Journal Pre-proof

A systematic review and indirect treatment comparison of perampanel

versus brivaracetam as adjunctive therapy in patients with focal-onset
seizures with or without secondary generalization

Eugen Trinka, Wan Tsong, Sydney Toupin, Anna Patten, Katy

Wilson, Jaana Isojarvi, Daniel James

PII: S0920-1211(20)30171-6
DOI: https://doi.org/10.1016/j.eplepsyres.2020.106403
Reference: EPIRES 106403

To appear in: Epilepsy Research

Received Date: 12 March 2020

Revised Date: 9 June 2020
Accepted Date: 20 June 2020

Please cite this article as: Trinka E, Tsong W, Toupin S, Patten A, Wilson K, Isojarvi J, James
D, A systematic review and indirect treatment comparison of perampanel versus brivaracetam
as adjunctive therapy in patients with focal-onset seizures with or without secondary
generalization, Epilepsy Research (2020),
doi: https://doi.org/10.1016/j.eplepsyres.2020.106403

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Title

A systematic review and indirect treatment comparison of perampanel versus brivaracetam as

adjunctive therapy in patients with focal-onset seizures with or without secondary generalization

Authors and affiliations

Dr. Mag. Eugen Trinka, FRCP [Department of Neurology, Christian Doppler University Hospital,
Paracelsus Medical University, Harrerstrasse 79, A-5020 Salzburg, Austria; E-mail address:
eugen@trinka.at and e.trinka@salk.at]

Wan Tsong [Formerly Eisai Inc, 100 Tice Blvd, Woodcliff Lake, NJ 07677, United States. E-mail

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address: wtsong.esi@gmail.com]

Sydney Toupin [Quantics Biostatistics, Exchange Tower, 19 Canning Street Fourth Floor, Edinburgh,

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EH3 8EG, United Kingdom. E-mail address: sydney.toupin@outlook.com]

Anna Patten [Eisai Ltd. [European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire, AL10
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9SN, United Kingdom] E-mail address: Anna_Patten@eisai.net]
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Katy Wilson [York Health Economics Consortium, Enterprise House, Innovation Way, University of
York, York, YO10 5NQ, United Kingdom. E-mail address: katy.wilson@york.ac.uk]
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Jaana Isojarvi [York Health Economics Consortium, Enterprise House, Innovation Way, University of
York, York, YO10 5NQ, United Kingdom. E-mail address: jaana.isojarvi@york.ac.uk]

Daniel James [Quantics Biostatistics, Exchange Tower, 19 Canning Street Fourth Floor, Edinburgh,
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EH3 8EG, United Kingdom. E-mail address: Daniel.James@quantics.co.uk]

Highlights
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 Comparisons of efficacy and safety between perampanel and brivaracetam made

 No evidence of a difference in the efficacy of perampanel and brivaracetam
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 Perampanel and brivaracetam effective in adjunctive treatment of focal-onset seizures

 Perampanel improves responder rate in patients taking concomitant levetiracetam
 The adverse event profiles of perampanel and brivaracetam are similar

Page 1 of 20
Abstract

Purpose
To date, there has not been a single randomized controlled trial (RCT) conducted to directly compare
the efficacy and safety of perampanel to brivaracetam in the adjunctive treatment of focal-onset
seizures. This study makes these comparisons through the use of indirect treatment comparison
(ITC) methods.

Methods
A systematic review was conducted to identify RCTs that evaluated either one of perampanel or

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brivaracetam in the treatment of patients with focal-onset seizures. The Bucher ITC method was
then used to compare efficacy and safety outcomes between perampanel and brivaracetam.
Additional subgroup analyses, by levetiracetam usage (prior or concomitant), were conducted.

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Results
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Eight RCTs (four comparing perampanel to placebo, four comparing brivaracetam to placebo) were
included in the ITC. For patients taking concomitant levetiracetam, perampanel showed a
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significantly better responder rate compared to brivaracetam [relative risk (RR) and 95% confidence
interval (CI): 2.62 (1.15, 5.99)]. For patients who had previously, or never, taken levetiracetam, there
was no difference in the responder rate. In the overall population, both perampanel and
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brivaracetam were more effective than placebo in terms of responder rate, seizure freedom, and
secondarily generalized tonic-clonic seizure responder rate; however, for these outcomes, no
evidence of a difference between perampanel and brivaracetam was found. Patients taking
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brivaracetam showed significantly less dizziness compared to patients taking perampanel. No

differences for any other safety outcome were found.
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Conclusion
Perampanel and brivaracetam are effective for the adjunctive treatment of focal-onset seizures and
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display similar adverse event profiles. Perampanel demonstrated an improved focal-onset seizure
responder rate compared to brivaracetam in patients taking concomitant levetiracetam. This may be
due to the similarity in the mechanism of action between brivaracetam and levetiracetam.

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Keywords: perampanel, brivaracetam, partial-onset seizures, meta-analysis, indirect treatment
comparison

1. Introduction
Worldwide, 65 million people suffer from epilepsies, which are the most common group of chronic,
serious neurological disease [1, 2]. Although many patients can be treated successfully with
antiepileptic drugs (AEDs), at least one third of people are pharmacoresistant [3, 4]. Most of the

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burden of the disease is attributable to drug-resistant epilepsy [5], due to frequently occurring
comorbid illnesses [6], psychological dysfunction, social stigmatization [7, 8], reduced quality of life,

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increased risk of mortality [9-11], and, ultimately a decreased life expectancy [11, 12].

Focal-onset seizures (FOS; previously known as partial-onset seizures) [13] are the most prevalent
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type of seizures, often starting in childhood or adolescence and accounting for approximately two
thirds of all epileptic seizures [14-16]. While the cure for epilepsy does not exist [17], the goal of
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current treatment management is to prevent seizure recurrence [18-20].

Perampanel, launched in 2014, and brivaracetam, launched in 2016, are the two most recently
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available therapeutic options for the treatment of focal-onset seizures. Perampanel is an orally
active, noncompetitive, and highly selective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) receptor antagonist. It is indicated as adjunctive therapy for the treatment of focal-onset
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seizures with or without secondarily generalized tonic-clonic seizure (SGTCS) and primary
generalized tonic-clonic seizures (PGTCS) in patients with epilepsy aged 12 years and older [21].
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Brivaracetam is a new anti-epileptic drug, structurally related to levetiracetam, but with a higher
selective affinity for the synaptic vesicle 2A (SV2A) protein in the brain, by which it is assumed to
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exert its pharmacological action [22]. It is approved as an adjunctive treatment for focal-onset
seizures with or without secondary generalization in adult and adolescent patients 16 years and
older [23].

To date, there has not been a single randomized controlled trial (RCT) conducted to directly compare
the efficacy and safety of perampanel to brivaracetam in the adjunctive treatment of focal-onset
seizures. This study makes these comparisons through the use of indirect treatment comparison

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(ITC) methods. ITC is an extension of meta-analysis to situations where there are more than two
relevant treatments. ITC methods are now widely used and are accepted by health technology
assessment bodies such as the National Institute for Health and Care Excellence in England and the
Canadian Agency for Drugs and Technologies in Health [24, 25].

Although Brigo et al. [26] have previously used ITC to compare perampanel and brivaracetam along
with eslicarbazepine acetate and lacosamide, this systematic review and ITC add to their work by
exploring responder rate by levetiracetam usage and evaluating a wider range of outcomes,
including specific adverse events (AEs). This study will aid clinicians and payers to make informed
decisions, and further understand the relative efficacy and safety of perampanel and brivaracetam.

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2. Methods

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A systematic review was conducted to identify eligible studies, according to a protocol developed a
priori. The systematic searches, study selection and risk of bias assessment were undertaken
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according to the relevant principles of systematic reviewing embodied in the Cochrane handbook
[27] and guidance published by the Centre for Reviews and Dissemination [28]. Following the
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identification of eligible studies, meta-analysis and the Bucher ITC method were used to compare
efficacy and safety outcomes between perampanel and brivaracetam.
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2.1 Eligibility criteria

RCTs were eligible for inclusion in the analysis if they evaluated adjunctive oral perampanel or
adjunctive oral brivaracetam in patients aged 12 years and over with uncontrolled or refractory
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focal-onset seizures both with and without SGTCS. Eligible RCTs compared oral perampanel or
brivaracetam (any dose) to each other or placebo. Studies were required to be phase III and
published in English from 2007. Only studies published from 2007 onward were chosen because
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perampanel and brivaracetam were launched 5 or more years following 2007, providing an
appropriate window to capture all available studies. Studies evaluating generalized onset seizures
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and studies investigating children under the age of 12 were excluded.

2.2 Search methods

Systematic literature searches were conducted in May 2017 and an updated search was performed
in January 2019. The databases searched were MEDLINE, PubMed, Embase, Cochrane Database of
Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews
of Effects, Health Technology Assessment Database, Drugs@FDA Database, and the European Public
Page 4 of 20
Assessment Reports database. The search strategies used both in 2017 and 2019 can be found in
Table S2 of the supplementary material.

2.3 Study selection

The search results were assessed against the eligibility criteria. Obviously irrelevant records, such as
animal studies, commentaries and news items, and records on issues unrelated to the topic of
interest were removed. The titles and abstracts of records were then screened against the eligibility
criteria within Covidence software by two independent reviewers, with any disagreements
adjudicated by a third reviewer. Where a study was clearly relevant or possibly relevant, the full text
document was obtained. The full text documents were assessed against the review’s eligibility
criteria by two independent reviewers, with disagreements adjudicated by a third reviewer.

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2.4 Data extraction
For the eligible studies, data were extracted into Excel by one reviewer and checked by another.

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Discrepancies were resolved through discussion or by consulting a third reviewer. The data extracted
included study design characteristics, baseline patient characteristics [age, gender, race, region,
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weight, duration of epilepsy, baseline seizure frequency, concomitant AEDs], efficacy outcomes
[responder rate (50% seizure reduction) (for the full population and according to levetiracetam
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usage), seizure freedom (all seizure types) and secondarily SGTCS responder rate (50% reduction in
SGTCS)] and safety outcomes [any AE, serious AEs, severe AEs, discontinuation due to AE and
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specific AEs (specific AEs were included if they were available for all of the eligible studies)]. For
perampanel, additional data were extracted from the clinical study reports [29-32] and the
integrated summaries of efficacy and safety [33, 34]. Where available, data were extracted for the
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intent-to-treat (ITT) population.

2.5 Risk of bias assessment

Two reviewers independently assessed the risk of bias of the eligible studies using the Cochrane risk
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of bias tool [35]. Any conflicts were adjudicated by a third reviewer.

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2.6 Similarity assessment

For the eligible studies, the study design and baseline patient characteristics and the definitions of
the outcomes were reviewed in order to determine whether it was reasonable to combine the
studies in an ITC.

Page 5 of 20
2.7 Indirect treatment comparison
ITC was conducted using the Bucher method [36]. The Bucher method combines a standard meta-
analysis for perampanel versus placebo, with a standard meta-analysis for brivaracetam versus
placebo, to obtain an overall estimate of the effect of perampanel versus brivaracetam. Meta-
analysis was conducted by applying a random-effects model to the log relative risks (RRs) and the log
odds ratios (ORs). Both the meta-analysis and ITC results were summarized using RRs and ORs, and
their 95% confidence intervals (CIs). All analysis was conducted using the statistical software R [37].
The package ‘meta’ was used to conduct the meta-analyses [38].

Figure 1: PRISMA diagram

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3. Results
3.1 Searches and study selection
The database searches identified a total of 4700 records; 20 records were identified through other
sources. After duplicates were removed, 1828 records remained for screening. Following screening

Page 6 of 20
of their titles and abstracts, 135 records were evaluated based on their full text articles. A total of 46
records, reporting data for 9 studies met the eligibility criteria. A list of the eligible studies (Table S3)
and a list of the excluded studies (Table S4) can be found in the supplementary material. For
perampanel, 5 studies were identified: studies 304 [39], 305 [40], 306 [41], 307 [42] and 335 [43].
For brivaracetam, 4 studies were identified: studies N01252 [44], N01253 [45], N01254 [46] and
N01358 [47]. The study selection process is shown in Figure 1.

3.2 Risk of bias assessment

Since study 307 [42] was an extension study of studies 304 [39], 305 [40] and 306 [41] , a separate
risk of bias assessment for this study was not conducted. Overall the studies were found to have a
low to unclear risk of bias predominantly due to the limited reporting by each study (supplementary

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material, Table S5 and Table S6). However, it should be noted that in seven of the studies (Study
304, Study 305, Study 306, N01252, N01253, N01254, and Study 335) it was possible for the dose of

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perampanel or brivaracetam to be reduced according to tolerability. Therefore, it is possible that the
efficacy outcomes may have been confounded by patients who were unable to achieve their target
randomised dose. Hence, these studies were rated as having a high risk of bias for this criterion.
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3.3 Similarity assessment
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The study design and for the primary studies are summarized in Table 1. Baseline patient
demographics, epilepsy characteristics and concomitant AEDs are summarized in Table 2. Study 307
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[42] is not included as it did not include a control arm for the extension period, and therefore does
not provide new data beyond that provided by studies 304 [39], 305 [40] and 306 [41].

All perampanel studies consisted of a 6 week baseline period, a 6 week titration period and a 13 week
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maintenance period. Three of the brivaracetam studies (N01252 [44], N01253 [45], and N01358 [47])
consisted of an 8 week baseline period and a 12 week treatment period, while study (N01254 [46])
consisted of a 4 week baseline period, an 8 week titration period and an 8 week treatment period. The
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titration periods are excluded from the efficacy analyses. Efficacy was measured over a similar time
frame, with most studies using a 12 or 13 week period. However, study N01254 [46] was an exception,
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where efficacy was measured over only an 8 week period. Safety was measure over a 19 week period
for all perampanel studies, over a 12 week period for three brivaracetam studies (N01252 [44],
N01253 [45], and N01358 [47]) and over a 16 week for the fourth brivaracetam study (N01254 [46]).

Page 7 of 20
Table 1: Summary of the eligible studies

Region
Asia /
Eligible North Latin

f
Study Study Date Key Phases N Europe Pacific /
treatments America America

oo
Other
n % n % n % n %
Placebo 100
N01252 Sep 2007 - Baseline: 8 wks
BRV 50mg/day 99 Not reported
[44]1 Feb 2009 Treatment: 12 wks
BRV 100mg/day 100

pr
N01253 Sep 2007 - Baseline: 8 wks Placebo 98
Not reported
[45]1 Jan 2009 Treatment: 12 wks BRV 50mg/day 101
Baseline: 4 wks Placebo 121
N01254 Oct 2007 -

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Titration: 8 wks Not reported
[46]1 Dec 2008 BRV 150mg/day3 359
Maintenance: 8 wks
Placebo 261 62 23.9 29 11.2 136 52.5 32 12.4
N01358 Dec 2010 - Baseline: 8 wks
BRV 100mg/day 253 64 25.4 27 10.7 130 51.6 31 12.3

Pr
[47]2 May 2014 Treatment: 12 wks
BRV 200mg/day 250 61 24.5 28 11.2 132 53.0 28 11.2
Baseline: 6 wks Placebo 121 73 59.8 49 40.2 0 0.0 0 0.0
Apr 2008 -
304 [39]2 Titration: 6 wks PER 8mg/day3 133 74 55.6 59 44.4 0 0.0 0 0.0
Nov 2010
Maintenance: 13 wks PER 12mg/day3 134 81 60.0 54 40.0 0 0.0 0 0.0
Baseline: 6 wks Placebo 136 33 23.9 0 0.0 73 52.9 32 23.2
305 [40]2 l
May 2008
Titration: 6 wks PER 8mg/day3 129 31 23.8 0 0.0 62 47.7 37 28.5
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- Jan 2011
Maintenance: 13 wks PER 12mg/day3 121 27 22.3 0 0.0 59 48.8 35 28.9
Baseline: 6 wks Placebo 185 0 0.0 0 0.0 107 57.2 80 42.8
2 Aug 2008 - 3
306 [41] Titration: 6 wks PER 4mg/day 172 0 0.0 0 0.0 96 55.2 78 44.8
Jul 2010
Maintenance: 13 wks PER 8mg/day3 169 0 0.0 0 0.0 105 61.4 66 38.6
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Placebo 175 0 0.0 0 0.0 0 0.0 175 100.0

Baseline: 6 wks 3
May 2012- PER 4mg/day 174 0 0.0 0 0.0 0 0.0 174 100.0
335 [43]2 Titration: 6 wks
Sep 2014 PER 8mg/day3 175 0 0.0 0 0.0 0 0.0 175 100.0
Maintenance: 13 wks
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3
PER 12mg/day 180 0 0.0 0 0.0 0 0.0 180 100.0
BRV: brivaracetam, N/n: number of patients, PER: perampanel, SD: standard deviation.
1. Intention-to-treat (ITT) population, unless otherwise specified. 2. Safety population, unless otherwise specified. 3. Titrated. 4. Based on 132 patients. 5. Based on 172 patients. 6. Based on
178 patients.

Page 8 of 20
Table 2: Baseline patient characteristics

Age (years) Gender Weight (kg) Epilepsy duration Baseline focal-onset seizure
Number of concomitant AEDs LEV status
(years) frequency/week
Study Treatment N
Female Mean Mean 1 2 >=3 No Prior Concomitant

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Mean (SD) Median Q1-Q3 (min, max)
n (%) SD SD
n (%) n (%) n (%) n (%) n (%) n (%)

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Placebo 100 36.4 (13.0) 46 (46.0) 70.1 (17.3) 20.4 (12.3) 2.07 1.35-6.04 14 (14.0) 83 (83.0) 3 (3.0) 55 (55.0) 27 (27.0) 18 (18.0)

N01252 [44]1 BRV 50mg/day 99 38.9 (13.6) 45 (45.5) 71.1 (14.4) 22.3 (13.0) 1.80 1.25-3.47 20 (20.2) 77 (77.8) 2 (2.0) 51 (51.5) 28 (28.3) 20 (20.2)

BRV 100mg/day 100 38.0 (13.1) 42 (42.0) 72.0 (18.1) 22.1 12.8) 2.02 1.26-3.25 16 (16.0) 77 (77.0) 7 (7.0) 58 (58.0) 22 (22.0) 20 (20.0)

Placebo 37.5 (12.6) 55 (56.1) 77.0 (21.4) 24.3 (12.2) 2.6 1.6-4.5 13 (13.3) 80 (81.6) 4 (4.1) 55 (56.1) 22 (22.4) 19 (19.4)

pr
98
N01253 [45]1
BRV 50mg/day 101 38.9 (12.3) 50 (49.5) 75.0 (20.1) 26.2 (12.0) 2.9 1.5-7.2 13 (12.9) 82 (81.2) 6 (5.9) 62 (61.4) 20 (19.8) 19 (18.8)

Placebo 121 36.5 (11.5) 52 (43.0) 69.1 (14.9) 22.0 (11.8) 2.297 1.23-4.23 24 (19.8) 44 (36.4) 53 (43.8) 867,10 (79.6) 22 (20.4)
N01254 [46]1
BRV 150mg/day3 35.6 (11.5) 178 (49.6) 69.4 (15.4) 21.2 (12.2) 2.218 1.25-4.51 58 (16.2) 174 (48.5) 126 (35.1) 2628,10 (81.1) 61 (18.9)

e-
359
Placebo 259 39.8 (12.5) 128 (49.0) 76.1 (20.0) 22.7 (13.3) 2.50 (0.8, 140) 75 (29.0) 181 (69.9) 3 (1.2) 116 (44.8) 143 (55.2) 011 (0.0)

N01358 [47]1 BRV 100mg/day 252 39.1 (13.4) 151 (59.7) 74.1 (16.8) 22.2 (13.3) 2.38 (0.5, 89) 70 (27.8) 182 (72.2) 0 (0.0) 116 (46.0) 136 (54.0) 011 (0.0)

39.8 (12.8) 117 (46.8) 75.4 (19.0) 23.4 (14.6) 2.33 (0.8, 178) 69 (27.7) 179 (71.9) 1 (0.4) 115 (46.2) 134 (53.8) 011 (0.0)

Pr
BRV 200mg/day 249

Placebo 121 35.6 (14.7) 67 (55.4) 72.6 (20.5) 24.1 (12.9) 3.42 (0.8, 57) 15 (12.4) 64 (52.9) 42 (34.7) 80 (66.1) 12 (9.9) 29 (24.0)

304 [39]2 PER 8mg/day3 133 35.8 (14.2) 68 (51.1) 71.14 (18.0) 23.6 (13.5) 3.59 (0.6, 258) 26 (19.5) 70 (52.6) 37 (27.8) 81 (60.9) 15 (11.3) 37 (27.8)

PER 12mg/day3 134 36.7 (14.6) 65 (48.5) 73.7 (18.7) 23.34 (14.4) 3.004 (0.7, 271) 19 (14.2) 82 (61.2) 33 (24.6) 83 (61.9) 10 (7.5) 41 (30.6)

Placebo 136 34.4 (13.6) 65 (47.8) 71.6 (17.6) 22.0 (12.9) 2.95 (0.9, 90) 17 (12.5) 64 (47.1) 55 (40.4) 66 (48.5) 17 (12.5) 53 (39.0)

305 [40]2 PER 8mg/day3 36.7 (14.4) l

64 (49.6) 72.0 (19.0) 22.5 (13.6) 3.26 (0.8, 163) 16 (12.4) 68 (52.7) 45 (34.9) 63 (48.8) 17 (13.2) 49 (38.0)
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129
PER 12mg/day3 121 35.5 (14.1) 71 (58.7) 71.9 (18.7) 21.3 (13.2) 3.42 (0.4, 150) 9 (7.4) 63 (52.1) 49 (40.5) 56 (46.3) 19 (15.7) 46 (38.0)

Placebo 185 33.4 (12.6) 90 (48.6) 67.5 (16.0) 17.5 (10.7) 2.339 (0.8, 142) 28 (15.1) 90 (48.6) 67 (36.2) 115 (62.2) 25 (13.5) 45 (24.3)

306 [41]2 PER 4mg/day3 172 33.6 (12.2) 84 (48.8) 69.5 (17.2) 19.75 (12.2) 2.51 (0.7, 1126) 19 (11.0) 88 (51.2) 65 (37.8) 94 (54.7) 33 (19.2) 45 (26.2)
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PER 8mg/day3 169 34.6 (12.8) 92(54.4) 68.5 (16.3) 20.06 (11.9) 2.73 (0.9, 181) 27 (16.0) 82 (48.5) 60 (35.5) 95 (56.2) 29 (17.2) 45 (26.6)

Placebo 175 34.5 (13.2) 89 (50.9) 61.85 (14.5) 17.5 (10.9) 2.50 (0.8, 155) 11 (6.3) 67 (38.3) 97 (55.4) 99 (56.6) 2 (1.1) 74 (42.3)

PER 4mg/day3 174 33.1 (13.2) 94 (54.0) 61.75 (14.4) 17.4 (11.1) 2.48 (0.8, 78) 9 (5.2) 70 (40.2) 95 (54.6) 90 (51.7) 6 (3.4) 78 (44.8)
335 [43]2
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PER 8mg/day3 175 33.6 (14.1) 84 (48.0) 62.1 (16.2) 16.9 (11.5) 2.28 (0.8, 97) 15 (8.6) 60 (34.3) 100 (57.1) 108 (61.7) 4 (2.3) 63 (36.0)

PER 12mg/day3 180 32.3 (12.3) 93 (51.7) 60.96 (15.5) 17.4 (11.2) 2.48 (0.7, 74) 13 (7.2) 75 (41.7) 92 (51.1) 98 (54.4) 8 (4.4) 74 (41.1)

AED: anti-epileptic drug, BRV: brivaracetam, LEV: Levetiracetam, N/n: number of patients, PER: perampanel, Q1: lower quartile, Q3: upper quartile, SD: standard deviation.1. Intention-to-treat (ITT) population,
unless otherwise specified. 2. Safety population, unless otherwise specified. 3. Titrated. 4. Based on 133 patients. 5. Based on 171 patients. 6. Based on 168 patients. 7. ITT focal-onset population, 108 patients. 8.
ITT focal-onset population, 323 patients. 9. Based on 184 patients. 10. No LEV during the treatment period. Includes patients who may have previously received LEV. 11. Patients receiving LEV were not eligible for
Klein et al.

Page 9 of 20
For the perampanel studies, dosages were optimised during the titration period, with all patients,
initiated at a dose of 2mg/day. The dose was then increased at weekly intervals in increments of 2 mg
up to a target randomized dose level of between 2mg/day and 12mg/day. Subjects experiencing
intolerable AEs, according to the investigators’ clinical judgment, could remain on the same dose or
have their dose reduced to the previously tolerated dose. Subjects whose dose was down-titrated
could have their dose increased again, as soon as the tolerability improved. For the purpose of the
meta-analysis it is assumed that each of these doses is equally safe and effective. Note that, the target
dose of 2mg/day is excluded from further analysis as it is not licensed by the United States Food and
Drug Administration (FDA) or the European Medicines Agency (EMA).

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Three of the brivaracetam studies (N01252 [44], N01253 [45], and N01358 [47]) investigated fixed
doses ranging from 5mg/day to 200mg/day. The fourth brivaracetam study (N01254 [46]) used a

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titration scheme with a target dose of 150mg/day. In this study, brivaracetam was initiated at 20
mg/day and titrated in a stepwise manner to 50, 100, or 150 mg/day, at 2-weekly intervals based on
the investigator’s assessment of efficacy and tolerability.-p The meta-analysis only includes
brivaracetam doses between 50mg/day and 200mg/day (including the titrated dose of up to
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150mg/day), since these are the doses licensed by the FDA and the EMA.

Generally, patients’ baseline characteristics were similar across the studies. However, patients in three
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of the brivaracetam studies (N01252 [44], N01253 [45], and N01358 [47]) received fewer concomitant
AEDs than patients in any of the perampanel studies. In these three studies less than 5% of patients
were on more than 2 AEDs. In all of the other studies [39-41, 43, 46], at least 25% of patients were on
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more than 2 AEDs. Concomitant levetiracetam was allowed in all but one of the brivaracetam studies,
N01358 [47], where patients receiving concomitant levetiracetam were ineligible for inclusion.
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Figure 2: Network diagram

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3.4 Indirect treatment comparison

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The network diagram is shown in Figure 2. For most outcomes in the overall population, the studies
showed a minimal degree of heterogeneity (I2 ≤ 40%); of notable exception were for the perampanel
outcomes of dizziness (I2 = 61%) and somnolence (I2 = 58%). The results of the meta-analyses and

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ITCs using the pooled dose data on the risk ratio scale are summarized in Figure 3. Based on all
patients, both perampanel and brivaracetam were found to be more effective than placebo in terms
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of responder rate, seizure freedom and SGTCS responder rate; however, for these outcomes, there
was no evidence of a difference between perampanel and brivaracetam.
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For patients taking concomitant levetiracetam, perampanel showed a significantly better responder
rate compared to brivaracetam [relative risk (RR) and 95% confidence interval (CI): 2.62 (1.15, 5.99)].
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For patients who had previously taken levetiracetam, or never taken levetiracetam, brivaracetam
demonstrated a statistically significant improvement compared to placebo; whereas, perampanel
showed a significantly improved responder rate when compared to placebo for either patients
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taking concomitant levetiracetam, or for patients that had never taken levetiracetam. However,
there was no evidence of a difference in the responder rate between brivaracetam and perampanel
among patients who had previously taken levetiracetam, or never taken levetiracetam.
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The meta-analyses indicated that, compared with placebo, patients receiving either perampanel or
brivaracetam have greater risks of any AE, discontinuation due to AEs, dizziness, fatigue, irritability
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and somnolence. Compared with placebo, patients receiving perampanel also have a greater risk of
severe AEs. There was no evidence that either perampanel or brivaracetam increased the risk of
serious AEs, headache, nausea or insomnia, compared with placebo.

For the safety outcomes, it was found that patients taking both brivaracetam and perampanel had
increased dizziness compared to placebo, and patients taking brivaracetam had significantly less

Page 11 of 20
dizziness compared to patients taking perampanel. There is no evidence of a difference between the
two treatments for any of the other safety outcomes.

These analyses were repeated using the odds ratio (OR), with results found in supplementary Figure
S1. Overall, the conclusions are consistent with those for the RR, apart from the safety outcome of
having any AE, where it is shown that patients taking brivaracetam have a significantly reduced odds
when compared to patients taking perampanel. However, RR are easier to interpret so have been
presented here.

For the outcomes where the required data were available, an additional analysis was performed
whereby doses of perampanel and brivaracetam were not combined. Rather a Bucher indirect
treatment comparison [36] was conducted to compare ‘low’ (50mg/4mg), ‘medium’ (100mg/8mg)

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and ‘high’ (200mg/12mg) dose levels of brivaracetam/perampanel. No statistically significant
differences in relative risk were observed between the two treatments across the different dose

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levels (Figure 4).

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Figure 3: Results of the meta-analyses and indirect treatment comparisons (relative risk estimates and 95% confidence intervals)

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AE: adverse event, BRV: brivaracetam, CI: confidence interval, ITC: indirect treatment comparison, ITT: intention to treat, LEV: levetiracetam, PER: perampanel,
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P: proportion, RR: relative risk, SGTCS: secondarily generalized tonic-clonic seizures.

Page 13 of 20
Figure 4: Dose-level analysis comparing low, medium and high

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Page 14 of 20
4. Discussion
This analysis adds to our understanding of rational polytherapy by comparing brivaracetam
(structurally related to levetiracetam with a higher selective affinity for the SV2A protein) and
perampanel (a highly selective AMPA antagonist) in subpopulations of patients with prior and
concomitant levetiracetam. Perampanel demonstrated a significantly better responder rate
compared to brivaracetam in patients taking concomitant levetiracetam. This is consistent with
previous findings that have shown that brivaracetam does not provide a significant benefit over a
placebo in this group [48]. However, in the overall population, there was no evidence of a difference
between brivaracetam and perampanel for responder rate; this finding is consistent with Brigo et al.
[26].

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In contrast to Brigo et al. [26], where a lower number of AEs were observed with a high dose of
brivaracetam compared to a high dose of perampanel, this analysis found no evidence of a

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difference in overall safety outcomes between perampanel and brivaracetam. Brigo et al. [26]
conducted their analysis on the OR scale, while, we used the RR as it is easier to interpret. However,
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on the OR scale, we too find a significant difference between brivaracetam and perampanel. Note
that while perampanel has a black box warning for “serious psychiatric and behavioral reactions,”
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brivaracetam does not have such a warning. AE interpretations are limited by potential differences
in coding and higher baseline AEDs in the perampanel trials.
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These conclusions are similar to those presented in [49] and [50] that compared alternative AEDs to
those considered here. In these papers it was found that efficacy was comparable across treatment
options, but that safety outcomes may differ, and therefore the choice of treatment could be
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tailored to the individual patient.

These conclusions are similar to those presented in x and y that compared alternative AEDs to those
considered here. In these papers it was found that efficacy was comparable, but that safety
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outcomes may differ among treatment options, and therefore when selecting a treatment physicians
could tailor their decision to the individual patient.
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While the eight studies were considered to be sufficiently similar to be included in the ITC, some
differences remain that may pose limitations when drawing conclusions. As previously noted, the
perampanel studies all measured safety over 19 weeks, however for brivaracetam study ([N01254
[46]]) safety was measured over 16 weeks, while for the remaining three studies safety was
measured over only 12 weeks. A smaller time frame could reduce opportunity to measure the

Page 15 of 20
occurrence of a safety outcome, thereby underestimating the number of occurrences compared to a
study with a longer time frame.

Additionally, the studies differed in the number of concomitant AEDs taken by patients. In the four
perampanel studies and brivaracetam study (N01254) [46], at least one third of the patients were
taking three or more concomitant AEDs. However, in the remaining three brivaracetam studies, no
more than one tenth of the patients were taking three or more concomitant AEDs. Therefore, it
could be possible that fewer drug resistant patients were included in the brivaracetam trials when
compared to the perampanel trials. Furthermore, the higher number of concomitant AEDs in the
perampanel trials could also have resulted in an increased frequency of adverse events, when
compared to brivaracetam. This can make it difficult to determine if side effects are caused by one

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of the concomitant AEDs or the treatment of interest. Lastly, the EMA reported that the decreased
efficacy seen in brivaracetam treated patients with prior exposure to levetiracetam in trial N01358

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may be a result of the higher number of prior AEDs and baseline seizure frequency seen in this
subgroup [23]. In either case, it demonstrates the difference of patient populations represented in
the studies as patients with more concomitant AEDs might tend to suffer from a more severe form
of epilepsy.
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A limitation of this review is that only studies published in the English language were eligible and
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therefore there is the possibility that non-English language studies may exist that have evaluated the
drugs of interest in the chosen population. Another limitation is that whilst RCTs provided the
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highest standard of clinical trial evidence [49], it is often found that data on adverse events are
reported in observational studies and therefore restricting the eligibility to just RCTs is an
acknowledged limitation of this review. A possible limitation of seven of the studies is that as dose
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reductions were permitted due to issues relating to tolerability, the efficacy outcomes may have
been confounded by patients who were unable to achieve their target randomised dose.
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5. Conclusions
Perampanel demonstrated an improved responder rate compared to brivaracetam in patients taking
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concomitant levetiracetam. This may be due to the shared mechanism of action between
brivaracetam and levetiracetam. Both perampanel and brivaracetam were demonstrated to be
effective for the adjunctive treatment of focal-onset seizures with and without generalization when
compared to placebo. The adverse event profiles of the drugs are similar with the exception of a
difference in the incremental dizziness experienced over placebo. Across the perampanel studies
(304, 305, 306), 0.2% of placebo patients experienced severe dizziness whereas 2.7% of patients
Page 16 of 20
randomized to perampanel (2mg to 12mg). These results will assist physicians with individual
prescribing decisions to optimize care at the patient level as well as inform healthy policy decisions
regarding which drug should be preferred in certain populations.

Conflicts of interest
This work was supported by Eisai, Co., Ltd. ST and DJ are employees of Quantics Biostatistics. ET
reports personal fees from Everpharma, Medtronics, BIAL-Portela &C, Newbridge, GL Pharma,
GlasxoSmithKline, Boehringer, Viropharma, and Actavis; grants and personal fees from Biogen Idec,
UCB Pharma, and Eisai; and grants from Red Bull, Merck, the European Union, FWF Osterreichischer
Fond zur Wissenschaftsforderung, Bundesministerium fur Wissenschaft und Forschung, and
Jubilaumsfond der Osterreichischen Nationalbank outside the submitted work. KW and JI are

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employees of York Health Economics Consortium (YHEC). Quantics Biostatistics and YHEC received
funding from Eisai, Co., Ltd for conducting the searches, study selection and the risk of bias

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assessment for the systematic review and the indirect treatment comparison reported in this paper.
WT was an employee of Eisai Inc. during this study and AP is an employee of Eisai, Co., Ltd.

Acknowledgements
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The authors would like to thank Fiona Whiter, Mick Arber, Maria Cikalo and Erin Baragula (all
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employees of YHEC) for their contributions to the searches, study selection process and the
management of records.
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References
1. Thurman, D.J., et al., Standards for epidemiologic studies and surveillance of epilepsy.
Epilepsia, 2011. 52(s7): p. 2-26.
ur

2. Banerjee, P.N., D. Filippi, and W.A. Hauser, The descriptive epidemiology of epilepsy—a
review. Epilepsy research, 2009. 85(1): p. 31-45.
3. Gupta, S., et al., Pomerantz D. Health Status, Health Care Resource Use, And Treatment
Jo

Satisfaction In Patients With Partial Onset Seizures (Pos) In The United States. Value in
Health, 2014. 17(3): p. A61.
4. Gupta, S., et al., The Humanistic and Economic Burden of Partial Onset Seizures in the Europe
Five and Brazil Using a Patient Survey. Value in Health, 2014. 17(7): p. A402-A403.
5. Laxer, K.D., et al., The consequences of refractory epilepsy and its treatment. Epilepsy &
behavior, 2014. 37: p. 59-70.
6. Trinka, E., Epilepsy: comorbidity in the elderly. Acta Neurologica Scandinavica, 2003.
108(s180): p. 33-36.

Page 17 of 20
7. McCagh, J., J.E. Fisk, and G.A. Baker, Epilepsy, psychosocial and cognitive functioning.
Epilepsy research, 2009. 86(1): p. 1-14.
8. Spatt, J., et al., Predictors for negative attitudes toward subjects with epilepsy: a
representative survey in the general public in Austria. Epilepsia, 2005. 46(5): p. 736-742.
9. Trinka, E., et al., Cause‐specific mortality among patients with epilepsy: Results from a 30‐
year cohort study. Epilepsia, 2013. 54(3): p. 495-501.
10. Granbichler, C.A., et al., Cause-specific mortality in adult epilepsy patients from Tyrol,
Austria: hospital-based study. Journal of neurology, 2015. 262(1): p. 126-133.
11. Granbichler, C.A., et al., Potential years lost and life expectancy in adults with newly
diagnosed epilepsy. Epilepsia, 2017. 58(11): p. 1939-1945.
12. Gaitatzis, A., et al., Life expectancy in people with newly diagnosed epilepsy. Brain, 2004.
127(11): p. 2427-2432.
13. Angeles, D.K., Proposal for revised clinical and electroencephalographic classification of
epileptic seizures. From the Commission on Classification and Terminology of the
International League Against Epilepsy. Epilepsia, 1981. 22(4): p. 489-501.
14. National Institute for Health and Care Excellence, Newer drugs for epilepsy in adults.

of
Technology Appraisal 76. 2004.
15. Semah, F., M.C. Picot, and C. Adam, Is the underlying cause of epilepsy a major prognostic
factor for recurrence? Neurology, 1998. 51(5): p. 1256-1262.

ro
16. Rauchenzauner, M. and G. Luef, Update on treatment of partial onset epilepsy: role of
eslicarbazepine. Neuropsychiatr Dis Treat, 2010. 6: p. 723-730.
17. Trinka, E. and F. Brigo, Antiepileptogenesis in humans: disappointing clinical evidence and

18.
-p
ways to move forward. Current opinion in neurology, 2014. 27(2): p. 227-235.
Chung, S., Lacosamide: new adjunctive treatment option for partial-onset seizures. Expert
Opin Pharmacother, 2010. 11(9): p. 1595-1602.
19. Kothare, S.V., D.S. Khurana, and N. Mostofi, Oxcarbazepine monotherapy in children and
re
adolescents: a single-center clinical experience. Pediatr Neurol, 2006. 35(4): p. 235-239.
20. Ivanova, J.I., et al., Economic burden of epilepsy among the privately insured in the US.
Pharmacoeconomics, 2010. 28(8): p. 675-685.
lP

21. European Medicines Agency, Fycompa: Eurpoean Public Assessment Report,

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/002434/WC500130839.pdf. 2012 [accessed 28.03.17].
22. Wood, M.D. and M. Gillard, Evidence for a differential interaction of brivaracetam and
levetiracetam with the synaptic vesicle 2A protein. Epilepsia, 2017. 58(2): p. 255-262.
na

23. European Medicines Agency, Briviact: Eurpoean Public Assessment Report,

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/003898/WC500200208.pdf. 2015 [accessed 28.03.17].
24. National Institute for Health and Care Excellence, Guide to the methods of technology
ur

appraisal, https://www.nice.org.uk/process/pmg9. 2013 [accessed 28.03.17].

25. Canadian Agency for Drugs and Technologies in Health, Guidelines for the economic
evaluation of health technologies: Canada [4th Edition], https://www.cadth.ca/about-
Jo

cadth/how-we-do-it/methods-and-guidelines/guidelinesfor-the-economic-evaluation-of-
health-technologies-canada. 2017 [accessed 28.03.17].
26. Brigo, F., et al., Efficacy and tolerability of brivaracetam compared to lacosamide,
eslicarbazepine acetate, and perampanel as adjunctive treatments in uncontrolled focal
epilepsy: Results of an indirect comparison meta-analysis of RCTs. Seizure, 2016.
27. Higgins, J. and S. Green, Cochrane handbook for systematic reviews of interventions Version
5.1. 0 [updated March 2011]. 2011, The Cochrane Collaboration. Available from www.
cochrane-handbook. org, 2011.

Page 18 of 20
28. Centre for Reviews and Dissemination, editor. Systematic reviews. CRD's guidance for
undertaking reviews in health care. York: Centre for Reviews and Dissemination, 2009.
29. Eisai, Clinical Study Report. A Double-Blind, Placebo-Controlled, Dose-Escalation Parallel-
Group Study to Evaluate the Efficacy and Safety of E2007 (perampanel) Given as Adjunctive
Therapy in Subjects with Refractory Partial Seizures. E2007-G000-304. 11 April 2011.
30. Eisai, Clinical Study Report. A Double-Blind, Placebo-Controlled, Dose-Escalation Parallel-
Group Study to Evaluate the Efficacy and Safety of E2007 (perampanel) Given as Adjunctive
Therapy in Subjects with Refractory Partial Seizures. E2007-G000-305. 11 April 2011.
31. Eisai, Clinical Study Report. A Double-Blind, Placebo-Controlled, Dose-Escalation Parallel-
Group Study to Evaluate the Efficacy and Safety of E2007 (perampanel) Given as Adjunctive
Therapy in Subjects with Refractory Partial Seizures. E2007-G000-306. 7 April 2011.
32. Eisai, Clinical Study Report. A Double-Blind, Placebo-Controlled, Parallel-Group Study with an
Open-Label Extension Phase to Evaluate the Efficacy and Safety of Perampanel (E2007)
Administered as an Adjunctive Therapy in Subjects with Refractory Partial-Onset Seizures.
E2007-J000-335. 14 July 2015.
33. Eisai Inc., Perampanel Integrated Summary of Efficacy. 2011.

of
34. Eisai Inc., Perampanel Integrated Summary of Safety. 2011.
35. Higgins, J.P.T. and S. reen, Cochrane handbook for systematic reviews of interventions
Version 5.1. 0 [updated March 2011]. 2011, The Cochrane Collaboration. Available from

ro
www. cochrane-handbook. org.
36. Bucher, H.C., et al., The results of direct and indirect treatment comparisons in meta-analysis
of randomized controlled trials. J Clin Epidemiol, 1997. 50(6): p. 683-691.
37.

38.
for Statistical Computing. Vienna, Austria.
-p
R Core Team, R: A language and environment for statistical computing. 2017, R Foundation

Schwarzer, G., meta: An R package for meta-analysis. R News, 2007. 7(3): p. 40-45.
39. French, J.A., et al., Adjunctive perampanel for refractory partial-onset seizures Randomized
re
phase III study 304. Neurology, 2012. 79(6): p. 589-596.
40. French, J.A., et al., Evaluation of adjunctive perampanel in patients with refractory partial‐
onset seizures: results of randomized global phase III study 305. Epilepsia, 2013. 54(1): p.
lP

117-125.
41. Krauss, G., et al., Randomized phase III study 306 Adjunctive perampanel for refractory
partial-onset seizures. Neurology, 2012. 78(18): p. 1408-1415.
42. Montouris, G., et al., Efficacy and safety of perampanel in patients with drug-resistant partial
seizures after conversion from double-blind placebo to open-label perampanel. Epilepsy
na

Research, 2015. 114: p. 131-40.

43. Nishida, T., et al., Adjunctive perampanel in partial‐onset seizures: Asia‐Pacific, randomized
phase III study. Acta Neurologica Scandinavica, 2018. 137(4): p. 392-399.
44. Ryvlin, P., et al., Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: Results
ur

from a double‐blind, randomized, placebo‐controlled trial. Epilepsia, 2014. 55(1): p. 47-56.

45. Biton, V., et al., Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in
adults: A phase III randomized, double‐blind, placebo‐controlled trial. Epilepsia, 2014. 55(1):
Jo

p. 57-66.
46. Kwan, P., et al., Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies:
Results of a phase III, double‐blind, randomized, placebo‐controlled, flexible‐dose trial.
Epilepsia, 2014. 55(1): p. 38-46.
47. Klein, P., et al., A randomized, double‐blind, placebo‐controlled, multicenter, parallel‐group
study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with
uncontrolled partial‐onset seizures. Epilepsia, 2015. 56(12): p. 1890-1898.
48. Lattanzi, S., et al., Brivaracetam add-on for refractory focal epilepsy: a systematic review and
meta-analysis. Neurology, 2016. 86(14): p. 1344-1352.

Page 19 of 20
49. Lattanzi, S., et al., Antiepileptic drug monotherapy for epilepsy in the elderly: A systematic
review and network meta‐analysis. Epilepsia, 2019. 60(11): p. 2245-2254.
50. Lattanzi, S., et al., Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network
meta‐analysis. Acta Neurologica Scandinavica, 2019. 139(1): p. 33-41.

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re
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na
ur
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