Adjunctive Brivaracetam in Indian Patients with Uncontrolled Focal Epilepsy: Results from a Pooled Analysis of Two Double-Blind, Randomized, Placebo-Controlled Trials
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.304103
Source of Support: None, Conflict of Interest: None
Keywords: Brivaracetam, focal epilepsy, safety/tolerability, seizure control
Characterized by recurrent seizures, epilepsy is the second most commonly encountered neurological disorder globally., The disease affects around 50 million people worldwide, with an estimated 5 million new cases diagnosed annually. Nearly 80% of people with epilepsy live in developing countries. Non-syndromic (structural/metabolic and unknown cause) focal epilepsy is the most prevalent epilepsy in adults. The prevalence of epilepsy in India is estimated to be around 12 million, contributing to nearly one-sixth of the global burden. The disability and psychosocial effect caused by epilepsy in socio-culturally resolute traditional societies like India is phenomenal.
In the last two decades, several new antiepileptic drugs (AEDs) and improved formulations of older AEDs have been licensed for the treatment of epilepsy. Many AEDs target sodium channels, calcium channels, or the γ-aminobutyric acid (GABA) system. However, with almost one-third of patients not achieving seizure control with existing AEDs,, drugs that interact with alternative targets, such as synaptic vesicle protein 2A (SV2A), are likely to have clinical value. One of the most widely used third-generation AEDs, levetiracetam (LEV), was the first to target SV2A., In animal models, the binding affinity of LEV analogues to SV2A correlates closely with anti-seizure potency.
Brivaracetam (BRV) (UCB Pharma, Brussels, Belgium), is a new member of the racetam class of drug, rationally designed to selectively target SV2A with binding affinity 15- to 30-fold greater than that of LEV., Brivaracetam is more effective than LEV in slowing synaptic vesicle mobilization, and the two AEDs may act at different binding sites or interact with different conformational states of the SV2A protein. In animal models of focal and generalized epilepsy, BRV shows more potent seizure protection than LEV., At therapeutically relevant concentrations, BRV shows no effect on voltage-gated potassium channels or sustained repetitive firing in voltage-gated calcium channels, nor does it bind to AMPA or GABA-A receptors or transporters. The drug undergoes first-order pharmacokinetics with an elimination half-life of 7–8 hours. Brivaracetam is metabolized extensively; the main parent compound is unchanged brivaracetam. Around 95% of metabolites undergo renal elimination. Brivaracetam has a relatively low potential for clinically relevant pharmacokinetic drug interactions.
Brivaracetam was discovered during a large-scale program aimed at optimizing pharmacodynamic activity at a novel molecular AED target. Effectiveness and safety/tolerability of adjunct BRV in the treatment of uncontrolled partial-onset (focal) seizures, was first assessed in two placebo-controlled dose-ranging phase IIb clinical studies (N01193;NCT00175825 and N01114;NCT00175929). To further confirm the findings, the BRV clinical development program included four phase III studies. This comprised three fixed-dose studies (N01358;NCT01261325, N01252;NCT00490035, and N01253;NCT00464269) in patients with uncontrolled focal epilepsy; and one flexible-dose, safety and tolerability study in patients with focal or generalized epilepsy (N01254;NCT00504881). Brivaracetam is licensed in the Europe (as adjunctive therapy) and in USA (as mono or adjunctive therapy) for treatment of focal-onset seizures with or without secondary generalization in patients aged 4 years or older.,
Here, we present pooled efficacy and tolerability data of adjunct BRV (50, 100,, and 200 mg/day) compared with placebo in Indian patients with uncontrolled focal epilepsy, enrolled in the two randomized, double-blind, placebo-controlled, fixed-dose phase III studies, N01358; NCT01261325 and N01252; NCT00490035.
The methods, study design, assessments, and objectives of the two randomized, double-blind, placebo-controlled, fixed-dose phase III studies have been published previously in detail by, Klein et al. (N01358;NCT01261325) and Ryvlin et al. (N01252;NCT00490035). Both studies were conducted between September 2007 and December 2013. The BRV dosages ranged from 20 mg/day (N01252) to 200 mg/day (N01358), initiated without up-titration.
The studies comprised an 8-week prospective baseline period, with assessment at weeks -8 and -4, 12-week treatment period with follow-up at weeks 2, 4, 8, and 12, and 2-week down-titration period followed by a 2-week drug-free period for study N01252; and 4-week down-titration period followed by a 2-week drug-free period for study N01358. The time of final safety visit was 12 and 16-weeks for study N01252 and N01358, respectively. Patients were randomized (1:1:1:1) to receive BRV20, 50, 100 mg/day, or placebo, administered twice daily in equal doses in study N01252 and (1:1:1) to receive BRV100, 200 mg/day, or placebo administered in two equally divided doses per day, without up-titration in study N01358.
The study population included patients of both sexes aged 16 to 70 years in study N01252 and ≥ 16–80 years in study N01358. All patients had uncontrolled, focal seizures with or without secondary generalization, despite treatment with 1 or 2 AEDs. Vagus nerve stimulation was allowed but was not counted as a concomitant AED in study N01252. Patients must have had well-characterized focal epilepsy with a history of focal seizures with or without secondary generalization, and two or more focal seizures with or without secondary generalization/month for three months prior to screening and eight or more focal seizures during the 8-week prospective baseline period.,
Key exclusion criteria included non-motor simple partial seizures as the only seizure type, cluster seizures, psychogenic non-epileptic seizures, or history of status epilepticus during the year preceding screening or during baseline. Patients with a history or presence of rapidly progressing brain disorder or tumor, terminal illness, serious infection, were also excluded. Concomitant AEDs were kept stable for ≥ 1 month before study entry and throughout the treatment periods. Concomitant LEV use was restricted to < 20% of patients in study N01252 and in study N01358, patients taking concomitant LEV, or who had taken LEV within 90 days prior to visit 1 were excluded.
The studies were conducted in accordance with the International Conference on Harmonization notes for Guidance on Good Clinical Practice and the Declaration of Helsinki. The study protocols were approved by institutional review boards at all study sites and written informed consent was obtained from all patients or their legal representatives before enrollment. The trials were registered on ClinicalTrials.gov (NCT01261325 and NCT00490035).
For the Indian sub-group population analysis, data from studies N01252, and N01358 were pooled as per the BRV randomization dose. The 5 and 20 mg/day dosage groups were excluded because of limited efficacy. The efficacy population comprised all patients from the primary efficacy analyses, randomized to BRV dosages of 50, 100, or 200 mg/day, or placebo, excluding those taking concomitant LEV in study N01252. The safety population comprised all patients randomized to BRV dosages of 50, 100, or 200 mg/day, or placebo, who took ≥1 dose of study drug, including those taking concomitant LEV.
The primary endpoints were percentage reduction in focal seizure frequency/28 days over placebo. The co-primary efficacy outcomes were ≥50% responder rate defined as the percentage of patients achieving ≥50% reduction in seizure frequency from baseline to the end of the 12-week treatment period. Secondary endpoints included median percentage reduction from baseline in focal seizure frequency/28 days during the treatment period; seizure freedom during the treatment period; and categorized reduction in focal seizure frequency from baseline to treatment period (100%, 75%-<100%, 50%-<75%, 25%-<50%, -25%–<25% and <-25% reduction).
The percentages of patients who achieved sustained responder status were estimated by the Kaplan-Meier method. Patients were classified as sustained ≥ 50% responders on a particular day if they completed the entire treatment period through day 84 and were a ≥ 50% responder (based on the percentage reduction in the frequency of focal seizures [all subtypes] from baseline) both on that day and for every successive day through day 84. By definition, patients discontinuing during the treatment period could not achieve sustained responder status. Health-related quality of life (HRQoL) in the safety population was evaluated by the Patient-Weighted Quality of Life in Epilepsy Inventory-31 (QOLIE-31-P) questionnaire. The questionnaire comprises two factors (emotional and psychological effects, and medical and social effects), seven sub-scales, and 31 items. Items are measured on 4- to 6- point Likert scales, with a maximum total score of 100 and higher scores indicating a better QoL.
Due to the nature of post hoc analysis, all reported P values are interpreted in an exploratory manner.
Adverse events (AEs) were recorded at each study visit, with an assessment of their severity and relationship to study medication. Serious AEs were defined as those that resulted in death, were life-threatening, required hospitalization or prolonging of hospitalization, resulted in persistent or significant disability or incapacity, or were congenital anomalies or birth defects. Safety and tolerability outcomes were analyzed descriptively. Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA; Version 15.0). Recurrent AEs were counted only once.
A total of 399 and 768 patients were randomized globally in study N01252, and N01358, respectively. Data of 104 Indian patients from studies N01358 and N01252 were pooled for this sub-analysis. The safety population comprised 104 patients, 35 randomized to placebo, and 22, 36 and 11 patients randomized to BRV dosages of 50, 100, and 200 mg/day, respectively; 89.9% patients in BRV 50-200 mg group and 91.4% patients in placebo group completed the study. The patients' disposition is presented in [Figure 1]. The efficacy population comprised 101 patients: 21, 35 and 11 randomized to BRV dosages of 50, 100, and 200 mg/day, respectively, and 34 randomized to placebo.
Demographic and baseline characteristics as per the safety population are presented in [Table 1]. In the Indian sub-group population, the mean duration of epilepsy ranged from 12.7 to 17.2 years, with 76.0% (79/104) of patients having 1-2 previously failed AEDs. Most patients reported complex partial seizures followed by secondarily generalized focal seizures during the baseline period. The majority of patients were taking two concomitant AEDs at baseline, with carbamazepine being the most commonly used AED. Out of 101 patients in the efficacy population, 94 (93.1%) of patients (18 [85.7%], 34 [97.1%] and 11 [100%] on BRV 50 mg, 100 mg and 200 mg/day groups, respectively, and 31 [91.2%] on placebo) completed the 12-week treatment period. Demographic and baseline characteristics of the efficacy population were similar to the safety population.
≥50% responder rate
In the Indian sub-group population, ≥50% responder rates were 43.3% in 50-200 mg/day group. Responder rate in 50, 100, and 200 mg/day group was at 38.1%, 45.7% and 45.5% respectively, compared with 11.7% for placebo [Figure 2].
There were a larger proportion of Indian patients with 25% to 50%, 50% to 75% and 75% to 100% reduction in POS frequency from baseline for all BRV dosages compared with placebo [Figure 3]. Compared to placebo the categorized percent reduction in seizure frequency from baseline was statistically significant in BRV 50-200 (0.00049), 50 (p = 0.0010) and 100 (p = 0.00181) mg/day groups and numerically better in BRV 200 mg/day (0.12411), group.
Median percentage reduction from baseline in focal seizure frequency/28 days
Over the 12-week treatment period, median percent reduction from baseline in focal seizure frequency/28 days was greater in the three BRV dose groups compared with the placebo group, in the Indian sub-group population. Median percent reductions from baseline were 39.7%, 46.8%, 48.2% and 45.6% in the BRV 50, 100, 200 and 50-200 mg/day groups, respectively, compared with 20.6% in the placebo group. Median (95% CI) difference vs. placebo was 33.1% (9.0%-56.4%; P = 0.00868), 39.0% (15.3%-56.9%; P = 0.00180), 29.9% (-1.5%-62.1%; P = 0.05224) and 35.8% (16.5%-52.1%; P = 0.00048). for BRV 50, 100, 200 and 50-200 mg/day, respectively [Figure 4].
The median percent reduction from baseline in focal seizure frequency/28 days in patients receiving one, two or three and more concomitant AEDs along with BRV dosages (50-200 mg/day) was 55.4% (n = 9), 43.2% (n = 54) and 45.9% (n =4), respectively. Median (95% CI) difference vs. placebo, was 84.1% (-3.0-159.4; P = 0.06060) for patients receiving one concomitant AED, 31.4% (8.2-50.6; P = 0.00788) and 26.4% (-32.6-90.3; P = 0.66501), for patients receiving two or three and more concomitant AEDs, respectively.
Sustained ≥50% responder status
[Figure 5] presents the Kaplan-Meier estimates of the percentage of patients in the Indian sub-group population who achieved a sustained ≥50% responder status. Sustained responder status was achieved from day 1 for BRV 100 and 200 mg/day dosage, except for 50 mg/day. Kaplan-Meier estimates of the proportion of patients achieving sustained ≥ 50% responder status at day 1 were 4.8%, 20.0%, and 27.3% for BRV 50, 100, and 200 mg/day, respectively, versus 0.0% for placebo. The subsequent values on day 7 were 9.5%, 22.9%, and 27.3% versus 0.0% for placebo, and values remained unchanged on day 14. On day 28, the proportion of patients achieving sustained > 50% responder status was 14.3%, 37.1%, and 27.3% for BRV 50, 100, and 200 mg/day, respectively, versus 5.9% for placebo.
Seizure-freedom rate (all seizure types)
Complete seizure freedom from day one of therapy was achieved by 4.8% (1/21) of patients on BRV 50 mg/day (though the patient had discontinued therapy), 2.9% (1/35) of patients on BRV 100 mg/day, and none out of the 11 and 34 patients in the BRV 200 mg/day and placebo groups, respectively, in the Indian sub-group population.
Quality of life
In the Indian sub-group population, the mean improvement from baseline in total QOLIE-31-P score was numerically higher in the BRV groups, 4.28 in 50-200 mg/day, 9.73 in 50 mg/day, 0.73 and 3.75 in BRV 100 and 200 mg/day groups, respectively; as compared with 0.28 in placebo group. The mean improvement in the QOLIE-31-P score for all BRV dosages (50-200 mg/day) was higher for medication effects (8.74) followed by the overall quality of life (7.62) and seizure worry (6.05). Additionally, the medication effect increased with the BRV dose and was 4.86, 7.31 and 19.7 for BRV 50, 100 and 200 mg/day group, respectively. The mean changes in QOLIE-31P scores (total score and the seven subscales) from baseline in all the treatment groups are presented in [Table 2].
Overall, the incidences of treatment-emergent AEs (TEAEs), severe TEAEs, and serious TEAEs were similar across the BRV and placebo groups, in the Indian sub-group population [Table 3]. The incidence of drug-related TEAEs was 8.6% on placebo and 17.4% on BRV (50-200 mg/day). A similar proportion of patients on BRV 50, 100 and 200 mg/day reported drug-related TEAEs (18.2%, 16.7% and 18.2%, respectively). No incidence of behavioral and psychiatric TEAEs with BRV therapy was reported in the Indian sub-group population. The majority of TEAEs in the Indian sub-group population were considered to be mild or moderate in intensity, with only 1.4% patients reported severe and 1.4% reported serious TEAEs reported. The TEAEs most commonly reported by ≥ 5% of patients taking BRV were headache (7.2%) and cough (5.8%). No incidence of TEAEs related to study drug discontinuation was reported in the Indian sub-group population. One incidence of death due to septicemia was reported in the placebo group, during the study period.
Randomized control trials are pivotal for evaluating effectiveness, safety and tolerability of investigative drug in the study population. This pooled analysis of the Indian sub-group population from two phase III studies (NCT01261325 and NCT00490035) supports the efficacy and tolerability of adjunct BRV in Indian patients with uncontrolled focal epilepsy.
Since BRV and LEV both exert antiepileptic effects through SV2A, BRV had no added therapeutic benefit when co-administered with LEV. Study N01252 limited concomitant LEV to < 20% of patients, while study N01358 excluded patients taking concomitant LEV. To allow meaningful analysis, the pooled Indian sub-group efficacy population also excluded concomitant LEV. However, the pooled safety analysis included data from all the Indian patients who took ≥ 1 dose of study drug, regardless of LEV status.
For the Indian sub-group population, co-primary and secondary efficacy analyses supported BRV efficacy for all dosages in the Indian sub-group population, with the higher BRV dosages (100 and 200 mg/day) being more efficacious. Median percent reduction from baseline for all BRV dosages was numerically higher when compared to placebo, and higher than results reported in parent studies and by Ben-Menachem E et al. in the pooled analysis of 3 phase III studies of BRV (N01252, N01253, and N01358). Median percent reductions from baseline in the Indian sub-group population in the BRV 50 and 100 mg/day groups were 39.7% and 46.8% respectively, which were comparatively higher than 34.7% and 26.8% reported by Ben-Menachem E et al. and Ryvlin et al. (N01252) for BRV 50 mg/day; and 32.5%, 37.2% and 37.6% reported for BRV100 mg/day by Ryvlin et al., Klein et al. (N01358) and Ben-Menachem E et al. respectively. Likewise, median percentage reduction from baseline in the BRV 200 mg/day group in the Indian sub-group population was 48.2%, which was considerably higher than 35.6% reported for BRV 200 mg/day, by Ben-Menachem E et al. and Klein et al. (N01358).
Similarly, the ≥50% responder rate in the Indian sub-group population was 38.1%, 45.7%, and 45.5% for BRV 50, 100, and 200 mg/day, respectively. This was numerically higher than 27.3% and 34.2% reported by Ryvlin et al. (N01252) and Ben-Menachem E et al. respectively, for BRV 50 mg; 36.0%, 38.9% and 39.5%, reported by Ryvlin et al., Klein et al. (N01358) and Ben-Menachem E et al. respectively, for BRV 100 mg and 37.8%, reported for BRV200 mg/day, by Ben-Menachem E et al. and Klein et al. (N01358).
The sustained responder status is a more rigorous measure of response to treatment than the “standard” ≥50% responder rate. Firstly, the requirement for maintenance of ≥50% response indicates that only patients with a sustained (rather than transient) response are counted. This decreases the percentage of responders and focuses on patients who are more likely to have a clinically meaningful sustained response. Secondly, a sustained ≥50% responder needs to complete the entire treatment period, whereas standard ≥50% responder rates typically also include patients who discontinued treatment early. The percentage of Indian patients achieving sustained 50% response from the first day of treatment and over the entire 12-week period was higher in patients on BRV (50-200 mg/day) compare to placebo and the difference was more pronounced in patients on BRV 100 and 200 mg/day.
In this pooled analysis of an Indian sub-population, complete seizure freedom (for the entire treatment period) was achieved by 4.8% of patients on BRV 50 mg/day (although patient had discontinued the therapy), compared to 2.5% in the pooled analysis of three studies by Ben-Menachem E et al. and none in study N01252. However, compared to 4%, 5.2% and 5.1% of patients in the BRV 100 mg/day group in studies N01252, N013581 and the pooled analysis by Ben-Menachem E et al. respectively, only 2.9% of patients on BRV 100 mg/day in the Indian sub-group population achieved complete seizure freedom. Likewise, 4.0% achieved complete seizure freedom with BRV 200 mg/day in study N013581 andthepooled analysis by Ben-Menachem E et al., compared to none in the Indian sub-population.
The numerically higher efficacy outcomes observed in the pooled analysis of the Indian sub-population as compared to results reported from the pooled analysis by Ben-Menachem E et al. can be attributed to the following factors. The majority of Indian patients (73.9%) in BRV 50-200 mg/day group were on 1-2 prior AEDs, compared to 61.9% patients on 1-4 prior AEDs in BRV50-200 mg/day group, in results reported by Ben-Menachem E et al. This is not unexpected, as several studies have reported that an increase of the number of previous AEDs use is associated with a lower treatment response to newly administered AED., Additionally, the mean duration of epilepsy and median focal seizure frequency/28 days at baseline in Indian patients was 15.5 years and 7.1 (5.0-9.6) respectively, compared to the mean duration of 22 to 24 years and median focal seizure frequency rate of 9.3 (5.5-18.8), reported by Ben-Menachem E et al. in the pooled analysis of three studies. Studies have also reported that the longer the duration of epilepsy, the smaller the response to the AED for both seizure- freedom rates and rates of greater than 50% reduction in seizure frequency., In addition, studies have also reported that a larger number of seizures prior to initiation of AED treatment reduced the response to AEDs,,, and that a larger seizure frequency carried a greater chance for the development of drug-resistant epilepsy diminishing the response to AED treatments.,,,
Improving HRQoL is a significant part of epilepsy management, which must be considered in addition to seizure prevention. Improvements in HRQoL, as assessed by the QOLIE-31P, were seen for both the total score and the seven subscales, for the pooled BRV dosages (50-200 mg/day) in the Indian sub-group population, with the highest improvements in the subscales of medication effect (8.74), overall quality of life (7.62) and seizure worry (6.05). However, improvement in both the total score and the seven subscales was numerically best in the BRV 50-200 mg/day group. The HRQoL data reflects the known tolerability and efficacy profile of brivaracetam.
Brivaracetam at dosage (50-200 mg/day) was well tolerated in the Indian sub-group population, as demonstrated by the high completion rate (91.3%), with no patients discontinuing treatment due to TEAEs. Completion rates were numerically higher for the BRV 100 mg (94.4%) and 200 mg (90.9%) groups, compared to the 50 mg (81.8%) group. This may indicate that BRV has a wide therapeutic window, and suggests that the higher dose is well below the limit of tolerability.
The most commonly reported TEAE for BRV (50-200 mg/day) in the Indian sub-population was headache, similar to earlier findings as reported in N01358, N01252 andthe pooled analysis by Ben-Menachem E et al. Overall and drug-related incidences of TEAEs in the Indian sub-group population were 42.0% and 17.4%, respectively, which were numerically lower than 67.6% and 41.2%, the incidence of overall and drug-related TEAEs, respectively, reported in study N01358, 60.7% and 34.2%, respectively, reported in study N01252, and 68% and 42.8% respectively, reported by Ben-Menachem E et al. No incidence of TEAE related to discontinuation of BRV was reported in the Indian sub-group population, compared to 7.6%, 4.7% and 6.7% incidences reported in studies N01358, N01252 and Pooled data from 3 pivotal trials (Ben-Menachem E et al.), respectively.
Behavioral and psychiatric TEAEs are of particular concern in patients with epilepsy. Analysis of pooled safety data showed no incidence of behavioral and psychiatric TEAEs with BRV therapy reported in the Indian sub-group population. Only 1.4% incidence of severe TEAEs were reported in the Indian sub-group population compared to 4.0%, 6.2% and 5.6% incidence of severe TEAEs reported in study N01252, N01358 and the pooled analysis by Ben-Menachem E et al., respectively. Moreover, 2.3%, 3.2% and 3.0% incidence of serious TEAEs, respectively, were reported in study N01252, N01358 and by Ben-Menachem E et al., compared to 1.4% incidence serious TEAEs reported in the Indian sub-group population.
Overall, BRV at different dosages was well tolerated in the Indian sub-group population, with numerically lower incidences of TEAEs, when compared to the pooled data population. A limitation of this Indian sub-group tolerability analysis is the small population size, which may not have been sufficient to detect AEs. More studies with adequate sample size are required to evaluate the tolerability and safety of BRV in the Indian epileptic population.
Brivaracetam is a highly selective and high-affinity SV2A ligand with high lipid-solubility, rapid brain penetration, and rapid onset of action. In India, BRV 50, 75, and 100 mg dosages are approved as adjunctive therapy in the treatment of partial-onset seizures in epileptic patients' ≥16 years of age.
All three dosages of BRV evaluated in this pooled analysis (50, 100, and 200 mg/day) demonstrated efficacy across multiple endpoints, in Indian patients with uncontrolled focal epilepsy. The results also demonstrated that all BRV dosages were well tolerated in Indian patients, with no report of drug discontinuation due to AEs, psychiatric and behavior TEAEs, and a very low incidence of severe and serious TEAEs. In addition, the tolerability data analysis also suggests a favorable psychiatric AE profile of the drug, in Indian patients with uncontrolled focal epilepsy. However, as with any study that pools data from across studies, there are limitations associated with the analysis of this pooled data, which includes minor differences in study populations and methodology. Nevertheless, results from this pooled data have provided evidence that adjunct BRVwas effective, well-tolerated and improved health-related quality of life in Indian patients with uncontrolled focal epilepsy, along with a favorable tolerability profile.
The authors thank the volunteers/patients (as relevant) and their caregivers (as relevant), in addition to the investigators and their teams who contributed to this trial/study. The authors acknowledge Svetlana Dimova and Cedric Laloyaux, UCB Pharma (Brussels, Belgium) for critical review of the manuscript and Kyoko Hirano, UCB Pharma (Tokyo, Japan) for overseeing publication development. Writing/editorial assistance was provided by Sandeep K Bhat and MIS team at medONE pharma solutions, Gurugram, India, which was funded by UCB Pharma.
Financial support and sponsorship
This study was sponsored by UCB Pharma. UCB Pharma was involved in the design and conduct of the study, collection, management, and analysis of the data.
Conflicts of interest
Swaroop Suresh, Alok Rasal and Sami Elmoufti are employees of UCB Pharma.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]