Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2084 - 1/11
`
`

`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2084 - 2/11
`
`

`
`CNS Drugs (2013) 27:321–329
`DOI 10.1007/s40263-013-0049-y
`
`O R I G I N A L R E S E A R C H A R T I C L E
`
`Safety and Efficacy of Intravenous Lacosamide for Adjunctive
`Treatment of Refractory Status Epilepticus: A Comparative
`Cohort Study
`
`Raoul Sutter • Stephan Marsch • Stephan Ru¨ egg
`
`Published online: 27 March 2013
`Ó Springer International Publishing Switzerland 2013
`
`Abstract
`Background Refractory status epilepticus (RSE) is an
`emergency with high mortality requiring neurointensive
`care. Treatment paradigms include first-generation antiep-
`ileptic drugs (AEDs) and anesthetics. Lacosamide (LCM)
`is a new AED, holding promise as a potent treatment
`option for RSE. High-level evidence regarding safety and
`efficacy in the treatment of RSE is lacking.
`Objective The objective of the study was to evaluate the
`safety profile and efficacy of intravenous (i.v.) LCM as an
`add-on treatment in adult RSE patients.
`Methods All consecutive RSE patients treated in the
`intensive care units (ICUs) of an academic tertiary care
`center between 2005 and 2011 were included. Severity of
`
`Electronic supplementary material The online version of this
`article (doi:10.1007/s40263-013-0049-y) contains supplementary
`material, which is available to authorized users.
`R. Sutter S. Marsch
`Clinic for Intensive Care Medicine, University Hospital Basel,
`Basel, Switzerland
`
`Present Address:
`R. Sutter (&)
`Division of Neurosciences Critical Care, Departments of
`Anesthesiology, Critical Care Medicine and Neurology, Johns
`Hopkins University School of Medicine, 600 N. Wolfe Street,
`Meyer 8-140, Baltimore, MD 21287, USA
`e-mail: SutterR@uhbs.ch
`R. Sutter S. Ru¨egg
`Division of Clinical Neurophysiology, Department of
`Neurology, and Intensive Care Unit, University Hospital Basel,
`Basel, Switzerland
`
`status epilepticus (SE) was graded by the SE Severity Scale
`(STESS), and SE etiology was categorized according to the
`guidelines of the International League Against Epilepsy
`(ILAE). Outcomes were seizure control, RSE duration, and
`death.
`Results Of 111 RSE patients, 53 % were treated with
`LCM. Twenty-five
`patients with
`hypoxic-ischemic
`encephalopathy were excluded. Mortality was 30 %. Mean
`number of AEDs, duration, severity, and etiology of SE, as
`well as critical medical conditions did not differ between
`patients with and without LCM. While age tended to be
`higher, critical interventions, such as the use of anesthetics
`and mechanical ventilation, tended to be less frequent in
`patients with LCM. Seizure control tended to be achieved
`more frequently in patients with LCM (odds ratio, OR 2.34,
`95 % CI 0.5–10.1, p = 0.252). Among patients with LCM,
`51 % received LCM as the last AED (including hypoxic-
`ischemic
`encephalopathy),
`allowing
`the
`reasonable
`assumption that LCM was responsible for seizure control,
`which was achieved in 91 %. Multivariable analysis
`revealed a decreased mortality in patients with LCM (OR
`0.34, 95 % CI 0.1–0.9, p = 0.035). A possible confounder
`in this context was the implementation of continuous
`video-electroencephalography (EEG) monitoring 6 months
`prior to the first use of i.v. LCM. There were no serious
`LCM-related adverse events.
`Conclusion LCM had a favorable safety profile as
`adjunctive treatment for RSE. Its use was associated with
`decreased mortality of RSE—a finding that might have
`been confounded by the implementation of continuous
`video-EEG monitoring in the ICU prior to the use of i.v.
`LCM, leading to heightened awareness as well as earlier
`diagnosis and treatment of SE. Randomized trials are
`warranted to further strengthen the evidence of efficacy of
`LCM for RSE treatment.
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2084 - 3/11
`
`

`
`322
`
`1 Introduction
`
`Status epilepticus (SE) is the most severe manifestation of
`epilepsy, which requires intensive care. Its incidence ran-
`ges from 15 to 20 per 100,000 per year [1, 2]. Several
`treatment guidelines for SE suggest a four-step algorithm
`depending on the persistence of SE [3–6]. Briefly, benzo-
`diazepines are recommended as first-line antiepileptic
`drugs (AEDs), followed by one further intravenous (i.v.)
`second-line AED if SE persists, such as phenytoin, valproic
`acid, a combination of both, or levetiracetam. For further
`ongoing seizure activity non-sedating third-line AEDs are
`often used, followed by anesthetic drugs to induce a deep
`coma titrated at least to burst-suppression or even flat-line
`electroencephalography (EEG). However, the latter is only
`based on recommendations [7, 8]. Without prompt inter-
`ventions, ongoing seizures can cause deleterious neuronal
`injury or death [9]. This causality is underscored by the
`association of treatment failure and unfavorable prognosis
`with increasing SE duration [10]. Failure of first-line AED
`and second-line treatment with at
`least one i.v. AED
`defines refractory status epilepticus (RSE) [11], which is
`found in up to 43 % of patients with SE and is predomi-
`nantly associated with fatal underlying etiologies, severe
`impairment of consciousness, and a mortality rate of up to
`40 % [12–14]. Therefore, rapid treatment escalation is
`essential. The importance of extensive therapeutic inter-
`vention in these patients is further emphasized by reported
`favorable outcomes after extensive long-term RSE treat-
`ment [15]. To date, treatment escalation in RSE remains
`challenging as interactions and adverse effects of multiple
`co-administrated drugs are hazardous, and effective add-on
`treatment options are limited. Thus, novel
`treatment
`options with new targets and additional modes of action
`with less adverse effects and risks would be highly
`welcome.
`Lacosamide (LCM) (SPM 927, formerly harkoseride),
`the R-enantiomer of 2-acetamido-N-benzyl-3-methoxy-
`propionamide, is a promising new AED approved in 2009
`with enteral and i.v. formulations. It has a bimodal action
`and almost no interactions. The selective enhancement of
`the slow inactivation of voltage-gated sodium channels
`may help normalize activation thresholds and decrease
`pathophysiological neuronal activity [16, 17]. Uncoupling
`of the collapsin-responsive mediator protein-2 from the
`presynaptic Ca2? channel complex may contribute to the
`decreased neuronal loss [18, 19] and may provide some
`neuroprotective effect. LCM has been shown to reduce
`seizure frequency in patients with uncontrolled partial-
`onset seizures [20] and i.v. LCM has a comparable safety
`profile and tolerability to those of oral formulations when
`used as replacement therapy for patients with partial-onset
`seizures [21]. Aside from induction of atrial flutter,
`
`R. Sutter et al.
`
`reported PQ interval prolongation on the electrocardiogram
`(ECG) in a dose-dependent manner and clinically relevant
`atrioventricular block, in one case associated with high
`doses of LCM [22–24], no severe adverse effects or sig-
`nificant laboratory abnormalities were shown to be asso-
`ciated with LCM.
`Interactions of LCM with plasma
`concentrations of other AEDs could not be demonstrated
`in vivo so far [20]. A few studies reported on LCM for the
`treatment of SE [25]. The use of LCM in RSE has been
`described in some case reports [26, 27] and smaller case
`series [28–30]. Randomized controlled trials on the effi-
`cacy of LCM in RSE are lacking and not registered in the
`National Institutes of Health (NIH)-sponsored database
`(clinicaltrials.org), possibly because of ethical restrictions
`in these critically ill patients.
`The aim of this study was to explore the feasibility,
`efficacy, safety profile, and effect on outcome of i.v. LCM
`in a large cohort of critically ill adult patients suffering
`from RSE.
`
`2 Methods
`
`2.1 Setting and Study Design
`
`This retrospective comparative cohort study was performed
`at the University Hospital Basel (Switzerland), a tertiary
`care center with more than 4,000 intensive care unit (ICU)
`admissions per year. On the basis of the hospital’s policy,
`all patients with SE were treated in the ICU. The study was
`approved by the local ethics committee in accordance with
`the standards laid down in the 1975 Declaration of Hel-
`sinki, as revised in 2000 (World Medical Association
`Declaration of Helsinki 2000). The requirement
`for
`informed consent was waived.
`
`2.2 Patients and Data Collection
`
`We identified all consecutive adult patients with RSE in the
`medical, cardiac, and surgical ICUs between January 2005
`and December 2011 by searching the medical records and
`the EEG database of the University Hospital Basel. All
`RSE patients had to have no prior treatment with i.v. LCM.
`We decided to present the individual detailed information
`of all patients who received LCM, including patients with
`hypoxic-ischemic encephalopathy as electronic supple-
`mental material, as we believe that treatment experience in
`this distinct group should not be withheld. However, we
`excluded them from all multivariable analyses, as this
`etiology of RSE is considered to be different from other
`causes, owing to the largely irreversible brain damage and
`poor outcome [31–34]. At our institution, treatment of SE
`was standardized according to the guidelines of the Swiss
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2084 - 4/11
`
`

`
`Lacosamide for Refractory Status Epilepticus
`
`323
`
`Status Epilepticus Consensus Conference from 2005 [3,
`35]. Briefly, benzodiazepines were applied as first-line
`AEDs when there was high suspicion of SE or immediately
`after SE diagnosis, followed by one further i.v. second-line
`AED if SE persisted, such as phenytoin, valproic acid, a
`combination of both, or levetiracetam. Anesthetics or non-
`sedating third-line AEDs were applied after failure of first-
`and second-line AEDs. LCM was administered after failure
`of first- and second-line AEDs and in selected patients as
`the second drug, based on the treating neurologist’s judg-
`ment. In 2009 i.v. LCM was introduced as an add-on AED
`for the treatment of SE in our hospital. No patients with SE
`were treated with LCM before April 2009. Of note, while
`not all patients with SE were treated with LCM, all con-
`secutive patients with RSE were treated with LCM as an
`add-on AED from May 2009 to December 2011. i.v. LCM
`twice a day with 200 mg per application without an initial
`‘loading dose’. Patients with renal failure received 150 mg
`twice daily (b.i.d.) (creatinine clearance 30–50 ml) or
`100 mg b.i.d. (creatinine clearance less than 30 ml); one
`obese patient (110 kg) was treated with 600 mg per day.
`Aside from characteristics that allow gradation of SE
`severity and duration (as mentioned in Sect. 2.3), etiologies
`of RSE [including hypoxic-ischemic encephalopathy],
`critical medical conditions, such as infections during SE,
`information from continuous ECG monitoring during the
`ICU stay, mechanical ventilation, and the use of anesthetic
`drugs during SE were compiled for all patients. Data on the
`exact sequential arrangement of all AEDs and i.v. anes-
`thetic drugs were assessed for all patients treated with and
`without LCM.
`
`2.3 Status Epilepticus: Definition, Categorization,
`and Graduation of Severity
`
`SE was diagnosed if seizures lasted at least 5 min or if a
`series of seizures emerged without recovery of mental
`status in between [36–38]. RSE was defined as SE refrac-
`tory to first-line AEDs and second-line treatment with at
`least one i.v. AED [11]. These widely accepted definitions
`allow a comparison with previous works on RSE treatment.
`Regarding etiologies of SE, seizures were categorized as
`recommended by the International League Against Epi-
`lepsy (ILAE) [39] as follows: acute symptomatic seizures,
`remote symptomatic unprovoked seizures, symptomatic
`seizures due to progressive CNS disorders, and unprovoked
`seizures of unknown etiology. Severity of SE was graded
`using the validated Status Epilepticus Severity Score
`(STESS) [40, 41]. According to this, the following integral
`components of STESS were used and categorized as fol-
`lows: worst seizure types at presentation (simple partial,
`complex
`partial,
`and
`absence
`seizures = 0
`points;
`
`generalized convulsive seizures = 1 point; and noncon-
`vulsive status epilepticus (NCSE) in coma = 2 points),
`history of prior seizures (0 points) or no history of seizures
`(1 point), age of at least 65 years (2 points) and less than
`65 years (0 points), and level of consciousness at SE onset
`(awake or somnolent = 0 points; stuporous or coma-
`tose = 1 point). Duration of SE was defined as the period
`from the time of SE diagnosis to the time when SE stopped.
`Seizure control was confirmed if there was no evidence of
`clinical manifestations and seizure activity on EEG. All
`patients had at least one routine EEG at admission, and
`follow-up recordings with at least two conventional EEGs
`in 24 h or continuous EEG monitoring were performed in
`all patients without seizure control.
`
`2.4 Outcomes
`
`Primary outcomes were SE duration, seizure control, and
`death. Secondary outcomes included destination at dis-
`charge. Safety was defined as the absence of adverse
`events, signs, or symptoms like rash, blood dyscrasias,
`impairment of cardiovascular, renal, liver, and pulmonary
`function closely related to the administration of LCM and
`requiring acute medical intervention.
`
`2.5 Statistics
`
`Patients with hypoxic-ischemic encephalopathy were
`excluded from all comparative analyses, as mentioned
`above [31–34]. Patients were categorized into the follow-
`ing two groups: with and without treatment with i.v. LCM
`during RSE. Categorical variables were summarized as
`counts and proportions and continuous variables as means
`and standard deviations. The Shapiro–Wilk test was used to
`distinguish between normal and non-normal distributions.
`Continuous variables were analyzed with the Student’s
`t test if normally distributed, or the Mann–Whitney U test
`if non-normally distributed. For comparisons of propor-
`tions, Chi-square and Fisher’s exact
`test were applied
`where appropriate. Robust multiple linear
`regression
`models were fitted using bootstrapped interactively re-
`weighted least squares with 1,000 replications to reduce the
`effects of extreme or non-normal ‘RSE duration’ data.
`Univariable logistic regression was used to determine dif-
`ferences in categorical outcomes for patients with and
`without treatment with i.v. LCM. A multivariable logistic
`regression model was used to adjust for age. Hosmer–
`Lemeshow goodness-of-fit tests were applied to check the
`multivariable logistic regression models. p values of 0.05
`and less were considered significant. Statistical analysis
`Ò
`was performed with STATA
`version 12.0 (Stata Corpo-
`ration, College Station, TX, USA).
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2084 - 5/11
`
`

`
`324
`
`3 Results
`
`R. Sutter et al.
`
`Table 1 Demographics
`characteristics
`clinical
`and
`patients with hypoxic-ischemic encephalopathy; n = 111)
`
`(including
`
`Two hundred and sixty consecutive patients were identified
`with SE in our tertiary care center and 111 (43 %) devel-
`oped RSE. From January 2005 to April 2009, 52 patients
`(47 %) had no adjunctive treatment with i.v. LCM. While
`from May 2009 to December 2011 i.v. LCM was not
`administered in all patients with SE, i.v. LCM was used as
`an add-on AED in all consecutive 59 RSE patients (53 %).
`LCM was mostly administered as a third or fourth AED.
`Demographics and clinical characteristics of the cohort are
`summarized in Table 1. Comparisons of demographics and
`clinical characteristics including SE severity gradation by
`STESS and categorization of SE etiology according to the
`ILAE guidelines in patients with and without i.v. LCM is
`presented in Table 2 after excluding patients with hypoxic-
`ischemic encephalopathy. Overall, there were no signifi-
`cant differences in SE severity and etiology or critical
`medical conditions between both groups. Presumed RSE
`etiologies categorized according to the ILAE guidelines
`and SE severity graded by STESS did not differ signifi-
`cantly between patients with and without i.v. LCM. While
`age tended to be higher in patients receiving i.v. LCM,
`critical interventions tended to be less frequent in patients
`with i.v. LCM.
`The mean number of administered AEDs did not differ
`significantly between patients treated with and without i.v.
`LCM (4.3 ± 1.0 vs. 4.9 ± 1.7; Table 3). i.v. LCM was
`used as an add-on treatment after 1 to 5 (mean 3 ± 0.9)
`prior administered AEDs had failed. The antiepileptic
`treatment of RSE is summarized in Table 3. Detailed,
`individual characteristics and sequential AED arrange-
`ments of all patients with i.v. LCM are presented as elec-
`tronic supplemental material. Among all patients with i.v.
`LCM, 51 % (23/45) received LCM as the last AED
`(including RSE in hypoxic-ischemic encephalopathy).
`Among those, seizure control was achieved in 91 % (21/
`23). One or more AEDs were needed after beginning LCM
`with topiramate,
`lamotrigine and oxcarbazepine as the
`most frequent following AEDs.
`Overall mortality was 30 % (26/86; Table 4). Analysis
`regarding significant differences in outcome in dependence
`of sequential arrangement of AEDs was not performed
`because of the small sample sizes in these subgroups. Uni-
`and multivariable comparisons of continuous and categor-
`ical outcomes in patients with and without i.v. LCM are
`presented in Table 5. In the univariable analysis, patients
`with i.v. LCM tended to have both shorter SE duration
`(regression coefficient -47.2, 95 % CI -122.4 to 28.0) and
`more often seizure control (OR 2.34, 95 % CI 0.5–10.1);
`however, these trends did not reach statistical significance.
`Administration of i.v. LCM was associated with lower odds
`for death (OR 0.39, 95 % CI 0.2–1.0)—a result that was
`
`Demographics
`
`Gender
`
`Female
`
`Male
`
`Age (mean ± SD), years
`
`Clinical features
`
`SE severity (STESS characteristics)
`
`Awake or somnolent
`
`Stuporous or comatose
`
`Worst seizure type
`
`Simple partial/complex/absence
`
`Generalized convulsive
`
`NCSE in coma
`Age \65 years
`Age C65 years
`
`History of seizures
`
`No history of seizures
`
`Presumed RSE etiology
`
`Brain tumor
`
`Uncontrolled epilepsy
`
`Ischemic stroke
`
`Meningitis/encephalitis
`
`Traumatic brain injury
`
`Intracerebral hemorrhage
`
`Metabolic problem
`
`Alcohol withdrawal
`
`Neurodegenerative
`
`Others
`
`Not known
`Hypoxic-ischemic encephalopathya
`
`n (%)
`
`51 (46)
`
`60 (54)
`
`62 ± 16
`
`27 (24)
`
`84 (76)
`
`29 (26)
`
`10 (9)
`
`72 (65)
`
`58 (52)
`
`53 (48)
`
`32 (29)
`
`79 (71)
`
`15 (14)
`
`11 (10)
`
`9 (8)
`
`8 (7)
`
`7 (6)
`
`6 (5)
`
`4 (4)
`
`3 (3)
`
`3 (3)
`
`10 (9)
`
`10 (9)
`
`25 (23)
`
`NCSE nonconvulsive status epilepticus, RSE refractory status epi-
`lepticus, SE status epilepticus, STESS Status Epilepticus Severity
`Score,
`a Excluded from further analyses
`
`even more pronounced after adjustment for age (OR 0.34,
`95 % CI 0.1–0.9). Hosmer–Lemeshow goodness-of-fit tests
`revealed insignificant p values for the multivariable logistic
`regression models,
`indicating an adequate model fit
`(Table 5).
`As stated, patients with hypoxic-ischemic encephalop-
`athy were excluded from all comparative analyses. Only
`descriptive analyses were performed for patients with
`hypoxic-ischemic encephalopathy. Of the 14 patients with
`hypoxic-ischemic encephalopathy who were treated with
`i.v. LCM for RSE, 9 received LCM as the last AED with a
`resulting seizure control in 78 % (7/9). Overall, 7 patients
`died, 5 of them after seizure control following LCM as the
`last AED.
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2084 - 6/11
`
`

`
`Lacosamide for Refractory Status Epilepticus
`
`325
`
`Table 2 Demographics and clinical characteristics in patients with and without intravenous (i.v.) lacosamide (excluding patients with hypoxic-
`ischemic encephalopathy; n = 86)
`
`Patients with i.v.
`lacosamide (n = 45)
`n (%)
`
`Patients without i.v.
`lacosamide (n = 41)
`n (%)
`
`p values
`
`Demographics
`
`Gender
`
`Female
`
`Male
`
`Age (mean ± SD), years
`
`Clinical features
`SE severity (STESS characteristics)a
`
`Awake or somnolent
`
`Stuporous or comatose
`
`Worst seizure type
`
`Simple partial/complex/absence
`
`Generalized convulsive
`
`NCSE in coma
`Age \65 years
`Age C65 years
`
`History of seizures
`
`25 (56)
`
`20 (44)
`
`16 (39)
`
`25 (61)
`
`64.7 ± 15.2
`
`59.8 ± 17.1
`
`18 (40)
`
`27 (60)
`
`17 (38)
`
`1 (2)
`
`27 (60)
`
`20 (44)
`
`25 (56)
`
`15 (33)
`
`30 (67)
`
`12 (27)
`
`33 (73)
`
`9 (22)
`
`32 (78)
`
`12 (29)
`
`4 (10)
`
`25 (61)
`
`25 (61)
`
`16 (39)
`
`17 (41)
`
`24 (59)
`
`11 (27)
`
`30 (73)
`
`0.125
`
`0.124*
`
`0.103**
`
`0.288**
`
`0.125
`
`0.436
`
`0.986
`
`No history of seizures
`STESS \3 indicating favorable outcome
`STESS C3 indicating unfavorable outcome
`RSE etiology grouped according to the ILAEb
`
`Acute symptomatic seizures
`
`Remote symptomatic unprovoked seizures
`
`Symptomatic seizures due to progressive CNS disorders
`
`Unprovoked seizures of unknown etiology
`
`Critical medical conditions
`
`Infections during SE
`
`Coronary heart disease/cardiopathy
`
`25 (56)
`
`17 (38)
`
`0 (0)
`
`3 (7)
`
`17 (38)
`
`8 (18)
`
`Pulmonary diseases/acute lung injury/acute respiratory distress syndrome
`
`4 (9)
`
`Metabolic derangements
`
`Tumors
`
`Interventions
`
`Mechanical ventilation
`
`Use of continuous i.v. anesthetic drugs
`
`8 (18)
`
`13 (29)
`
`34 (76)
`
`31 (69)
`
`21 (51)
`
`12 (29)
`
`3 (7)
`
`5 (12)
`
`20 (49)
`
`9 (22)
`
`2 (5)
`
`9 (22)
`
`9 (22)
`
`34 (83)
`
`35 (85)
`
`0.687
`
`0.404
`
`0.104**
`
`0.470**
`
`0.303
`
`0.627
`
`0.678**
`
`0.627
`
`0.461
`
`0.438**
`
`0.080**
`
`ILAE International League Against Epilepsy, NCSE nonconvulsive status epilepticus, RSE refractory status epilepticus, SE status epilepticus
`
`* Mann–Whitney U test
`
`** Fisher’s exact test
`a Status Epilepticus Severity Score (STESS) [40, 41]
`b Grouping of etiologies according to the guidelines of the International League Against Epilepsy (ILAE) [39]
`
`In the entire cohort, there were no adverse events due to
`antiepileptic treatment except for 1 patient with a rash
`related to the use of lamotrigine and severe hypotension in
`3 patients, most likely caused by the use of i.v. anesthetic
`drugs.
`
`4 Discussion
`
`This study explored the efficacy and safety of i.v. LCM as
`an antiepileptic add-on treatment for critically ill adult
`patients suffering from RSE in the ICUs of a single tertiary
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2084 - 7/11
`
`

`
`326
`
`R. Sutter et al.
`
`Table 3 Antiepileptic treatment in patients with and without intra-
`venous (i.v.) lacosamide (LCM) (excluding patients with hypoxic-
`ischemic encephalopathy; n = 86)
`
`Patients
`with i.v.
`LCM (n = 45)
`n (%)
`
`Patients
`without i.v.
`LCM (n = 41)
`n (%)
`
`Number of AEDs (mean ± SD)
`
`4.3 ± 1.0
`
`4.9 ± 1.7
`
`AEDs during RSE
`
`First-line
`
`MDL (via bolus)
`
`LZP
`
`CLB
`
`CLP
`
`Second-line
`
`VPA
`
`LEV
`
`PHT
`
`Third-line
`
`TPM
`
`LTG
`
`OXC
`
`CZP
`
`MSX
`
`25 (61)
`
`16 (39)
`
`0 (0)
`
`3 (7)
`
`27 (66)
`
`36 (88)
`
`27 (66)
`
`18 (44)
`
`6 (15)
`
`1 (2)
`
`2 (5)
`
`0 (0)
`
`25 (61)
`
`16 (39)
`
`0 (0)
`
`3 (7)
`
`27 (66)
`
`36 (88)
`
`27 (66)
`
`18 (44)
`
`6 (15)
`
`1 (2)
`
`2 (5)
`
`0 (0)
`
`Order in which i.v. lacosamide was administered
`
`Started simultaneously
`with 2nd AED
`
`3rd AED
`
`4th AED
`
`5th AED
`
`6th AED
`
`3 (7)
`
`22 (49)
`
`14 (31)
`
`3 (7)
`
`3 (7)
`
`AED(s) antiepileptic drug(s), CLB clobazam, CLP clonazepam, CZP
`carbamazepine, LTG lamotrigine, LEV levetiracetam, LZP lorazepam,
`MDL midazolam, MSX mesuximide, OXC oxcarbazepine, PHT phe-
`nytoin, PRO propofol, RSE refractory status epilepticus, TPM topi-
`ramate, VPA valproate
`
`care center. To our knowledge, this is the largest compar-
`ative cohort study of i.v. LCM for the treatment of RSE to
`date. After adjustment for age, mortality was significantly
`lower in patients with i.v. LCM—a finding that might have
`been confounded by the implementation of continuous
`video-EEG monitoring in the ICU prior to the use of i.v. LCM
`leading to heightened awareness as well as earlier diagnosis
`and treatment of SE possibly contributing to a better outcome
`and decreased mortality. In patients with i.v. LCM, RSE
`ceased in the vast majority and tended to be more frequently
`controlled than in patients without i.v. LCM. No significant
`differences regarding SE severity and etiology or critical
`medical conditions and interventions between patients with
`and without i.v. LCM could be identified as possible con-
`founders of this association in our cohort—underscoring the
`strength of this finding. Among all patients with i.v. LCM,
`
`Table 4 Continuous and categorical outcomes in patients with
`refractory status epilepticus with and without
`intravenous (i.v.)
`lacosamide (excluding patients with hypoxic-ischemic encephalopa-
`thy; n = 86)
`
`Patients with i.v.
`lacosamide (n = 45)
`n (%)
`
`Patients without i.v.
`lacosamide (n = 41)
`n (%)
`
`87.2 ± 159.4
`
`134.3 ± 188.7
`
`Discharge (secondary outcome)
`
`Duration of SE
`(mean ± SD), h
`
`Seizure control
`
`Death
`
`Back home
`
`Rehabilitation
`
`Other hospital
`(for palliative
`care)
`
`Nursing home
`(for palliative
`care)
`
`SE status epilepticus
`
`41 (93)
`
`9 (20)
`
`5 (11)
`
`21 (47)
`
`2 (4)
`
`35 (85)
`
`16 (39)
`
`3 (7)
`
`14 (34)
`
`5 (12)
`
`7 (16)
`
`3 (7)
`
`51 % received LCM as the last AED, allowing the reasonable
`assumption that LCM was responsible for seizure control,
`which was achieved in 91 % of these patients. No adverse
`events could be related to the administration of i.v. LCM,
`indicating a favorable safety profile.
`The experience of LCM for SE treatment in adults is
`limited to a few reports on LCM [25, 42] and even more
`restricted for the treatment of patients with RSE to a few
`case reports and recent case series [27–30]. Although LCM
`is not a ‘broad spectrum’ AED, successful adjunctive
`treatment with LCM has been recently reported in two
`young women with refractory idiopathic generalized epi-
`lepsy (IGE) [43]. In our study, only one patient with
`hypoxic-ischemic encephalopathy also had IGE. Patients’
`demographics, clinical characteristics, and presumed eti-
`ologies of RSE were similar to those in previous studies on
`the treatment of RSE [28–30]. In contrast to prior reports
`on the use of i.v. LCM in SE, LCM was not administered
`with a ‘loading bolus’ of 400 mg [25, 42], an important
`difference that might have reduced its efficacy.
`In this study, overall mortality was 30 %, i.e., higher
`than observed in one prior study (up to 17 %) [44], but
`lower than in others (39–65 %) [9, 14, 45]. Overall,
`decreased mortality in patients with i.v. LCM might still be
`the result of multiple effects, such as improvement of
`critical care in general, which is difficult to address. The
`implementation of continuous video-EEG monitoring in
`the ICU in 2008 might have led to heightened awareness
`and subsequent earlier diagnosis and treatment of SE as
`reported earlier [46], possibly contributing to a better
`outcome and decreased mortality in patients treated with
`i.v. LCM. Except for the introduction of i.v. LCM and
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2084 - 8/11
`
`

`
`Lacosamide for Refractory Status Epilepticus
`
`327
`
`Table 5 Uni- and multivariable
`analysis of outcomes in patients
`with refractory status
`epilepticus in dependence of
`treatment with lacosamide
`(excluding patients with
`hypoxic-ischemic
`encephalopathy; n = 86)
`
`H–L X2 Hosmer–Lemeshow
`statistics, OR odds ratio, SE
`status epilepticus
`a Adjusted for age
`b Regression coefficient
`
`Treatment with lacosamide
`
`OR
`
`95 % CI
`
`p values
`
`H–L X2
`
`p values
`
`Univariable analysis
`
`Duration
`of SE (h)
`
`Seizure
`control
`
`Death
`Multivariable analysisa
`Duration
`of SE (h)
`
`Seizure control
`
`Death
`
`-47.2b
`
`-122.4 to 28.0
`
`0.216
`
`2.34
`
`0.39
`
`0.5 to 10.1
`
`0.2 to 1.0
`
`0.252
`
`0.054
`
`-35.9b
`
`-111.2 to 39.4
`
`0.346
`
`2.40
`
`0.34
`
`0.6 to 10.5
`
`0.1 to 0.9
`
`0.246
`
`0.035
`
`4.34
`
`15.1
`
`0.825
`
`0.062
`
`continuous video-EEG monitoring, further changes in the
`treatment strategies for RSE or changes in the team of
`epileptologists involved in critical care were not imple-
`mented at our institution during the entire study. In addi-
`tion,
`there was no significant difference in underlying
`etiologies and SE duration—both important determinants
`for outcome [45, 47–50]. However, SE duration tended to
`be longer in patients who did not receive LCM and
`therefore might have influenced outcome.
`Clinical monitoring of LCM-related adverse effects in
`patients with RSE was challenging, because all patients
`were in a stuporous or comatose state. There were no i.v.
`LCM-related changes observed in cardiopulmonary, renal,
`hepatic, or hematological parameters. In particular, new
`onsets of atrial flutter or fibrillation (which were recently
`reported in association with LCM [24]) were not identified
`in the continuous ECG monitoring during their ICU stay.
`Overall, this study demonstrates that i.v. LCM as an add-on
`treatment in patients with RSE is safe and the potential
`benefits might outweigh the risks by far, underscoring
`findings from recent case series on patients with seizure
`clusters and SE, where seizure control was achieved in
`100 % of patients with LCM as the first or second drug [42].
`
`4.1 Strengths and Limitations
`
`The strengths of this study are the large cohort, the com-
`parison to controls with similar SE etiologies categorized
`according to the guidelines of the ILAE [39], SE severity
`graded by STESS (with the integral components of age,
`prior history of seizures, worst seizure type, and level of
`consciousness at SE onset) [40, 41], and finally critical
`medical conditions and interventions to exclude possible
`confounding by indication. The last of these seems par-
`ticularly important, as physicians may tend to use newer
`AEDs more frequently in patients with particular clinical
`and EEG characteristics.
`Limitations of the study include its retrospective data
`collection and single-center source. The use of historical
`
`controls impedes the interpretation, as patients enrolled in
`recent times may benefit from more effective treatment
`facilities resulting in more favorable outcomes. Therefore,
`we cannot rule out the potential of residual confounding
`and only assumptions could be made regarding the cause
`for termination of RSE. Owing to the retrospective nature
`of this study only the sequential order of AEDs and not the
`exact timing relative to the diagnosis of RSE could be
`assessed. In addition, all patients had several AEDs, a fact
`that hampers analyses regarding isolated effects of LCM.
`Furthermore, the sequential order in which i.v. LCM was
`administered was mainly determined by the treating phy-
`sicians, thereby impeding further analysis regarding the
`efficacy of i.v. LCM. However, as the clinical character-
`istics of the two compared groups were very similar (as
`mentioned above), a direct association of i.v. LCM with
`decreased mortality in RSE seems likely.
`
`5 Conclusion
`
`tolerated and had a
`i.v. LCM was well
`To conclude,
`favorable safety profile as adjunctive treatment for RSE. Its
`use was associated with decreased mortality of RSE—a
`finding that might have been confounded by the imple-
`mentation of continuous video-EEG monitoring in the ICU
`prior to the use of i.v. LCM leading to heightened aware-
`ness as well as earlier diagnosis and treatment of SE.
`Prospective randomized trials with larger sample sizes are
`warranted to further strengthen the evidence of efficacy of
`LCM for the treatment of RSE.
`
`Acknowledgments There was no financial support of this study.
`This study was performed and designed independently of any
`pharmaceutical company or other commercial interest. It was spon-
`sored by the institution and explicitly not funded by the manufacturer
`of lacosamide.
`We thank Dr. S. Tschudin-Sutter for her statistical work.
`We confirm that all persons who contributed significantly to the
`work are listed as authors. Dr. R. Sutter and Dr. S. Ru¨egg conceived
`and planned the work, acquired, analyzed and interpreted the data,
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2084 - 9/11
`
`

`
`328
`
`R. Sutter et al.
`
`and wrote the first draft of the manuscript. Dr. S. Marsch interpreted
`the data, edited, and revised the manuscript. All authors approved the
`final submitted version.
`Dr. R. Sutter is supported by the Research Fund of the University of
`Basel, the Scientific Society Basel, and the Gottfried Julia Bangerter-
`Rhyner Foundation.
`Dr. S. Marsch reports no disclosures.
`Dr. S. Ru¨egg received unconditional research grants from UCB
`(Union Chimique Belge). He received honoraria from serving on the
`scientific advisory boards of Desitin, Eisai, GlaxoSmithKline, and
`UCB, travel grants from GlaxoSmithKline, Janssen-Cilag, and UCB,
`speaker fees from UCB and from serving as a consultant for Eisai,
`GlaxoSmithKline, Janssen-Cilag, Pfizer, Novartis, and UCB. He does
`not hold any stocks of any pharmaceutical industries or manufacturers
`of medical devices.
`
`References
`
`1. Knake S, Rosenow F, Vescovi M, et al. Incidence of status epi-
`lepticus in adults in Germany: a prospective, population-based
`study. Epilepsia. 2001;42(6):714–8.
`2. Hesdorffer DC, Logroscino G, Cascino G, et al. Incidence of
`status epilepticus in Rochester, Minnesota, 1965–1984. Neurol-
`ogy. 1998;50(3):735–41.
`3. Leppert