PeerJ
`
`Submitted 30 May 2013
`Accepted 4 July 2013
`Published 6 August 2013
`
`Corresponding author
`Sonja C. Sawh,
`sonja.sawh@lhsc.on.ca
`
`Academic editor
`Benjamin J. Whalley
`
`Additional Information and
`Declarations can be found on
`page 19
`
`DOI 10.7717/peerj.114
`
`0 Copyright
`2013 Sawh et al.
`
`Distributed under
`Creative Commons CC-BY 3.0
`
`OPEN ACCESS
`
`Lacosamide adjunctive therapy for
`partial-onset seizures: a meta-analysis
`
`Sonja C. Sawh , Jennifer J. Newman , Santosh Deshpande and
`Philip M. Jones
`
`Evidence-Based Medicine/Drug & Therapeutics Committee Resource, London Health Sciences
`Centre, Pharmacy Department, University Hospital, London, ON, Canada
`Evidence-Based Medicine, London Health Sciences Centre, Victoria Hospital, London, ON,
`Canada
`Department of Anesthesia & Perioperative Medicine, University of Western Ontario, London,
`ON, Canada
`Department of Epidemiology & Biostatistics, University of Western Ontario, London, ON,
`Canada
`
`ABSTRACT
`Background. The relative efficacy and safety of lacosamide as adjunctive therapy
`compared to other antiepileptic drugs has not been well established.
`Objective. To determine if lacosamide provides improved efficacy and safety, re-
`duced length of hospital stay and improved quality of life compared with other
`anti-epileptic therapies for adults with partial-onset seizures.
`Data Sources. A systematic review of the medical literature using Medline
`(1946-Week 4, 2012), EMBASE (1980-Week 3, 2012), Cochrane Central Register
`of Controlled Trials (Issue 1 of 12, January 2012). Additional studies were identified
`(through to February 7, 2012) by searching bibliographies, the FDA drug approval
`files, clinical trial registries and major national and international neurology meeting
`abstracts. No restrictions on publication status or language were applied.
`Study Selection. Randomized controlled trials of lacosamide in adults with partial-
`onset seizures were included.
`Data Extraction. Study selection, extraction and risk of bias assessment were per-
`formed independently by two authors. Authors of studies were contacted for missing
`data.
`Data Synthesis. All pooled analyses used the random effects model.
`Results. Three trials (1311 patients) met inclusion criteria. Lacosamide increased
`the 50% responder rate compared to placebo (RR 1.68 [95% CI 1.36 to 2.08];
`12 = 0%). Discontinuation due to adverse events was statistically significantly higher
`in the lacosamide arm (RR3.13 [95% CI 1.94 to 5.06];12 = 0%). Individual adverse
`events (ataxia, dizziness, fatigue, and nausea) were also significantly higher in the
`lacosamide group.
`Limitations. All dosage arms from the included studies were pooled to make a single
`pair-wise comparison to placebo. Selective reporting of outcomes was found in all of
`the included RCTs.
`Conclusions. Lacosamide as adjunctive therapy in patients with partial-onset
`seizures increases the 50% responder rate but with significantly more adverse events
`compared to the placebo. (cid:9)
`
`EXHIBIT
`
`/9z1/ -/
`
`How to cite this article Sawh et al. (2013), Lacosamide adjunctive therapy for partial-onset seizures: a meta-analysis. PeerJ 1:e114;
`DOI 10.7717/peerj.114
`ARGENTUM Exhibit 1062
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
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`Page 00001
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`

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`PeerJ (cid:9)
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`Subjects Clinical Trials, Drugs and Devices, Evidence Based Medicine, Neurology
`Keywords Systematic review, Meta-analysis, Lacosamide, Partial-onset seizures, Epilepsy,
`Antiepileptic drugs, Randomized controlled trials
`
`INTRODUCTION
`Epilepsy affects 15,500 new Canadians annually (Epilepsy Canada, 2011) with partial-onset
`seizures being the most common seizure type in adults - affecting up to 60% of adults who
`have epilepsy (Epilepsy Canada, 2011). Up to one-third of newly-diagnosed patients are
`refractory to drug therapy and this presents a therapeutic challenge (Beyenburg, Stavein &
`Schmidt, 2010). Adjunctive therapy with antiepileptic drugs (AEDs) is the standard of care
`for patients with refractory epilepsy (French, Kanner & Bautista, 2004). However, current
`guidelines (French, Kanner & Bautista, 2004) do not address the more recently-available
`AEDs, including lacosamide, for the treatment of refractory epilepsy.
`Lacosamide is a novel AED, consisting of a functionalized amino acid molecule believed
`to stabilize hyperexcitable neuronal membranes and inhibit repetitive neuronal firing
`(Lexi-Drugs, 2011). Health Canada has approved lacosamide for use as adjunctive therapy
`in the management of partial-onset seizures in adult patients with epilepsy who are not
`satisfactorily controlled with conventional therapy (Canadian Pharmacists Association,
`2011).
`All previously-published systematic reviews of lacosamide (Beyenburg, Stavem &
`Schmidt, 2010; Beydoun et al., 2009; Chung et al., 2010a; Simoens, 2011; Costa et al., 2011;
`Ryvlin, Cucherat Rheims, 2011) have concluded that lacosamide is efficacious in reducing
`seizure frequency compared to placebo, but each review had methodological challenges
`limiting its interpretability. To better estimate the effect size of lacosamide, this systematic
`review was designed to include all doses of lacosamide studied, using the intention to treat
`population, and considering all important outcomes, in addition to closely examining
`lacosamide's adverse events (which have not been adequately explored in the previous
`reviews).
`The objective of this systematic review was to determine the relative benefits and harm
`of lacosamide therapy compared to other AEDs or placebo, as adjunctive therapy for adults
`with partial-onset seizures.
`
`METHODS
`Protocol and registration
`The search strategy, methods of analysis and inclusion criteria were specified in advance
`and documented in a protocol. The protocol for this systematic review was registered with
`the Prospective International Register of Systematic Reviews (PROSPERO) and can be
`found online (Sawh e, Newman, 2012).
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`Information sources/search strategy
`Studies were identified by searching the following electronic databases: Medline (OVID
`1946 to Week 4, 2012), EMBASE (OVID, 1980 to Week 3 2012), Cochrane Central Register
`of Controlled Trials (CENTRAL) (Wiley Issue 1 of 12, January 2012).
`We contacted the manufacturer of lacosamide and experts in the field for information
`about unpublished or ongoing studies. The Food and Drug Administration's (FDA)
`Approved Drug Products database was searched for clinical trials used to support
`marketing approval and/or labelling changes in the United States. Conference abstracts
`and posters were searched from selected meetings of the American Epilepsy Society, World
`Congress of Neurology, International Epilepsy Congress, and the European Congress on
`Epileptology. We also searched the metaRegister of Controlled Trials (mRCT) to identify
`ongoing trials.
`Reference lists of all retrieved studies were reviewed for additional relevant studies.
`The search was developed and conducted by one of the authors (SS) and reviewed by a
`Research Librarian (KC). The last search was run February 7, 2012. We used the following
`search terms to search all trial registers and databases (modified to suit each specific
`database): randomized controlled trials, epilepsy, seizures, partial epilepsy, lacosamide,
`and Vimpat. No language restrictions were imposed on the electronic database searches.
`The online protocol provides the detailed search strategy used in this review.
`
`Study selection
`Title and abstract screening was conducted in duplicate to identify potentially eligible
`papers using a standardized guide for trial inclusion based on title and abstract screening.
`Two reviewers (JN and SS) underwent a calibration process to identify potential
`discrepancies in interpretation of the form (with the first 100 citations as a sample).
`Publications that could possibly have met the selection criteria were retrieved as full-text
`articles and examined.
`Full-text screening was conducted, independently by two reviewers, to confirm
`eligibility using a standardized screening form (Table S1). We used Fleiss and Cohen's
`weighted Kappa (using the program Kappa.exe (Cyr & Francis, 1992)) to assess agreement
`between the two reviewers on the selection of full-text articles for inclusion (Fleiss
`Cohen, 1973). All disagreements were resolved by discussion.
`We documented the study selection process in a flow chart as recommended in the
`PRISMA statement (Liberati et al., 2009) showing the total numbers of retrieved references
`and the numbers of included and excluded studies, and the reasons for exclusion (Fig. I ).
`
`Data collection process & data items
`Data were extracted independently by two reviewers (JN and SS) using an a priori
`standardized data extraction form with the aid of a data and validity extraction manual.
`The two sets of extracted data were compared and all discrepancies were resolved by
`discussion. Data was extracted from each included trial on the following general areas
`of information:
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`Medline
`1946 - Week 4 of 2012
`42 Citation(s)
`
`EMBASE
`1980 - Week 5 of 2012
`138 Citation(s)
`
`Cochrane Central
`Issue 1 of 12, 2012
`20 Citation(s)
`
`Expert consultations
`
`FDA Drug Approval Files
`
`Clinical trials databases
`
`Conference abstracts
`
`ECE Epilepsia Supplements
`
`UCB Pharma Inc
`
`2 Citation(s)
`
`I Citation(s)
`
`77 Citation(s)
`
`91 Citation(s)
`
`29 Citation(s)
`
`7 Citation(s)
`
`357 Non-Duplicate
`Records Screened
`
`Cnclusion/Exclusion
`
`Criteria Applied
`
`280 Articles Excluded
`After Title/Abstract Screen
`
`77FuII-text articles assessed for eligibility
`
`Inclusion/Exclusion
`Criteria Applied
`
`66FuII text articles excluded with reasons
`Non-randomized (57)
`Lacosamide in both arms(2)
`Duplication publication (6)
`Ongoing trial no results (I)
`
`0 Articles Excluded
`During Data Extraction
`
`11Publications representing 3 RCTs
`
`Figure ' Flow diagram of study selection.
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`Trial characteristics
`• Number of participating centres and countries
`• Inclusion criteria
`• Exclusion criteria
`• Number of patients eligible and randomized
`• Treatment duration and length of follow-up of patient outcomes
`• Data collection time points
`• Treatment arms in the trials
`• Ethics review board approval and patient consent to participate
`• Funding source
`
`Participant characteristics
`• Number of patients randomized and with available outcome data
`• Epilepsy diagnosis
`• AED use (number and types)
`
`Primary and secondary outcomes
`• Outcome definition
`• Direction of outcome (i.e., harm or benefit)
`• Time point(s) of outcome evaluation
`• Outcome unit of measurement and measure of error (if continuous). Where possible,
`for continuous measures, mean outcome values and standard deviations were recorded
`or determined as measurements of outcome.
`
`Study authors were contacted by e-mail to request information about missing data
`for included trials. For studies with multiple publications, all versions of the study were
`reviewed to ensure complete access to maximal trial data. In the event of inconsistency
`of study data between multiple publications (for example, between a Food and Drug
`Administration submission and a peer-reviewed paper published in a journal), the
`peer-reviewed publication was used as the primary data set.
`
`Risk of bias in individual studies
`Two reviewers (JN and SS) independently assessed the risk of bias for each included
`study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of
`Interventions (Higgins, Altman & Sterne, 2011). Reviewers were not blinded to the study
`authors, journal or outcome data. We specifically assessed the trial characteristics as
`specified in the protocol.
`
`• sequence generation;
`• allocation concealment;
`• blinding of the study (participants, personnel, outcome assessors, data collectors, data
`analysts) as defined by AO et al. (2012);
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`• incomplete outcome data;
`• selective outcome reporting;
`• other sources of bias.
`
`A summary table and a graph for risk of bias were created using Review Manager
`software 5.1 (The Nordic Cochrane Centre, 2011).
`
`Synthesis of results
`We calculated the pooled relative risks (RRs) and 95% confidence intervals (CI) for
`dichotomous variables using the Mantel-Haenszel method (peeks, Higgins & Altman,
`2011). For continuous variables measured using the same scales, the mean differences
`(MD) and its 95% CI were calculated using the inverse variance method. If a continuous
`outcome variable was measured using different scales across studies, we calculated the
`standardized mean difference (SMD).
`All of our analyses included the total numbers of participants in the treatment groups
`to which they had been allocated (intention to treat analysis). Participants not completing
`follow up or with inadequate seizure data were assumed to be non-responders.
`We contacted study authors for clarification if more information was needed, and to
`request missing data.
`Randomized trials included multiple dosages of lacosamide in separate randomized
`arms. For the purpose of the meta-analysis, all lacosamide dosages were combined into one
`"lacosamide" arm (Cochrane Handbook for Systematic Reviews of Interventions, 2011).
`We tested statistically for heterogeneity with a chi-square test and used 12 to measure
`inconsistency (the percentage of total variation across studies due to heterogeneity).
`We used "small," (<25%), "moderate" (between 25% and 50%) and "large" (>50%) to
`describe the statistical heterogeneity as measured by 12 (Higgins et al., 2003). Forest plots
`were visually inspected for possible sources of heterogeneity.
`A summary of findings table was created using GRADEpro software for the three
`primary outcomes of this review (Brozek, Oxman & Schilnemann, 2008). We planned to
`assess the possibility of publication bias by using funnel plots (Egger & Davey Smith, 1995).
`
`Additional analyses
`The following subgroup analyses were pre-specified for primary outcomes: patients
`younger than 18 years old (if the pediatric outcome data was reported as a discrete
`subgroup), placebo vs. active comparators, intravenous vs. oral lacosamide, and com-
`paring studies with high vs. low risk of bias. Post-hoc, the potential of a dose-response
`relationship of lacosamide was explored using subgroup analysis to look at the various
`dosage levels studied for all three primary outcomes.
`The a priori sensitivity analyses for the primary outcomes were: (1) Best case -
`Participants not completing follow-up or with inadequate seizure data were assumed to
`be responders in the lacosamide group and non-responders in the control group. For the
`primary safety outcome, participants not completing follow-up or with inadequate data
`were assumed to have continued in the trial in the lacosamide arms and discontinued
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`if in the control arm. (2) Worst case - Participants not completing follow-up or with
`inadequate seizure data were assumed to be non-responders in the lacosamide group
`and responders in the control group. For the primary safety outcome, participants not
`completing follow-up or with inadequate data were assumed to have discontinued due to
`adverse events in their respective lacosamide groups and to have stayed in if in the control
`group.
`
`RESULTS
`Study selection
`A total of 11 reports involving 3 studies were identified for inclusion in the review. The
`search of Medline, EMBASE, and CENTRAL provided a total of 200 citations. The search
`for unpublished literature (expert survey, manufacturer request, clinical trial registries,
`and conference abstract proceedings) provided a total of 207 citations. After removing
`duplicates, 357 citations independently underwent abstract review and 77 citations were
`considered potentially relevant studies. Of the 77 full-text articles screened, 66 citations
`were excluded. Three randomized controlled trials (Ben-Menachem et al., 2007; Chung
`et al., 2010b; Haltisz et al., 2009) (located as 11 publications (Massie, 2007; Kaiviainen et
`al., 2007; Halasz et al., 2006; Chung et al., 20070; Chung et al., 2009b; Jatuzis et al., 2005;
`Ben-Menachem et al., 2005; Chung et al., 2007b), that studied 1311 participants, met the
`inclusion criteria for this review. The weighted kappa statistic for inter-rater agreement
`on including or excluding potential trials was "excellent" [k = 0.90, 95% CI (0.83, 0.97)]
`(Fleiss & Cohen, 1973). See flow diagram (cid:9)
`1.
`
`e S2 for the table of
`
`Study characteristics
`See Table 1 for the characteristics of the included studies and
`excluded studies.
`Methods
`All three studies selected for the review were randomized, controlled, parallel group studies
`published in English. The duration of the intervention was 18 weeks for the Ben-Menachem
`et al. (2007) and Chung et al. (2010b) trials and 16 weeks for the Halasz et al. (2009) trial.
`All trials had an 8-week monitoring period before baseline and a 2-week taper or transition
`to off or open-label continuation of lacosamide at the end of the maintenance phases. The
`maintenance phase extension trials (Husain et al., 2011; Rosenfeld et al., 2011b; Rosenow
`et al., 2011) did not meet the criteria for inclusion in this review and are not considered
`further.
`Participants
`The included studies involved 1311 randomized participants from Australia, Europe,
`and the USA. Three participants in the Ben-Menachem trial (Ben-Menachem et al.,
`2007) were removed from the study after randomization for protocol violations and it
`could not be determined which dosage arm they belonged to. Patients were included in
`
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`
`First
`author
`& Publica-
`tion year
`
`Meinichein
`el al. (2007)
`
`Sawh et al. (2013), PeerJ, DOI 10.7717/peerj.114
`
`I able I Characteristics of included studies.
`
`Methodologic
`Quality (cid:9)
`
`Patients
`
`Intervention &
`comparator
`
`Outcomes
`
`Funding
`
`N (cid:9)
`
`Characteristics
`
`Primary
`
`Secondary
`
`Adequate sequence 421 (cid:9)
`generation ;
`AC; Blinding of
`patients, physi-
`cians, outcome
`assessors and data
`collectors; not
`ITT; incomplete
`reporting of
`pre-specified
`outcomes; follow-
`up to 18 weeks
`
`Mean age (SD) 39.9 (11.3)
`Gender: 54% female
`Concomitant AEDs:
`84% of the population were
`taking 2 AEDs at baseline,
`the rest were on 1 AED
`Median seizure frequency
`per 28 days across all
`treatment groups during
`the baseline period:
`12
`
`Chung ct al.
`(20101) )
`
`405 (cid:9)
`
`Adequate sequence
`generation; AC;
`Blinding of
`patients, physi-
`cians, outcome
`assessors and data
`collectors; not
`ITT; incomplete
`reporting of pre-
`specified outcomes
`follow-up to 18
`weeks
`
`Mean Age (SD): 38.3 (12.1)
`Gender: 50.6% female
`Concomitant AEDs:
`Throughout the trial
`82.1% were taking 2-3
`concomitant AEDs
`Median seizure frequency
`per 28 days across all
`treatment groups during
`the baseline period:
`P 15.0
`IA00 11.5
`L600 16.5
`
`• Lacosamide
`100 mg
`PO BID
`• Lacosamide
`200 mg
`PO BID
`• Lacosamide
`300 mg
`PO BID
`• Placebo
`PO BID
`Duration of
`treatment:
`18 weeks
`(after 8 week
`baseline
`monitoring
`- 6 week
`dose-titration
`& 12 week
`• Lacosamide
`200 mg
`PO BID
`• Lacosamide
`300 mg
`PO BID
`• Placebo
`PO BID
`Duration of
`treatment:
`18 weeks
`(after 8 week
`baseline
`monitoring - 6
`week titration
`& 12 week
`maintenance
`phase)
`
`••Change in seizure
`frequency per 28
`days from baseline
`to maintenance
`• 50 % responder rate
`Outcomes assessed at:
`Weeks 0 & 18
`
`Schwarz
`Bio-
`sciences
`Inc.
`
`• Adverse event (AE) data: in-
`cluding serious adverse events,
`and discontinuation due to AEs
`• Achievement of
`seizure-free status
`Efficacy outcomes as-
`sessed at: weeks 0 & 18
`• QOL scales (CGIC & QOLIE-
`31 — only in UK & USA)
`assessed at Week 0, 6, & 18
`• Adverse effects (assessed
`Weekly 0-6 weeks and 10, 14
`and 18 weeks)
`
`• Change in seizure
`frequency per 28
`days from baseline
`to maintenance
`• 50 % responder rate
`Outcomes assessed at:
`Week 0 & 18
`
`Schwarz
`Bio-
`sciences
`Inc., UCB
`Group
`
`• Adverse event (AE) data: in-
`cluding serious adverse events,
`and discontinuation due to AEs
`• % change in seizure fre-
`quency per 28 days from
`baseline to maintenance
`• 75% responder rate (the
`proportion of patients who
`experienced a 75% or greater
`reduction in seizure frequency
`from baseline to maintenance
`• Number & proportion of
`patients achieving seizure-
`free status throughout the
`maintenance period for
`patients completing the
`maintenance period and
`having complete efficacy data
`• Change in seizure frequency
`and 50% responder rate
`differentiated by seizure type
`•Adverse effects
`Outcomes assessed at: weeks 0
`& 18
`
`(continued on next page)
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`Page 00008
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`(cid:9)
`

`
`Table 1 (continued)
`First
`Methodologic
`author (cid:9)
`Quality
`& Publica-
`tion year
`
`N (cid:9)
`
`485 (cid:9)
`
`lialasz et al. Adequate sequence
`(2(X)91 (cid:9)
`generation; AC;
`Blinding of pa-
`tients, physicians,
`outcome assessors
`and data collectors;
`not ITT, incom-
`plete reporting of
`pre-specified out-
`comes, follow-up
`to 16 weeks
`
`Patients
`
`Intervention &
`comparator
`
`Outcomes
`
`Funding
`
`Primary
`
`• Change in seizure
`frequency per 28
`days from baseline
`to maintenance
`• 50 % responder rate
`Outcomes assessed at:
`weeks 0 & 16
`
`Characteristics
`Mean Age (SD): 37.8 (11.9)
`Gender: 48.5% female
`Concomitant AEDs:
`37% were taking 3 AEDs,
`50% were taking 2 AEDs
`and 13% were taking
`1 AED in addition to
`the trial medication
`Median seizure frequency
`per 28 days across all
`treatment groups during
`the baseline period:
`P 9.9
`L200 11.5
`MOO 10.3
`
`• Lacosamide
`100 mg
`PO BID
`• Lacosamide
`200 mg
`PO BID
`• Placebo
`PO BID
`Duration of
`treatment:
`16 weeks
`(after 8 week
`baseline - 4
`week titration
`and 12 week
`maintenance
`phase)
`
`UCB
`Group
`
`Secondary
`• Number & Proportion of (cid:9)
`patients achieving seizure-free (cid:9)
`status through the maintenance
`period for patients completing
`the maintenance period
`• Proportion of seizure-free
`days during the maintenance
`period for patients entering
`the maintenance period
`Efficacy Outcomes as-
`sessed at: weeks 0 & 16
`•Adverse effects
`Outcomes assessed:
`weekly 0-16 weeks
`• QOL scores (PGIC,
`CGIC, SSS, QOLIE-31)
`QOL Outcomes assessed at:
`weeks 0 & 18
`
`Notes.
`AC = allocation concealed, ITT = intention-to-treat analysis; N = total number of patients randomized; P = placebo; PO = oral; BID = twice daily; L200 = lacosamide
`200 mg/day; L400 = lacosamide 400 mg/day; L600 = lacosamide 600 mg/day; CGIC = Clinical Global Impression of Change score; QOL — quality of life; QOLIE-31 =
`quality of life in epilepsy; PGIC = Patient's Global Impression of Change Score; SSS = seizure severity scale.
`* Randomization method or details not provided by author/manufacturer.
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`these studies if they had a diagnosis of partial-onset seizures (with or without secondary
`generalizations) that was objectively confirmed (with electroencephalogram (EEG) and
`magnetic resonance imaging (MR) or computed tomography (CT) scan). In order to be
`eligible, patients must have had partial-onset seizures for at least the previous two years
`despite treatment with at least two AEDs. For all three trials, to be counted as having
`"current seizures", participants must have had at least 4 partial-onset seizures per 28 days
`on average with no seizure-free period longer than 21 days. For the Ben-Menachem trial,
`the above inclusion criteria applied to the 8 week baseline period, whereas in the Chung et
`al. (2010b) and Halasz et al. (2009) trials, the seizure frequency criteria also applied to the
`8 weeks prior to baseline. All patients needed to have stable AED regimens for the 4 weeks
`prior to enrollment and the baseline period. In the Ben-Menachem trial, regimens could be
`1 or 2 AEDs with or without vagal nerve stimulation (VNS). In the Chung et al and Halasz
`et al trials, patients' regimens could consist of 1-3 AEDs with or without VNS. Participant
`age was restricted to over 16 years in two trials (Chung et al., 2007b; Halasz et al., 2009) and
`over 18 years in one trial (Ben-Menachein et al., 2007). Pediatric data was not presented
`separately in the two studies that included patients less than 18 years of age.
`
`Intervention
`All three studies compared adjunctive oral lacosamide in multiple doses to placebo
`(no active comparators) in a minimum of three comparator arms. All three trials had
`a lacosamide 200 mg twice daily arm. Ben-Menachem et al. and Halasz et al. both
`had lacosamide 100 mg twice daily arms. Chung et al and Ben-Menachem included a
`lacosamide 300 mg twice daily arm. No studies included intravenous lacosamide.
`
`Outcomes
`The primary outcomes for the three studies were change in seizure frequency (per 28 days
`from baseline to the maintenance period) and 50% responder rate. All three publications
`reported 50% responder rate in percentage, so the efficacy analysis denominators
`were used to convert to the number of patients who achieved the 50% response rate.
`Discontinuation due to adverse events was reported in all studies, as were individual
`adverse events. If percentages were provided for adverse event endpoints, they were
`converted to numbers of patients experiencing an event using the denominators provide
`for the safety analysis in the full publications. Quality of life outcomes were measured by
`two of the three studies (Ben-Menachern et al., 2007; Halasz et al., 2009) , but only reported
`by Ben-Menachem et al. (2007). Timing of outcome measures varied with the end of the
`maintenance period as defined by the individual studies.
`
`Risk of bias within studies
`See I i g. 2.
`All three studies were randomized-controlled trials, and all studies except Ben-
`Menachem presented the method of random sequence generation. Allocation concealment
`and blinding of participants, personnel, and outcome assessors were adequately reported
`for all trials. Incomplete outcome data reporting was present for all three trials. Selective
`outcome reporting was noted for all three included trials, as assessed by comparison of
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`Page 00010
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`
`
`0)
`
`a)
`..c
`0
`
`Selective reporting (reporting bias)
`
`Incomplete outcome data (attrition bias)
`
`Blinding of outcome assessment (detection bias)
`
`Blinding of participants and personnel (performance bias)
`
`ment (selection bias)
`
`Allocation conce
`
`Random sequence generation (selection bias)
`
`• • • • • • •
`•
`•
`•
`•
`•
`•
`
`Ben-Menachem 2007
`
`Chung 2010
`
`Halasz 2009
`
`Figure 2 Risk of bias summary.
`
`the published trials to the studies submitted for FDA approval. None of the three trials
`did a formal ITT analysis, but used all patients who received at least one dose of study
`medication as their definition of the study population.
`
`Results of individual studies
`Primary outcomes
`The mean change in seizure frequency from maintenance phase to baseline was not
`provided in any of the three included studies. The authors of each study were contacted in
`an attempt to procure the seizure frequency change data, but no information was provided.
`The primary outcome data available from the three trials ("percent reduction in seizure
`frequency") is presented in (cid:9)
`. There was a larger median percent change (as noted by
`the trial authors) with the higher dosage arms of lacosamide compared to placebo.
`The 50% responder rate was reported for all three included trials and the results are
`presented in (cid:9)
`. In the meta-analysis of this primary outcome (ITT), lacosamide
`
`Sawh et al. (2013), PeerJ, DOI 10.7717/peerj.114
`
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`
`

`
`J (cid:9)
`
`
`
`Median percentage reduction in seizure frequency.
`
`Trial
`
`Placebo
`
`Lacosamide
`200 mg/day
`
`Lacosamide
`400 mg/day
`
`Lacosamide
`600 mg/day
`
`— —......._
`-Ben-Menaci,,
`Chung et al. (201(16,
`Halasz et al. (2009)
`
`N
`
`96
`104
`159
`
`%
`
`10%
`20.8%
`20.5%
`
`N
`
`107
`—
`160
`
`%
`
`26%
`—
`35.3%
`
`N
`
`107
`201
`158
`
`%
`
`39%
`37.3%
`36.4%
`
`N
`
`105
`97
`
`96
`
`40%
`37.8%
`
`Notes.
`* Compares maintenance phase to baseline period.
`
`Study or Subgroup (cid:9)
`Ben-Menachem 2007 (cid:9)
`Chung 2010 (cid:9)
`Halasz 2009 (cid:9)
`
`Placebo
`Lacosamide (cid:9)
`Events (cid:9)
`Total Events (cid:9) Total Weight
`119 (cid:9)
`21
`97
`27 0%
`321 (cid:9)
`19
`118 (cid:9)
`301 (cid:9)
`104
`23.9%
`120 (cid:9)
`322 (cid:9)
`41
`163
`49.0%
`
`Risk Ratio
`M-H, Random, 95% CI
`1 71
`11.14,
`2 571
`2.15
`(1.40,
`3.301
`1.48
`[1.10,
`2 001
`
`Total (95% CI) (cid:9)
`81
`Total events (cid:9)
`357 (cid:9)
`Heterogeneity. Tau2 = 0.00, CYO= 1.94, df = 2 (P =
`Test for overall effect: Z= 4.85 (P 4 0.00001)
`
`944
`
`364
`
`100.0%
`
`1.68
`[1.36.
`2.08]
`
`
`
`0.38), 12 = 0%
`
`Risk Ratio
`M-H. Random, 95% CI
`
`1
`0.1 (cid:9)
`100
`10 (cid:9)
`0.01 (cid:9)
`Favours placebo
`Favours lacosamide
`
`Figure 3 50% responder rate (ITT). Primary outcome (ITT) lacosamide (all dosage arms pooled) compared to placebo.
`
`(all dosage arms pooled) was associated with a significantly higher 50% response rate
`compared to placebo (RR 1.68, 95% CI 1.36, 2.08). There was no evidence of statistical
`heterogeneity (12 = 0%). The analyses of worst-case scenarios and best —case scenarios
`both produced similar results to the base analysis (RR = 1.62, 95% CI 1.24, 2.11; /2 = 37%)
`and (RR = 1.73, 95% CI 1.40, 2.13; /2 = 0), respectively.
`Discontinuation of study drug due to adverse events was reported in all three trials.
`In the meta-analysis of this outcome (ITT), lacosamide (all dosage arms pooled) was
`associated with a significantly higher rate of discontinuation with an RR 3.13 (95% CI
`1.94, 5.06). There was no evidence of heterogeneity (P = 0%), see Fig. 4. Best-case and
`worst-case scenarios were not calculated for this outcome as no patient data was missing.
`
`Secondary outcomes
`Adverse effects outcomes
`Statistically significant changes (higher rates in the lacosamide pooled dosage arm) were
`seen in the following adverse event outcomes: ataxia (RR 5.03, 95% CI 2.23, 11.37, see
`Fig. 3), dizziness (RR 3.49, 95% CI 2.43, 5.01, see Fig. 6), fatigue (RR 2.04, 95% CI 1.08,
`3.85, see Fig. 7) and nausea (RR 2.36, 95% CI 1.22, 4.58, see Fig. 8). No heterogeneity was
`found in any of the adverse events (P = 0), except for nausea, which showed moderate
`inconsistency, with an /2 = 34%. For the outcome of ataxia, data were included if outcomes
`were reported as ataxia or "coordination abnormal".
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`(cid:9)
`

`
`PeerJ (cid:9)
`
`
`
`Study or Subgroup
`Ben-Menachem 2007
`Chung 2010
`Halasz 2009
`
`Placebo
`Lacosamide (cid:9)
`Total Events Total Weiltd
`Events (cid:9)
`97 29.5%
`64
`321
`5
`5 104 29.4%
`62
`301
`8 163 41.1%
`34
`322
`
`Risk Ratio (cid:9)
`M-H, Random, 95% CI (cid:9)
`3.87 [1.60, 9.34]
`4.28 [1.77,10.37]
`2.15 [1.02, 4.54]
`
`Risk Ratio
`M-H, Random, 95% CI
`
`Total (95% CI)
`18
`160
`Total events
`Heterogeneity: Tale= 0.00; che= 1.71, df= 2 (P = 0.43); l'= 0%
`Test for overall effect: Z= 4.67 (P c 0.00001)
`
`364 100.0%
`
`944
`
`3.13 [1.94, 5.06]
`
`411,
`
`10 (cid:9)
`1
`0.1 (cid:9)
`100
`0.01 (cid:9)
`Favours lacosamide Favours placebo
`
`Figure 4 Discontinuation due to adverse events (ITT). Lacosamide (all dosage arms pooled) compared to placebo.
`
`Study or Subgroup (cid:9)
`Ben-Menachem 2007 (cid:9)
`Chung 2010 (cid:9)
`Halasz 2009 (cid:9)
`
`Placebo
`Lacosamide (cid:9)
`Events (cid:9)
`Total Events Total Weight
`42 (cid:9)
`321 (cid:9)
`3 (cid:9)
`97 (cid:9)
`50.3%
`29 (cid:9)
`301 (cid:9)
`2 (cid:9)
`104 (cid:9)
`33.2%
`17 (cid:9)
`322 (cid:9)
`1 (cid:9)
`163 (cid:9)
`16.5%
`
`Risk Ratio
`M-14, Random, 95% CI
`4.23
`
`[1.34, 13.35]
`5.01
`[1.22,
`20.63]
`64.10]
`8.61
`[1.16,
`
`Risk Ratio
`M-H, Random, 95% CI
`-in-
`
`Total (95% CI) (cid:9)
`6
`Total events (cid:9)
`88 (cid:9)
`Heterogeneity: Tale= 0.00; Chi' = 0.36, df= 2 (P= 0.83);12= 0%
`Test for overall effect: Z= 3.88 (P = 0.0001)
`
`364 (cid:9) 100.0%
`
`944