M.D.; Meena, Angamuthu Kanikannad, M.D.; Pandit, Lekha, M.D.; Ravat, Sangeeta, M.D.; Shah, Arun, M.B.B.S.; Singh, Maneesh Kumar, M.D.; and Singh, Gagandeep, M.D. Malaysia: Lim, Kheng Seang, M.B.B.S. M.R.C.P. and Viswanathan, Shanthi, M.B.B.S. M.C.R.P. People’s Republic of China: Ding, Meiping, M.D.; Hong, Zhen, M.D.; Wang, Yuping, M.D.; Zhao, Zhongxin, M.D.; and Zhou, Liemin, M.D. Republic of Korea: Hong, Seung Bong, M.D., Ph.D.; Kang, Joong Koo, M.D., Ph.D.; Lee, Byung-in; and Lee, Sang-kun, M.D., Ph.D. Russia: Avakyan, Gagik, M.D.; Barbarash, Olga, M.D., Ph.D.; Belova, Anna, M.D.; Grigoryeva, Elena, M.D., Ph.D.; Kalinin, Vladimir, M.D., Ph.D.; Maslova, Natalia, M.D.; Neznanov, Nikolay, M.D.; Petrukhin, Andrey, M.D.; Pizova, Natalia, M.D.; Poverennova, Irina, M.D.; Reshetko, Olga, M.D.; Suchkov, Yuri, M.D.; and Yakupov, Eduard, M.D. Sweden: Ben-menachem, Elinor, M.D., Ph.D.; Kallen, Kristina, M.D., Ph.D.; Landtblom, Anne-marie, M.D., Ph.D. and Tomson, Torbjorn, M.D., Ph.D. United States of America: Bell, William, M.D.; Brower, Richard, M.D.; Cochran, John, M.D.; Drazkowski, Joseph, M.D.; Friedman, Sheri, M.D.; Halford, Jonathan, M.D.; Harden, Cynthia, M.D.; Holmes, Gregory, M.D.; Imbus, Charles, M.D.; Inglese, Christopher, M.D.; Jackel, Roy, M.D.; Jacobson, Mercedes, M.D.; Kanner, Andres, M.D.; Kirzinger, Stephen, M.D.; Kudrow, David, M.D.; Labiner, David, M.D.; Moore, David, M.D.; Neer, Jody, M.D.; Rosenfeld, William, M.D.; Shah, Aash, M.D.; Sheth, Raj, M.D.; Shnekar, Bassel, M.D.; Sperling, Michael, M.D.; Todorov, Alexandre, M.D.; and Ziman, Ronald, M.D..

EPY 3002:Bulgaria: Ganeva, Guergana, M.D.; Minchev, Dimitar, M.D.; and Naydenov, Valcho, M.D. Canada: Arts, Rudolf, M.D.; Carlen, Peter, M.D.; Desbiens, Richard, M.D.; Mclachlan, Richard, M.D.; Schneiderman, Jacob, M.D. and Wiebe, Sam, M.D. Hong Kong: Kwan, Patrick, M.D. Hungary: Balogh, Attila; Csiba, László, M.D.; Csányi, Attila, M.D.; Horvath, ágnes, M.D.; Rajna, Péter, M.D.; Rásonyi, György, M.D.; and Sólyom, András, M.D. India: Murthy, Jagarlapudi Murali Krishna, M.D.; Prabhakar, Subhasini, M.D.; Shankar, Nellikunja, M.D.; Sinha, Sanjib, M.D.; Sridharan, Ramaratnam, M.D.; Srinivasa, Rangashetty, MBBS; Velmurugendran, Cungaiper, M.D.; Vengamma, Bhuma, MBBS Norway: Kristensen, Terje, M.D.; and Nakken, Karl Otto, M.D. PhD; People’s Republic of China: Liao, Weiping, M.D.; Wang, Xuefeng, M.D.; Wu, Liwen, M.D.; and Zhou, Dong, M.D. Poland: Blaszczyk, Barbara, M.D., Ph.D.; Chwedorowicz, Roman, M.D.; Czapinski, Piotr, M.D.; Czlonkowska, Anna, M.D.; Fryze, Waldemar, M.D., Ph.D.; Jedrzejczak, Joanna, M.D., Ph.D.; Kapustecki, Janusz, M.D., Ph.D.; Kazibutowska, Zofia, M.D.; Kleczkowska, Magdalena, M.D.; Kowalski, Jacek, M.D., Ph.D.; Pruchnik-wolinska, Danuta, M.D., Ph.D.; and Stelmasiak, Zbigniew, M.D. Taiwan: Hsieh, Pei-yuan, M.D., M.S.; Lai, Shung-lon, M.D., Ph.D.; Liou, Horng-huei, M.D., Ph.D.; Tsai, Jing-jane, M.D. Dr. Med.; Wu, Tony, M.D. MS; and Yen, Der-jen, M.D. M.S. Thailand: Boonyapisit, Kanokwan, M.D.; Chinvarun, Yotin, M.D., Ph.D.; and Tiamkao, Somsak, M.D. Ukraine: Bitenskyy, Valeriy, M.D. Ph.D.; Buchakchyys`ka, Natalia, M.D. Ph.D.; Demchenko, Vladislav, M.D.; Dubenko, Andriy, M.D. Ph.D.; Goloborodko, Alla, M.D. Ph.D.; Golubkov, Oleg, M.D. Ph.D.; Ipatov, Anatoliy, M.D. Ph.D.; Kharchuk, Sergey, M.D. Ph.D.; Lytovchenko, Tetyana, M.D. Ph.D.; Marienko, Lidiya, M.D. Ph.D.; Smolanka, Volodymyr, M.D. Ph.D.; Smolko, Nadiya, M.D. Ph.D.; Studzinskyy, Oleg, M.D. Ph.D.; and Verbenko, Viktoriya, M.D. Ph.D. United States of America: Abou-khalil, Bassell, M.D.; Brandes, Jan, M.D.; Burch, John, M.D.; Chung, Steven, M.D.; Fisch, Bruce, M.D.; Frucht, Michael, M.D.; Gurru, Mandher, M.D.; Herrman, Craig, M.D.; Ko, David, M.D.; Leroy, Robert, M.D.; Liow, Kore, M.D.; Penovich, Patricia, M.D.; Rogin, Joanne, M.D.; Shojaei-moghaddam, Jalil, M.D.; So, Norman K, M.D.; Syed, Athar, M.D.; and Van Orman, Colin, M.D..

Conflict of interest: Dr. Sperling and Ms. Cramer were consultants in the design of both the studies, and have received honoraria from Johnson & Johnson Pharmaceutical Research & Development, L.L.C. for consulting. Dr. Halford was a principal investigator for study 1 and has received honoraria from Johnson & Johnson Pharmaceutical Research & Development, L.L.C. for consulting. Dr. Patrick Kwan was a principal investigator for study 2, has provided advisory board service and participated in speakers’ bureau of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Dr. Kälviäinen was an investigator for study 1, has provided advisory board service and participated in speakers’ bureau of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Drs. Greenspan, Schmitt, Yuen, Haas and Novak are employed by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Dr. Cook received salary support through a contract between the University of Wisconsin and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Some of these data were previously presented at American Epilepsy Society, December 2008.

Registration: These studies are registered at http://www.clinicaltrials.gov: NCT 00425282 (study 1); NCT00433667 (study 2).

Study support: Funded by Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, U.S.A.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References