Health-related quality of life in double-blind Phase III studies of brivaracetam as adjunctive therapy of focal seizures: A pooled, post-hoc analysis Academic research paper on "Clinical medicine"

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Epilepsy & Behavior

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Health-related quality oflife in double-blind Phase III studies of brivaracetam as adjunctive therapy of focal seizures: A pooled, post-hoc analysis

Christian Brandta, Simon Borghs b,*< Sami Elmouftic, Knut Mueller d, Rebecca Townsend e, Christine de la Loge ^

a Department of General Epileptology, Bethel Epilepsy Centre, Mara Hospital, Maraweg2l, D-33617 Bielefeld, Germany b UCB Pharma, 208 Bath Road, Slough, Berkshire SL1 3WE, UK c UCB Pharma, 8010 Arco Corporate Drive, Raleigh, NC 27617, USA d UCB Pharma, Alfred-Nobel-Strasse 10,40789 Monheim, Germany e UCB Pharma, 1950 Lake Park Drive South East, Smyrna, GA 30080, USA f 57, rue de Lyon, 89200 Avallon, France

ARTICLE INFO ABSTRACT

Purpose: The effect of adjunctive brivaracetam on health-related quality oflife (HRQoL) was assessed in a post-hoc analysis using pooled data from three randomized, double-blind, placebo-controlled Phase III studies in patients with refractory focal seizures (NCT00490035, NCT00464269, and NCT01261325). Methods: The Patient-Weighted Quality of Life in Epilepsy Questionnaire (QOLIE-31-P) was completed at randomization, and weeks 4, 8 (in two of three studies), and 12 (end of the treatment period). Mean change from baseline to week 12 or early discontinuation, and percentage of patients with clinically meaningful improvement were reported for the placebo and brivaracetam 50,100, and 200 mg/day groups.

Results: At baseline, mean QOLIE-31-P scores were similar between treatment groups. At week 12 or early discontinuation, mean (standard deviation) changes from baseline in QOLIE-31-P total score were 2.8 (12.7), 3.0 (14.0), 2.4 (14.0), and 3.0 (12.1) points forthe placebo and brivaracetam 50,100, and 200 mg/day groups, respectively, indicating HRQoL improved slightly over time during the treatment period, but was similar for placebo and brivaracetam groups. All subscale score changes were positive, indicating stable or improved HRQoL over time. The brivaracetam 100 and 200 mg/day groups showed the largest differences compared with placebo in Seizure Worry subscale scores (7.3 and 8.8 vs. 5.0 points). Approximately 40% of patients had improvements in QOLIE-31-P scores beyond the Minimal Important Change (MIC) thresholds. The subgroup of > 50% focal seizure frequency responders had higher improvements for all treatment arms and all subscales than for those in the overall pooled population.

Conclusion: In this post-hoc analysis, adjunctive brivaracetam treatment was shown to be associated with stable or improving overall HRQoL over time, similar to placebo, with modest improvements in subscales sensitive to efficacy, and no deterioration in subscales sensitive to tolerability. These results reflect the known efficacy and tolerability profile of brivaracetam.

© 2016 Ellen Carey, UCB Brussels, Belgium. 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/).

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Article history: Received 9 September 2016 Revised 22 November 2016 Accepted 22 November 2016 Available online xxxx

Keywords: Brivaracetam Focal seizures Adjunctive QOLIE-31 Seizure Worry Refractory epilepsy

1. Introduction

Epilepsy significantly affects patients' health-related quality oflife (HRQoL). Seizures and their frequency, seizure severity, comorbidities such as depression and anxiety, and stigma in relation to epilepsy are

* Corresponding author. E-mail addresses: christian.brandt@mara.de (C. Brandt), simon.borghs@ucb.com (S. Borghs), sami.elmoufti@ucb.com (S. Elmoufti), knut.mueller@ucb.com (K. Mueller), rebecca.townsend@ucb.com (R. Townsend), cdelaloge@hotmail.fr (C. de la Loge). 1 UCB Pharma employee at the time the studies were conducted.

among the factors which can contribute to poor patient HRQoL. Side effects attributable to antiepileptic drug (AED) treatment can also impact patients' HRQoL [1-3]. Studies indicate that approximately 30% of patients with focal (partial-onset) seizures do not achieve seizure control on their current AED treatment [4-6] and hence require a new treatment. HRQoL is an important consideration in AED treatment choice and when assessing the effectiveness of AED treatment in clinical studies.

The objective of this post-hoc analysis was to assess the effect on HRQoL of approved doses of brivaracetam, as measured using the Patient-Weighted Quality of Life in Epilepsy Questionnaire (QOLIE-31-

http://dx.doi.org/10.1016/j.yebeh.2016.11.031

1525-5050/©2016Ellen Carey, UCB Brussels, Belgium. 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/).

P) [7]. Brivaracetam is a selective, high-affinity synaptic vesicle protein 2A ligand [8], which has been shown to be efficacious and generally well tolerated as adjunctive treatment of refractory focal seizures in adults [9-11]. Brivaracetam is approved as adjunctive therapy for focal seizures in adults.

2. Methods

2.1. Pooled studies

Six double-blind Phase II and III studies were conducted with adjunctive brivaracetam. Studies with similar study designs were selected for pooling. Three studies were excluded due to lack of QOLIE-31-P as a variable in one, presence of an up-titration period and shorter (10-week) treatment period in another, and the flexible-dose design of the third. The current analysis used pooled data from three randomized, double-blind, placebo-controlled, fixed-dose Phase III studies of adjunc-tive brivaracetam in adults with refractory focal seizures, all reported previously: NCT00490035 [11]; NCT00464269 [9]; NCT01261325 [10]. Briefly, each study comprised an 8-week prospective baseline period and a 12-week treatment period without titration, followed by either a down-titration period (1-4 weeks) or entry into long-term follow-up studies (NCT00175916, NCT00150800, or NCT01339559). After the baseline period, patients were randomized to placebo or brivaracetam 5, 20, 50,100, or 200 mg/day, according to study, administered in two equally divided doses. Details of the study designs and inclusion criteria are available in the original papers [9-11 ] and in Table 1.

Data were pooled from patients who were randomized to placebo (all studies) or the approved brivaracetam doses of 50, 100, and 200 mg/day (doses were different in each study).

2.2. Assessments

The QOLIE-31-P was a secondary or exploratory efficacy variable in all the original studies. It was completed at randomization, at weeks 4, 8 (in studies NCT00490035 and NCT00464269 only), and 12 of the treatment period, or at early discontinuation.

The QOLIE-31-P was adapted from an earlier epilepsy-specific HRQoL measure, the QOLIE-31. Both measures consist of 30 items making up 7 subscales (Emotional Well-being, Daily Activities/Social Functioning, Energy/Fatigue, Cognitive Functioning, Seizure Worry, Medication Effects, Overall Quality of Life), a health status item, and an item on the relative importance of each subscale. The QOLIE-31-P also includes 7 items assessing the degree of 'distress' reported by the patient related to each subscale topic (distress scores). The total score is a weighted sum of the subscale scores [12]. Total score and subscale scores range from 0 to 100, with higher scores representing better HRQoL. Distress scores also range from 0 to 100, with higher scores indicating higher distress.

2.3. Statistical analysis

This analysis was conducted post-hoc on pooled data from three different brivaracetam studies. As in the original studies, the intent-to-treat (ITT) population was defined as all randomized patients who received at least one dose of study medication.

Mean baseline scores, and mean change from baseline to week 12 (or early discontinuation), are reported using the last observation carried forward method. Mean change from baseline was compared between each brivaracetam dose and placebo using analysis of covariance (ANCOVA), controlling for baseline score. As this analysis was exploratory and p-values were not controlled for multiple testing, the p-values were nominal and are presented for illustrative purposes.

Percentages of patients with clinically meaningful improvements in QOLIE-31-P scores were determined using Minimal Important Change (MIC) thresholds defined in the literature [13]. The MIC threshold is

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Table 2

Patient demographics and disease characteristics at baseline (ITT population).

Placebo (n = 455) BRV 50 mg/day (n = 200) BRV 100 mg/day (n = 352) BRV 200 mg/day (n = 249)

Mean age (SD), years 38.1 (12.7) 38.3 (12.9) 38.6 (13.3) 39.7 (12.8)

Female, n (%) 225 (49.5) 95 (47.5) 192 (54.5) 116 (46.6)

Region, n (%)

North America 103 (22.6) 47 (23.5) 64 (18.2) 61 (24.5)

Latin America 72 (15.8) 44 (22.0) 27 (7.7) 28 (11.2)

Western Europe 116 (25.5) 47 (23.5) 111 (31.5) 67 (26.9)

Eastern Europe 97 (21.3) 30 (15.0) 96 (27.3) 65 (26.1)

Asia/Pacific/Other 67 (14.7) 32 (16.0) 54 (15.3) 28 (11.2)

Mean weight (SD), kg 75.0 (19.9) 73.1 (17.6) 73.5 (17.2) 75.4 (19.0)

Baseline focal seizure frequency/28 days, median (Q1, Q3) 9.7 (5.5,24.3) 8.9 (5.7, 20.6) 8.9 (5.5, 21.7) 9.3 (5.5,18.8)

Seizure types reported during baseline, n (%)a

Simple partial (IA) 184 (40.4) 63 (31.5) 123 (34.9) 98 (39.4)

Complex partial (IB) 358 (78.7) 174(87.0) 290 (82.4) 215 (86.3)

Partial evolving to secondarily generalized (IC) 127 (27.9) 73 (36.5) 106 (30.1) 75 (30.1)

Number of prior AEDs, n (%)b

0-1 114(25.1) 67 (33.5) 86 (24.4) 45 (18.1)

2-4 186 (40.9) 99 (49.5) 127 (36.1) 84 (33.7)

> 5 155 (34.1) 34 (17.0) 139 (39.5) 120 (48.2)

Most common concomitant AEDs, n (%)

Carbamazepine 181 (39.8) 87 (43.5) 135 (38.4) 93 (37.3)

Lamotrigine 119 (26.2) 50 (25.0) 90 (25.6) 61 (24.5)

Valproate 90 (19.8) 47 (23.5) 87 (24.7) 48 (19.3)

Oxcarbazepine 64(14.1) 25 (12.5) 62 (17.6) 50 (20.1)

Topiramate 84 (18.5) 12 (6.0) 47 (13.4) 28 (11.2)

Phenytoin 47 (10.3) 23 (11.5) 30 (8.5) 21 (8.4)

Levetiracetam 37 (8.1) 39 (19.5) 20 (5.7) 0

AED, antiepileptic drug; BRV, brivaracetam; ITT, intent-to-treat; SD, standard deviation. a Patients included in every applicable category of baseline seizures.

b AEDs discontinued before study entry were collected for 5 years prior to study entry for studies N01252 and N01253; all AED history collected for study N01358.

defined as a change in score representing a clinically meaningful improvement in HRQoL. No statistical testing was conducted for this variable.

Mean QOLIE-31-P score changes from baseline to week 12 (or early discontinuation) and percentages of patients with clinically meaningful improvements were also reported in a subgroup of patients who experienced a >50% reduction in focal seizure frequency (responders). No statistical testing was conducted for these variables.

3. Results

Demographics and baseline disease characteristics are presented in Table 2, and point to a patient population with refractory seizures. Patients experienced a median of 8.9-9.7 focal seizures/28 days. Approximately 1 in 3 patients experienced secondarily generalized focal seizures (Type IC) (27.9-36.5%). A high proportion of patients had previously taken more than one AED: 33.7-49.5% had taken 2-4 AEDs and 17.0-48.2% had taken > 5 prior AEDs. Prior AEDs were recorded for the previous 5 years only in studies NCT00490035 and NCT00464269, and over the patient's lifetime in the third study. There was some variation between the treatment groups with regard to region and prior and

concomitant treatment. At baseline, mean QOL1E-31-P total scores were similar between treatment groups, ranging between 55.0 and 57.5 (Table 3).

At the end of the 12-week treatment period or early discontinuation, adjunctive brivaracetam treatment was associated with stable or improving HRQoL over time, in the total QOL1E-31-P score and all subscale scores (Fig. 1; values given in Supplementary Table 1). Mean (standard deviation [SD]) change from baseline in QOL1E-31-P total score was 2.8 (12.7) versus 3.0 (14.0), 2.4 (14.0), and 3.0 (12.1) points for the placebo and brivaracetam 50,100, and 200 mg/day groups, respectively. Higher doses of brivaracetam were associated with larger improvements in the Daily Activities/Social Functioning and the Seizure Worry subscales. The brivaracetam 100 and 200 mg/day groups showed the largest differences compared with placebo in Seizure Worry subscale scores (7.3 and 8.8 vs. 5.0 points; p < 0.05). Mean change from baseline for the distress scores (Supplementary Table 2) were similar to those of the subscale scores in direction and magnitude of change, though with higher variability.

Brivaracetam treatment was associated with improvements in QOL1E-31-P scores that were beyond the MIC threshold for approximately 40% of patients, ranging from 29.7% for Energy/Fatigue to 48.6% for Daily Activities/Social Functioning (Table 4) [13]. These rates

Table 3

Mean QOLIE-31-P scores at baseline (ITT population).

QOLIE-31-P scores, mean (SD) Placebo (n = 455) BRV 50 mg/day (n = 200) BRV 100 mg/day (n = 352) BRV 200 mg/day (n = 249)

Total score 57.4 (16.2) 55.0 (16.1) 57.5 (16.6) 56.9 (15.8)

Cognitive Functioning 56.1 (24.9) 54.9 (24.1) 57.8 (25.3) 57.2 (23.6)

Emotional Well-being 65.1 (19.2) 61.8 (19.8) 65.5 (18.6) 63.4 (19.0)

Energy/Fatigue 54.6 (19.4) 54.0 (17.9) 53.1 (20.1) 53.3 (19.3)

Medication Effects 60.6 (27.3) 54.4 (26.8) 60.6 (27.0) 62.8 (26.0)

Overall Quality of life 60.9 (17.9) 59.6 (17.7) 60.3 (17.9) 60.2 (17.7)

Seizure Worry 45.6 (27.7) 43.2 (28.5) 47.5 (27.2) 44.3 (28.6)

Daily Activities/Social Functioning 56.9 (24.1) 52.9 (24.6) 55.6 (23.9) 56.1 (24.4)

BRV, brivaracetam; ITT, intent-to-treat; QOL1E-31-P, Patient-Weighted Quality of Life in Epilepsy Questionnaire; SD, standard deviation.

Total Cognitive Emotional Energy/Fatigue Medication Overall Seizure Dally Activities/

Score Functioning Well-being Effects Quality of Life Worry Social Function

Fig. 1. Mean QOLIE-31-P score changes from baseline to week 12 or early discontinuation. *p < 0.05. BRV, brivaracetam; QOLIE-31-P, Patient-Weighted Quality of Life in Epilepsy Questionnaire.

of responders were similar between placebo and all brivaracetam doses for most subscales.

In the subgroup of patients who were > 50% responders, mean (SD) change from baseline in total QOLIE-31-P scores was 5.4 (15.1) versus 7.3 (14.5), 4.5 (14.9), and 6.4 (12.3) points for the placebo and brivaracetam 50,100, and 200 mg/day groups, respectively. The > 50% responder subgroup had larger improvements for all treatment arms and all subscales than for those in the overall pooled population (Fig. 2). The percentages of responders with clinically meaningful improvements (Table 4) were larger than in the overall population, with similar treatment group differences.

4. Discussion

In this analysis of the effect of adjunctive brivaracetam on HRQoL in adults with refractory focal seizures, using pooled data from three Phase III studies, mean changes from baseline in QOLIE-31-P over time were modest but positive, and similar between placebo and the brivaracetam treatment groups. The brivaracetam 100 and 200 mg/day groups showed larger differences in the Seizure Worry subscale compared with placebo (both p < 0.05, p-values considered illustrative only). Minimal important improvements in QOLIE-31-P scores were observed in 30-50% of patients, depending on the score. The improvements from baseline in subscales sensitive to efficacy, such as Seizure Worry, were consistent with the statistically significant reduction in focal seizure frequency reported in the pooled clinical studies [14]. Subscales sensitive to tolerability, such as the Medication Effects, Cognitive Functioning, and Energy/Fatigue subscales, showed no worsening from baseline, which appears

consistent with the favorable tolerability profile of brivaracetam in clinical trials. Mean changes from baseline for the distress scores (data not shown) showed a generally similar trend to those of the subscale scores. Perhaps unsurprisingly, patients who responded to brivaracetam, as shown by the > 50% responder rate, had substantially larger mean improvements from baseline in QOLIE-31-P than the overall population. Consequently, patients who have a response to brivaracetam in clinical practice may expect an associated improvement in HRQoL.

In publications of Phase III studies of other second- and third-generation AEDs in the adjunctive treatment of focal epilepsy, mean changes from baseline and differences between treatment groups in QOLIE-31-P or QOLIE-31 total scores have generally also been reported as small. It must be noted that data are often not reported in detail, and few data on subscale scores from other studies are available. Available mean changes from baseline in QOLIE-31-P and QOLIE-31 total scores - as questions used for calculation of the total and subscale scores are the same for both instruments - show that in many studies there was little difference between treatment groups. Examples include topiramate extended release (XR) [15]; perampanel [16,17]; oxcarbazepine XR [18]; eslicarbazepine [19]; retigabine [20]; lacosamide [21]; and levetiracetam [22]. Other studies reported small decreases (worsening) from baseline: for instance, in studies of lamotrigine XR [23] and retigabine [20].

There have been few publications describing MICs in QOLIE-31-P scores. Different values for MICs have been estimated in different populations (patients undergoing epilepsy surgery, patients receiving monotherapy, patients with refractory seizures receiving adjunctive therapy), making comparisons between studies difficult [13,24,25].

Percentage of patients with improvement in QOLIE-31-P scores beyond the Minimal Important Change threshold from baseline to week 12 or early discontinuation (ITT population).

Patients with minimal important change in QOLIE-31-P (%) Overall population Minimal important change threshold (improvement^ >50% focal seizure frequency responders

Placebo (n = 455) BRV 50 mg/day (n = 200) BRV 100 mg/day (n = 352) BRV 200 mg/day (n = 249) Placebo (n = 88) BRV 50 mg/day (n = 53) BRV 100 mg/day (n = 124) BRV 200 mg/day (n = 87)

Total score 38.6 43.6 41.7 36.6 5.19 46.6 54.7 49.2 48.3

Cognitive Functioning 39.9 42.3 42.2 40.0 5.34 43.8 53.7 49.6 43.3

Emotional Well-being 35.7 38.8 33.6 35.4 4.76 50.6 44.4 35.4 42.2

Energy/Fatigue 37.7 39.8 36.2 29.7 5.25 45.5 39.6 43.8 37.8

Medication Effects 40.8 42.3 45.5 42.3 5.00 44.9 50 50.8 41.6

Overall Quality of life 35.7 36.3 37.8 31.5 6.42 44.9 46.3 46.9 42.9

Seizure Worry 41.6 40.1 46.2 47.7 7.42 49.4 61.1 50.8 57.3

Daily Activities/Social Functioning 49.0 48.6 47.9 47.7 3.95 55.1 63 53.5 48.9

BRV, brivaracetam; ITT, intent-to-treat; QOLIE-31-P, Patient-Weighted Quality of Life in Epilepsy Questionnaire. a Borghs, et al. (2012) [13].

■ Placebo (n = 88) BRV 50 mg/day (n = 53) ■ BRV 100 mg/day (n = 124) ■ BRV 200 mg/day (n = 87)

Total Cognitive Emotional Energy/Fatigue Medication Overall Seizure Daily Activities/

Score Functioning Well-being Effects Quality of Life Worry Social Function

Fig. 2. Mean QOLIE-31-P score changes from baseline to week 12 or early discontinuation in a subgroup of patients who were >50% focal seizure frequency responders. BRV, brivaracetam; QOLIE-31-P, Patient-Weighted Quality of Life in Epilepsy Questionnaire.

The generally modest improvements from baseline in QOLIE-31-P scores seen both in the current analysis and in other Phase III randomized, controlled trials (RCTs) might suggest that the timeframe of a typical RCT may not be long enough to allow improvements to be observed. Longer-term assessments in trials designed to be more relevant to real-world settings may be more informative [26]. A longer period of follow-up appeared to result in larger improvements in QOLIE-31-P scores from baseline in some studies. In pooled data from the brivaracetam long-term follow up (LTFU) studies, mean change in QOLIE-31-P total scores from baseline were approximately 5 points between Month 2 to Month 42 [27]. In contrast, in other studies, such as eslicarbazepine LTFU studies [28,29], improvements from baseline (3.8 and 2.1, respectively) were not greater than those observed in a short-term study (800 mg 5.35; 1200 mg4.64) [19].

Other factors may affect HRQoL effect sizes. The refractory nature of the patients' epilepsy in these studies, as reflected in their baseline characteristics, and indicated by parameters such as number of prior AEDs, might lead to smaller improvements in QOLIE-31-P scores than those in newly-diagnosed patients with epilepsy. For example, patients taking open-label lacosamide as first add-on after their seizures did not adequately respond to monotherapy had a mean (SD) change from baseline in QOLIE-31-P total score of 7.1 (16.0) points, compared with a change from baseline of 4.8 (14.7) points in patients taking lacosamide as a later add-on after > 2 prior AEDs [30]. An indication of the trend towards increasing medication refractoriness among patients with epilepsy recruited in clinical trials can also be seen in the lower baseline QOLIE-31/QOLIE-31-P scores published from more recent studies [20] and the current study compared with earlier studies [22,31]. Fixed, randomized doses that may not represent target doses in clinical practice may neutralize the positive impact of treatment efficacy by the negative impact of adverse events in the active treatment arm. The modest levels of seizure freedom commonly seen in studies in populations with refractory seizures may also lead to smaller mean improvements in HRQoL. A previous randomized, controlled study of adjunctive vigabatrin found that significant improvements in QOLIE-31 over the short term (28 weeks) were only observed in patients who experienced complete freedom from seizures [32]. This is consistent with the observation that patients can experience good HRQoL during seizure-free periods, which is then reduced following a seizure [33]. Furthermore, larger improvements in QOLIE-31-P total scores have been observed in responders to study drug compared with the overall population [22,34,35], consistent with the results reported in the current study. Therefore, in terms of clinical practice, brivaracetam responders might expect to experience an improvement in HRQoL.

Limitations of the data presented herein are the post-hoc and exploratory nature of this analysis. It should also be noted that the three studies had some differences in inclusion and exclusion criteria. Two studies enrolled patients < 70 years old, up to >45 kg in weight, and allowed concomitant levetiracetam, while the third study enrolled patients < 80 years old, >40 kg in weight, and did not allow concomitant levetiracetam [14].

In conclusion, in this post-hoc analysis, adjunctive brivaracetam treatment was shown to be associated with stable or improving overall HRQoL over time, with modest improvements in subscales sensitive to efficacy and no deterioration in subscales sensitive to tolerability. The most favorable trend for brivaracetam versus placebo was seen for the Seizure Worry subscale. These subscale results are consistent with the known efficacy and tolerability profile of brivaracetam demonstrated in the pivotal trials, and should be viewed with the refractoriness of the patients enrolled in these studies in mind. Among > 50% responders, mean improvements in HRQoL were substantially larger than those observed in the overall population, suggesting that those whose seizures respond to brivaracetam in wider clinical practice may expect an associated improvement in HRQoL.

Conflicts of interest

Christian Brandt reports personal fees from Desitin, Eisai, Otsuka, Pfizer, and UCB Pharma, and grants from Otsuka and UCB Pharma outside the submitted work. Simon Borghs, Sami Elmoufti, Knut Mueller, and Rebecca Townsend are employees of UCB Pharma. Christine de la Loge was an employee of UCB Pharma at the time that the studies were conducted and has no other conflicts of interest to declare. All authors disclosed medical writing support which was funded by UCB Pharma.

Role of the funding source

The studies were sponsored by UCB Pharma. UCB Pharma was responsible for the design and conduct of the study, and collection, management, and analysis of the data. UCB Pharma was involved in the preparation and review of the manuscript and covered all related costs. The authors had the final responsibility for the content.

Acknowledgments

The authors thank the patients and their caregivers, in addition to the investigators and their team who contributed to the original studies.

Medical writing support was provided by Sally Cotterill, PhD (QXV Communications, an Ashfield Business, part of UDG Healthcare plc, Macclesfield, UK), which was funded by UCB Pharma.

Appendix A. Supplementary data

Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.yebeh.2016.11.031.

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