Scholarly article on topic 'A long-term noninterventional safety study of adjunctive lacosamide therapy in patients with epilepsy and uncontrolled partial-onset seizures'

A long-term noninterventional safety study of adjunctive lacosamide therapy in patients with epilepsy and uncontrolled partial-onset seizures Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Bernhard J. Steinhoff, Klaus Eckhardt, Pamela Doty, Marc De Backer, Marcus Brunnert, et al.

Abstract This noninterventional, observational, postauthorization safety study (SP0942, NCT00771927) evaluated the incidence of predefined cardiovascular- (CV) and psychiatric-related treatment-emergent adverse events (TEAEs), in patients with epilepsy and uncontrolled partial-onset seizures, when initiating adjunctive therapy with lacosamide or another approved antiepileptic drug (AED) according to standard medical practice. Active recording of predefined TEAEs of interest took place at three-monthly recommended visits for up to 12months. Of 1004 patients who received at least one dose of adjunctive AEDs, 511 initially added lacosamide therapy, 493 added another AED, 69 were ≥65years of age, and 72 took concomitant antiarrhythmic drugs. Patients in the lacosamide cohort had a higher median frequency of partial-onset seizures (6.0 versus 3.5 per 28days) despite taking more concomitant AEDs (84.9% versus 66.9% took ≥2) at baseline. Patients who added lacosamide took a modal dose of 200mg/day over the treatment period (n=501), and 50.1% (256/511) completed 12months of treatment. Fifty-one point nine percent (256/493) of patients who added another AED completed the study, with the most commonly added AED being levetiracetam (28.4%). Four patients (0.8%) in each cohort, all <65years of age, reported predefined CV-related TEAEs. None were considered serious or led to discontinuation. One event each of sinus bradycardia (lacosamide), atrioventricular block first degree (lacosamide), and syncope (other AED) were judged to be treatment-related. Another patient in the other AED cohort reported bradycardia while taking concomitant antiarrhythmic drugs. Predefined psychiatric-related TEAEs were reported by 21 patients (4.1%) in the lacosamide cohort and 27 patients (5.5%) in the other AED cohort. Depression was the most common to be treatment-related (7/11 and 12/18 of patients reporting treatment-related psychiatric TEAEs, respectively). Serious psychiatric-related TEAEs were reported by four patients who added lacosamide (two cases of depression, two of suicide attempt) and one who added another AED (depression). Seven deaths occurred, all of which were considered unrelated/unlikely related to study medication. This thorough evaluation revealed a low incidence of predefined CV- and psychiatric-related TEAEs in patients taking adjunctive AED therapy according to standard medical practice. No specific safety concerns related to adjunctive lacosamide therapy were noted.

Academic research paper on topic "A long-term noninterventional safety study of adjunctive lacosamide therapy in patients with epilepsy and uncontrolled partial-onset seizures"

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Epilepsy & Behavior

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

A long-term noninterventional safety study of adjunctive lacosamide therapy in patients with epilepsy and uncontrolled partial-onset seizures

Bernhard J. Steinhoff a* Klaus Eckhardtb, Pamela Dotyc, Marc De Backer d, Marcus Brunnertb, Andreas Schulze-Bonhage e

a Kork Epilepsy Centre, Kehl-Kork, Germany b UCB Pharma, Monheim am Rhein, Germany c UCB Pharma, Raleigh, NC, USA d UCB Pharma, Brussels, Belgium e University Hospital Freiburg Freiburg, Germany

ARTICLE INFO ABSTRACT

This noninterventional, observational, postauthorization safety study (SP0942, NCT00771927) evaluated the incidence of predefined cardiovascular- (CV) and psychiatric-related treatment-emergent adverse events (TEAEs), in patients with epilepsy and uncontrolled partial-onset seizures, when initiating adjunctive therapy with lacosamide or another approved antiepileptic drug (AED) according to standard medical practice. Active recording of predefined TEAEs of interest took place at three-monthly recommended visits for up to 12 months. Of 1004 patients who received at least one dose of adjunctive AEDs, 511 initially added lacosamide therapy, 493 added another AED, 69 were >65 years of age, and 72 took concomitant antiarrhythmic drugs. Patients in the lacosamide cohort had a higher median frequency of partial-onset seizures (6.0 versus 3.5 per 28 days) despite taking more concomitant AEDs (84.9% versus 66.9% took >2) at baseline. Patients who added lacosamide took a modal dose of200mg/day over the treatment period (n = 501), and 50.1% (256/511) completed 12 months of treatment. Fifty-one point nine percent (256/493) of patients who added another AED completed the study, with the most commonly added AED being levetiracetam (28.4%). Four patients (0.8%) in each cohort, all < 65 years of age, reported predefined CV-related TEAEs. None were considered serious or led to discontinuation. One event each of sinus bradycardia (lacosamide), atrioventricular block first degree (lacosamide), and syncope (other AED) were judged to be treatment-related. Another patient in the other AED cohort reported bradycardia while taking concomitant antiarrhythmic drugs. Predefined psychiatric-related TEAEs were reported by 21 patients (4.1%) in the lacosamide cohort and 27 patients (5.5%) in the other AED cohort. Depression was the most common to be treatment-related (7/11 and 12/18 of patients reporting treatment-related psychiatric TEAEs, respectively). Serious psychiatric-related TEAEs were reported by four patients who added lacosamide (two cases of depression, two of suicide attempt) and one who added another AED (depression). Seven deaths occurred, all of which were considered unrelated/unlikely related to study medication. This thorough evaluation revealed a low incidence of predefined CV- and psychiatric-related TEAEs in patients taking adjunctive AED therapy according to standard medical practice. No specific safety concerns related to adjunctive lacosamide therapy were noted.

© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license

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

CrossMark

Article history:

Received 22 December 2015 Revised 26 February 2016 Accepted 27 February 2016 Available online xxxx

Keywords:

Postmarketing product surveillance Consumer product safety Cardiovascular system Psychiatry

Drug-related side effects Adverse reactions

Abbreviations: AE, adverse event; AED, antiepileptic drug; AV, atrioventricular; CV, cardiovascular; ECG, electrocardiogram; PASS, postauthorization safety study; POS, partial-onset seizures; PTSD, posttraumatic stress disorder; SAE, serious adverse event; SS, safety set; TEAE, treatment-emergent adverse event.

* Corresponding author.

E-mail addresses: BSteinhoff@epilepsiezentrum.de (B.J. Steinhoff), Klaus.Eckhardt@ucb.com (K. Eckhardt), Pamela.Doty@ucb.com (P. Doty), Marc.DeBacker@ucb.com (M. De Backer), Marcus.Brunnert@ucb.com (M. Brunnert), Andreas.Schulze-Bonhage@uniklinik-freiburg.de (A. Schulze-Bonhage).

1. Introduction

Lacosamide is a functionalized amino acid with proven efficacy as an antiepileptic drug (AED). In Europe, lacosamide is currently approved as an adjunctive therapy for the treatment of partial-onset seizures (POS) in adult and adolescent (16-18 years of age) patients with epilepsy, at dosages up to 400 mg/day (200 mg twice a day) [1]. Lacosamide is approved in several other countries, including the United States, where it is licensed for use as a monotherapy or adjunctive therapy in patients (> 17 years of age) with POS [2].

Pharmacokinetic studies have shown lacosamide to have minimal protein binding, high oral absorption, dose-proportional bioavailability,

http: //dx.doi.org/10.1016/j.yebeh.2016.02.041

1525-5050/© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/40/).

a half-life that allows twice-daily dosing, and low risks of drug-drug interactions [3,4]. Three Phase II/III, double-blind, randomized registration trials confirmed the safety and efficacy of lacosamide in more than 1300 patients with POS, each randomized to receive 200,400, or 600 mg/day lacosamide or placebo, to be taken adjunctive to one to three baseline AEDs [5-7]. The treatment-emergent adverse events (TEAEs) most frequently reported during the registration trials were central nervous system- and gastrointestinal-associated. The most common drug-related adverse events (AEs), namely dizziness and nausea, also showed a relationship with dose [5-7]. Similar types of TEAEs were observed in short-term studies of adjunctive lacosamide therapy via intravenous administration, in long-term open-label studies for up to 8 years, and when taken as monotherapy [8-13].

Cardiac conduction side effects are associated with the use of several AEDs, particularly those that block sodium channels [14-17]. A small dose-related increase in the PR interval has been observed in trials of oral and intravenous lacosamide, with no significant change in blood pressure or QTc interval [11-13,18-20]. There have also been some published reports of cardiac AEs in patients receiving lacosamide [9,18,21-28].

Some AEDs have a known potential for recreational abuse [29-31]. While a few euphoria cases were reported during pharmacokinetic and human abuse studies, overall, euphoria was rarely (< 1% of patients) reported during the lacosamide development program [2,32].

Psychiatric conditions exist at a higher prevalence among patients with epilepsy than in the general population, including depression, anxiety, and aggression disorders [33,34]. Some AEDs have shown potential associations with psychiatric AEs and behavioral changes [35-37]. Psychiatric-related AEs (such as depression) are commonly listed in AED labeling, including that for lacosamide [1,2].

AEDs in general may increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. A class warning is in place and acknowledged in all AED product labeling [35,38-40]; however, the mechanism for this increased risk is unknown. The overall efficacy and safety of adjunctive lacosamide use for the treatment of uncontrolled POS was established in well-controlled clinical studies.

Postauthorization, noninterventional studies provide data which are complementary to that obtained from randomized, placebo-controlled studies, which are generally conducted in more optimized treatment settings. Postauthorization, observational studies include patients with diverse characteristics and comorbidities, reflective of the patient population who receive that medication in real-life, according to the product label and summary of product characteristics. Flexible drug selection and dosing reflects the standard medical care received by patients in the real-world, where medical supervision may also be less intensive than in controlled studies, and treatment decisions may be influenced by additional factors. Patients in these studies may also have more control over their own treatment, including care decisions and medication compliance. In this way, the lack of controlled factors during postauthorization, noninterventional studies is of great benefit, as the results provide a 'snap-shot' on the effectiveness of medications in the way that they are currently used in real-life. This observational, postauthorization safety study (PASS) of lacosamide provides complementary data to that obtained during the three registration trials, and was conducted as a commitment to the European Medicines Agency to specifically assess the incidence of predefined cardiovascular (CV)-and psychiatric-related TEAEs in patients with uncontrolled POS who use lacosamide in routine clinical practice.

2. Methods

2.1. Study design

This noninterventional PASS (SP0942, NCT00771927) was conducted at 71 sites in France, Germany, the Netherlands, Spain, and the United Kingdom. Patients were assigned to one of two cohorts based on the

decision to prescribe lacosamide or another AED, made by the treating physician prior to enrollment and according to standard medical practice. Eligible patients were enrolled within 2 days of treatment initiation in blocks of 10 per physician: five who added lacosamide and five who added another AED. These patients formed the "lacosamide cohort" and the "other AED cohort", respectively. Treatment continued per standard local medical practice for up to 12 months, allowing flexible treatment according to individual patient need and physician's judgment. It was recommended that follow-up visits occurred at 3, 6, 9, and 12 months, with an additional safety visit 2 weeks after the end of treatment if adjunctive treatment was discontinued before the end of the study. A routine electrocardiogram (ECG) was conducted at each study visit if part of the site's standard medical practice.

2.2. Patients

Patients aged 16 years or older with a diagnosis of epilepsy and experiencing POS considered by the treating physician to be uncontrolled on current therapy were assigned adjunctive AED therapy. The study protocol was approved by an independent ethics committee. All patients provided written consent and were treated in accordance with local regulations and the Declaration of Helsinki.

2.3. Study variables

The primary safety variables for this study were the incidence of predefined CV- and psychiatric-related TEAEs (Table 1). Treatment-emergent adverse events were defined as AEs occurring during treatment or within 30 days of the last dose. All AEs were reported to or observed by the physician at every visit, with additional active collection of predefined CV- and psychiatric-related TEAEs using a checklist. The recording physician also assessed the intensity and relationship of each AE to the study treatment. Relationships of "possible", "probable", or "highly probable", or entries with missing relationship data, were classified as drug-related. The intensity of each TEAE was categorized based on the impact caused to routine activities in daily life. Adverse events with missing intensity entries were categorized as severe. Other safety variables included the overall incidence of TEAEs and serious AEs (SAEs), and TEAEs leading to discontinuation of the added AED.

The modal daily dose of lacosamide taken during the treatment period was calculated for each patient. This was used to calculate the overall mode of the modal daily doses in the lacosamide cohort.

Although not predefined, several other variables were evaluated, if captured as part of routine clinical practice: the occurrence of TEAEs, changes in vital signs and body weight, the median percent change in seizure frequency per 28 days from the 2-month retrospective baseline, the Clinical Global Impression of Change questionnaire for the

Table 1

Predefined cardiovascular- and psychiatric-related treatment-emergent adverse events.

Cardiovasculara Adams-Stokes syndrome AV block

AV block complete AV block first degree

Psychiatrica Depression Major depression Depressed mood Depression suicidal Completed suicide Suicidal behavior Suicidal ideation Suicide attempt

AV block second degree Syncope Bradycardia Bradyarrhythmia

Intentional self-injury Self-injurious behavior Self-injurious ideation Poisoning deliberate Drug abuse Drug abuser Drug dependence

Sinus bradycardia ECG PR prolongation (201-209 ms)

Substance abuse Substance abuser Polysubstance dependence Intentional drug misuse Intentional overdose Multiple drug overdose, intentional

AV, atrioventricular; ECG, electrocardiogram. a Medical Dictionary for Regulatory Activities (MedDRA, Version 15.0) preferred terms.

preceding 4 weeks compared with baseline, and adjunctive AED retention time (assessed using the Kaplan-Meier method).

2.4. Data analysis

Statistical summaries of the data employed descriptive statistics. Based on a sample size of 500 patients per cohort, the probability of observing at least one TEAE within a category of interest (i.e., CV- or psychiatric-related) was 99.3%, assuming an overall incidence of 1.0% for the category of interest. All safety variables were summarized using the safety set (SS), comprising all patients with baseline characteristic data who received at least one dose of study treatment. Two additional analyses were conducted on special patient subgroups: those > 65 years of age versus < 65 years and those taking concomitant antiarrhythmic medications (coded to one of the following World Health Organization Anatomical Therapeutic Chemical codes: C01B, C07, or C08D) versus those who were not taking those medications.

3. Results

3.1. Patient disposition

Of the 1005 patients enrolled in the study, all but one (who did not meet the entry criteria) constituted the SS. In total, 511 patients initiated adjunctive lacosamide therapy at enrollment and formed the lacosamide cohort, while 493 received another adjunctive AED and formed the other AED cohort. Overall, 512/1005 patients (50.9%) completed the study, 256 patients per cohort (Fig. 1).

In the lacosamide cohort, 17 patients (3.3%) were considered potential therapy switchers, as they discontinued lacosamide but had not withdrawn from the study at their next visit. Forty-eight patients (9.7%) in the other AED cohort took lacosamide and were considered potential therapy switchers.

Pooled safety and efficacy analyses of all patients who received lacosamide at any time during the study (559/1005, lacosamide cohort plus therapy switchers in the other AED cohort) did not produce

Fig. 1. Patient disposition. aOne patient did not meet entry criteria and was later excluded from the SS. bPatients who discontinued lacosamide and did not discontinue study at next visit. cPatients treated with one AED for 3 or more consecutive months. dPatients treated with lacosamide at any time during the study and did not discontinue at the next visit. AED, antiepileptic drug; SS, safety set.

substantial outcome changes compared with those of the lacosamide cohort.

3.2. Baseline demographics, patient, and epilepsy characteristics

Baseline demographics and patient characteristics were similar between patients in each cohort (Table 2), although patients in the lacosamide cohort had a higher median POS frequency per 28 days and took a greater number of concomitant AEDs (84.9% versus 66.9% took >2) at baseline. Nearly all patients (99.6% in the lacosamide cohort and 98.4% in the other AED cohort) took one or more concomitant AEDs during the study. Most patients (60.5% in the lacosamide cohort and 64.9% in the other AED cohort) had no prior AED use other than the AEDs taken at baseline. A similar proportion of patients in each cohort reported a medical history of cardiac or psychiatric disorders (Table 2).

In the SS, 69/1004 (6.9%) patients were > 65 years of age (24/511 who added lacosamide [4.7%] and 45/493 who added another AED [9.1%]), and 72/1004 (7.2%) concurrently took antiarrhythmic drugs (29/511 patients who added lacosamide [5.7%] and 43/493 patients who added another AED [8.7%]). No patients took a combination of beta-blocker and calcium antagonist.

3.3. Treatment exposure

For patients who added lacosamide to their baseline treatment regimen, the median duration of exposure was 324.5 days (n = 504). The modal dose over the treatment period was 200 mg/day (50 mg/day minimum/700 mg/day maximum, n = 501) and at month 12 was 400 mg/day (50 mg/day minimum/600 mg/day maximum, n = 70). Five patients took lacosamide as monotherapy for 3 or more consecutive months.

For patients who added an AED other than lacosamide, the median duration of treatment exposure was 321.0 days (n = 489). Levetirace-tam was the AED most commonly added to baseline treatment (28.4%). Others were lamotrigine (14.0%), zonisamide (12.2%), oxcarbazepine (11.4%), topiramate (10.1%), eslicarbazepine acetate (7.9%), pregabalin (6.7%), valproate medications (2.8%), and carbamazepine (2.0%); 4.5% of patients added an alternative AED.

A similar percentage of patients in the lacosamide cohort (33.3%) and the other AED cohort (29.4%) withdrew from the study because of lack of efficacy, loss of efficacy, or AEs. A Kaplan-Meier analysis showed that the adjunctive treatment retention time for the first 25% of patients discontinuing because of lack of efficacy, loss of efficacy, or AEs was 195 days for patients who added lacosamide (95% confidence interval: 148-270) and 190 days for patients who added another AED (95% confidence interval: 143-267).

3.4. incidence of predefined CV-related TEAEs

Predefined CV-related TEAEs were experienced by four patients (0.8%) in each cohort, all of whom were < 65 years of age. All predefined CV-related TEAEs were mild or moderate in intensity, none were serious, and none led to discontinuation of adjunctive AED by any patient (Tables 3 and 4).

Among the four patients in the lacosamide cohort who experienced a predefined CV-related TEAE, two reported sinus bradycardia, one reported bradycardia, and one reported first-degree atrioventricular (AV) block. One case of sinus bradycardia (55 bpm, reduced from baseline by 9 bpm) was possibly related to the patient's study medication (200 mg/day lacosamide adjunctive to lamotrigine and levetiracetam). The other occurred in a patient taking 50 mg/day lacosamide adjunctive to lamotrigine and was not considered treatment-related (between 56 and 70 bpm throughout enrollment). The case of bradycardia (78 bpm on the first day of treatment) was considered mild in intensity, not treatment-related, and occurred in a patient taking 100 mg/day lacosamide adjunctive to levetiracetam, lorazepam, and topiramate.

Table 2

Baseline demographics, patient, and epilepsy characteristics.

Characteristic Lacosamide Other AED

n = 511 n = 493

Age, mean ± SD, years 39.8 ± 13.58 42.3 ± 15.38

>65 years, n (%) 24 (4.7) 45 (9.1)

Female, n (%) 266 (52.1) 282 (57.2)

Race, n (%)

White 481 (94.1) 464(94.1)

Othera 6(1.2) 7 (1.4)

POS frequency/28 days, median (range)b 6(0-600) 3.5 (0-1000)

Secondarily generalized seizure frequency о(0-100) 0(0-12)

per 28 days, median (range)b

Seizure frequency/28 days, n (%)b,c

0-2 122 (23.9) 197 (40.0)

>2-5 106 (20.7) 112 (22.7)

>5-10 100 (19.6) 54 (11.0)

>10 161 (31.5) 121 (24.5)

Missing 22 (4.3) 9 (1.8)

AED(s) discontinued prior to baseline, any, n (%) 202 (39.5) 173 (35.1)

In >10% of patients in either cohort

Lamotrigine 69 (13.5) 46 (9.3)

Levetiracetam 68 (13.3) 49 (9.9)

Carbamazepine 66 (12.9) 55 (11.2)

Topiramate 62 (12.1) 33 (6.7)

Number of prior AEDs, n (%)

0 309 (60.5) 320 (64.9)

1 77 (15.1) 83 (16.8)

2 35 (6.8) 36 (7.3)

>2 90 (17.6) 54(11.0)

Concomitant AED use, n (%) 509 (99.6) 485 (98.4)

In > 20% patients in either cohort

Levetiracetam 250 (48.9) 196 (39.8)

Lamotrigine 217 (42.5) 167 (33.9)

Carbamazepine 135 (26.4) 112 (22.7)

Oxcarbazepine 123 (24.1) 84 (17.0)

Valproate sodium 100 (19.6) 99 (20.1)

Number of concomitant AEDs, n (%)

0 2 (0.4) 8 (1.6)

1 75 (14.7) 155 (31.4)

2-3 311 (60.9) 259 (52.5)

>3 123 (24.1) 71 (14.4)

Concomitant use of a sodium channel-blocking AED 384(75.1) 302 (61.3)

at any time during treatment, n (%)

Concomitant antiarrhythmic drug use, n (%)d 29 (5.7) 43 (8.7)

Any concomitant cardiac disorder, n (%) 19 (3.7) 18 (3.7)

Any concomitant psychiatric disorder, n (%) 101 (19.8) 99 (20.1)

Table 3

Incidence of predefined cardiovascular- and psychiatric-related TEAEs during the first 12 months of adjunctive lacosamide or other AED therapy in patients with uncontrolled partial-onset seizures.

AED, antiepileptic drug; POS, partial-onset seizure; SD, standard deviation. a Race not recorded in France.

b From number of reported seizures during the 2 months prior to baseline. c Both partial-onset and secondarily generalized seizures.

d World Health Organization Anatomical Therapeutic Chemical codes: C01B (antiarrhythmics, class I and III), C07 (^.-blocking agents), or C08D (selective calcium channel blockers with direct cardiac effects).

This patient had a familial history of cardiac disease. The case of first-degree AV block was categorized as possibly treatment-related and occurred in a patient taking 350 mg/day lacosamide adjunctive to lamotrigine and levetiracetam. None of the TEAEs occurred in patients taking concomitant antiarrhythmic treatment.

Among the four patients in the other AED cohort who experienced a predefined CV-related TEAE, three reported bradycardia. One patient was receiving valproate adjunctive to lamotrigine and was taking anti-arrhythmic treatment at the time of the bradycardia event (54 bpm on the first day of treatment). This patient had a relevant medical history including Factor V Leiden mutation and ongoing hypertension. The two other patients were taking levetiracetam at the time ofbradycardia onset, one as monotherapy (52 bpm, reduced from baseline by 13 bpm) and one adjunctive to lamotrigine (between 48 and 56 bpm at follow-up visits, reduced from 76 bpm at baseline). In all three cases, bradycar-dia was considered unlikely to be, or not related to, adjunctive AED treatment. One other patient reported a TEAE of syncope, which was possibly related to treatment. This patient was taking phenobarbital

No. of patients (%) Lacosamide n = 511 Other AED n = 493

Predefined cardiovascular-related TEAEs

Anya 4 (0.8) 4 (0.8)

Judged to be seriousb 0 0

Leading to discontinuationc 0 0

Judged to be treatment-relatedd 2 (0.4) 1 (0.2)

Patients with relevant medical history 1 (0.2) 2 (0.4)

Sinus bradycardia 2 (0.4) 0

Judged to be treatment-related 1 (0.2) 0

AV block first degree 1 (0.2) 0

Judged to be treatment-related 1 (0.2) 0

Bradycardia 1 (0.2) 3 (0.6)

Patients with relevant medical history 1 (0.2) 1 (0.2)

Syncope 0 1 (0.2)

Judged to be treatment-related 0 1 (0.2)

Patients with relevant medical history 0 1 (0.2)

Predefined psychiatric-related TEAEs

Anya 21 (4.1) 27 (5.5)

Judged to be seriousb 4 (0.8) 1 (0.2)

Leading to discontinuationc 2 (0.4) 4 (0.8)

Judged to be treatment-relatedd 11 (2.2) 18 (3.7)

Patients with relevant medical history 7(1.4) 7 (1.4)

Depression 15 (2.9) 21 (4.3)

Judged to be serious 2 (0.4) 1 (0.2)

Leading to discontinuation 2 (0.4) 3 (0.6)

Judged to be treatment-related 7(1.4) 12 (2.4)

Patients with relevant medical history 5(1.0) 4 (0.8)

Depressed mood 4 (0.8) 5(1.0)

Leading to discontinuation 0 1 (0.2)

Judged to be treatment-related 3 (0.6) 4 (0.8)

Patients with relevant medical history 1 (0.2) 2 (0.4)

Suicide attempt 2 (0.4) 0

Judged to be serious 2 (0.4) 0

Judged to be treatment-related 1 (0.2) 0

Patients with relevant medical history 1 (0.2) 0

Suicidal ideation 1 (0.2) 1 (0.2)

Judged to be treatment-related 0 1 (0.2)

Patients with relevant medical history 1 (0.2) 1 (0.2)

Major depression 0 1 (0.2)

Judged to be treatment-related 0 1 (0.2)

AED, antiepileptic drug; AV, atrioventricular; TEAE, treatment-emergent adverse event. Coded using Medical Dictionary for Regulatory Activities preferred terms.

a Predefined cardiovascular and psychiatric TEAE terms with no reported incidence are not shown.

b Serious AE defined as event leading to death, life-threatening adverse experience, initial or prolonged inpatient hospitalization, significant or persistent disability/incapacity, congenital anomaly, or other important medical event based on the judgment of the physician.

c Leading to discontinuation of add-on AED treatment.

d Treatment relationship defined as "highly probable", "probable", "possible", or "not assessable" as judged by the physician.

adjunctive to carbamazepine, slow-release valproic acid, clobazam, and levetiracetam, and had an ongoing medical history of vertigo.

3.5. Incidence of predefined psychiatric-related TEAEs

Predefined psychiatric-related TEAEs were experienced by 21 patients (4.1%) in the lacosamide cohort and 27 patients (5.5%) in the other AED cohort (Table 3). Most of these TEAEs were mild or moderate in intensity. The most frequently reported psychiatric-related TEAE in both cohorts was depression: 15 patients (2.9%) who added lacosamide and 21 patients (4.3%) who added another AED. In the lacosamide cohort, all psychiatric-related TEAEs were reported by patients < 65 years of age. Four patients > 65 years of age in the other AED cohort reported a psychiatric-related TEAE (Table 4).

Table 4

Incidence of predefined cardiovascular- and psychiatric-related TEAEs of interest during the first 12 months of adjunctive lacosamide or other AED therapy in patients <65 years and >65 years of age with uncontrolled partial-onset seizures.

Age <65 years > 65 years

Lacosamide Other AED Lacosamide Other AED

No. of patients (%) n = 487 n = 448 n = 24 n = 45

Cardiovascular-relateda

Any predefined 4 (0.8) 4 (0.9) 0 0

Sinus bradycardia 2 (0.4) 0 0 0

AV block first degree 1 (0.2) 0 0 0

Bradycardia 1 (0.2) 3 (0.7) 0 0

Syncope 0 1 (0.2) 0 0

Psychiatric-relateda

Any predefined 21 (4.3) 23 (5.1) 0 4 (8.9)

Depression 15(3.1) 17 (3.8) 0 4 (8.9)

Depressed mood 4 (0.8) 5(1.1) 0 0

Suicide attempt 2 (0.4) 0 0 0

Suicidal ideation 1 (0.2) 1 (0.2) 0 0

Major depression 0 0 0 1 (2.2)

AED, antiepileptic drug; AV, atrioventricular; TEAE, treatment-emergent adverse event.

a Predefined cardiovascular- and psychiatric-related TEAE terms with no reported incidence are not shown.

3.5.1. Major depression

Major depression was reported by one patient, 71 years old, in the other AED cohort. This TEAE was assessed as probably related to leveti-racetam, which was added to gabapentin therapy. This patient later discontinued levetiracetam owing to a TEAE of depression.

3.5.2. Depression

Among the 15 patients (2.9%) in the lacosamide cohort who reported depression, two cases were considered an SAE of moderate intensity. Neither patient discontinued lacosamide treatment or withdrew from the study owing to this SAE. One had a history of depression and was taking 200 mg/day lacosamide adjunctive to carbamazepine and topiramate at the time of onset, the other had discontinued lacosamide 16 days previously. Two other patients discontinued lacosamide because of a TEAE of depression. Seven of the 15 cases of depression were judged to be related to adjunctive lacosamide treatment. Five of the 15 cases were reported in patients who had relevant medical history: two of depression, one of anxiety and depression, one of posttraumatic stress disorder (PTSD), and one had a familial history of major depressive disorder. Another patient was taking higher than the approved dosage of lacosamide at the time of depression onset (700 mg/day), and the TEAE was not considered related to study treatment.

Of the 21 patients (4.3%) in the other AED cohort who reported a TEAE of depression, one experienced an SAE of moderate intensity while taking topiramate as monotherapy. This patient had a medical history of PTSD and sleep disorder. Depression led to discontinuation of adjunctive AED treatment in three of the 21 patients. Twelve patients (2.4%) experienced depression judged to be related to adjunctive AED treatment. One patient was a therapy switcher; however, the TEAE resolved shortly after onset, and was classified as mild and not related to treatment with pregabalin taken adjunctive to lacosamide and leveti-racetam. Four of the 21 patients had a relevant medical history: two of depression, one of sleep disorder and PTSD, and one of anxiety and depression.

In the other AED cohort, four of the patients reporting depression were > 65 years of age. Two of the four discontinued adjunctive AED treatment owing to this TEAE. One other had a medical history of depression.

3.5.3. Depressed mood

Depressed mood was reported in four patients (0.8%) in the lacosamide cohort; no cases were considered serious or led to lacosamide discontinuation. Three of the four reports were considered

possibly treatment-related, and one of these was in a patient with a history of depression. Five patients (1.0%) in the other AED cohort reported a TEAE of depressed mood, of which two cases were considered highly probably related to study treatment and two were possibly related. One unrelated case was reported in a patient with a medical history of insomnia and depression. Depressed mood led to discontinuation of study treatment in one patient who was taking pregabalin adjunctive to lamotrigine and had a medical history of insomnia. This TEAE was considered severe and highly probably related to study treatment. One patient in the other AED cohort was concomitantly taking lacosamide at the time of the TEAE onset. This TEAE was classified as moderate intensity and possibly related to study treatment (vigabatrin taken adjunctive to lacosamide, lamotrigine, levetiracetam, phenobarbital, phenytoin, and valproate). The TEAE resolved, and the patient continued the study.

3.5.4. Predefined psychiatric-related TEAEs relating to suicide

Suicide attempt was reported in two patients (0.4%) who added lacosamide and in no patients who added another AED. One event was considered possibly treatment-related and occurred in a patient taking 200 mg/day lacosamide adjunctive to levetiracetam. No medical history was available for this patient. The other patient had an ongoing medical history of depression and was taking 450 mg/day lacosamide adjunctive to carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, and topiramate. This TEAE was not considered treatment related.

One patient in each cohort reported a TEAE of suicidal ideation. The patient in the lacosamide cohort had a history of depression and was taking 300 mg/day lacosamide adjunctive to lamotrigine at the time of onset. The suicidal ideation was considered unlikely to be related to lacosamide therapy. The patient from the other AED cohort had a history of ongoing suicidal ideation, and the TEAE was considered as probably related to zonisamide treatment taken adjunctive to carbamazepine.

3.6. Other safety outcomes

3.6.1. Overall incidence of TEAEs

The overall incidence of any TEAE is presented in Table 5. Treatment-emergent adverse events reported by > 5% of patients in the lacosamide cohort, and at double the incidence than that reported by patients in the other AED cohort, were dizziness (21.7% versus 9.1%), diplopia (10.6% versus 3.7%), nausea (9.6% versus 4.7%), and vertigo (8.8% versus 2.2%).

3.6.2. SAEs

Serious adverse events were most commonly associated with the nervous system (43/78 patients in the lacosamide cohort and 39/64 in the other AED cohort, Table 5). Convulsion was the most commonly reported SAE (16 patients [3.1%] who added lacosamide and 17 patients [3.4%] who added another AED) and was the most common SAE considered to be treatment-related (6/16 and 3/17 in each cohort, respectively). Other SAEs occurring in two or more patients in either cohort and considered to be treatment-related were grand mal (two patients in the lacosamide cohort and four patients in the other AED cohort), dizziness (three and 0), hyponatremia (one and two), and status epilepticus (two and 0).

3.6.3. AEs leading to discontinuation

In total, 100 patients (19.6%) who added lacosamide, and 105 patients (21.3%) who added another AED, discontinued from the study owing to AE(s). In the lacosamide cohort, TEAEs led to permanent discontinuation of lacosamide by 96 patients (18.8%) and temporary interruption of lacosamide treatment by seven patients (1.4%). In the other AED cohort, TEAEs led to permanent discontinuation of the added AED by 94 patients (19.1%) and temporary interruption of the add-on treatment by three patients (0.6%) (Table 5).

Table 5

Incidence of any TEAE during the first 12 months of adjunctive lacosamide or other AED therapy in patients with uncontrolled partial-onset seizures.

Table 6

Incidence of nonpredefined TEAEs of interest during the first 12 months of adjunctive lacosamide or other AED therapy in patients with uncontrolled partial-onset seizures.

No. of patients (%) Lacosamide Other AED

n = 511 n = 493

Any TEAE 377 (73.8) 323 (65.5)

Judged to be treatment-relateda 309 (60.5) 258 (52.3)

Most common TEAEsb

Dizziness 111 (21.7) 45 (9.1)

Fatigue 81 (15.9) 62 (12.6)

Headache 56 (11.0) 30 (6.1)

Diplopia 54 (10.6) 18 (3.7)

Nausea 49 (9.6) 23 (4.7)

Vertigo 45 (8.8) 11 (2.2)

Convulsion 36 (7.0) 32 (6.5)

Any 78 (15.3) 64(13.0)

Judged to be treatment-relateda 28 (5.5) 19 (3.9)

Most common SAEsd

Convulsion 16 (3.1) 17(3.4)

Epilepsy 7 (1.4) 3 (0.6)

Grand mal convulsion 3 (0.6) 11 (2.2)

Partial seizures 1 (0.2) 5 (1.0)

Most common TEAEs leading to permanent

discontinuation of add-on AEDe

Any 96 (18.8) 94(19.1)

Dizziness 27 (5.3) 8 (1.6)

Fatigue 13 (2.5) 15 (3.0)

Diplopia 11 (2.2) 3 (0.6)

Nausea 10 (2.0) 8 (1.6)

Convulsion 10 (2.0) 8 (1.6)

Deaths 3 (0.6)f 4 (0.8)g

Judged to be treatment-relateda 0 0

AED, antiepileptic drug; SAE, serious adverse event; TEAE, treatment-related adverse event.

a Treatment relationship defined as "highly probable", "probable", "possible", or "not assessable", as judged by the physician. b TEAEs reported by >5% of patients in either treatment cohort. c Serious TEAE defined as event leading to death, life-threatening adverse experience, initial or prolonged inpatient hospitalization, significant or persistent disability/incapacity, congenital anomaly, or other important medical event based on the judgment of the physician. d In >1% of patients in either group. e In >2% patients in either treatment cohort.

f One each of: sudden unexplained/unexpected death in epilepsy, fall, malignant glioma. g One each of: left ventricular failure, grand mal convulsion, death (no further details), road traffic accident. Two patients were taking lacosamide at the time of their deaths.

3.6.4. Deaths

During the study, seven patients died (Table 5): three who added lacosamide and four who added another AED. Two of the patients in the other AED cohort were considered therapy switchers, and were taking lacosamide at the time of their deaths. None of the deaths were thought to be linked to the added AED therapy (lacosamide or other AED).

3.6.5. Other cardiac-, ECG-, and cognition-related TEAEs (not predefined)

Cardiac-related TEAEs (cardiac disorders system organ class, MedDRA v15.0) that were judged to be treatment-related and were not part of the predefined analysis are presented in Table 6.

Five patients in the lacosamide cohort and three patients in the other AED cohort experienced cardiac-related SAEs which were not part of the predefined analysis (Table 6). One was considered treatment-related (palpitations in a potential therapy switcher, taking an unknown dose of lacosamide adjunctive to carbamazepine, phenobarbital, and zonisamide), and two led to study discontinuation (one of left ventricular failure in a therapy switcher, and one of acute coronary syndrome). Cardiac TEAEs which were not predefined or considered serious caused one additional patient in each cohort to discontinue the study (Table 6).

No. of patients (%)

Lacosamide

n = 511

Other AED

n = 493

Any nonpredefined TEAEs of interest judged to be treatment-relateda Cardiac disorders

Angina pectoris 2 (0.4) 0

Palpitations 2 (0.4) 1 (0.2)

Right bundle branch block 1 (0.2) 0

Ventricular extrasystoles 1 (0.2) 0

Left bundle branch block 0 1 (0.2)

Supraventricular extrasystoles 0 1 (0.2)

Atrial fibrillation 0 1 (0.2)

Tachycardia 0 1 (0.2) ECG abnormalities

QT prolongation 1 (0.2) 1 (0.2)

ST segment elevation 1 (0.2) 0 Most common cognition-related (reported in >3 patients in either cohort)b

Memory impairment Disturbance in attention Cognitive disorder Confusional state Amnesia

Any nonpredefined cardiac SAEsc

Atrial flutter

Atrial fibrillation

Palpitations

Tachycardia

Acute coronary syndrome Left ventricular failure

11 (2.2) 7(1.4) 5 (1.0) 3 (0.6) 3 (0.6)

2 (0.4) 1 (0.2) 1 (0.2)d 1 (0.2) 0 0

Any nonpredefined cardiac TEAEs leading to study discontinuationf Palpitations 1 (0.2)

Acute coronary syndrome 0

Left bundle branch block 0

Left ventricular failure 0

Supraventricular extrasystoles 0

10 (2.0) 7 (1.4) 5 (1.0) 5 (1.0) 1 (0.2)

1 (0.2) 0

1 (0.2)e 1 (0.2)d,e

1 (0.2) 1 (0.2)g 1 (0.2)h 1 (0.2)g

AED, antiepileptic drug; ECG, electrocardiogram; SAE, serious adverse event; TEAE, treatment-related adverse event.

a Treatment relationship defined as "highly probable", "probable", "possible", or "not assessable", as judged by the physician.

b MedDRA 15.0 preferred terms that were judged to be associated with learning, memory, perception, or problem solving.

c Serious TEAE defined as event leading to death, life-threatening adverse experience, initial or prolonged inpatient hospitalization, significant or persistent disability/incapacity, congenital anomaly, or other important medical event based on the judgment of the physician.

d Confirmed/potential therapy switcher. e Led to study discontinuation, see section below. f Any intensity or severity. g Same patient.

h Due to death. TEAE not considered treatment-related.

Electrocardiogram data were available for less than ~20% of patients who attended each recommended visit (including patients who were discontinuing at that visit). ECG abnormalities that were reported as TEAEs and judged to be treatment-related are presented in Table 6. There were no reports of PR interval prolongation or other ECG abnormalities that led to study discontinuation.

Cognition-related TEAEs (those considered to be associated with learning, memory, perception or problem solving) that were judged to be treatment-related and reported in >3 patients of either cohort are presented in Table 6. All others were reported in <3 patients overall: disorientation, hypoesthesia, hallucination, sedation (all in 2/1004), altered state of consciousness, delirium, depressed level of consciousness, dysesthesia, dysgeusia, and impaired reasoning (all in 1/1004). Ten patients (2.0%) who added lacosamide and eleven patients (2.2%) who added another AED discontinued from the study due to any cognition-related TEAE.

3.6.6. Changes to vital signs or body weight

No clinically relevant changes from baseline in vital signs or body weight were observed in patients of either cohort.

3.7. Seizure control

After 3 months of treatment, the median percent change in POS frequency from 2-month retrospective baseline was — 46.2% in patients who added lacosamide and — 58.0% in patients who added other AEDs. After 12 months of treatment, median changes were — 67.1% and — 86.0%, respectively. Furthermore, 53.8% (242/450 at 3 months) to 62.9% (161/256 at 12 months) of patients who added lacosamide showed improvement on the Clinical Global Impression of Change questionnaire compared with 52.2% (221/423 at 3 months) to 69.8% (173/248 at 12 months) of patients who added another AED.

4. Discussion

This was a comprehensive observational PASS in patients initiating adjunctive lacosamide or another approved AED in real-life medical practice. A low incidence of predefined CV- and psychiatric-related TEAEs was revealed in both treatment cohorts.

Epilepsy has associated CV risks [41], with AED use bringing additional concerns due to the inhibitory actions of these drugs on neuronal conductance. This leads to a pragmatic approach to epilepsy treatment in patients with cardiac risk factors [ 15,42,43]. Clinical studies have shown a small, dose-related increase in PR interval associated with lacosamide use [11-13,18], with a magnitude similar to that observed with other AEDs including carbamazepine, eslicarbazepine acetate, and lamotrigine [14,44-48]. Despite these findings, cases of serious cardiac conduction abnormalities during lacosamide use are rare. The LACO-IV real-world observational safety study reported one case of PR prolongation and one case of third-degree AV block among 98 patients with diverse medical histories who were treated in the emergency department setting with intravenous lacosamide for status epilepticus or acute repetitive seizures [18]. Both patients had ischemic cardiomy-opathy and continued, or returned to, lacosamide therapy after the event. The safety of lacosamide is further supported by a comprehensive analysis of the cardiac safety data pooled from 1304 patients who took part in the registration trials for lacosamide in the treatment of POS. This analysis showed no specific cardiac risks, aside from the small, dose-related increase in PR interval, with no evident symptomatic consequence [19]. Furthermore, a positively controlled QTc trial in healthy volunteers showed no detrimental effect associated with lacosamide use at approved dosages [20].

Several case reports have described cardiac conduction abnormalities in patients with epilepsy receiving lacosamide therapy. Four cases were in patients taking lacosamide as recommended under the current local marketing authorization for the treatment of POS: one experienced bradycardia and second-degree AV block [21], one experienced bradycardia [9], one experienced ventricular tachycardia during a cardiac stress test [22], while the other experienced atrial fibrillation [23]. Two additional cases were in patients with POS taking lacosamide at a higher than approved dosage: one experienced atrial flutter/fibrillation (600 mg/day)

[24], while the other experienced sinus node dysfunction (500 mg/day)

[25]. Three additional patients experienced third-degree AV block while receiving lacosamide for the treatment of nonconvulsive status epilepticus—all were > 65 years of age [18,26,27]. Another case was in a child with subclinical seizures, hypoplastic left-heart syndrome, and previously well-controlled atrial tachycardia, who experienced atrial tachycardia coinciding with lacosamide treatment [28]. Among these 10 cases, five were in patients also taking traditional sodium channel-blocking AEDs, including carbamazepine [9,21,22,25] and lamotrigine [22,24]. All patients completely recovered after discontinuing lacosamide.

The published case reports highlight rare CV-related AEs occurring in patients taking lacosamide in real-world clinical practice, often

alongside numerous comorbidities. Case reports should be viewed in the context of the estimated 544,257 patient years of experience with lacosamide, accrued during the clinical development program and from pharmacovigilance data [UCB Pharma data on file. Lacosamide Development Safety Update Report Number 4 for the Period 01-Sept.-2013 to 31-Aug.-2014]. In the current study, specific CV-related TEAEs (both predefined and nonpredefined) were observed in three or fewer patients (< 1%) in each cohort during the first year of adjunctive AED therapy, demonstrating a low overall incidence of CV-related events in routine clinical practice. These results suggest that lacosamide use is unlikely to augment the risk of experiencing a CV-related AE compared with other adjunctive AEDs approved for the treatment of POS.

Patients with epilepsy are also known to be at increased risk of psychiatric-related disorders [33-35]. Several AEDs have known psychiatric and behavioral side effects in patients with epilepsy, possibly representing a drug class effect [44,46-53]. Depression was the most common predefined psychiatric-related TEAE reported in this study for patients in both treatment cohorts. The proportion of patients reporting predefined psychiatric-related TEAEs was numerically higher in patients adding an AED other than lacosamide (5.5% versus 4.1% in patients who added lacosamide), but few cases were considered to be related to treatment in either cohort. This suggests that lacosamide use is unlikely to augment the risk of experiencing a relevant psychiatric AE compared with other adjunctive AEDs approved for the treatment of POS.

Based on the compulsory class product labeling, suicidality is a recognized risk defined in the product characteristics of AEDs, including lacosamide [1-3,40]. In the current study, the numbers of suicidal ideation reports were similar among patients in both treatment cohorts. Suicide attempt was the only predefined psychiatric TEAE reported with a higher incidence in the lacosamide cohort than in the other AED cohort (two patients versus 0). One patient had a relevant medical history, and neither discontinued lacosamide treatment because of this TEAE. Furthermore, the overall death rate in this noninterventional postauthorization study (1 per 100 patient years) was in the lower range of those observed in other safety studies [46,47].

Additional subgroup analyses exploring the incidence of predefined CV- and psychiatric-related events in patients > 65 years of age, and in those taking antiarrhythmic drugs, were limited by low patient numbers. Although no clear conclusions can be drawn, these analyses did not suggest any specific vulnerabilities for these populations. Furthermore, outcomes were not altered when therapy switchers were discounted (patients who either added or discontinued lacosamide after initial cohort assignment but did not discontinue the study at the next visit).

Incidences of all TEAEs in patients who added lacosamide were comparable to those observed in the registration trials for use in the treatment of POS, with the most common being dizziness, fatigue, headache, diplopia, nausea, and vertigo [5-7]. In the current study, many of these TEAEs occurred at double the incidence in patients adding lacosamide as compared with patients adding other AEDs. This is likely attributable to the heterogeneous nature of the added AEDs in the other AED cohort (including both sodium channel-blocking AEDs and nonsodium channel-blocking AEDs with diverse mechanisms of action). A broader TEAE profile could therefore be anticipated among patients in the other AED cohort owing to the increased diversity of treatment regimens taken.

Overall patient retention was similar in both cohorts, with ~49% discontinuing from each during the first year of adjunctive AED therapy. This percentage may be reflective of the flexible, noninterventional nature of the study design. A slightly higher proportion of patients (13.7%) who added lacosamide discontinued therapy owing to lack of efficacy, compared with those who added another AED (8.5%). In part, this may be explained by the observation that patients in the lacosamide cohort enrolled with more severe, treatment-refractory epilepsy, as indicated by a greater number of seizures during the baseline period (6.0 versus

3.5) despite taking more concomitant AEDs. This is also reflected in lower median percentage reductions in POS frequency per 28 days from baseline achieved after 12 months of treatment ( — 67.1% and — 86.0%, respectively). Such an imbalance between the two cohorts was difficult to avoid given the noninterventional, nonrandomized study design, where treatment allocation was determined by the investigator's judgment, representing decisions taken in real-life clinical practice. These decisions may also have been influenced by the physician's limited experiences of lacosamide, which was relatively newly approved at the time of the study.

Limitations of this study include the noninterventional, non-randomized design, which led to baseline imbalances between the treatment cohorts. Additionally, the flexible nature of the dosing regimens prevented direct comparison of outcomes between cohorts, or attribution of TEAEs to specific adjunctive AEDs or dosages. In particular, adaptable dosing and the ability to add or discontinue concomitant AEDs at any time during the study allowed for therapy switching, making it challenging to evaluate TEAEs in terms of the prescribed AED's mode of action (e.g., sodium channel blocking versus nonsodium channel blocking). However, use of individually optimized regimens for each patient permits a real-world assessment of lacosamide and avoids the more artificial fixed-dose approach used in clinical trials. The current study included a relatively large patient cohort, facilitating sensitive detection of TEAEs, but is limited to the first 12 months of exposure. Open-label extension trials of lacosamide have followed patients for up to 8 years and have not reported the emergence of CV or psychiatric risks associated with longer-term treatment [11,13].

4.1. Conclusions

Patients with POS, uncontrolled by their current AED regimen and who added lacosamide or another AED to current therapy, reported few CV- or psychiatric-related AEs during the first 12 months of treatment. Furthermore, no specific safety concerns were associated with adjunctive lacosamide versus other adjunctive AED use.

Acknowledgments

The authors thank all patients who contributed to the SP0942 study; Barbara Pelgrims, Ph.D. (UCB Pharma, Brussels, Belgium) for overseeing the manuscript development; Christel Baukens (UCB Pharma, Brussels, Belgium) and Didier Wuiame M.Sc. (UCB Pharma, Brussels, Belgium) for clinical project management, the SP0942 study group, and all investigators who enrolled patients. The authors acknowledge Jennifer Bodkin, Ph.D. (Evidence Scientific Solutions, Horsham, UK) for writing assistance, which was funded by UCB Pharma.

Sources of funding

This study was funded by UCB Pharma, who had a role in the study design, collection, analysis, and interpretation of data, writing the report, and decision to submit the article.

Disclosures and conflicts of interest

Bernhard J. Steinhoff has received speaker honoraria from, or gave advice in advisory boards to Desitin, Eisai, Medtronic, UCB, and Viropharm. He and his institution received grants and support from Cerbomed, Eisai, Novartis, PPD, UCB, and the European Union. Andreas Schulze-Bonhage has received honoraria for lectures and consultations from Cerbomed, Cyberonics, Desitin, Eisai, Precisis, and UCB. Klaus Eckhardt, Pamela Doty, Marc De Backer, and Marcus Brunnert are employees of UCB Pharma.

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