Cindy McShea

Long‐term safety and efficacy in patients with uncontrolled partial‐onset seizures treated with adjunctive lacosamide: Results from a phase III open‐label extension trial

Purpose:  To evaluate the long‐term (up to 5 years exposure) safety and efficacy of lacosamide as adjunctive therapy in patients with uncontrolled partial‐onset seizures taking one to three concomitant antiepileptic drugs (AEDs) in open‐label extension trial SP756 (NCT00522275).

Safety and efficacy of adjunctive lacosamide among patients with partial-onset seizures in a long-term open-label extension trial of up to 8 years

Long-term (up to 8 years of exposure) safety and efficacy of the antiepileptic drug lacosamide was evaluated in this open-label extension trial (SP615 [ClinicalTrials.gov identifier: NCT00552305]). Patients were enrolled following participation in a double-blind trial or one of two open-label trials of adjunctive lacosamide for partial-onset seizures. Dosage adjustments of lacosamide (100-800 mg/day) and/or concomitant antiepileptic drugs were allowed to optimize tolerability and seizure reduction. Of the 370 enrolled patients, 77%, 51%, and 39% had >1, >3, or >5 years of lacosamide exposure, respectively. Median lacosamide modal dose was 400mg/day. Common treatment-emergent adverse events (TEAEs) were dizziness (39.7%), headache (20.8%), nausea (17.3%), diplopia (17.0%), fatigue (16.5%), upper respiratory tract infection (16.5%), nasopharyngitis (16.2%), and contusion (15.4%). Dizziness (2.2%) was the only TEAE that led to discontinuation in >2% of patients. Ranges for median percent reductions in seizure frequency were 47-65%, and those for ≥ 50% responder rates were 49-63% for 1-, 3-, and 5-year completer cohorts. Exposure to lacosamide for up to 8 years was generally well tolerated, with a safety profile similar to previous double-blind trials, and efficacy was maintained.

Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: A double-blind, randomised, multicentre, historical control study

This double-blind, randomised, multicentre, conversion to monotherapy, historical control study (N01280; NCT00419094) evaluated the efficacy, safety and tolerability of levetiracetam extended release (LEV XR) 2000mg/day once daily for the treatment of patients with partial-onset seizures compared with a historical control. Patients aged 12-75 years with 2-40 partial-onset seizures per 4 weeks, taking 1-2 antiepileptic drugs (AEDs) and receiving a stable dosage for ≥4 weeks prior to screening were randomised in a 3:1 ratio to LEV XR 2000 or 1000 mg/day. The study comprised baseline (8 weeks), LEV XR up-titration (2 weeks), baseline AED tapering (6 weeks), LEV XR monotherapy (10 weeks), and entry into open-label follow-up study or down-titration (1 week). The primary efficacy variable was the cumulative exit rate at Day 112 due to predefined exit criteria compared with the historical control. Of the 171 patients randomised to LEV XR 2000 mg/day and 57 randomised to 1000 mg/day, 141 (82.5%) and 50 (87.7%) completed the study. The cumulative exit rate for patients on LEV XR 2000 mg/day (0.375 [95% CI 0.297, 0.453]) was significantly lower than historical control (0.653). Both LEV doses were well tolerated. The most common adverse events during the treatment period were somnolence (21.9%), headache (19.7%) and convulsion (14.9%).

Long-term adjunctive lacosamide treatment in patients with partial-onset seizures.

To evaluate long‐term (up to 5.5 years) safety, seizure reduction, and maintenance of efficacy of the antiepileptic drug (AED) lacosamide as adjunctive treatment in an open‐label extension trial (SP774; ClinicalTrials.gov: NCT00515619).

Levetiracetam extended release for the treatment of patients with partial-onset seizures: A long-term, open-label follow-up study

This was an open-label study (N01281 [NCT00419393]) assessing the long-term safety of extended-release levetiracetam (LEV XR) in patients with partial-onset seizures (POS); the study was a follow-up to a double-blind, randomized, historical controlled, multicenter, conversion to monotherapy study (N01280 [NCT00419094]). Eligible patients initially received LEV XR 2000 mg/day; dose adjustments and the addition of other antiepileptic drugs (AEDs) were permitted. Overall, 190 patients were enrolled, 189 (99.5%) received LEV XR (safety and efficacy populations) and 166 patients (87.4%) completed the study. The study duration in completed patients was 5.5-24.6 months. Mean daily dose of LEV XR was 2131 mg/day. Treatment-emergent adverse events (TEAEs) occurred in 126 patients (66.7%); most were of mild or moderate severity. Five patients (2.6%) had a TEAE that led to treatment discontinuation. Treatment-emergent serious adverse events occurred in 22 patients (11.6%). Twenty-six patients (13.8%) experienced a psychiatric TEAE. The median 7-day normalized POS frequency was: 1.38 at N01280 study baseline; 0.50 at the first visit of N01281 (last visit of N01280); and 0.00-0.36 between all subsequent visits. Overall, 171 patients (90.5%) entered the N01281 study on LEV XR monotherapy; 65.3% (32/49) of patients remained on monotherapy for 12 months and 47.1% (8/17) for 18 months. While remaining on LEV XR monotherapy, 27/139 patients (19.4%) were seizure-free at 6 months and 8/49 (16.3%) at 12 months. In conclusion, LEV XR was well tolerated when administered as long-term monotherapy or in combination with other AEDs in patients with inadequately controlled POS.

Conversion to brivaracetam monotherapy for the treatment of patients with focal seizures: Two double-blind, randomized, multicenter, historical control, Phase III studies

Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) approved for monotherapy (in the USA) and adjunctive treatment of focal (partial-onset) seizures in adults, at a dose range of 50-200 mg/day taken in two equal doses, with a recommended starting dose of 100 mg/day. Two Phase III, randomized, double-blind, multicenter, historical-controlled, conversion-to-monotherapy studies (N01276, NCT00698581; N01306, NCT00699283) were conducted to evaluate the efficacy, safety, and tolerability of conversion to BRV 50 mg/day monotherapy in adults with uncontrolled focal seizures. Patients aged 16-75 years, with 2-40 focal seizures per 4 weeks during an 8-week baseline, and on stable doses of 1-2 AEDs were enrolled. Patients were randomized to BRV 50 or 100 mg/day (3:1) in two equal doses without titration. The treatment period comprised 1-week BRV add-on, 8-week baseline AED tapering, and 8-week BRV monotherapy periods. Primary efficacy endpoint was Kaplan-Meier estimate of the cumulative exit rate due to pre-defined exit criteria at Day 112 (50 mg/day, efficacy population). The upper 95% confidence interval (CI) was compared with the historical control threshold (0.722). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs; intent-to-treat population). After randomization of 150 patients (N01276: 88; N01306: 62), both studies were terminated due to the confounding effects of a higher-than-expected discontinuation rate. For BRV 50 mg/day, ≥1 exit criterion was met by 26/67 (38.8%) patients (study N01276) and 18/45 (40.0%) patients (study N01306). In both studies, the cumulative exit rate was lower than the historical control threshold (N01276: 0.487, 95% CI 0.347, 0.626; N01306: 0.474, 95% CI 0.310, 0.638). However, with maximum 10% censoring due to early withdrawal (sensitivity analysis), cumulative exit rates were above historical control (N01276: 0.652, 95% CI 0.532, 0.772; N01306: 0.704, 95% CI 0.563, 0.844). Overall incidence of TEAEs was 110/150, 73.3% (treatment period); 78/147, 53.1% (baseline AED tapering period); 41/84, 48.8% (BRV monotherapy period). In conclusion, BRV 50 mg/day monotherapy demonstrated an exit rate lower than historical control. Results should be interpreted with caution as, following termination of both studies, patient numbers were too low to evaluate the efficacy of BRV monotherapy. These are the first published safety and tolerability data for BRV monotherapy. Monotherapy was well tolerated, with a relatively low incidence of TEAEs, though this should be interpreted with the caveat that the majority of common TEAEs were likely to have occurred earlier in the course of treatment with BRV. No new safety concerns were identified, supporting the favorable safety profile of BRV observed in adjunctive studies.