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Keywords:

  • Clinical trial;
  • Antiepileptic drugs;
  • Absence seizures;
  • Myoclonic seizures;
  • Tonic–clonic seizures;
  • Idiopathic generalized epilepsy

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

Purpose:  To evaluate the long-term efficacy and tolerability of adjunctive levetiracetam (LEV) in patients with uncontrolled idiopathic generalized epilepsy (IGE).

Methods:  This phase III, open-label, long-term, follow-up study (N167; NCT00150748) enrolled patients (4 to <65 years) with primary generalized seizures (tonic–clonic, myoclonic, absence). Patients received adjunctive LEV at individualized doses (1,000–4,000 mg/day; 20–80 mg/kg/day for children/adolescents weighing <50 kg). Efficacy results are reported for all seizure types [intention-to-treat (ITT) population, N = 217] and subpopulations with tonic–clonic (n = 152), myoclonic (n = 121), and/or absence (n = 70) seizures at baseline.

Key Findings:  One hundred twenty-five (57.6%) of 217 patients were still receiving treatment at the end of the study. Mean (standard deviation, SD) LEV dose was 2,917.5 (562.9) mg/day. Median (Q1–Q3) exposure to LEV was 2.1 (1.5–2.8) years, and the maximum duration was 4.6 years. Most patients were taking one (124/217, 57.1%) or ≥2 (92/217, 42.4%) concomitant antiepileptic drugs (AEDs). Seizure freedom of ≥6 months (all seizure types; primary efficacy end point) was achieved by 122 (56.2%) of 217 patients, and 49 (22.6%) of 217 patients had complete seizure freedom. Seizure freedom of ≥6 months from tonic–clonic, myoclonic, and absence seizures was achieved by 95 (62.5%) of 152, 75 (62.0%) of 121, and 44 (62.9%) of 70 patients, respectively. Mean (SD) maximum seizure freedom duration was 371.7 (352.4) days. At least one treatment-emergent adverse event (TEAE) was reported by 165 (76%) of 217 patients; most TEAEs were mild/moderate in severity, with no indication of an increased incidence over time. Seventeen (7.8%) of 217 patients discontinued medication because of TEAEs. The most common psychiatric TEAEs were depression (16/217, 7.4%), insomnia (9/217, 4.1%), nervousness (8/217, 3.7%), and anxiety (7/217, 3.2%).

Significance:  Adjunctive LEV (range 1,000–4,000 mg/day) demonstrated efficacy as a long-term treatment for primary generalized seizures in children, adolescents, and adults with IGE, and was well tolerated.

The idiopathic generalized epilepsies (IGEs) are a distinct group of epilepsies defined by combinations of three main seizure subtypes: tonic–clonic, myoclonic, and absence seizures (International League Against Epilepsy, 1989; Mattson, 2003). IGE diagnosis is based on clinical symptoms and electroencephalography (EEG) abnormalities, presenting as generalized discharges (≥3 Hz) with normal background activity (International League Against Epilepsy, 1989). Approximately 15–20% of all patients with epilepsy have IGE (Jallon & Latour, 2005). Proper management of the disorder is dependent on an accurate diagnosis (Benbadis, 2005), and IGEs often respond well to appropriate treatment. However, many of the antiepileptic drugs (AEDs) currently used for the treatment of partial-onset seizures may not be effective, may have unacceptable adverse effects, or may exacerbate myoclonic and/or absence seizures in patients with IGEs (Knake et al., 1999; Biraben et al., 2000; Genton et al., 2000; Benbadis et al., 2003; Gelisse et al., 2004; Crespel et al., 2005). There remains, therefore, a clear need for newer AEDs with improved efficacy and fewer adverse effects to treat these patients. However, few well-designed studies have investigated the potential of newer AEDs in patients with IGE, especially in long-term treatment.

Levetiracetam (LEV) is a novel and well-established AED, which binds to synaptic vesicle protein 2A (SV2A) (Lynch et al., 2004). SV2A has been implicated in the modulation of synaptic vesicle exocytosis and neurotransmitter release (Crowder et al., 1999; Xu & Bajjalieh, 2001). Affinity for SV2A has been correlated with protection against seizures in animal models of both partial and generalized epilepsies, and results from these studies support SV2A as an important target for new AEDs, with potential broad-spectrum efficacy (Lynch et al., 2004; Kaminski et al., 2008).

In partial-onset seizures, LEV has demonstrated efficacy as adjunctive therapy in adults, children, and infants (Ben-Menachem & Falter, 2000; Cereghino et al., 2000; Shorvon et al., 2000; Glauser et al. 2006; Piña-Garza et al. 2009a) and also as monotherapy in adults (Brodie et al., 2007). In addition, LEV has been evaluated as adjunctive therapy in two double-blind, placebo-controlled trials in patients with IGE presenting with uncontrolled myoclonic (N166/NCT00150774) (Noachtar et al. 2008) or tonic–clonic seizures (N01057/NCT00160550) (Berkovic et al., 2007) and has been shown to be an effective and well-tolerated treatment in this patient population. Additional post hoc analysis of the results of these double-blind trials has suggested LEV efficacy in patients with insufficiently controlled IGE syndromes with onset at adolescence: juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalized tonic–clonic seizures on awakening (Rosenfeld et al., 2009). This article reports data from patients aged ≥4 years with IGE enrolled from studies N166 and N01057 in a follow-up study (N167; NCT00150748), designed to evaluate the long-term efficacy, safety, and tolerability of adjunctive LEV in patients who were experiencing seizures despite previous AED therapy.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

Study design

This was a phase III, open-label, noncomparative, multicenter, long-term, follow-up study (N167) of LEV as adjunctive treatment for uncontrolled primary generalized seizures (tonic–clonic, myoclonic, and absence seizures). The study was a follow-up of two positive, randomized, double-blind, placebo-controlled trials in patients with IGE: study N166, which focused on patients aged 12–65 years with myoclonic seizures (Noachtar et al. 2008), and study N01057, which focused on patients aged 4–65 years with tonic–clonic seizures (Berkovic et al., 2007) (Table S1, Fig. S1). In the prior studies, an 8-week prospective, single-blind (N166) or 4-week historical plus 4-week prospective, single-blind (N01057) baseline was followed by a 16- (N166) or 24-week (N01057) double-blind treatment period, including a 4-week up-titration. The follow-up study selection visit (visit 1) was planned to occur on the same day as the last visit of study N166 or N01057. For study N01057 only, patients who discontinued the study due to lack of efficacy were eligible to enter study N167, provided they had completed at least 12 weeks of the stable-dose maintenance period. Study visits were planned at 6-monthly intervals, including a full yearly evaluation, until regulatory approval of LEV for the indication targeted in the prior study [either by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency], or until the study was closed. If patients discontinued before the study closed, they were required to attend an early discontinuation visit. Patients who were still taking study medication at the time of study closure in each country were considered to have completed the study.

During N166 and N01057, patients were titrated to a maximum LEV dose of 3,000 mg/day (dose reduction to 2,000 mg/day was allowed if required). During N167, all patients received open-label LEV at an individualized dose (range of 1,000–4,000 mg/day; or 20–80 mg/kg/day in children/adolescents weighing <50 kg) administered twice daily (b.i.d.).

The study was conducted in accordance with International Conference on Harmonisation notes for Guidance on Good Clinical Practice (ICH/CPMP/135/95) and the Declaration of Helsinki. The study protocol and any related amendments were approved by an independent ethics committee at each study center. Written informed consent was obtained from all patients (or from the patient’s parent or legal guardian) prior to inclusion in the study.

Study population

Sixty-nine centers in 16 countries (Australia, Austria, Belgium, Canada, Estonia, France, Germany, Ireland, Italy, Mexico, New Zealand, Poland, Russia, Spain, United Kingdom, and U.S.A.) entered patients into the study between 1 November 2001 and 10 July 2007.

All study participants had primary generalized epileptic seizures (International League Against Epilepsy, 1989) and were considered by the investigator to be patients for whom a reasonable benefit (in terms of efficacy or tolerability) from the long-term administration of LEV could be expected. All female patients of childbearing potential had to have been using a medically accepted contraceptive method and regular pregnancy tests had to be negative. Concomitant AEDs had to remain at a stable dosage during the study, unless circumstances obliged the investigator to adapt the dosage for safety or efficacy reasons. There were no restrictions on the number of AEDs used concomitantly. Exclusion criteria included: treatment with any drug with possible central nervous system (CNS) effects, excluding other AEDs, or that may have influenced the metabolism of the concomitant AED(s), unless at a stable dose for a sufficient length of time before entry in the prior study; clinically significant acute or chronic illness (e.g., cardiac, renal, or hepatic dysfunction); poor compliance with visit schedule or with study medication intake in the prior study.

Assessments

Efficacy

Patients recorded the type and number of seizures using daily record cards. At each visit, the investigator confirmed the seizure assessment and added appropriate International League Against Epilepsy (ILAE) codes. Seizure frequency was measured as seizure days per week for all, myoclonic, and absence seizures; and as seizure frequency per week for tonic–clonic seizures. The primary efficacy end point was the number and percentage of patients having ≥6 months of seizure freedom at any time. Secondary outcome measures included: complete seizure freedom during the evaluation period (i.e., from study entry to study closeout or discontinuation); maximum duration of seizure freedom; time to first seizure from study entry; seizure frequency; percentage reduction from baseline in seizure frequency; and ≥50% and ≥75% responder rates. A post hoc analysis focusing on duration of LEV monotherapy was conducted. Exploratory end points included assessments from the health-related quality of life (HRQoL) questionnaire [Patient Quality of Life Inventory in Epilepsy-31 (QOLIE-31-P)] (Cramer et al., 1998), which was completed at each yearly evaluation visit and at the final visit or early discontinuation visit by patients who had completed the questionnaire in the prior studies. Study medication compliance was calculated based on the number of LEV tablets returned by the patient at each visit.

Tolerability and safety

Treatment-emergent adverse events (TEAEs) were recorded throughout the study. Their severity and relationship to study medication, as judged by the investigator, was also recorded. Electrocardiography (ECG) and physical and neurologic examinations were performed at the selection visit, at each yearly full evaluation visit, at the final visit, and at any early discontinuation visit. Vital signs and laboratory tests were performed at the selection visit, at each 6-monthly evaluation visit, at the final visit, and at the early discontinuation visit. Any clinically significant treatment-emergent clinical examination abnormality (including physical, neurological, or laboratory findings) was reported as a TEAE.

Statistical analyses

The intent-to-treat (ITT) population was defined as all patients (any seizure type) who took at least one dose of LEV in this long-term follow-up study (N167). All efficacy and safety analyses were performed on the ITT population. Three additional analysis groups were defined as all patients who experienced at least one of the following seizure subtypes during baseline: tonic–clonic, myoclonic, or absence seizures. These subtype analysis groups were not mutually exclusive.

Epilepsy characteristics used for this follow-up study were those recorded in the prior studies: N166 (Noachtar et al. 2008) and N01057 (Berkovic et al., 2007). All efficacy baselines used for analyses were obtained from these prior studies. Demographics were recorded at N167 study entry. Concomitant AEDs were recorded during N167.

Efficacy analyses were based upon data collected during the evaluation period. Safety analyses were based upon data collected during all periods combined: evaluation, down-titration (after early discontinuation), and posttreatment.

Primary efficacy analysis

Seizure freedom for ≥6 months at any time was analyzed for all seizures and by seizure subtype. Seizure freedom intervals were counted from the first day of seizure freedom and continued until the day before the day of the first new seizure, until and including the day of the early discontinuation visit, if the patient discontinued, or until study close-out. Days without seizures were not entered into the patient’s seizure diary; days with seizures were entered into the seizure diary. Each seizure diary record with a partial date or missing seizure type or missing number of seizures, and days when a patient reported noncompliance with seizure diary upkeep, were assumed to be seizure days. It was possible for a patient to have had more than a single interval of consecutive days of seizure freedom. Only the longest interval of seizure freedom is described in this primary analysis.

Secondary efficacy analyses

Maximum duration of seizure freedom was the greatest interval of seizure freedom at any time during the evaluation period. Complete seizure freedom was a maximum duration of seizure freedom spanning study entry until the end of the evaluation period. The time to first seizure from study entry was analyzed using the Kaplan-Meier method (Allison, 1995). A mixed-model repeated measure (MMRM) method was used as an exploratory analysis of seizure days/frequency per week to account for missing data (Dmitrienko et al., 2005). Estimates of least square (LS) means and 95% confidence intervals (CIs) for seizure days per week (all seizure types, myoclonic seizures, and absence seizures) and seizure frequency per week (tonic–clonic seizures) over time by 6-month analysis intervals were calculated. Subjects who had no reported seizures within an interval were treated as though they had one seizure during that interval. Log-transformed seizure days/frequency per week was used for MMRM calculations. Retransformed estimates are reported.

Descriptive statistics were used to calculate the percentage reduction from baseline in seizure frequency. The number and percentage of patients considered responders (patients with a ≥50% or ≥75% reduction from baseline in seizure frequency) were presented. Also evaluated were the ≥50% responder rates, windowed around years 1, 2, and 3; and subgroup analyses of all seizure types, by demographic characteristics (gender, ethnicity) and use of concomitant AEDs (valproic acid).

For a post hoc analysis, time on LEV monotherapy was determined. Monotherapy intervals of ≥3 months were considered to be of clinical relevance.

Baseline Quality of Life in Epilepsy (QOLIE-31-P) scores were those that were collected at randomization (i.e., before study treatment began) in the prior studies. The change from baseline was calculated for each of seven multiitem subscales: Seizure Worry (five items), Overall Quality of Life (two items), Emotional Well-being (five items), Energy/Fatigue (four items), Cognitive Functioning (six items), Medication Effects (three items), and Social Function (five items)—and one health status item.

Safety analyses

Safety analyses were based upon data collected during all periods combined: evaluation, downtitration (after early discontinuation), and posttreatment.

Descriptive statistics were used to summarize TEAEs. Those TEAEs that occurred in ≥5% of patients and selected TEAEs based upon clinical interest (somnolence, dizziness, convulsion, tonic–clonic seizure, aggression, depression, nervousness, and insomnia) were analyzed according to the analysis interval using the life table method (Allison, 1995). Hazard ratios for each event were calculated by analysis interval to evaluate the risk of an event over time.

Descriptive statistics were used to summarize electrocardiography (ECG), physical and neurologic examinations, vital signs, and laboratory test results.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

Patients

A total of 217 patients were included in the ITT population, corresponding to 76% of patients enrolled in the two prior studies (Fig. S1). In the prior studies, 114 and 103 patients had received LEV and placebo, respectively. Mean (SD) age was 28.0 (10.9) years and 126 (58.1%) of 217 patients were female (Table S2). Overall, 125 (57.6%) of 217 patients completed the study; the most common reason for withdrawal was lack (26/217, 12.0%) or loss (2/217, 0.9%) of efficacy (28/217, 12.9%). Median (Q1–Q3) baseline seizure frequency (all seizure types) was 1.36 (0.68–3.06) seizure days per week. Seizure subtypes experienced at baseline, by decreasing frequency, were tonic–clonic, myoclonic, and absence seizures in 152 (70.0%) of 217, 121 (55.8%) of 217, and 70 (32.3%) of 217 patients, respectively. All patients except one were taking concomitant AEDs at the study entry visit, with most patients (124/217, 57.1%) taking one concomitant AED. The three most common concomitant AEDs taken at any time during the study were valproic acid (132/217; 60.8%), lamotrigine (65/217; 30.0%), and carbamazepine (30/217; 13.8%).

Overall, the mean (SD) LEV dose during the evaluation period was 2,917.5 (562.9) mg/day (min–max 788.2–3993.0 mg/day). The median (Q1–Q3) exposure to LEV was 2.1 (1.5–2.8) years, and the maximum duration was 4.6 years. At each study visit, treatment compliance ranged from 85.8% to 100%.

Efficacy

Primary efficacy analysis

For all seizure types, 122 (56.2%) of 217 patients experienced at least one ≥6-month interval of seizure freedom (Fig. 1A). Similar results were seen across the seizure subtype groups: tonic–clonic (95/152; 62.5%), myoclonic (75/121; 62.0%), and absence seizures (44/70; 62.9%). Overall, 9 (7.4%) of 122 patients who experienced at least one ≥6-month interval of seizure freedom (all seizure types) had another concomitant AED added to their treatment regimen during the follow-up study.

image

Figure 1.   (A) Percentage of patients with seizure-free interval ≥6 months and (B) ≥50% and ≥75% responder rates, for all seizure types (ITT population) and by seizure subtype (baselines were obtained from the prior studies). ITT, intent-to-treat.

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Secondary efficacy analyses

Forty-nine (22.6%) of 217 patients had complete seizure freedom from all seizure types during the evaluation period (seizure subtypes are shown in Table 1). One (2.0%) of these 49 patients was prescribed an additional concomitant AED during the follow-up study. Mean (SD) maximum seizure freedom duration from all seizure types was 371.7 (352.4) days (seizure subtypes are shown in Table 1). After 65 weeks, 170 (78.3%) of 217 patients were still in the study, of whom 48 (28.2%) were continuously free from all types of seizure; 22 (22.2%) of 99 patients who were still in the study at 117 weeks remained free from all types of seizure (Table S3). Twenty-three (60.0%) of 39 patients who had been seizure free during the prior randomized studies remained seizure-free throughout the follow-up study while on LEV, comprising 6 (75.0%) of 8 and 17 (54.8%) of 31 patients who had received placebo and LEV, respectively, during the prior studies. Figure 2 displays the Kaplan-Meier plot of time to first seizure for all seizures and each seizure subtype. From study start, time to first absence seizure was greater than time to first myoclonic or tonic–clonic seizure. The times to first myoclonic or tonic–clonic seizure were similar.

Table 1.   Complete seizure freedom, maximum duration of seizure freedom, and percentage reduction from baseline in seizure frequency for all seizure types (ITT population) and by seizure subtype
 NLEV
  1. ITT, intent-to-treat; LEV, levetiracetam; SD, standard deviation.

  2. aBaselines were obtained from the prior studies.

  3. bSeizure days/week.

  4. cSeizure frequency/week.

Complete seizure freedom, n (%)  
 All seizure types21749 (22.6)
  Tonic–clonic seizures15242 (27.6)
  Myoclonic seizures12133 (27.3)
  Absence seizures7024 (34.3)
Maximum seizure free duration, days  
 All seizure types  
  Mean (SD)217371.7 (352.4)
  Median, min–max272.0, 0–1,573
 Tonic–clonic seizures  
  Mean (SD)152409.2 (347.9)
  Median, min–max303.0, 1–1,573
 Myoclonic seizures  
  Mean (SD)121459.0 (399.1)
  Median, min–max363.0, 0–1,400
 Absence seizures  
  Mean (SD)70487.9 (401.7)
  Median, min–max527.5, 0–1,417
Median reduction from baselinea in seizure frequency, %  
 All seizure typesb21791.4
  Tonic–clonic seizuresc15287.7
  Myoclonic seizuresb12197.9
  Absence seizuresb7096.2
image

Figure 2.   Kaplan-Meier analysis of time to first seizure from visit 1 for all seizure types (ITT population) and by seizure subtype. O, all seizures censored; B, myoclonic seizures censored; A, absence seizures censored; E, tonic–clonic seizures censored. Six months was defined to be 182 days. ITT, intent-to-treat.

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LS mean seizure days/frequency by analysis interval remained well below baseline median values and were relatively stable throughout the study for all seizure types and each seizure subtype (Fig. S2). For all seizure types, the median seizure days/week at baseline was 1.36 (N = 217). During treatment, the LS mean (95% CI) seizure days/week was 0.17 (0.14, 0.21; n = 213) during weeks 1–13, and 0.15 (0.06, 0.38; n = 17) during weeks 196–221.

For all seizure types, the median percentage reduction from baseline in seizure days/week was 91.4% (seizure subtypes are shown in Table 1). Greater than or equal to 50% and ≥75% responder rates over the evaluation period are shown in Fig. 1B. Greater than or equal to 50% responder rates were stable over time for all seizure types: 83.0% for weeks 40–65 (n = 161); 85.8% for weeks 92–117 (n = 127); and 85.7% for weeks 144–169 (n = 48), and for each of the seizure subtypes (data not shown).

Gender, ethnicity, or use of valproic acid (VPA) did not appear to influence the efficacy of adjunctive LEV (data not shown).

During the study, a total of 37 (17.1%) of 217 patients received LEV monotherapy for an interval of ≥3 months; 26 (12.0%) of 217 patients received LEV monotherapy for an interval of ≥12 months. Mean (SD) maximum LEV monotherapy duration was 19.3 (11.2) months.

Patient functioning and HRQoL, as assessed by mean change from baseline in QOLIE-31-P subscale scores, improved slightly or remained stable during the first year (data not shown). All aspects of HRQoL remained stable after the first year to the end of the study. The majority of patients reported their overall quality of life to be “a little better” (34/116; 29.3%) or “a lot better” (52/116; 44.8%) at the first yearly evaluation visit compared with baseline.

Tolerability and safety

At least one TEAE was reported by 165 (76%) of 217 patients. The most common TEAEs, those reported by ≥10% of patients, were headache and nasopharyngitis (Table 2). The most frequent treatment-related TEAEs were headache (10/217; 4.6%), dizziness, and depression (both 9/217; 4.1%).

Table 2.   Incidence of treatment-emergent adverse events (ITT population)
 LEV (N = 217) n (%)
  1. ITT, intent-to-treat; TEAE, treatment-emergent adverse event; LEV, levetiracetam.

  2. aBy MedDRA (Medical Dictionary for Regulatory Activities) preferred term.

Total number of TEAEs848
Patients with 
 At least ≥1 TEAE165 (76.0)
 Drug-related TEAEs66 (30.4)
 TEAEs leading to permanent study drug discontinuation17 (7.8)
 Severe TEAEs29 (13.4)
 Serious TEAEs31 (14.3)
TEAEs reported in ≥5% patientsa 
 Headache40 (18.4)
 Nasopharyngitis24 (11.1)
 Influenza20 (9.2)
 Dizziness18 (8.3)
 Weight gain17 (7.8)
 Depression16 (7.4)
 Tremor15 (6.9)
 Vomiting13 (6.0)
 Urinary tract infection13 (6.0)
 Convulsion13 (6.0)

Hazard ratio calculations showed that the risk of developing selected TEAEs (somnolence, dizziness, convulsion, tonic–clonic seizure, aggression, depression, nervousness, insomnia) and all other TEAEs that occurred in ≥5% of patients (headache, nasopharyngitis, influenza, weight gain, tremor, vomiting, urinary tract infection) was not more likely to increase with extended exposure to adjunctive LEV (data not shown).

The majority of TEAEs were of mild or moderate intensity. Severe TEAEs that occurred in >1% of patients were convulsion, headache and status epilepticus (each 3/217, 1.4%). A total of 31 patients (14.3%) reported serious TEAEs, of whom 10 patients (4.6%) had serious TEAEs that were considered by the investigator to be treatment-related (convulsion; atrial fibrillation/arrhythmia; epilepsy; intrauterine death; depression; hand and wrist fracture; psychotic disorder/suicidal ideation; schizophrenia; erythematous rash; and status epilepticus).

The most common psychiatric and behavioral TEAEs reported were depression (16 patients, 7.4%), insomnia (nine patients, 4.1%), nervousness (eight patients, 3.7%), and anxiety (seven patients, 3.2%), and were similar in patients who had been randomized to either LEV or placebo in the prior studies (data not shown).

Nine patients discontinued because of pregnancy (two unintended, seven intended), and one patient each discontinued due to the following TEAEs: arrhythmia, convulsion, tremor, aggression, completed suicide, depression, psychotic disorder, and exanthem. One patient with worsening of comorbid schizophrenia subsequently committed suicide 1,185 days after the first visit in N167 and 43 days after having taken the last LEV dose (aggregate total exposure to LEV, from the first dose in the prior study to the last dose in N167, was 1,142 days). Schizophrenia had been diagnosed 9 years prior to study entry, and one suicide attempt had been reported the year before this diagnosis.

There were no clinically relevant changes from baseline in observed blood chemistry and hematology laboratory parameters, electrocardiography (ECG) results over time, or vital signs (data not shown).

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

In this long-term, open-label, follow-up study to two preceding, positive, double-blind, placebo-controlled trials (N166 and N01057) (Berkovic et al., 2007; Noachtar et al. 2008), adjunctive LEV continued to demonstrate good seizure control in children, adolescents, and adults with IGE during an average follow-up duration of 2.1 years (maximum 4.6 years). The results of the primary efficacy analysis (seizure freedom for ≥6 months at any time during the study) demonstrated similar efficacy for all seizure types combined and across the three main seizure subtypes (tonic–clonic, myoclonic, and absence). Secondary efficacy and quality-of-life analyses also demonstrated favorable trends for adjunctive LEV.

The successful management of IGE depends on an accurate diagnosis and selection of an appropriate treatment. IGE usually responds well to adequate treatment: 80–90% of patients achieve good seizure control (Benbadis, 2005). Most treatment failures result from an incorrect diagnosis and, therefore, a poor choice of AED (Benbadis, 2005). VPA is widely regarded as the most effective first-line treatment for patients with IGE (Marson et al. 2007). However, other AEDs may be preferred for some patients, particularly women of child-bearing age or those who are unable to tolerate VPA.

Approximately one third of people with epilepsy are women of child-bearing age, and the increased risk of major congenital malformations (MCMs) in the offspring of patients exposed to certain AEDs during pregnancy has to be considered, particularly with VPA (Holmes et al., 2001; Artama et al., 2005; Harden et al. 2009). In utero exposure to VPA has been associated with an increased risk of impaired cognitive function in children aged 3 years compared with exposure to other AEDs (Meador et al. 2009), especially at higher valproate doses and in terms of language development (Meador et al. 2011). Results from a prospective, observational study of children aged up to 24 months indicated that those who had been exposed to LEV in utero were not at an increased risk of delayed early cognitive development, whereas in utero exposure to VPA was associated with poorer developmental outcome (Shallcross et al. 2011). Although robust data on the risk of congenital malformations with LEV are not yet available, recently updated information from cases monitored by the United Kingdom epilepsy and pregnancy register suggests that the risk is low, with no MCMs reported in 197 cases on LEV monotherapy and 8 of 301 on LEV polytherapy (Kennedy et al., 2010). Limited information available from the UCB Pharma AED pregnancy registry reported congenital malformations following first trimester LEV use in 8 of 187 patients on monotherapy and 9 of 90 on polytherapy (Alekar et al., 2009). The malformations observed on LEV monotherapy were peripheral pulmonary artery stenosis and patent foramen ovale, subaortic ventricular septal defect, bilateral club feet, pulmonary stenosis and dysplastic pulmonary valve, positional plagiocephaly, cleft lip, congenital torticollis, and polydactyly.

Several of the second generation AEDs have been investigated for the treatment of IGE. Recently, VPA monotherapy has been reported to be superior to lamotrigine monotherapy in a retrospective evaluation of the long-term treatment of IGE (mean treatment duration of 28 months) (Mazurkiewicz-Beldzinska et al., 2010) and in a double-blind, 16-week study in childhood absence epilepsy (Glauser et al. 2010). The Standard and New Antiepileptic Drugs (SANAD) study reported that VPA is better tolerated than topiramate and more efficacious than lamotrigine as a treatment for patients with generalized or unclassified seizures (Marson et al. 2007). However, open-label, long-term studies have reported favorable results for topiramate in the treatment of generalized tonic–clonic seizures (Montouris et al., 2000) and zonisamide in a pediatric population with a variety of both partial and generalized epilepsy syndromes (Shinnar et al., 2009). In these studies the mean duration of treatment was approximately 1 year. Based on results from this study and its preceding double-blind studies, LEV may be a good choice of treatment in patients with IGE. This open-label study showed similar efficacy for each of the three seizure subtypes associated with IGE. The preceding double-blind trials demonstrated the efficacy of LEV over placebo in patients with IGE with myoclonic (N166) (Noachtar et al. 2008) and generalized tonic–clonic (N01057) (Berkovic et al., 2007) seizures. Neither of these studies was designed to assess absence seizures. Although studies with some other AEDs have shown aggravation of absence and/or myoclonic seizures (Benbadis et al., 2003; Gelisse et al., 2004), no aggravation of absence seizures was reported with LEV in comparison with placebo in the prior double-blind studies or in this long-term study. In addition, a pooled analysis of data from the prior studies concluded that there was no evidence that adjunctive treatment with LEV aggravates tonic–clonic or myoclonic seizures (Somerville, 2008).

Sustained long-term efficacy and good tolerability have been reported for LEV in patients with partial-onset seizures (adults and children) at doses similar to those used in this study (up to 4,000 mg/day) (Abou-Khalil & Schaich, 2005; Bauer et al., 2006; Piña-Garza et al., 2009b; Yang et al., 2009). Long-term treatment with adjunctive LEV was generally well tolerated in this study. The most commonly reported TEAEs were headache and nasopharyngitis, and most of the side effects that patients experienced were mild or moderate in severity. In addition, there was no evidence of an increased risk of side effects with longer exposure to LEV. Nine patients (4.1%) discontinued therapy because of pregnancy (which was recorded as a TEAE); few patients (8/217, 3.7%) discontinued as a result of other TEAEs. LEV has previously been associated with a low but important risk of psychiatric and behavioral adverse events (Mula et al., 2003). With respect to cognition, a double-blind study indicated that the effects of adjunctive LEV on memory and attention were no different from placebo over 8–12 weeks in children aged 4–16 years with epilepsy (Levisohn et al. 2009). In study N167, a low incidence of psychiatric adverse events (<7.5% for each TEAE) was reported during long-term administration of LEV and the risk did not increase over time. Very few psychiatric adverse events resulted in treatment discontinuation (4/217 patients, 1.8%).

The main limitations of this study were the lack of a comparator and the variable length of time that patients participated in the study. The treatment duration for each patient was dependent on the date that they enrolled and whether they discontinued early or continued until study close-out. The study does, however, provide long-term safety and efficacy data on patients enrolled from the two positive, placebo-controlled, double-blind studies, supported by a wide observation window (as much as 4 years of exposure). In addition, it had a design reflective of clinical practice, with flexible individualized dose regimens for LEV and concomitant AEDs.

In summary, this long-term, open-label study contributes broadened significant observational evidence that adjunctive LEV provides clinically relevant long-term seizure control in children, adolescents, and adults with IGE. It also shows that adjunctive LEV is well tolerated during long-term treatment. The results of this study support the long-term use of adjunctive LEV in patients who present with IGE in clinical practice.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

Study N167 was sponsored by UCB Pharma, who was responsible for the design and conduct of the study, and collection, management, analysis, and interpretation of the data. UCB Pharma was involved in the preparation and review of this report, along with the listed authors, and covered all related costs. The authors would like to thank the patients and their parents/legal guardians for their contribution to the study, and would also like to acknowledge the members of the N167 Levetiracetam Study Group for their contribution to the study, including data collection. The authors thank Robert Chan, M.D. (UCB Pharma, Brussels, Belgium) for critical review of the manuscript; Svetlana Dimova, M.D., Ph.D. (UCB Pharma, Brussels, Belgium) and Laurent Turet, Ph.D. (UCB Pharma, Brussels, Belgium) for critical review and coordination of the manuscript preparation; and Helen Attisha, M.Sc., Ph.D. (formerly QXV Communications, Macclesfield, United Kingdom) and Jenny Stewart, M.Sc. (QXV Communications, Macclesfield, United Kingdom) for their assistance in the manuscript preparation, which was funded by UCB Pharma.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

Norman Delanty has been a paid consultant and advisory board member for UCB Pharma, and has received an unrestricted educational grant from UCB as principal investigator for the Irish Epilepsy & Pregnancy Register. John Jones was a full-time employee of UCB Pharma (Raleigh, VA, U.S.A.). at the time when the N167 study was conducted, the results were analyzed, and the preparation of this report was initiated. Françoise Tonner was a full-time employee of UCB Pharma (Brussels, Belgium) at the time when the N167 study was conducted, the results were analyzed, and the preparation of this report was initiated. We confirm that we have read the Journal’s position on issues involved in ethical publication and confirm that this report is consistent with those guidelines.

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  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

Figure S1. Patient disposition.

Figure S2. LS mean (95% CI) seizure days/frequency per week by analysis interval for (A) all seizure types (ITT population), and (B) tonic-clonic seizures (C) myoclonic seizures and (D) absence seizures sub-types.

Table S1. Study design of prior randomized controlled trials (N166 and N1057).

Table S2. Demographics and epilepsy characteristics (ITT population).

Table S3. Percentage of patients continuously seizure free by continuous analysis interval for all seizure types (ITT population) and by seizure sub-type.

FilenameFormatSizeDescription
EPI_3300_sm_FigS1.tif346KSupporting info item
EPI_3300_sm_FigS2.tif390KSupporting info item
EPI_3300_sm_supplementaryLegends.doc11KSupporting info item
EPI_3300_sm_TableS1-S2.doc109KSupporting info item

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