An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam Academic research paper on "Clinical medicine"

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Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

Brief Communication

An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam

Stephen L. Yates a,*< Toufic Fakhoury b, Wei Liang a, Klaus Eckhardtc, Simon Borghs d, Joseph D'Souza e

a UCB Pharma, Raleigh, NC, USA b Kentucky One Health, Lexington, KY, USA c UCB Pharma, Monheim, Germany d UCB Pharma, Slough, UK e UCB Pharma, Smyrna, GA, USA

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ARTICLE INFO

ABSTRACT

Article history: Received 27 July 2015 Revised 2 September 2015 Accepted 3 September 2015 Available online 29 September 2015

Keywords:

Behavioral adverse event

Brivaracetam

Epilepsy

Quality of life

Levetiracetam

We evaluated nonpsychotic behavioral adverse events (BAEs) in patients receiving levetiracetam (LEV) who switched to brivaracetam (BRV). Patients > 16 years of age, receiving 2-3 antiepileptic drugs (AEDs), including LEV 1-3 g/day, and experiencing BAEs within 16 weeks of LEV treatment initiation, enrolled in an open-label Phase 3b study (NCT01653262) comprising a < 1-week screening period, an immediate switch from LEV to BRV 200 mg/day (without titration), and a 12-week treatment period. The percentages of patients with investigator-assessed clinically meaningful reduction in BAEs, shift in maximum BAE intensity, and change in health-related quality of life (HRQoL) (Patient-Weighted Quality of Life in Epilepsy Inventory—Form 31 [QOLIE-31-P]) were assessed. Of 29 patients enrolled, 26 (89.7%) completed the study. At the end of the treatment period, 27/29 (93.1%) patients switched to BRV had clinically meaningful reductions in BAEs. Physicians reported a reduction in the maximum intensity of primary BAEs in 27/29 (93.1%) patients. Mean change from baseline to Week 12 in QOLIE-31-P total score was 12.1, indicating improved HRQoL. During the treatment period, 23/29 (79.3%) patients reported treatment-emergent adverse events (TEAEs). One patient reported a serious TEAE (suicidal ideation and suicide attempt). Two patients discontinued BRV because of TEAEs. Findings from this small study suggest that patients experiencing BAEs associated with LEV may benefit from switching to BRV.

© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Drug tolerability is a significant limiting factor in the treatment of patients with epilepsy, and long-term retention rates are often determined by adverse event profiles [1]. Levetiracetam (LEV) treatment has been reported to be associated with nonpsychotic behavioral adverse events (BAEs; classified by the Medical Dictionary for Regulatory Activities, e.g., agitation, antisocial reaction, anxiety, apathy, depersonalization, depression, emotional lability, euphoria, hostility, nervousness, neurosis, and personality disorder) in patients with epilepsy [2]. Previous analyses of LEV pivotal studies showed that ~13% of adult patients treated with LEV reported behavioral symptoms compared with ~ 6% of those who received placebo [3,4]. However, it has been suggested that patients taking LEV in clinical practice experience more behavioral symptoms than reported in clinical trials. In a study evaluating retention rates of newer

* Corresponding author at: UCB Pharma, 8010 Arco Corporate Drive Suite 100, Raleigh, NC 27617, USA. Tel.: +1 9197671665; fax: +1 9197672571. E-mail address: Stephen.Yates@ucb.com (S.L. Yates).

antiepileptic drugs (AEDs), 105/196 (53.6%) patients continued to take LEV adjunctive therapy after 2 years, while 91 (46.4%) had discontinued therapy [1]. BAEs accounted for 40.4% of the reasons for discontinuation (N = 94). Other leading causes of discontinuation were sedation (24.5%) and ineffectiveness (23.4%) [1]. Similar results were observed in elderly patients with newly diagnosed epilepsy; the retention rate for LEV monotherapy was 61.5%, and BAEs were reported in 29/122 (23.8%) patients [5].

Brivaracetam (BRV) is a selective, high-affinity ligand of the synaptic vesicle protein 2A (SV2A); it has a binding affinity approximately 15- to 30-fold higher than LEV [6], another SV2A ligand. In addition to this higher affinity for the SV2A binding site, BRV also differs from LEV in that it does not show modulatory activity at a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [7], whereas LEV does [8], suggesting that BRV has a distinct pharmacological profile compared with LEV. In Phase 3 clinical trials, BRV (50-200 mg/day) has demonstrated efficacy and a good tolerability profile in patients with partial-onset seizures (POS) [9-12].

The primary objective of this study was to evaluate potential changes in BAEs among patients who switched to BRV, without titration, after

http://dx.doi.org/10.1016/j.yebeh.2015.09.005

1525-5050/© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

discontinuing LEV because of the occurrence of drug-limiting BAEs considered by the investigators to be related to LEV.

2. Materials and methods

2.1. Study design

This was a Phase 3b, open-label, single-arm, prospective, multicenter study (N01395; NCT01653262) conducted between July 2012 and November 2013. Patients were enrolled from North America (USA) and Europe (France, Germany, and Spain).

The study comprised a screening period of < 1 week, a retrospective baseline period during LEV treatment where seizure counts were recorded for 4 weeks and BAEs for up to 16 weeks before switching to BRV, and a treatment period of 12 weeks. On Day 1 of the treatment period, the last dose of LEV was taken in the morning, and patients received the first dose of BRV100 mg b.i.d. (200 mg/day) without titration in the evening. Dose adjustments within the range of 50-200 mg/day were allowed if necessary. Completers were down-titrated over a maximum of 4 weeks followed by a 2- to 3-week study-drug-free period or entered into a long-term follow-up study without down-titration (N01372; NCT01728077).

The study was conducted in accordance with the International Conference on Harmonization notes for Guidance on Good Clinical Practice and the Declaration of Helsinki. The study protocol was approved by institutional review boards at all study sites, and written informed consent was obtained from all patients or their legal representatives before enrolment.

2.2. Study population

Patients recruited were adults > 16 years old, with well-characterized POS or primary generalized epilepsy [13]. Patients, receiving LEV in clinical practice at a recommended therapeutic dose (1-3 g/day), could participate if the investigator expected that they would have benefitted or were benefitting from LEV, but discontinuation of LEV was warranted within 16 weeks of initiation because of BAEs. Patients must have been receiving 2-3 AEDs, including LEV at a dosage that had been stable for >4 weeks (> 12 weeks for phenobarbital, phenytoin, and primidone) prior to screening.

Women without childbearing potential (postmenopausal or surgically sterilized) were eligible to participate. Women of childbearing potential were eligible with the use of a medically accepted contraceptive method. A family member/caregiver or close contact person, knowledgeable on a daily basis of the patient's adverse events, was required to be available during all study visits.

Key exclusion criteria included experience of cluster or flurry seizures, a history or presence of psychogenic nonepileptic seizures, or status epilepticus during the year preceding the study. Patients receiving LEV at a recommended therapeutic dose (1-3 g/day) for > 16 weeks were not eligible for this study. Other exclusion criteria included rapidly progressing brain disorder, brain tumor, or other serious uncontrolled disease.

23. Assessments

The primary safety variable was the proportion of patients achieving a clinically meaningful reduction in BAEs at the end of the treatment period, based on the investigator's overall assessment. Investigators answered 'yes' or 'no' to the following question: "Has there been a clinically meaningful reduction of nonpsychotic behavioral side effects since the start of BRV?". Secondary safety variables included investigator-assessed shift in maximum intensity ('resolved', 'mild', 'moderate', or 'severe') of primary BAEs (i.e., the BAE[s] associated with discontinuation of LEV) over the treatment period, Investigator Global Evaluation of Behavioral Side Effects (I-GEBSE; a 7-point scale ranging from

'marked worsening' to 'marked improvement'), complete abatement of primary BAEs based on investigator assessment, freedom from BAEs, treatment-emergent adverse events (TEAEs), withdrawal due to an adverse event, and occurrence of serious adverse events. Patients were asked at each study visit whether they had experienced any adverse events, and they could also spontaneously report adverse events. Other safety evaluations were collection of blood and urine samples for routine laboratory investigations, monitoring of electrocardiograms, vital signs, and physical and neurologic examinations.

Secondary efficacy variables included POS frequency during the treatment period, seizure days during the treatment period for patients with idiopathic generalized epilepsy, seizure freedom (all seizure types), change in health-related quality of life (HRQoL) assessed using Patient-Weighted Quality of Life in Epilepsy Inventory—Form 31 (QOLIE-31-P), Patient Global Evaluation Scale (P-GES), and Investigator Global Evaluation Scale (I-GES). Baseline seizures were collected retrospectively and, thereafter, were recorded on the patient's daily record card. A specific effect of BRV on the occurrence of generalized seizures was not assessed.

2.4. Analysis

As this was an exploratory study, there was no sample size calculation, and all analyses were descriptive. The aim was to recruit 30 patients. Analyses of the safety and efficacy variables were based on the final data available for each patient (last observation carried forward).

3. Results

Because of unexpected recruitment difficulties, enrollment was closed at 29 patients. This decision was not made because of any safety or compliance concerns. The slightly lower sample size was considered as insignificant and not expected to affect the planned analyses. Of the 29 patients enrolled, 26 (89.7%) patients completed the study. During the treatment period, 7/29 (24.1%) patients required a dose adjustment. Reasons for discontinuation were: TEAEs (2/29 [6.9%]) and lack of efficacy (1/29 [3.4%]). The mean (standard deviation [SD]) age was 35.8 (11.8) years (range: 19-55 years); 15 (51.7%) were male, and 24 (82.8%) were Caucasian. Baseline demographics and disease characteristics are reported in Table 1. The primary BAEs that led to discontinuation of LEV treatment in more than one patient were (preferred term, in order of frequency) irritability, anxiety, anger (including verbatim term short temper), agitation, depression, mood swings, aggression, fatigue, and insomnia.

3.1. Safety

The majority of patients (n = 27 [93.1%]) who switched from LEV to BRV had a clinically meaningful reduction in BAEs, as determined by the investigator, at the end of the treatment period. The secondary safety analyses also showed improvements in BAEs. A reduction in the maximum intensity of primary BAEs associated with discontinuation of LEV was seen in 27/29 (93.1%) patients, and no patients reported a worsened intensity from baseline to the end of the treatment period (Table 2).

A total of 20/29 (69.0%) patients showed a marked or moderate improvement in BAEs, measured by the I-GEBSE. There was a slight improvement of BAEs in 4/29 patients. One patient (3.4%) had slight worsening, and one patient (3.4%) had marked worsening of BAEs. I-GEBSE data were missing for one patient (3.4%).

At the end of the treatment period, complete abatement (events which ended during the treatment period) from primary BAEs was reported for 18 (62.1%) patients. Of these, three (10.3%) had freedom from BAEs throughout the treatment period. The median time to primary BAE resolution (defined as the time between the date of the first dose

Table 1

Baseline demographics and disease characteristics.

Characteristic Brivaracetam

(N = 29)

Age, mean (SD) 35.8 (11.8)

Sex, n (%)

Male 15 (51.7)

Female 14 (48.3)

Weight, mean (kg) 82.3 (23.1)

Height, mean (cm) 172.6 (10.6)

BMI, mean (kg/m2) 27.6 (7.1)

Race, n (%)

White 24 (82.8)

Black 0 (0.0)

Asian 0 (0.0)

Other 1 (3.4)

Missing 4 (13.8)

Ethnicity, n (%)

Hispanic or Latino 3 (10.3)

Not Hispanic or Latino 22 (75.9)

Missing 4 (13.8)

Epilepsy duration (years), mean (SD) 16.2 (12.7)

Epileptic seizure profile, n (%)

Partial-onset seizures 22 (75.9)

Simple partial seizures 10 (34.5)

Complex partial seizures 15 (51.7)

Partial evolving to secondarily generalized seizures 16 (55.2)

Primary generalized seizures 9 (31.0)

Absence 4 (13.8)

Atypical absence 1 (3.4)

Myoclonic 5 (17.2)

Clonic 1 (3.4)

Tonic 0 (0.0)

Tonic-clonic 8 (27.6)

Atonic 1 (3.4)

Unclassifiable 1 (3.4)

Concomitant AEDs in > 10% of the patient population, n (%)

Lamotrigine 11 (37.9)

Topiramate 4 (13.8)

Carbamazepine 3 (10.3)

Lacosamide 3 (10.3)

Oxcarbazepine 3 (10.3)

Valproate 3 (10.3)

Clobazam 3 (10.3)

of BRVand the last reported occurrence plus 1) was 15 days after the first BRV dosage.

Non-behavioral TEAEs were reported in 23/29 (79.3%) patients; the most frequently reported TEAEs were headache (17.2%), fatigue (10.3%), and back pain (10.3%) (Table 3). The majority ofTEAEs were mild or moderate in intensity. TEAEs leading to discontinuation of the study drug occurred in two (6.9%) patients; one case of myoclonic epilepsy was considered treatment-related, and one patient, with a history of altered moods and morbid thoughts that had been attributed to LEV treatment, reported a serious TEAE (suicidal ideation and suicide attempt) which was not considered related to the study drug. One patient discontinued treatment because of lack of efficacy.

Table 2

Shift in maximum intensity of nonpsychotic behavioral adverse events primarily associated with discontinuation of levetiracetam over the treatment period.

Intensity of BAEs at baseline Intensity of BAEs at end of treatment period, n (%)

Resolved Mild Moderate Severe

Mild 1 (3.4) 1 (3.4) 0 0

Moderate 10 (34.5) 3 (10.3) 1 (3.4) 0

Severe 8 (27.6) 2 (6.9) 3 (10.3) 0

Total 19 (65.5) 6 (20.7) 4(13.8) 0

BAE, nonpsychotic behavioral adverse event.

Table 3

Overall summary of treatment-emergent adverse events reported during the treatment period.

Number of patients (%) N = 29

Any TEAEs 23 (79.3)

Drug-related TEAEs 10 (34.5)

Severe TEAEs 3 (10.3)

Discontinuation due to TEAEs 2 (6.9)

Serious TEAEs 1 (3.4)

Deaths 0 (0)

TEAEs with reported frequency >5%

Headache 5(17.2)

Fatigue 3 (10.3)

Back pain 3 (10.3)

Depression 2 (6.9)

Dizziness 2 (6.9)

Insomnia 2 (6.9)

Nasopharyngitis 2 (6.9)

Tremor 2 (6.9)

TEAE, treatment-emergent adverse event.

32. Efficacy

The median number of POS during the treatment period was similar to baseline during LEV treatment (median increase of 0.6 seizures/28 days). Seizure freedom (all seizure types) during the treatment period was observed in 7/29 (24.1%) patients. A specific effect ofBRV on the occurrence of generalized seizures was not assessed.

Administration ofBRV resulted in improved HRQoLas indicated by a mean (SD) increase of 12.1 (11.4) from baseline to the end of the treatment period in QOL1E-31-P total score. There was a consistent mean (SD) improvement in all QOL1E-31-P subscale scores from baseline to the end of the treatment period: cognitive functioning 10.4 (19.0), emotional well-being 14.0 (17.4), energy/fatigue 10.6 (13.7), medication effects 27.6 (25.5), overall quality of life 13.8 (13.3), seizure worry 12.1 (26.0), social functioning 10.3 (23.3), and health status 6.5 (16.5).

Improvements in P-GES and I-GES at Week 12 were observed for the majority of patients; the level of improvement as reported by patients and investigators was similar. For the P-GES, 20/26 (76.9%) patients reported an improvement, and 1/26 (3.8%) reported worsening. Based on the I-GES, 24/26 (92.3%) investigators reported improvement, and 1/26 (3.8%) reported worsening.

4. Discussion

A marked number of patients experienced a clinically meaningful reduction in BAEs which, when combined with the observed increase in QOL1E-31-P scores and the improvements reported in both the P-GES and I-GES assessments, suggests that a switch from LEV to BRV may have a positive impact on patients' behavioral profile, quality of life, and health status. It should be noted that this study recruited patients for whom the investigator had already decided to discontinue LEV because of the occurrence of drug-limiting BAEs.

Improvements in QOL1E-31-P were substantial in comparison with other fixed-dose [14,15] and long-term extension [16,17] studies of adjunctive AEDs. Those aspects of quality of life associated with medication effects were particularly improved, which is likely to be related to the reduction of BAE incidence. The large improvements observed in QOL1E-31-P may be due to the open-label nature of the study and the flexible dose design which allowed for adjustments to optimize tolerability and response.

During treatment with BRV, POS frequency was comparable to the retrospective baseline. BRV appeared to be well tolerated, and discontinuations due to TEAEs were low (2/29 [6.9%]), which is consistent with a previous large flexible dose study [11].

Overall, results from this small study suggest that patients who experience BAEs warranting the discontinuation of LEV treatment might benefit from a switch to BRV without titration. However, results should be interpreted with caution owing to the small sample size, lack of prospective baseline seizure data, short treatment period, and open-label design. Therefore, further confirmation of these results in future randomized, blinded studies would be of interest.

Acknowledgments

The authors thank the members of the N01395 Study Group and the patients who participated in the study for their contribution to the research. This study was sponsored by UCB Pharma. UCB Pharma was involved in the design and conduct of the study and the collection, management, and analysis of the data. Katie Alexander, Ph.D. (QXV Communications, an Ashfield business, part of UDG Healthcare plc), provided editorial support which was funded by UCB Pharma. Cédric Laloyaux (UCB Pharma) provided critical review of the manuscript.

Disclosures

SY, WL, KE, SB, and JD are current employees of UCB Pharma. TF has received personal fees and other fees from UCB, Marinus, Upsher-Smith, and Sunovion outside the submitted work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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