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Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate
Epilepsy & Behavior 53 (2015) 149–153
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate Joyce A. Cramer a,⁎, Fulton F. Velez b, Kathryn P. Anastassopoulos c, T. Christopher Bond c, Frank G. Gilliam d, Philippe Ryvlin e, Luigi M. Specchio f, Xuezhe Wang c,1, David Blum b, Joana Moreira g, Francisco Rocha g a
Department of Medical Research, Health Outcomes, Houston, TX, USA Sunovion Pharmaceuticals Inc., Marlborough, MA, USA Covance Market Access Services Inc., Gaithersburg, MD, USA d Department of Neurology, Penn State University College of Medicine, Hershey, PA, USA e Department of Clinical Neurosciences, CHUV, Lausanne, Switzerland f Epilepsy Center, Clinic of Nervous System Diseases, University of Foggia, Riuniti Hospital, Foggia, Italy g BIAL — Portela & Cª S.A., S. Mamede do Coronado, Portugal b c
a r t i c l e
i n f o
Article history: Received 7 August 2015 Revised 14 September 2015 Accepted 15 September 2015 Available online 12 November 2015 Keywords: All epilepsy/seizures Antiepileptic drugs Partial seizures Seizure severity All clinical trials
a b s t r a c t Objective: The objective of this study was to compare posttreatment seizure severity in a phase III clinical trial of eslicarbazepine acetate (ESL) as adjunctive treatment of refractory partial-onset seizures. Methods: The Seizure Severity Questionnaire (SSQ) was administered at baseline and posttreatment. The SSQ total score (TS) and component scores (frequency and helpfulness of warning signs before seizures [BS]; severity and bothersomeness of ictal movement and altered consciousness during seizures [DS]; cognitive, emotional, and physical aspects of postictal recovery after seizures [AS]; and overall severity and bothersomeness [SB]) were calculated for the per-protocol population. Analysis of covariance, adjusted for baseline scores, estimated differences in posttreatment least square means between treatment arms. Results: Out of 547 per-protocol patients, 441 had valid SSQ TS both at baseline and posttreatment. Mean posttreatment TS for ESL 1200 mg/day was significantly lower than that for placebo (2.68 vs 3.20, p b 0.001), exceeding the minimal clinically important difference (MCID: 0.48). Mean DS, AS, and SB were also significantly lower with ESL 1200 mg/day; differences in AS and SB exceeded the MCIDs. The TS, DS, AS, and SB were lower for ESL 800 mg/day than for placebo; only SB was significant (p = 0.013). For both ESL arms combined versus placebo, mean scores differed significantly for TS (p = 0.006), DS (p = 0.031), and SB (p = 0.001). Conclusions: Therapeutic ESL doses led to clinically meaningful, dose-dependent reductions in seizure severity, as measured by SSQ scores. Classification of evidence: This study presents Class I evidence that adjunctive ESL (800 and 1200 mg/day) led to clinically meaningful, dose-dependent seizure severity reductions, measured by the SSQ. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Assessment of improvement among patients with treatment-resistant seizures is usually measured as seizure frequency. However, this metric does not incorporate other effects of treatment. A new approach to treatment change is based on assessing seizure severity as well as frequency. ⁎ Corresponding author at: Department of Medical Research, Health Outcomes, 49 Briar Hollow Lane, Houston, TX 77027, USA. Tel.: +1 713 552 0289. E-mail addresses: [email protected] (J.A. Cramer), [email protected] (F.F. Velez), [email protected] (K.P. Anastassopoulos), [email protected] (T.C. Bond), [email protected] (F.G. Gilliam), [email protected] (P. Ryvlin), [email protected] (L.M. Specchio), [email protected] (X. Wang), [email protected] (D. Blum), [email protected] (J. Moreira), [email protected] (F. Rocha). 1 Xuezhe Wang, MS, of Covance Market Access Services Inc. carried out the biostatistical analysis.
http://dx.doi.org/10.1016/j.yebeh.2015.09.018 1525-5050/© 2015 Elsevier Inc. All rights reserved.
The Seizure Severity Questionnaire (SSQ), developed by Cramer et al. [1], is accepted by regulatory agencies as a secondary outcome in clinical trials. In phase III clinical trials, 800 mg/day and 1200 mg/day of eslicarbazepine acetate (ESL; Aptiom®, Sunovion Pharmaceuticals Inc., Marlborough, MA, USA) led to statistically significant reductions in standardized seizure frequency vs baseline compared with that of placebo [2–4]. The severity of seizures and the extent to which they were perceived as a burden by each patient was evaluated as a secondary endpoint in one of the trials (study 304) [4], and is presented here. 2. Methods 2.1. Patients and treatment regimen The design and methodology of the trial (BIA-2093-304; registered at ClinicalTrials.gov [NCT00988429]) have been reported previously
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[4]. Briefly, patients aged ≥16 years with ≥8 partial-onset seizures (POS) during baseline, ≥3 seizures in each 4-week period, and no seizure-free period for N 28 consecutive days, were eligible for the trial. After an 8week prospective baseline period, patients were randomized equally to receive placebo or ESL (800 mg once-daily [QD] or 1200 mg QD) during a 2-week, double-blind, titration period and a 12-week, fixed-dose, double-blind maintenance period. Patients continued to receive stable dosages of baseline concomitant antiepileptic drugs (AEDs), although use of oxcarbazepine (OXC) was prohibited due to similarities in metabolites between OXC and ESL. Following completion of the 14-week double-blind phase, patients entered a 2-week tapering-off period. 2.2. Seizure Severity Questionnaire The SSQ [1] was developed as a clinical research tool to quantify the severity of seizures over time. The questionnaire was validated in a multistage process and has demonstrated sensitivity to change across types of seizures [5,6]. The SSQ assessments gather information about seizurerelated events and the patient's perceptions and feelings about those events, over the past 4 weeks. This allows a longitudinal evaluation of how much the patient is affected by seizures, independent of seizure frequency. Additional analyses defined minimal clinically important difference (MCID) scores that facilitate clinical interpretations of scores [6]. Unlike some health-related quality-of-life questionnaires that are completed independently by the patient, the SSQ is a structured interview in which an epilepsy professional guides the patient and a person who observes the patient's seizures in responding to questions. The trained coordinator or investigator can ensure that the patient and observer comprehend all questions and complete all sections. This approach compensates for patients' amnesia about events, cognitive deficits, and age. 2.3. Data source and SSQ administration During the trial, administration of the SSQ was facilitated by the investigators, who were trained on use of the questionnaire. The SSQ was completed at the end of the 8-week baseline period (day 1 of treatment; baseline assessment), during the efficacy period (week 8 assessment), and at the end of the 12-week double-blind maintenance period (week 14 assessment). The SSQ specifically asks patients about their experiences in the previous 4 weeks. Thus, in the current study, the baseline score reflects the patient's experience during the 4 weeks before initiation of ESL treatment, and the week 14 score reflects their experience during the last 4 weeks of ESL treatment. In order to ensure consistency and reliability of assessments across multiple investigative sites, an independent interrater qualification service provided training at North American sites, and the study medical monitor provided similar training for sites outside North America. 2.4. Scoring the SSQ The SSQ scoring scheme [7] was based on the scoring algorithm developed by J. Cramer, and was adapted for use in the current study. The SSQ total score (TS) was derived from four component scores: frequency and helpfulness of warning signs before seizures (BS); severity and bothersomeness of ictal movement and altered consciousness during seizures (DS); cognitive, emotional, and physical aspects of postictal recovery after seizures (AS); and overall severity and bothersomeness (SB). The range of scores was 1–7 for BS, DS and SB, and 0–7 for AS, with lower scores indicating lower severity and/or burden. Total score was calculated as the average of all completed component scores. The scoring algorithm accounts for the fact that not all patients will have ‘before’ or ‘after’ effects. Consequently, BS is not included in the calculation of TS for patients without ‘before’ effects, and AS is assigned a value of 0 for patients without ‘after’ effects. Therefore, TS has a possible range of values of 0.67 to 7.00. Validation
criteria for each component score were applied separately in this analysis; however, actively completed DS and SB sections were required for the calculation of TS. Patients who indicated that they had no seizures during the 4 weeks prior to the week 14 SSQ assessment were assigned the minimum scores for DS, AS, and SB at follow-up. Because the BS score represents helpfulness of warning signs (rather than seizure severity), in patients who were seizure-free, a minimum score was not applied but the score was set to missing. The following rules were applied when patients provided two mutually exclusive responses to questions about whether they had experienced: 1) movements or actions during their seizures and 2) altered consciousness only. Those who responded “yes” to both questions (13.9%) were defaulted to ‘yes’ for question 1 and ‘no’ for question 2 (assuming that they did have movements/actions during seizures, and had made a mistake in answering question 2). Scores for subquestions about severity and bothersomeness were then derived from the first question only. Patients who answered ‘no’ to both questions (7.9%) did not complete any of the subquestions, so they were assigned the minimum DS score of 1. A sensitivity analysis was conducted in which, for patients who answered ‘no’ to both questions, the whole questionnaire was deemed to be invalid. The MCIDs for TS and three component scores have previously been defined (TS: 0.48, DS: 0.50, AS: 0.39, SB: 0.48) [6]. In this study, MCIDs were used to compare the difference between treatment arms (i.e., the difference between effects of the 2 doses of ESL). An MCID has not been defined for the BS score, because this score reflects potentially helpful warning signs occurring immediately before a seizure. 2.5. Descriptive and statistical analyses The intent-to-treat population comprised 640 patients, 547 of whom had no major protocol violations and were included in the per-protocol population and this analysis. Mean SSQ TS and component scores were calculated for patients with useable questionnaires at baseline. Analysis of covariance was used to calculate baseline-adjusted least square mean scores (adjusted mean scores) at week 14 and compare differences in adjusted mean scores between treatment arms, for patients who completed the baseline and week 14 SSQ [8]. In this context, the final measure of severity was considered most significant. Therefore, potentially more powerful analyses (including comparison of scores at week 8) were not conducted. Statistical significance was claimed at alpha 0.05. No adjustments were made for multiple comparisons of component scores. The MCIDs were used to evaluate the clinical relevance of changes in seizure severity with ESL vs placebo. Student's t-tests were used to compare the differences in adjusted mean scores between each active treatment arm (ESL 800 mg QD and ESL 1200 mg QD) and the placebo arm and also between the combined ESL arms (ESL 800 mg QD and 1200 mg QD) and the placebo arm. The first analysis mirrored the design of the clinical trial and allowed assessment of the improvement in seizures with each dose of ESL. The comparison between the combined ESL arms and the placebo arm provided greater analytic power to assess the improvement in SSQ scores with either of the 2 approved therapeutic doses combined. 2.6. Standard protocol approvals, registrations, and patient consents Study BIA 2-093-304 (NCT00988429) was undertaken between December 2008 and January 2012, at 173 centers in 19 countries worldwide. The study was conducted in accordance with the principles of the Declaration of Helsinki; the International Conference on Harmonization guidelines; and all national, state, and local laws of the pertinent regulatory authorities. The trial protocol, amendments, and informed consent were reviewed and approved by the relevant independent ethics
J.A. Cramer et al. / Epilepsy & Behavior 53 (2015) 149–153
committees/institutional review boards for each site. Written informed consent was obtained from all patients before enrollment. 2.7. Classification of evidence This analysis presents Class I evidence from BIA 2-093-304 that the use of therapeutic doses of ESL (800 mg QD and 1200 mg QD) leads to clinically meaningful and dose-dependent reductions in patientreported seizure severity, as measured by SSQ scores (at week 14, the adjusted mean TS was 2.68 for ESL 1200 mg QD, 3.02 for ESL 800 mg QD, and the adjusted mean difference (− 0.52) exceeded the MCID of 0.48). 3. Results Among the 547 per-protocol patients, 544 completed the SSQ at baseline. There were no significant differences in demographic characteristics between treatment arms (Table 1). Of the 544 patients with a completed baseline SSQ, 537 had a valid score for at least 1 component. Baseline mean scores were 3.62 for TS, and 3.53, 3.73, 2.99, and 4.23 for BS, DS, AS and SB, respectively (Table 2). The week 14 SSQ was completed by 458 (84.2%) of the 544 patients who had completed the baseline SSQ: 170 patients (90.9%) in the placebo arm, 157 (85.8%) in the ESL 800 mg QD arm, and 131 (75.3%) in the ESL 1200 mg QD arm. Of these, 6 (3.5%) in the placebo arm, 8 (5.1%) in the ESL 800 mg QD arm, and 18 (13.7%) in the ESL 1200 mg QD arm reported no seizures during the 4 weeks prior to the week 14 assessment, and so they were assigned minimum scores for DS, AS, and SB. Patients were not required to report all components for their data to be included in the analysis. The number with valid scores at both baseline and week 14 was: TS, 441; DS, 441; AS, 427; and SB, 454. Only 180 patients had BS scores, because many did not report warnings before seizures. The proportion of patients with scores at both baseline and week 14 differed between treatment arms. For TS, the proportions were 88.2% (165/187) for the placebo arm, 80.9% (148/183) for the ESL 800 mg QD arm, and 73.1% (128/174) for the ESL 1200 mg QD arm. At week 14, the adjusted mean TS for the ESL 1200 mg QD arm was significantly lower than that for the placebo arm (2.68 vs 3.20, p b 0.001; Table 3). The adjusted mean difference (−0.52) was clinically significant, exceeding the MCID of 0.48. The adjusted mean TS for the ESL
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800 mg QD arm was also lower than that for the placebo arm, but the difference was not statistically significant (3.02 vs 3.20, p = 0.195). Similarly, DS and AS adjusted mean scores for the ESL 1200 mg QD arm were significantly lower than those for the placebo arm (DS: 3.05 vs 3.46, p = 0.027; AS: 1.95 vs 2.51, p = 0.019) but not for the ESL 800 mg QD arm (Table 3). For DS, the adjusted mean difference (− 0.42) in the ESL 1200 mg QD arm did not exceed the MCID (0.50), whereas for AS, the difference of 0.56 in the ESL 1200 mg QD arm was clinically significant, exceeding the MCID of 0.39. For SB, the adjusted mean scores were 3.65 for the placebo arm, 3.09 for the ESL 1200 mg QD arm (p b 0.001), and 3.28 for the ESL 800 mg QD arm (p = 0.013). The difference of −0.55 between the ESL 1200 mg QD arm and placebo exceeded the MCID (0.48; Table 3). Adjusted mean BS scores in both ESL arms were not significantly lower than that in the placebo arm. The findings at week 14 for the 2 ESL arms combined were similar to those for the individual ESL treatment arms (Table 3). Baseline-adjusted mean scores were significantly lower in the combined ESL group than that in the placebo arm for TS (2.86 vs 3.20, p = 0.006), DS (3.12 vs 3.46, p = 0.031), and SB (3.19 vs 3.65, p = 0.001), but not for AS (2.18 vs 2.51, p = 0.092) or BS (3.06 vs 3.26, p = 0.407). None of the differences between the combined ESL group and the placebo arm exceeded the respective MCID. The results of a sensitivity analysis (excluding questionnaire data for 56 patients with mutually exclusive responses) were consistent with the main analysis (data not shown). Adjusted TS and DS scores were both higher when these patients were excluded (the main analysis sets the DS score to the minimum). However, conclusions about the statistical and clinical significances of the differences between ESL-treated and placebo-treated patients were not affected. The BS, AS, and SB scores were not impacted by the sensitivity analysis. 4. Discussion The results of this study are based on a well-validated questionnaire that captures the patient's experience of seizure severity and bothersomeness. The findings complement other published assessments of seizure frequency, supplement other published assessments of seizure severity [9–11], and confirm the sensitivity of the SSQ in this population. In this analysis, approved therapeutic doses of ESL led to dosedependent reductions in seizure severity, as indicated by SSQ scores.
Table 1 Demographic characteristics.
Age
Gender, n (%) BMI
Duration of epilepsy, years
Race, n (%)
Region, n (%)
†
n Mean (SD) Median Female Male n† Mean (SD) Median n† Mean (SD) Median White Asian Black Other North America Latin America Eastern Europe Western Europe Other
Total (n = 544)
Placebo (n = 187)
ESL 800 mg QD (n = 183)
ESL 1200 mg QD (n = 174)
p⁎
543 38.4 (12.2) 38.0 278 (51.1) 266 (48.9) 536 26.2 (6.0) 25.3 539 20.9 (13.3) 18.3 346 (63.6) 102 (18.8) 21 (3.9) 75 (13.8) 198 (36.4) 92 (16.9) 90 (16.5) 52 (9.6) 112 (20.6)
186 38.4 (12.6) 37.0 94 (50.3) 93 (49.7) 183 25.6 (5.6) 24.7 185 20.9 (14.1) 17.8 116 (62.0) 41 (21.9) 6 (3.2) 24 (12.8) 64 (34.2) 30 (16.0) 31 (16.6) 20 (10.7) 42 (22.5)
183 38.8 (12.2) 39.0 95 (51.9) 88 (48.1) 181 26.4 (5.7) 25.7 180 20.8 (13.0) 18.7 117 (63.9) 31 (16.9) 7 (3.8) 28 (15.3) 67 (36.6) 34 (18.6) 28 (15.3) 17 (9.3) 37 (20.2)
174 37.9 (11.9) 38.0 89 (51.1) 85 (48.9) 172 26.7 (6.7) 25.3 174 20.9 (12.9) 18.1 113 (64.9) 30 (17.2) 8 (4.6) 23 (13.2) 67 (38.5) 28 (16.1) 31 (17.8) 15 (8.6) 33 (19.0)
0.792
Abbreviations: BMI = body mass index, ESL = eslicarbazepine acetate, QD = once-daily. ⁎ p values calculated using Student's t-tests for continuous variables and chi-square tests for categorical variables. † n for individual demographic characteristics may not equal total n due to missing data.
0.951 0.185
0.998
0.859
0.973
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Table 2 SSQ: baseline scores.
TS BS DS AS SB
All (n = 544)
Placebo (n = 187)
ESL 800 mg QD (n = 183)
ESL 1200 mg QD (n = 174)
ESL 800/1200 mg QD (n = 357)
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
537 291 537 536 543
3.62 (1.285) 3.53 (2.078) 3.73 (1.685) 2.99 (2.449) 4.23 (1.351)
187 116 187 187 187
3.69 (1.283) 3.69 (2.132) 3.81 (1.734) 3.07 (2.459) 4.27 (1.442)
176 92 176 180 182
3.48 (1.365) 3.26 (2.005) 3.68 (1.725) 2.72 (2.470) 4.16 (1.359)
174 83 174 169 174
3.69 (1.197) 3.59 (2.078) 3.69 (1.596) 3.18 (2.406) 4.26 (1.242)
350 175 350 349 356
3.59 (1.286) 3.42 (2.041) 3.69 (1.660) 2.95 (2.446) 4.21 (1.302)
Abbreviations: AS = after seizures, BS = before seizures, DS = during seizures, ESL = eslicarbazepine acetate, QD = once-daily, SB = severity and bothersomeness, TS = total score.
At the end of the treatment period, the baseline-adjusted SSQ total score and the component mean scores for the cognitive, emotional, and physical aspects of postictal recovery AS, and overall SB were significantly lower for patients treated with ESL 1200 mg QD than for those treated with placebo; these changes exceeded the threshold for clinically meaningful change. The DS scores were also significantly lower, although the MCID was not achieved. Differences in baseline-adjusted SSQ mean scores between ESL 800 mg QD and placebo were less pronounced; only the difference in the mean SB score was statistically significant. As previously reported [12], parallel analyses among patients in these clinical trials also demonstrated improvement in Quality of Life in Epilepsy—31 (QOLIE-31) scores for those with ≥50% reduction in seizure frequency. These results indicate that quality-of-life benefits were not limited to complete responders [13]. We postulate that the scope of seizure severity components evaluated with the SSQ is related to quality-of-life domains, thereby contributing to the overall improvement found for these patients. One limitation of this analysis is that the results are drawn from patients who completed the double-blind period of the trial without major protocol violations (85.8%, 84.0%, and 69.6% of the placebo, ESL 800 mg, and ESL 1200 mg arms, respectively); therefore, the conclusions cannot be generalized to all patients. The analysis could not have been conducted on the intent-to-treat population, however, because the SSQ was not completed by patients who dropped out prior to the end of the study. Another potential limitation is that some patients did not follow the skip-pattern in the DS section of the SSQ. Although a facilitator assisted patients and observers, to ensure they understood the difference between altered consciousness in the presence or absence of altered movements or actions, as well as other components of the questionnaire, misunderstandings still occurred. The results, however, were robust and were not affected by the sensitivity analysis conducted to address this limitation. The SSQ, a multidimensional, patient-reported assessment designed for use in clinical research, demonstrated improved experiences of seizure severity and bothersomeness during ESL treatment.
Author contributions Ms. Cramer: conceptualization and design of the secondary analysis, analysis and interpretation of data, and drafting/revision of the manuscript for content. Dr. Velez: conceptualization and design of the secondary analysis, analysis and interpretation of data, and drafting/revision of the manuscript for content. Ms. Anastassopoulos: conceptualization and design of the secondary analysis, statistical analysis and interpretation of data, supervision and coordination of the study, and drafting/revision of the manuscript for content. Dr. Bond: conceptualization and design of the secondary analysis, analysis and interpretation of data, and drafting/revision of the manuscript for content. Dr. Gilliam: analysis and interpretation of data and drafting/revision of the manuscript for content. Dr. Ryvlin: acquisition of data and drafting/revision of the manuscript for content. Dr. Specchio: acquisition of data and drafting/revision of the manuscript for content. Mr. Wang: analysis and interpretation of data and statistical analysis. Dr. Blum: conceptualization and design of the secondary analysis, obtaining funding for the study, supervision and coordination of the study, acquisition, statistical analysis and interpretation of data, and drafting/revision of the manuscript for content. Dr. Moreira: acquisition of data, supervision and coordination of the study, and drafting/revision of the manuscript for content. Mr. Rocha: drafting/revision of the manuscript for content.
Study sponsorship/funding This study was supported by Sunovion Pharmaceuticals Inc. and BIAL — Portela & Ca.
Table 3 SSQ: baseline-adjusted scores at week 14, and differences vs placebo. Placebo (n = 187)
TS BS DS AS SB
ESL 800 mg QD (n = 183)
ESL 1200 mg QD (n = 174)
ESL 800/1200 mg QD (n = 357)
n
LSM (SE)
n
LSM (SE)
Δ (SE)
p
n
LSM (SE)
Δ (SE)
p
n
LSM (SE)
Δ (SE)
p
165 78 165 160 169
3.20 (0.096) 3.26 (0.180) 3.46 (0.124) 2.51 (0.157) 3.65 (0.103)
148 55 148 146 155
3.02 (0.102) 3.28 (0.215) 3.19 (0.131) 2.37 (0.165) 3.28 (0.107)
−0.18 (0.140) 0.02 (0.282) −0.28 (0.181) −0.14 (0.228) −0.37 (0.149)
0.195 0.953 0.129 0.528 0.013
128 47 128 121 130
2.68 (0.109) 2.82 (0.231) 3.05 (0.141) 1.95 (0.180) 3.09 (0.117)
−0.52 (0.146) −0.44 (0.292) −0.42 (0.188) −0.56 (0.239) −0.55 (0.156)
b0.001 0.131 0.027 0.019 b0.001
276 102 276 267 285
2.86 (0.075) 3.06 (0.157) 3.12 (0.096) 2.18 (0.121) 3.19 (0.079)
−0.34 (0.122) −0.20 (0.240) −0.34 (0.157) −0.34 (0.199) −0.46 (0.130)
0.006 0.407 0.031 0.092 0.001
Abbreviations: AS = after seizures, BS = before seizures, DS = during seizures, ESL = eslicarbazepine acetate, LSM = least square mean, MCID = minimum clinically important difference, QD = once-daily, SB = severity and bothersomeness, SE = standard error, TS = total score. LSM scores were calculated by analysis of covariance model, adjusted for the corresponding baseline score. Scores for the combined 800 mg/1200 mg ESL group were calculated from the combined data for the two treatment arms. Δ = difference in LSM scores vs placebo; differences that exceed the relevant MCID are shown in bold. p values are for differences in LSM score vs placebo (Student's t-test; p values b 0.05 are shown in bold).
J.A. Cramer et al. / Epilepsy & Behavior 53 (2015) 149–153
Acknowledgments The authors thank Keri Davies of FireKite, an Ashfield company, part of UDG Healthcare plc, and Natalie Edwards of Health Services Consulting Corporation, for assistance with editing the manuscript for nonintellectual content. Editorial support was funded by Sunovion Pharmaceuticals Inc., Marlborough, MA, USA. Disclosures Ms. Cramer is a consultant for Sunovion Pharmaceuticals Inc. Dr. Velez is an employee of Sunovion Pharmaceuticals Inc. Ms. Anastassopoulos is an employee of Covance Market Access Services, which was contracted to conduct this analysis and funded by Sunovion Pharmaceuticals Inc. Dr. Bond is an employee of Covance Market Access Services, which was contracted to conduct this analysis and funded by Sunovion Pharmaceuticals Inc. Dr. Gilliam received honoraria from UCB Pharma and served on an advisory board for Upsher-Smith. Dr. Ryvlin received speaker and consultant fees from UCB Pharma, Eisai, BIAL — Portela & Ca, Cyberonics, and Medtronic. Dr. Specchio served on a scientific advisory board for GlaxoSmithKline, UCB Pharma, and Eisai; received travel expenses and/or honoraria for lectures or educational activities for UCB Pharma and FB Health; served on the editorial board of the Journal of Epileptology, Epilepsy Research and Treatment, Clinical Cases, and Reviews in Epilepsy; acted as a consultant on behalf of Medtronic; and in the past two years and during the course of the study, received financial support for trials from BIAL — Portela & Ca, GlaxoSmithKline, and Pfizer. Mr. Wang is an employee of Covance Market Access Services, which was contracted to conduct this analysis and funded by Sunovion Pharmaceuticals Inc. Dr. Blum is an employee of Sunovion Pharmaceuticals Inc.
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Dr. Moreira is an employee of BIAL — Portela & Ca. Mr. Rocha is an employee of BIAL — Portela & Ca.
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate Joyce A. Cramer a,⁎, Fulton F. Velez b, Kathryn P. Anastassopoulos c, T. Christopher Bond c, Frank G. Gilliam d, Philippe Ryvlin e, Luigi M. Specchio f, Xuezhe Wang c,1, David Blum b, Joana Moreira g, Francisco Rocha g a
Department of Medical Research, Health Outcomes, Houston, TX, USA Sunovion Pharmaceuticals Inc., Marlborough, MA, USA Covance Market Access Services Inc., Gaithersburg, MD, USA d Department of Neurology, Penn State University College of Medicine, Hershey, PA, USA e Department of Clinical Neurosciences, CHUV, Lausanne, Switzerland f Epilepsy Center, Clinic of Nervous System Diseases, University of Foggia, Riuniti Hospital, Foggia, Italy g BIAL — Portela & Cª S.A., S. Mamede do Coronado, Portugal b c
a r t i c l e
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Article history: Received 7 August 2015 Revised 14 September 2015 Accepted 15 September 2015 Available online 12 November 2015 Keywords: All epilepsy/seizures Antiepileptic drugs Partial seizures Seizure severity All clinical trials
a b s t r a c t Objective: The objective of this study was to compare posttreatment seizure severity in a phase III clinical trial of eslicarbazepine acetate (ESL) as adjunctive treatment of refractory partial-onset seizures. Methods: The Seizure Severity Questionnaire (SSQ) was administered at baseline and posttreatment. The SSQ total score (TS) and component scores (frequency and helpfulness of warning signs before seizures [BS]; severity and bothersomeness of ictal movement and altered consciousness during seizures [DS]; cognitive, emotional, and physical aspects of postictal recovery after seizures [AS]; and overall severity and bothersomeness [SB]) were calculated for the per-protocol population. Analysis of covariance, adjusted for baseline scores, estimated differences in posttreatment least square means between treatment arms. Results: Out of 547 per-protocol patients, 441 had valid SSQ TS both at baseline and posttreatment. Mean posttreatment TS for ESL 1200 mg/day was significantly lower than that for placebo (2.68 vs 3.20, p b 0.001), exceeding the minimal clinically important difference (MCID: 0.48). Mean DS, AS, and SB were also significantly lower with ESL 1200 mg/day; differences in AS and SB exceeded the MCIDs. The TS, DS, AS, and SB were lower for ESL 800 mg/day than for placebo; only SB was significant (p = 0.013). For both ESL arms combined versus placebo, mean scores differed significantly for TS (p = 0.006), DS (p = 0.031), and SB (p = 0.001). Conclusions: Therapeutic ESL doses led to clinically meaningful, dose-dependent reductions in seizure severity, as measured by SSQ scores. Classification of evidence: This study presents Class I evidence that adjunctive ESL (800 and 1200 mg/day) led to clinically meaningful, dose-dependent seizure severity reductions, measured by the SSQ. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Assessment of improvement among patients with treatment-resistant seizures is usually measured as seizure frequency. However, this metric does not incorporate other effects of treatment. A new approach to treatment change is based on assessing seizure severity as well as frequency. ⁎ Corresponding author at: Department of Medical Research, Health Outcomes, 49 Briar Hollow Lane, Houston, TX 77027, USA. Tel.: +1 713 552 0289. E-mail addresses: [email protected] (J.A. Cramer), [email protected] (F.F. Velez), [email protected] (K.P. Anastassopoulos), [email protected] (T.C. Bond), [email protected] (F.G. Gilliam), [email protected] (P. Ryvlin), [email protected] (L.M. Specchio), [email protected] (X. Wang), [email protected] (D. Blum), [email protected] (J. Moreira), [email protected] (F. Rocha). 1 Xuezhe Wang, MS, of Covance Market Access Services Inc. carried out the biostatistical analysis.
http://dx.doi.org/10.1016/j.yebeh.2015.09.018 1525-5050/© 2015 Elsevier Inc. All rights reserved.
The Seizure Severity Questionnaire (SSQ), developed by Cramer et al. [1], is accepted by regulatory agencies as a secondary outcome in clinical trials. In phase III clinical trials, 800 mg/day and 1200 mg/day of eslicarbazepine acetate (ESL; Aptiom®, Sunovion Pharmaceuticals Inc., Marlborough, MA, USA) led to statistically significant reductions in standardized seizure frequency vs baseline compared with that of placebo [2–4]. The severity of seizures and the extent to which they were perceived as a burden by each patient was evaluated as a secondary endpoint in one of the trials (study 304) [4], and is presented here. 2. Methods 2.1. Patients and treatment regimen The design and methodology of the trial (BIA-2093-304; registered at ClinicalTrials.gov [NCT00988429]) have been reported previously
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[4]. Briefly, patients aged ≥16 years with ≥8 partial-onset seizures (POS) during baseline, ≥3 seizures in each 4-week period, and no seizure-free period for N 28 consecutive days, were eligible for the trial. After an 8week prospective baseline period, patients were randomized equally to receive placebo or ESL (800 mg once-daily [QD] or 1200 mg QD) during a 2-week, double-blind, titration period and a 12-week, fixed-dose, double-blind maintenance period. Patients continued to receive stable dosages of baseline concomitant antiepileptic drugs (AEDs), although use of oxcarbazepine (OXC) was prohibited due to similarities in metabolites between OXC and ESL. Following completion of the 14-week double-blind phase, patients entered a 2-week tapering-off period. 2.2. Seizure Severity Questionnaire The SSQ [1] was developed as a clinical research tool to quantify the severity of seizures over time. The questionnaire was validated in a multistage process and has demonstrated sensitivity to change across types of seizures [5,6]. The SSQ assessments gather information about seizurerelated events and the patient's perceptions and feelings about those events, over the past 4 weeks. This allows a longitudinal evaluation of how much the patient is affected by seizures, independent of seizure frequency. Additional analyses defined minimal clinically important difference (MCID) scores that facilitate clinical interpretations of scores [6]. Unlike some health-related quality-of-life questionnaires that are completed independently by the patient, the SSQ is a structured interview in which an epilepsy professional guides the patient and a person who observes the patient's seizures in responding to questions. The trained coordinator or investigator can ensure that the patient and observer comprehend all questions and complete all sections. This approach compensates for patients' amnesia about events, cognitive deficits, and age. 2.3. Data source and SSQ administration During the trial, administration of the SSQ was facilitated by the investigators, who were trained on use of the questionnaire. The SSQ was completed at the end of the 8-week baseline period (day 1 of treatment; baseline assessment), during the efficacy period (week 8 assessment), and at the end of the 12-week double-blind maintenance period (week 14 assessment). The SSQ specifically asks patients about their experiences in the previous 4 weeks. Thus, in the current study, the baseline score reflects the patient's experience during the 4 weeks before initiation of ESL treatment, and the week 14 score reflects their experience during the last 4 weeks of ESL treatment. In order to ensure consistency and reliability of assessments across multiple investigative sites, an independent interrater qualification service provided training at North American sites, and the study medical monitor provided similar training for sites outside North America. 2.4. Scoring the SSQ The SSQ scoring scheme [7] was based on the scoring algorithm developed by J. Cramer, and was adapted for use in the current study. The SSQ total score (TS) was derived from four component scores: frequency and helpfulness of warning signs before seizures (BS); severity and bothersomeness of ictal movement and altered consciousness during seizures (DS); cognitive, emotional, and physical aspects of postictal recovery after seizures (AS); and overall severity and bothersomeness (SB). The range of scores was 1–7 for BS, DS and SB, and 0–7 for AS, with lower scores indicating lower severity and/or burden. Total score was calculated as the average of all completed component scores. The scoring algorithm accounts for the fact that not all patients will have ‘before’ or ‘after’ effects. Consequently, BS is not included in the calculation of TS for patients without ‘before’ effects, and AS is assigned a value of 0 for patients without ‘after’ effects. Therefore, TS has a possible range of values of 0.67 to 7.00. Validation
criteria for each component score were applied separately in this analysis; however, actively completed DS and SB sections were required for the calculation of TS. Patients who indicated that they had no seizures during the 4 weeks prior to the week 14 SSQ assessment were assigned the minimum scores for DS, AS, and SB at follow-up. Because the BS score represents helpfulness of warning signs (rather than seizure severity), in patients who were seizure-free, a minimum score was not applied but the score was set to missing. The following rules were applied when patients provided two mutually exclusive responses to questions about whether they had experienced: 1) movements or actions during their seizures and 2) altered consciousness only. Those who responded “yes” to both questions (13.9%) were defaulted to ‘yes’ for question 1 and ‘no’ for question 2 (assuming that they did have movements/actions during seizures, and had made a mistake in answering question 2). Scores for subquestions about severity and bothersomeness were then derived from the first question only. Patients who answered ‘no’ to both questions (7.9%) did not complete any of the subquestions, so they were assigned the minimum DS score of 1. A sensitivity analysis was conducted in which, for patients who answered ‘no’ to both questions, the whole questionnaire was deemed to be invalid. The MCIDs for TS and three component scores have previously been defined (TS: 0.48, DS: 0.50, AS: 0.39, SB: 0.48) [6]. In this study, MCIDs were used to compare the difference between treatment arms (i.e., the difference between effects of the 2 doses of ESL). An MCID has not been defined for the BS score, because this score reflects potentially helpful warning signs occurring immediately before a seizure. 2.5. Descriptive and statistical analyses The intent-to-treat population comprised 640 patients, 547 of whom had no major protocol violations and were included in the per-protocol population and this analysis. Mean SSQ TS and component scores were calculated for patients with useable questionnaires at baseline. Analysis of covariance was used to calculate baseline-adjusted least square mean scores (adjusted mean scores) at week 14 and compare differences in adjusted mean scores between treatment arms, for patients who completed the baseline and week 14 SSQ [8]. In this context, the final measure of severity was considered most significant. Therefore, potentially more powerful analyses (including comparison of scores at week 8) were not conducted. Statistical significance was claimed at alpha 0.05. No adjustments were made for multiple comparisons of component scores. The MCIDs were used to evaluate the clinical relevance of changes in seizure severity with ESL vs placebo. Student's t-tests were used to compare the differences in adjusted mean scores between each active treatment arm (ESL 800 mg QD and ESL 1200 mg QD) and the placebo arm and also between the combined ESL arms (ESL 800 mg QD and 1200 mg QD) and the placebo arm. The first analysis mirrored the design of the clinical trial and allowed assessment of the improvement in seizures with each dose of ESL. The comparison between the combined ESL arms and the placebo arm provided greater analytic power to assess the improvement in SSQ scores with either of the 2 approved therapeutic doses combined. 2.6. Standard protocol approvals, registrations, and patient consents Study BIA 2-093-304 (NCT00988429) was undertaken between December 2008 and January 2012, at 173 centers in 19 countries worldwide. The study was conducted in accordance with the principles of the Declaration of Helsinki; the International Conference on Harmonization guidelines; and all national, state, and local laws of the pertinent regulatory authorities. The trial protocol, amendments, and informed consent were reviewed and approved by the relevant independent ethics
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committees/institutional review boards for each site. Written informed consent was obtained from all patients before enrollment. 2.7. Classification of evidence This analysis presents Class I evidence from BIA 2-093-304 that the use of therapeutic doses of ESL (800 mg QD and 1200 mg QD) leads to clinically meaningful and dose-dependent reductions in patientreported seizure severity, as measured by SSQ scores (at week 14, the adjusted mean TS was 2.68 for ESL 1200 mg QD, 3.02 for ESL 800 mg QD, and the adjusted mean difference (− 0.52) exceeded the MCID of 0.48). 3. Results Among the 547 per-protocol patients, 544 completed the SSQ at baseline. There were no significant differences in demographic characteristics between treatment arms (Table 1). Of the 544 patients with a completed baseline SSQ, 537 had a valid score for at least 1 component. Baseline mean scores were 3.62 for TS, and 3.53, 3.73, 2.99, and 4.23 for BS, DS, AS and SB, respectively (Table 2). The week 14 SSQ was completed by 458 (84.2%) of the 544 patients who had completed the baseline SSQ: 170 patients (90.9%) in the placebo arm, 157 (85.8%) in the ESL 800 mg QD arm, and 131 (75.3%) in the ESL 1200 mg QD arm. Of these, 6 (3.5%) in the placebo arm, 8 (5.1%) in the ESL 800 mg QD arm, and 18 (13.7%) in the ESL 1200 mg QD arm reported no seizures during the 4 weeks prior to the week 14 assessment, and so they were assigned minimum scores for DS, AS, and SB. Patients were not required to report all components for their data to be included in the analysis. The number with valid scores at both baseline and week 14 was: TS, 441; DS, 441; AS, 427; and SB, 454. Only 180 patients had BS scores, because many did not report warnings before seizures. The proportion of patients with scores at both baseline and week 14 differed between treatment arms. For TS, the proportions were 88.2% (165/187) for the placebo arm, 80.9% (148/183) for the ESL 800 mg QD arm, and 73.1% (128/174) for the ESL 1200 mg QD arm. At week 14, the adjusted mean TS for the ESL 1200 mg QD arm was significantly lower than that for the placebo arm (2.68 vs 3.20, p b 0.001; Table 3). The adjusted mean difference (−0.52) was clinically significant, exceeding the MCID of 0.48. The adjusted mean TS for the ESL
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800 mg QD arm was also lower than that for the placebo arm, but the difference was not statistically significant (3.02 vs 3.20, p = 0.195). Similarly, DS and AS adjusted mean scores for the ESL 1200 mg QD arm were significantly lower than those for the placebo arm (DS: 3.05 vs 3.46, p = 0.027; AS: 1.95 vs 2.51, p = 0.019) but not for the ESL 800 mg QD arm (Table 3). For DS, the adjusted mean difference (− 0.42) in the ESL 1200 mg QD arm did not exceed the MCID (0.50), whereas for AS, the difference of 0.56 in the ESL 1200 mg QD arm was clinically significant, exceeding the MCID of 0.39. For SB, the adjusted mean scores were 3.65 for the placebo arm, 3.09 for the ESL 1200 mg QD arm (p b 0.001), and 3.28 for the ESL 800 mg QD arm (p = 0.013). The difference of −0.55 between the ESL 1200 mg QD arm and placebo exceeded the MCID (0.48; Table 3). Adjusted mean BS scores in both ESL arms were not significantly lower than that in the placebo arm. The findings at week 14 for the 2 ESL arms combined were similar to those for the individual ESL treatment arms (Table 3). Baseline-adjusted mean scores were significantly lower in the combined ESL group than that in the placebo arm for TS (2.86 vs 3.20, p = 0.006), DS (3.12 vs 3.46, p = 0.031), and SB (3.19 vs 3.65, p = 0.001), but not for AS (2.18 vs 2.51, p = 0.092) or BS (3.06 vs 3.26, p = 0.407). None of the differences between the combined ESL group and the placebo arm exceeded the respective MCID. The results of a sensitivity analysis (excluding questionnaire data for 56 patients with mutually exclusive responses) were consistent with the main analysis (data not shown). Adjusted TS and DS scores were both higher when these patients were excluded (the main analysis sets the DS score to the minimum). However, conclusions about the statistical and clinical significances of the differences between ESL-treated and placebo-treated patients were not affected. The BS, AS, and SB scores were not impacted by the sensitivity analysis. 4. Discussion The results of this study are based on a well-validated questionnaire that captures the patient's experience of seizure severity and bothersomeness. The findings complement other published assessments of seizure frequency, supplement other published assessments of seizure severity [9–11], and confirm the sensitivity of the SSQ in this population. In this analysis, approved therapeutic doses of ESL led to dosedependent reductions in seizure severity, as indicated by SSQ scores.
Table 1 Demographic characteristics.
Age
Gender, n (%) BMI
Duration of epilepsy, years
Race, n (%)
Region, n (%)
†
n Mean (SD) Median Female Male n† Mean (SD) Median n† Mean (SD) Median White Asian Black Other North America Latin America Eastern Europe Western Europe Other
Total (n = 544)
Placebo (n = 187)
ESL 800 mg QD (n = 183)
ESL 1200 mg QD (n = 174)
p⁎
543 38.4 (12.2) 38.0 278 (51.1) 266 (48.9) 536 26.2 (6.0) 25.3 539 20.9 (13.3) 18.3 346 (63.6) 102 (18.8) 21 (3.9) 75 (13.8) 198 (36.4) 92 (16.9) 90 (16.5) 52 (9.6) 112 (20.6)
186 38.4 (12.6) 37.0 94 (50.3) 93 (49.7) 183 25.6 (5.6) 24.7 185 20.9 (14.1) 17.8 116 (62.0) 41 (21.9) 6 (3.2) 24 (12.8) 64 (34.2) 30 (16.0) 31 (16.6) 20 (10.7) 42 (22.5)
183 38.8 (12.2) 39.0 95 (51.9) 88 (48.1) 181 26.4 (5.7) 25.7 180 20.8 (13.0) 18.7 117 (63.9) 31 (16.9) 7 (3.8) 28 (15.3) 67 (36.6) 34 (18.6) 28 (15.3) 17 (9.3) 37 (20.2)
174 37.9 (11.9) 38.0 89 (51.1) 85 (48.9) 172 26.7 (6.7) 25.3 174 20.9 (12.9) 18.1 113 (64.9) 30 (17.2) 8 (4.6) 23 (13.2) 67 (38.5) 28 (16.1) 31 (17.8) 15 (8.6) 33 (19.0)
0.792
Abbreviations: BMI = body mass index, ESL = eslicarbazepine acetate, QD = once-daily. ⁎ p values calculated using Student's t-tests for continuous variables and chi-square tests for categorical variables. † n for individual demographic characteristics may not equal total n due to missing data.
0.951 0.185
0.998
0.859
0.973
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Table 2 SSQ: baseline scores.
TS BS DS AS SB
All (n = 544)
Placebo (n = 187)
ESL 800 mg QD (n = 183)
ESL 1200 mg QD (n = 174)
ESL 800/1200 mg QD (n = 357)
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
537 291 537 536 543
3.62 (1.285) 3.53 (2.078) 3.73 (1.685) 2.99 (2.449) 4.23 (1.351)
187 116 187 187 187
3.69 (1.283) 3.69 (2.132) 3.81 (1.734) 3.07 (2.459) 4.27 (1.442)
176 92 176 180 182
3.48 (1.365) 3.26 (2.005) 3.68 (1.725) 2.72 (2.470) 4.16 (1.359)
174 83 174 169 174
3.69 (1.197) 3.59 (2.078) 3.69 (1.596) 3.18 (2.406) 4.26 (1.242)
350 175 350 349 356
3.59 (1.286) 3.42 (2.041) 3.69 (1.660) 2.95 (2.446) 4.21 (1.302)
Abbreviations: AS = after seizures, BS = before seizures, DS = during seizures, ESL = eslicarbazepine acetate, QD = once-daily, SB = severity and bothersomeness, TS = total score.
At the end of the treatment period, the baseline-adjusted SSQ total score and the component mean scores for the cognitive, emotional, and physical aspects of postictal recovery AS, and overall SB were significantly lower for patients treated with ESL 1200 mg QD than for those treated with placebo; these changes exceeded the threshold for clinically meaningful change. The DS scores were also significantly lower, although the MCID was not achieved. Differences in baseline-adjusted SSQ mean scores between ESL 800 mg QD and placebo were less pronounced; only the difference in the mean SB score was statistically significant. As previously reported [12], parallel analyses among patients in these clinical trials also demonstrated improvement in Quality of Life in Epilepsy—31 (QOLIE-31) scores for those with ≥50% reduction in seizure frequency. These results indicate that quality-of-life benefits were not limited to complete responders [13]. We postulate that the scope of seizure severity components evaluated with the SSQ is related to quality-of-life domains, thereby contributing to the overall improvement found for these patients. One limitation of this analysis is that the results are drawn from patients who completed the double-blind period of the trial without major protocol violations (85.8%, 84.0%, and 69.6% of the placebo, ESL 800 mg, and ESL 1200 mg arms, respectively); therefore, the conclusions cannot be generalized to all patients. The analysis could not have been conducted on the intent-to-treat population, however, because the SSQ was not completed by patients who dropped out prior to the end of the study. Another potential limitation is that some patients did not follow the skip-pattern in the DS section of the SSQ. Although a facilitator assisted patients and observers, to ensure they understood the difference between altered consciousness in the presence or absence of altered movements or actions, as well as other components of the questionnaire, misunderstandings still occurred. The results, however, were robust and were not affected by the sensitivity analysis conducted to address this limitation. The SSQ, a multidimensional, patient-reported assessment designed for use in clinical research, demonstrated improved experiences of seizure severity and bothersomeness during ESL treatment.
Author contributions Ms. Cramer: conceptualization and design of the secondary analysis, analysis and interpretation of data, and drafting/revision of the manuscript for content. Dr. Velez: conceptualization and design of the secondary analysis, analysis and interpretation of data, and drafting/revision of the manuscript for content. Ms. Anastassopoulos: conceptualization and design of the secondary analysis, statistical analysis and interpretation of data, supervision and coordination of the study, and drafting/revision of the manuscript for content. Dr. Bond: conceptualization and design of the secondary analysis, analysis and interpretation of data, and drafting/revision of the manuscript for content. Dr. Gilliam: analysis and interpretation of data and drafting/revision of the manuscript for content. Dr. Ryvlin: acquisition of data and drafting/revision of the manuscript for content. Dr. Specchio: acquisition of data and drafting/revision of the manuscript for content. Mr. Wang: analysis and interpretation of data and statistical analysis. Dr. Blum: conceptualization and design of the secondary analysis, obtaining funding for the study, supervision and coordination of the study, acquisition, statistical analysis and interpretation of data, and drafting/revision of the manuscript for content. Dr. Moreira: acquisition of data, supervision and coordination of the study, and drafting/revision of the manuscript for content. Mr. Rocha: drafting/revision of the manuscript for content.
Study sponsorship/funding This study was supported by Sunovion Pharmaceuticals Inc. and BIAL — Portela & Ca.
Table 3 SSQ: baseline-adjusted scores at week 14, and differences vs placebo. Placebo (n = 187)
TS BS DS AS SB
ESL 800 mg QD (n = 183)
ESL 1200 mg QD (n = 174)
ESL 800/1200 mg QD (n = 357)
n
LSM (SE)
n
LSM (SE)
Δ (SE)
p
n
LSM (SE)
Δ (SE)
p
n
LSM (SE)
Δ (SE)
p
165 78 165 160 169
3.20 (0.096) 3.26 (0.180) 3.46 (0.124) 2.51 (0.157) 3.65 (0.103)
148 55 148 146 155
3.02 (0.102) 3.28 (0.215) 3.19 (0.131) 2.37 (0.165) 3.28 (0.107)
−0.18 (0.140) 0.02 (0.282) −0.28 (0.181) −0.14 (0.228) −0.37 (0.149)
0.195 0.953 0.129 0.528 0.013
128 47 128 121 130
2.68 (0.109) 2.82 (0.231) 3.05 (0.141) 1.95 (0.180) 3.09 (0.117)
−0.52 (0.146) −0.44 (0.292) −0.42 (0.188) −0.56 (0.239) −0.55 (0.156)
b0.001 0.131 0.027 0.019 b0.001
276 102 276 267 285
2.86 (0.075) 3.06 (0.157) 3.12 (0.096) 2.18 (0.121) 3.19 (0.079)
−0.34 (0.122) −0.20 (0.240) −0.34 (0.157) −0.34 (0.199) −0.46 (0.130)
0.006 0.407 0.031 0.092 0.001
Abbreviations: AS = after seizures, BS = before seizures, DS = during seizures, ESL = eslicarbazepine acetate, LSM = least square mean, MCID = minimum clinically important difference, QD = once-daily, SB = severity and bothersomeness, SE = standard error, TS = total score. LSM scores were calculated by analysis of covariance model, adjusted for the corresponding baseline score. Scores for the combined 800 mg/1200 mg ESL group were calculated from the combined data for the two treatment arms. Δ = difference in LSM scores vs placebo; differences that exceed the relevant MCID are shown in bold. p values are for differences in LSM score vs placebo (Student's t-test; p values b 0.05 are shown in bold).
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Acknowledgments The authors thank Keri Davies of FireKite, an Ashfield company, part of UDG Healthcare plc, and Natalie Edwards of Health Services Consulting Corporation, for assistance with editing the manuscript for nonintellectual content. Editorial support was funded by Sunovion Pharmaceuticals Inc., Marlborough, MA, USA. Disclosures Ms. Cramer is a consultant for Sunovion Pharmaceuticals Inc. Dr. Velez is an employee of Sunovion Pharmaceuticals Inc. Ms. Anastassopoulos is an employee of Covance Market Access Services, which was contracted to conduct this analysis and funded by Sunovion Pharmaceuticals Inc. Dr. Bond is an employee of Covance Market Access Services, which was contracted to conduct this analysis and funded by Sunovion Pharmaceuticals Inc. Dr. Gilliam received honoraria from UCB Pharma and served on an advisory board for Upsher-Smith. Dr. Ryvlin received speaker and consultant fees from UCB Pharma, Eisai, BIAL — Portela & Ca, Cyberonics, and Medtronic. Dr. Specchio served on a scientific advisory board for GlaxoSmithKline, UCB Pharma, and Eisai; received travel expenses and/or honoraria for lectures or educational activities for UCB Pharma and FB Health; served on the editorial board of the Journal of Epileptology, Epilepsy Research and Treatment, Clinical Cases, and Reviews in Epilepsy; acted as a consultant on behalf of Medtronic; and in the past two years and during the course of the study, received financial support for trials from BIAL — Portela & Ca, GlaxoSmithKline, and Pfizer. Mr. Wang is an employee of Covance Market Access Services, which was contracted to conduct this analysis and funded by Sunovion Pharmaceuticals Inc. Dr. Blum is an employee of Sunovion Pharmaceuticals Inc.
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Dr. Moreira is an employee of BIAL — Portela & Ca. Mr. Rocha is an employee of BIAL — Portela & Ca.
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