The
PER
a
M
panel pooled analys
I
s of effec
T
iveness and tolerability (PERMIT) study was a pooled analysis of data from 44 real-world studies from 17 countries, in which people with epilepsy (PWE; ...focal and generalized) were treated with perampanel (PER). Retention and effectiveness were assessed after 3, 6, and 12 months, and at the last visit (last observation carried forward). Effectiveness assessments included 50% responder rate (≥ 50% reduction in seizure frequency from baseline) and seizure freedom rate (no seizures since at least the prior visit); in PWE with status epilepticus, response was defined as seizures under control. Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs. The Full Analysis Set included 5193 PWE. Retention, effectiveness and safety/tolerability were assessed in 4721, 4392 and 4617, respectively. Retention on PER treatment at 3, 6, and 12 months was 90.5%, 79.8%, and 64.2%, respectively. Mean retention time on PER treatment was 10.8 months. The 50% responder rate was 58.3% at 12 months and 50.0% at the last visit, and the corresponding seizure freedom rates were 23.2% and 20.5%, respectively; 52.7% of PWE with status epilepticus responded to PER treatment. Overall, 49.9% of PWE reported AEs and the most frequently reported AEs (≥ 5% of PWE) were dizziness/vertigo (15.2%), somnolence (10.6%), irritability (8.4%), and behavioral disorders (5.4%). At 12 months, 17.6% of PWEs had discontinued due to AEs. PERMIT demonstrated that PER is effective and generally well tolerated when used to treat people with focal and/or generalized epilepsy in everyday clinical practice.
Carbamazepine (CBZ), oxcarbazepine (OXC), and eslicarbazepine acetate (ESL) belong to the dibenzazepine family of antiepileptic drugs and are all thought to primarily act as sodium channel blockers ...(SCBs). However, ESL is structurally distinct from CBZ and OXC, resulting in differences in metabolism, pharmacokinetics, and pharmacodynamics. Despite a lack of direct comparative data, evidence for potential differences in effectiveness and tolerability within the dibenzazepine family has emerged from studies in which patients being treated with one dibenzazepine agent have received adjunctive treatment with another (having achieved insufficient seizure control with the first) or have transitioned from one dibenzazepine agent to another because of lack of effectiveness or poor tolerability. Most of these studies have been conducted in the real-world clinical practice setting. ESL has been shown to be effective as adjunctive therapy in patients who have previously achieved inadequate seizure control with CBZ, indicating that the use of different dibenzazepine agents in combination can provide additive effectiveness benefits, which may reflect underlying differences in their mechanisms of action. Similarly, ESL monotherapy can be effective in patients who have switched from another dibenzazepine, such as CBZ or OXC, because of inadequate efficacy. There is also considerable evidence to demonstrate that patients transitioning from OXC or CBZ to ESL as a result of adverse events experience improvements in tolerability, which may also be associated with improvements in quality of life, alertness, and/or lipid profiles. Current evidence therefore demonstrates that ESL differs from other dibenzazepine agents in terms of effectiveness and tolerability.
Funding:
Eisai Ltd.
Introduction
Clinical practice studies help guide antiepileptic drug (AED) therapy in patient groups routinely excluded from clinical trials, such as the elderly. The Euro-Esli study investigated the ...effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) when used in everyday clinical practice in Europe. A subanalysis of data from elderly patients (≥ 60 years) included in the Euro-Esli study was conducted to assess these aspects of ESL use in this population.
Methods
Euro-Esli was a pooled analysis of 14 European clinical practice studies. Effectiveness parameters included responder (≥ 50% seizure frequency reduction) and seizure freedom rates after 3, 6 and 12 months of treatment and at last visit. Safety and tolerability were assessed throughout the follow-up by evaluating adverse events (AEs) and ESL discontinuation due to AEs, respectively. Data were compared for patients aged ≥ 60 versus those aged < 60 years at study entry.
Results
Euro-Esli included 2058 patients (mean age 44.0 years). Age at study entry was known for 2057 patients, of whom 358 (17.4%) and 1699 (82.6%) were aged ≥ 60 and < 60 years, respectively. Mean maximum ESL dose was 882.0 and 1008.2 mg/day in patients aged ≥ 60 and < 60 years, respectively (
p
< 0.001). At all timepoints, responder and seizure freedom rates were significantly higher in patients aged ≥ 60 versus < 60 years; for example, at 12 months, responder rates were 83.9 and 73.7%, respectively (
p
= 0.002), and seizure freedom rates were 58.5 and 37.1%, respectively (
p
< 0.001). The incidence of AEs was significantly higher in patients aged ≥ 60 versus < 60 years (41.4 vs. 32.5%;
p
= 0.001), but the rate of discontinuation due to AEs was comparable between age groups (16.2 vs 13.1%;
p
= not significant). The safety/tolerability of ESL in patients aged ≥ 60 years was consistent with its known profile.
Conclusion
Eslicarbazepine acetate was efficacious and generally well tolerated when used to treat elderly patients with focal epilepsy in clinical practice, with no new or unexpected safety signals emerging in this setting.
Funding
Eisai Ltd.
The PERMIT study is the largest pooled analysis of perampanel (PER) clinical practice data conducted to date.
This
analysis of PERMIT investigated the effectiveness, safety and tolerability of PER ...when used as early add-on therapy (after failure of one or two previous antiseizure medications) in comparison with late add-on therapy (after failure of three or more previous antiseizure medications). Retention and effectiveness were assessed after 3, 6, and 12 months, and at the last visit (last observation carried forward). Effectiveness was assessed by seizure type (total seizures, focal seizures, generalized tonic-clonic seizures GTCS) and assessments included seizure freedom rate and responder rate. Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs.
The Full Analysis Set included 1184 and 2861 PWE treated with PER as early and late add-on therapy, respectively. Compared to the late add-on subgroup, the early add-on subgroup was characterized by later mean age at epilepsy onset, shorter mean duration of epilepsy, lower rates of intellectual disability and psychiatric comorbidity, and lower frequency of seizures per month, suggesting a less severe form of epilepsy in this subgroup. After 12 months, retention was significantly higher in the early versus late add-on subgroup (67.7% vs. 62.4%;
= 0.004). At the last visit, responder rates in the early versus late add-on subgroup were significantly higher for total seizures (68.2% vs. 39.3%;
< 0.001), focal seizures (65.0% vs. 36.8%;
< 0.001) and GTCS (83.7% vs. 67.2%;
< 0.001), as were seizure freedom rates (total seizures, 35.9% vs. 11.9%
< 0.001; focal seizures, 29.4% vs. 8.7%
< 0.001; GTCS, 69.0% vs. 48.1%
< 0.001). Incidence of AEs was significantly lower in the early versus late add-on subgroup (42.1% vs. 54.7%;
< 0.001), as was the rate of discontinuation due to AEs over 12 months (15.0% vs. 18.1%;
= 0.031).
This study demonstrated that PER was effective and generally well tolerated when initiated as early or late add-on therapy, but it was significantly more effective and better tolerated when initiated early. These findings support PER's use as a broad-spectrum, early add-on therapy for use in PWE with focal and generalized seizures.
Summary
Objective
Drug development for patients with Lennox‐Gastaut syndrome (LGS) is based on clinical trials that use drop seizure counts. However, such counts do not assess total seizure burden ...and affect a patient's quality of life (QoL). In this post hoc analysis, we evaluated two novel seizure efficacy parameters related to QoL in pediatric patients with LGS, using seizure diary data from rufinamide Study 303 (NCT01405053).
Methods
Study 303 was a phase III, multicenter, randomized, controlled, open‐label study involving patients aged ≥1 to <4 years with inadequately controlled LGS. Patients were randomized 2:1 to receive add‐on therapy with rufinamide or any other approved antiseizure drug (ASD), in addition to their existing treatment of 1‐3 ASDs, across a 106‐week treatment phase. Seizure diaries, completed by parents or caregivers, recorded seizure occurrence, and were used in this post hoc analysis to evaluate two novel efficacy parameters comparing baseline vs postbaseline mean number of seizure‐free days and assessing time to reach the number of prerandomization seizures for patients receiving rufinamide or any other ASD.
Results
Patients received rufinamide (n = 25) or any other ASD (n = 12). For rufinamide, mean number of seizure‐free days was 42.2% greater postbaseline compared with baseline (P < 0.0001); only one rufinamide patient experienced a decrease in number of seizure‐free days postbaseline. Median time to reach the baseline number of seizures increased by 10.5 days for rufinamide and 0.5 days for the any‐other‐ASD group during the treatment phase, to 46.0 and 54.0 days, respectively.
Significance
Both of these novel and contrasting endpoints demonstrated potential improvements in seizure outcomes in patients receiving rufinamide postbaseline vs baseline. Although these parameters should be investigated in larger patient populations, our initial findings suggest that they could be applied as predefined primary endpoints for seizure assessment in future clinical trials for LGS drug development.
Introduction
Management of Lennox–Gastaut syndrome (LGS) in adulthood can be particularly challenging. Published reports describing the use of rufinamide specifically in adult patients with LGS are ...scarce. A post hoc subgroup analysis of data from a phase III trial was conducted to investigate the efficacy and safety/tolerability of rufinamide in adults with LGS.
Methods
A randomized, double-blind, placebo-controlled trial was conducted in patients with LGS, aged 4 years and above. During an 84-day, double-blind treatment period, patients received either adjunctive rufinamide therapy or placebo. Efficacy and safety/tolerability were assessed in a post hoc subgroup analysis of adult patients (≥18 years). Efficacy was assessed as change from baseline in 28-day seizure frequency, 50% responder rate, and seizure freedom rate; each calculated for total seizures and drop attacks. Safety/tolerability assessments included the evaluation of adverse events (AEs).
Results
Thirty-one adults aged 18–37 years with LGS received treatment with either rufinamide (
n
= 21) or placebo (
n
= 10). Three patients in the rufinamide group did not complete the trial. The median change from baseline in seizure frequency was −31.5% for rufinamide versus +22.1% for placebo (
P
= 0.008) for all seizures and −54.9% versus +21.7% (
P
= 0.002) for drop attacks. Responder rates were 33.3% for rufinamide versus 0% for placebo (
P
= 0.066) for all seizures and 57.1% versus 10.0% (
P
= 0.020) for drop attacks. No patient achieved freedom from all seizures but two rufinamide-treated patients (9.5%) became free of drop attacks. Overall, 71.4% of patients treated with rufinamide and 60.0% of patients treated with placebo experienced AEs; most commonly, somnolence (33.3% vs. 20.0%) and vomiting (19.0% vs. 0%). Most AEs were of mild or moderate intensity.
Conclusion
Rufinamide demonstrated favorable efficacy and was generally well tolerated when used as adjunctive treatment for adults with LGS.
Funding
Eisai.
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