Aptiom (Page 6 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a two-year carcinogenicity study in mice, eslicarbazepine acetate was administered orally at doses of 100, 250, and 600 mg/kg/day. An increase in the incidence of hepatocellular adenomas and carcinomas was observed at 250 and 600 mg/kg/day in males and at 600 mg/kg/day in females. The dose not associated with an increase in tumors (100 mg/kg/day) is less than the MRHD (1600 mg/day for monotherapy) on a mg/m2 basis.

Mutagenesis

Eslicarbazepine acetate and eslicarbazepine were not mutagenic in the in vitro Ames assay. In in vitro assays in mammalian cells, eslicarbazepine acetate and eslicarbazepine were not clastogenic in human peripheral blood lymphocytes; however, eslicarbazepine acetate was clastogenic in Chinese hamster ovary (CHO) cells, with and without metabolic activation. Eslicarbazepine acetate was positive in the in vitro mouse lymphoma tk assay in the absence of metabolic activation. Eslicarbazepine acetate was not clastogenic in the in vivo mouse micronucleus assay.

Impairment of Fertility

When eslicarbazepine acetate (150, 350, and 650 mg/kg/day) was orally administered to male and female mice prior to and throughout the mating period, and continuing in females to gestation day 6, there was an increase in embryolethality at all doses. The lowest dose tested is less than the MRHD on a mg/m2 basis.

When eslicarbazepine acetate (65, 125, 250 mg/kg/day) was orally administered to male and female rats prior to and throughout the mating period, and continuing in females to implantation, lengthening of the estrus cycle was observed at the highest dose tested. The data in rats are of uncertain relevance to humans because of differences in metabolic profile between species.

14 CLINICAL STUDIES

14.1 Monotherapy for Partial-Onset Seizures

The effectiveness of APTIOM as monotherapy for partial-onset seizures was established in two identical, dose-blinded historical control trials in a total of 365 patients with epilepsy (Study 1 and Study 2). In these trials, patients were randomized in a 2:1 ratio to receive either APTIOM 1600 mg or 1200 mg once daily, and their responses were compared to those of a historical control group. The historical control methodology is described in a publication by French et al. [see References (15)]. The historical control consisted of a pooled analysis of the control groups from 8 trials of similar design, which utilized a subtherapeutic dose of an AED as a comparator. Statistical superiority to the historical control was considered to be demonstrated if the upper limit from a 2-sided 95% confidence interval for the percentage of patients meeting exit criteria in patients receiving APTIOM remained below the lower 95% prediction interval of 65% derived from the historical control data.

In Study 1 and Study 2, patients ≥16 years of age experienced at least 4 seizures during the baseline period with no 28-day seizure free period while receiving 1 or 2 AEDs (both could not be sodium-channel blocking drugs, and at least one AED was limited to 2/3 of a typical dose). APTIOM was titrated over a 1- to 2-week period followed by the gradual withdrawal of the background AED over a 6-week period, followed by a 10-week monotherapy period.

The exit criteria were one or more of the following: (1) an episode of status epilepticus, (2) emergence of a generalized tonic-clonic seizure in patients who had not had one in the past 6 months, (3) doubling of average monthly seizure count during any 28 consecutive days, (4) doubling of highest consecutive 2-day seizure frequency during the entire treatment phase, or (5) worsening of seizure severity considered by the investigator to require intervention. The primary endpoint was the cumulative 112-day exit rate in the efficacy population. Additionally, in Studies 1 and 2, if the discontinuation rate exceeded 10%, patients were randomly reassigned to be counted as exits.

The most commonly used baseline AEDs were carbamazepine, levetiracetam, valproic acid, and lamotrigine. Oxcarbazepine was used as a baseline AED in 6.6% of patients.

In Study 1, the Kaplan-Meier (K-M) estimate of the percentage of patients meeting at least 1 exit criterion was 29% (95% CI: 21%, 38%) in the 1600 mg group and 44% (95% CI 33%, 58%) in the 1200 mg group. In Study 2, the K-M estimate of the percentage of patients meeting at least 1 exit criterion was 13% (95% CI: 8%, 22%) in the 1600 mg group and 16% (95% CI: 8%, 29%) in the 1200 mg group. The upper limit of the 2-sided 95% CI of both doses in both trials were below the threshold of 65% derived from the historical control data, meeting the pre-specified criteria for efficacy (see Figure 4).

Figure 4: Kaplan-Meier Estimates of Cumulative 112-Day Exit Rates for Studies 1 and 2

Figure 4
(click image for full-size original)

14.2 Adjunctive Therapy for Partial-Onset Seizures

The efficacy of APTIOM as adjunctive therapy in partial-onset seizures was established in three randomized, double-blind, placebo-controlled, multicenter trials in adult patients with epilepsy (Study 3, Study 4, and Study 5). Patients enrolled had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs. During an 8-week baseline period, patients were required to have an average of ≥4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days. In these three trials, patients had a median duration of epilepsy of 19 years and a median baseline seizure frequency of 8 seizures per 28 days. Two-thirds (69%) of subjects used 2 concomitant AEDs and 28% used 1 concomitant AED. The most commonly used AEDs were carbamazepine (50%), lamotrigine (24%), valproic acid (21%), and levetiracetam (18%). Oxcarbazepine was not allowed as a concomitant AED.

Studies 3 and 4 compared dosages of APTIOM 400, 800, and 1200 mg once daily with placebo. Study 5 compared dosages of APTIOM 800 and 1200 mg once daily with placebo. In all three trials, following an 8-week Baseline Phase, which established a baseline seizure frequency, subjects were randomized to a treatment arm. Patients entered a treatment period consisting of an initial titration phase (2 weeks), and a subsequent maintenance phase (12 weeks). The specific titration schedule differed amongst the three studies. Thus, patients were started on a daily dose of 400 mg or 800 mg and subsequently increased by 400 mg/day following one or two weeks, until the final daily target dose was achieved.

The standardized seizure frequency during the Maintenance Phase over 28 days was the primary efficacy endpoint in all three trials. Table 5 presents the results for the primary endpoint, as well as the secondary endpoint of percent reduction from baseline in seizure frequency. The APTIOM treatment at 400 mg/day was studied in Studies 3 and 4 and did not show significant treatment effect. A statistically significant effect was observed with APTIOM treatment at doses of 800 mg/day in Studies 3 and 4, but not in Study 5, and at doses of 1200 mg/day in all 3 studies.

Table 5: Standardized Seizure Frequency During the Maintenance Phase Over 28 Days and Percent Reduction from Baseline in Seizure Frequency
Placebo APTIOM
800 mg 1200 mg

*statistically significant compared to placebo

Study 3
N 95 88 87
Seizure Frequency (LS Mean seizures per 28 days)(p-value) 6.6 5.0(0.047*) 4.3(0.001*)
Median Percent Reduction from Baseline in Seizure Frequency (%) -15 -36 -39
Study 4
N 99 87 81
Seizure Frequency (LS Mean seizures per 28 days)(p-value) 8.6 6.2(0.006*) 6.6(0.042*)
Median Percent Reduction from Baseline in Seizure Frequency (%) -6 -33 -28
Study 5
N 212 200 184
Seizure Frequency (LS Mean seizures per 28 days)(p-value) 7.9 6.5(0.058) 6.0(0.004*)
Median Percent Reduction from Baseline in Seizure Frequency (%) -22 -30 -36

Figure 5 shows changes from baseline in the 28-day total partial seizure frequency by category of reduction in seizure frequency from baseline for patients treated with APTIOM and placebo in an integrated analysis across the three clinical trials. Patients in whom the seizure frequency increased are shown to the left as “Worse.” Patients in whom the seizure frequency decreased are shown in four categories.

Figure 5: Proportion of Patients by Category of Seizure Reduction for APTIOM and Placebo Across All Three Double-blind Trials

Figure 5
(click image for full-size original)

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