Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: LAM40124 Title: An Assessment of Behavioral Changes Associated with and in Patients with Epilepsy Rationale: Mood symptoms and associated behavioral changes can have a significant impact on the quality of life and functional ability of patients with epilepsy. The etiology of mood symptoms and associated behavioral changes in epilepsy has been attributed to several causes including endocrine and/or metabolic effects of seizures; the psychological response to epilepsy and its mental, physical, and social challenges; and side effects of certain antiepileptic drugs. Previous observations suggest that lamotrigine has a better tolerability profile than levetiracetam with respect to effects on mood. However, the medications have not been directly compared in a study prospectively designed to assess mood and related behavioral effects. This randomized, double-blind clinical trial was designed to compare the effects of adjunctive lamotrigine with those of adjunctive levetiracetam on mood, particularly anger and hostility, in subjects with partial seizures. Phase: IV Study Period: 15 September 2003 to 08 September 2006 Study Design: Randomized, double-blind, parallel-group, multicenter study Centres: 62 centers in North America Indication: Epilepsy Treatment: Subjects were titrated from an initial daily dose of 50mg of lamotrigine to a target maintenance dose of 400 mg/day or from an initial daily dose of 500mg levetiracetam to a target dose of 2000 mg/day over a period of 8 weeks during the Escalation Phase. Subjects were maintained at the target dose for 12 weeks during the Maintenance Phase. Dose adjustments were allowed during the Maintenance Phase to maintain seizure control or reduce adverse events. Objectives: Primary: To compare the occurrence of anger and hostility in subjects with partial seizures treated with lamotrigine or levetiracetam as adjunctive therapy Secondary: To compare the safety and tolerability of lamotrigine and levetiracetam as adjunctive therapy in subjects with partial seizures Primary Outcome/Efficacy Variable: Change in the Anger-Hostility subscale score of the Profile of Mood States (POMS) between and the end of the Maintenance Phase Secondary Outcome/Efficacy Variables: Change between and each weekly assessment in the Anger-Hostility subscale score of the POMS Change between and each weekly assessment in the Total Mood Disturbance score and the other subscale scores of the POMS Change between and the end of the Maintenance Phase in scores on the State Trait Anger Expression Inventory (STAXI), the Beck Depression Inventory, 2 nd edition (BDI-II), the Irritability-Depression-Anxiety Scale (IDAS), and the 31-item Quality of Life Inventory in Epilepsy (QOLIE-31) Change between and the ends of the Escalation Phase and the Maintenance Phase in scores on the Neurological Disorders Depression Inventory in Epilepsy (NDDI-E) and the Epworth Sleepiness Scale (ESS) Change between and the ends of the Escalation Phase and the Maintenance Phase in scores on the NDDI-E completed by a family member or friend The frequency and severity of antiepileptic drug-associated adverse events as scored by the Adverse Events Profile (AEP) at the ends of the Escalation Phase and the Maintenance Phase The investigator-rated assessment of mood and overall response to therapy scored on the Clinical Global Impression Scale (CGI) at the ends of the Escalation phase and the Maintenance Phase The frequency of seizures after treatment with lamotrigine or levetiracetam as adjunctive therapy The incidence of treatment-emergent adverse events The proportion of subjects who prematurely withdrew from the study and the reason(s) for premature withdrawal Statistical Methods: All data were analyzed for the Intent-to-Treat Population, defined as all enrolled subjects who took at least one dose of study medication. Differences between treatment groups on the primary endpoint were compared with nonparametric analysis of covariance (ANCOVA) methods. Differences between groups on the secondary health outcomes measures including the STAXI, BDI-II, IDAS, QOLIE-31, NDDI-E, ESS, and AEP were compared with parametric ANCOVA methods. CGI scores at the end of the Escalation Phase and the Maintenance Phase were compared between treatment groups with a chi-square test. Two-way ANOVAs based on ranks with 1

2 treatment group as a predictor variable were used to compare treatment groups with respect to seizure counts per month and absolute and percent changes from in seizure frequency during the Escalation Phase, the Maintenance Phase, and both phases combined. The percentage of subjects with 25%, 50%, and 75% reductions in seizure frequency and the percentage of subjects seizure free during the Escalation Phase, the Maintenance Phase, and both phases combined were compared between treatment groups with Fisher s Exact test. Adverse events reported during the study were summarized with descriptive statistics. Vital signs, results of clinical laboratory tests, and serum trough concentrations of study medication at the ends of the Escalation and Maintenance Phases were summarized for each treatment group with descriptive statistics. Study Population: The study enrolled men or women at least 16 years old who had a confident diagnosis of epilepsy with at least 2 simple partial seizures or complex partial seizures with or without secondary generalization during the 6 months before study entry and who at study entry were receiving monotherapy with a stable dose of carbamazepine or phenytoin or polytherapy that included carbamazepine or phenytoin and one other antiepileptic drug. Number of Subjects: Planned, N Randomised, N Completed, n (%) 89 (67) 89 (65) Total Number Subjects Withdrawn, N (%) 43 (33) 47 (35) Withdrawn due to Adverse Events n (%) 14 (11) 24 (18) Withdrawn due to Lack of Efficacy n (%) 0 (0) 0 (0) Withdrawn for other reasons n (%) 29 (22) 23 (17) Demographics N (ITT) Females: Males 63:69 56:80 Mean Age, years (SD) 38.3 (12.3) 39.1 (11.6) Race, n (%) Asian Black Hispanic White Other 0 (0) 22 (17) 11 (8) 94 (71) 5 (4) Primary Efficacy Results: Results for the Anger-Hostility Subscale of the POMS (Primary Endpoint) N= p value score (9.0) (8.7) NA Change from to the end of the Maintenance Phase (LOCF) (8.2) (8.4) Secondary Outcome Variables: Anger-Hostility Scale on POMS: Change from (LOCF) N= (9.0) (8.7) Week (6.5) (6.2) Week (7.0) (7.5) Week (8.0) (7.8) Week (8.1) (7.4) Week (8.0) (8.3) Week (8.7) (8.6) Week (9.1) (8.9) Week (8.1) (7.4) Week (8.5) (7.5) Week (8.0) (7.8) Week (8.2) (7.9) Week (8.5) (7.8) 2 (1) 23 (17) 11 (8) 99 (73) 1 (<1) 2

3 Week (8.4) (7.5) Week (8.5) (8.1) Week (8.4) (8.3) Week (8.4) (8.4) Week (8.8) (8.9) Week (8.8) (8.4) Week (8.7) (8.6) Week (8.2) (8.4) Total Mood Disturbance Score on POMS: Change from (LOCF) N= (39.8) (38.0) Week (24.7) (23.8) Week (29.1) (27.5) Week (30.4) (30.9) Week (31.9) (28.9) Week (32.1) (31.9) Week (33.1) (33.1) Week (35.5) (33.3) Week (31.8) (31.0) Week (32.7) (30.5) Week (33.5) (32.3) Week (34.2) (32.4) Week (34.4) (32.3) Week (36.1) (31.2) Week (36.5) (33.1) Week (35.3) (35.0) Week (35.7) (34.0) Week (36.9) (35.3) Week (36.8) (33.8) Week (37.4) (34.5) Week (33.9) (34.3) Tension-Anxiety Scale on POMS: Change from (LOCF) N= (7.6) (7.3) Week (5.2) (5.5) Week (6.0) (5.0) Week (6.3) (6.2) Week (6.9) (5.7) Week (6.7) (6.5) Week (6.7) (6.1) Week (7.3) (6.1) Week (7.0) (5.8) Week (7.1) (6.1) Week (7.4) (6.5) Week (6.9) (6.3) Week (7.5) (6.5) Week (7.2) (6.3) Week (7.2) (6.5) Week (7.1) (6.8) Week (7.1) (6.8) Week (7.3) (6.9) Week (7.2) (6.8) Week (7.5) (6.3) Week (7.3) (6.7) Depression-Dejection Scale on POMS: Change from (LOCF) N= 3

4 (11.3) (11.5) Week (7.3) (7.2) Week (9.3) (8.8) Week (8.8) (9.7) Week (9.2) (9.8) Week (9.5) (10.6) Week (10.1) (11.1) Week (10.5) (10.7) Week (8.9) (10.6) Week (9.1) (10.3) Week (9.4) (10.5) Week (10.1) (10.4) Week (10.2) (10.6) Week (10.7) (10.2) Week (10.8) (11.1) Week (10.3) (11.2) Week (10.6) (11.2) Week (10.8) (11.4) Week (10.7) (10.9) Week (10.9) (11.4) Week (9.9) (11.4) Vigor-Activity Scale on POMS: Change from (LOCF) N= (6.7) (6.5) Week (4.8) (5.1) Week (5.6) (5.8) Week (4.9) (5.7) Week (5.4) (5.9) Week (5.6) (5.8) Week (5.9) (5.7) Week (5.8) (6.3) Week (5.9) (6.2) Week (5.7) (6.4) Week (6.1) (6.6) Week (6.3) (6.2) Week (6.1) (5.8) Week (6.0) (5.8) Week (6.3) (6.0) Week (6.1) (6.6) Week (6.0) (6.2) Week (6.2) (6.0) Week (6.1) (6.2) Week (6.3) (6.5) Week (6.0) (5.7) Fatigue-Inertia Scale on POMS: Change from (LOCF) N= (6.6) (6.4) Week (5.6) (5.3) Week (6.0) (5.6) Week (6.4) (6.1) Week (6.5) (5.6) Week (6.6) (6.3) Week (6.6) (6.2) Week (7.2) (6.2) Week (6.4) (5.8) Week (6.8) (5.7) 4

5 Week (6.8) (5.7) Week (6.9) (6.0) Week (6.7) (6.0) Week (7.1) (6.2) Week (7.1) (6.3) Week (7.3) (6.8) Week (7.4) (6.2) Week (7.4) (6.7) Week (7.5) (6.3) Week (7.5) (6.3) Week (7.1) (6.1) Confusion-Bewilderment Scale on POMS: Change from (LOCF) N= (5.5) (5.4) Week (3.5) (4.1) Week (3.8) (4.4) Week (3.9) (4.5) Week (4.1) (4.0) Week (4.3) (4.6) Week (4.6) (4.9) Week (4.7) (5.2) Week (4.5) (4.6) Week (4.8) (4.6) Week (4.9) (4.9) Week (5.0) (4.9) Week (4.7) (4.9) Week (4.9) (4.8) Week (4.9) (5.0) Week (4.7) (5.1) Week (4.9) (5.1) Week (5.0) (5.2) Week (4.9) (5.3) Week (5.1) (5.2) Week (4.9) (4.9) STAXI: Change from Feeling Angry Feeling Expressing Anger Verbally Feeling Expressing Anger Physically Angry Temperament Angry Reaction Anger Expression-Out Anger Expression-In Anger Control-Out N= 6.6 (3.0) 0.4 (3.7) 6.2 (2.8) 0.2 (3.4) 5.6 (2.2) 0.3 (2.7) 6.7 (3.0) -0.1 (2.3) 7.6 (2.6) -0.4 (2.6) 15.8 (4.8) -0.4 (3.9) 16.4 (4.7) -0.9 (4.2) 6.2 (5.0) 0.7 (2.5) 5.7 (2.0) 0.4 (2.1) 5.4 (1.4) 0.0 (1.6) 6.2 (2.5) 0.0 (2.1) 7.3 (2.4) 0.0 (2.2) 14.7 (4.0) -0.3 (3.4) 16.3 (4.0) -0.1 (3.7) 5

6 Anger Control-In State Anger Scale Trait Anger Scale Anger Expression Index Total BDI-II: Change from IDAS: Change from Irritability Depression Anxiety QOLIE-31: Change from Seizure Worry Overall Quality of Life Emotional Well-Being Energy/Fatigue Cognitive Functioning Medication Effects Social Functioning Overall Score 23.2 (5.8) -0.5 (5.2) 22.3 (5.7) 0.0 (5.7) 18.3 (7.3) 0.8 (8.9) 17.5 (5.8) -0.6 (5.0) 34.9 (16.0) -0.8 (13.9) 23.9 (5.4) -1.0 (4.6) 23.2 (5.3) -0.7 (4.9) 17.3 (5.4) 1.1 (5.3) 16.6 (5.1) 0.1 (4.0) 31.7 (13.9) 1.2 (11.2) N= (10.6) 12.2 (10.6) (7.7) -0.7 (6.6) N= 4.1 (2.9) -0.3 (2. 2) 4.9 (3.1) -0.3 (2.6) 5.3 (3.2) -0.5 (3.0) 3.5 (2.4) 0.6 (2.1) 4.6 (2.9) 0.4 (2.0) 4.7 (3.0) 0.1 (2.3) N= NDDI-E completed by subjects: Change from 47.0 (26.6) 6.7 (21.9) 63.6 (19.1) 2.6 (17.0) 67.0 (20.3) 2.0 (16.7) 49.3 (22.3) 3.8 (20.9) 57.8 (23.2) 6.0 (17.7) 49.3 (29.4) 9.0 (25.0) 62.3 (26.0) 6.6 (23.6) 58.8 (18.5) 4.9 (14.2) 46.3 (28.1) 11.9 (24.3) 64.8 (20.4) -2.3 (16.4) 66.9 (18.8) -2.7 (16.6) 49.9 (20.5) -0.9 (17.8) 59.7 (24.5) 2.3 (18.2) 53.6 (30.1) 5.5 (27.3) 61.4 (26.6) 6.4 (22.9) 59.4 (18.2) 2.3 (12.7) 6

7 Change, Week 8 (LOCF) N= (3.9) (3.9) (3.5) (3.2) (3.5) (2.9) NDDI-E completed by family members/friends: Change from N= Change, Week 8 (LOCF) ESS: Change from Change, Week 8 (LOCF) AEP: Change from Change, Week 8 (LOCF) CGI Week 8 Very much improved Much improved Minimally improved No change Minimally worse Much worse Week 20 Very much improved Much improved Minimally improved No change Minimally worse Much worse (4.3) -1.5 (3.1) -2.0 (3.2) (3.8) -0.3 (3.6) -0.1 (4.1) N= (4.9) (4.5) (3.7) (4.2) (4.6) (4.2) N= 40.8 (11.4) 40.8 (10.7) -2.0 (8.7) -1.6 (7.1) -2.2 (8.8) -1.9 (7.6) N= n n (%) n n (%) (18) 17 (17) 37 (36) 29 (29) 22 (22) 29 (29) 19 (19) 20 (20) 6 (6) 6 (6) (44) 29 (33) 10 (11) 9 (10) 1 (1) 0 (0) Median % Decrease from in Seizure Frequency N= Escalation Maintenance Entire Treatment Period (35) 28 (31) 17 (19) 9 (10) 1 (1) 3 (3) n Median n Median Safety Results: An on-therapy adverse event was defined as an adverse event with onset on or after the start date of study medication but not later than one day after the last date of study medication. An on therapy serious adverse event was defined as a serious adverse event with onset on or after the start date of study medication and up to 30 days after the last dose of medication. Subjects with any Adverse Events, n(%) 108 (82) 115 (85) Most Frequent Adverse Events On-Therapy 7

8 Adverse Events Reported in >5% of Patients in Either Treatment Group N= n (%) n (%) Headache 42 (32) 34 (25) Dizziness 17 (13) 21 (15) Nausea 14 (11) 13 (10) Fatigue 10 (8) 15 (11) Somnolence 7 (5) 16 (12) Nasopharyngitis 8 (6) 13 (10) Irritability 8 (6) 13 (10) Rash 8 (6) 9 (7) Pharyngolaryngeal pain 11 (8) 4 (3) Vomiting 11 (8) 4 (3) Insomnia 8 (6) 6 (4) Depression 4 (3) 8 (6) Sinusitis 3 (2) 8 (6) Toothache 3 (2) 8 (6) Serious Adverse Events - On-Therapy Subjects with non-fatal serious adverse events, n (%) [drug-related] 3 (2) [0] 9 (7) [0] Dehydration 1 (<1) [0] 2 (1) [0] Failure to thrive 0 (0) [0] 1 (<1) [0] Congestive cardiac failure 1 (<1) [0] 1 (<1) [0] Myocardial infarction 0 (0) [0] 1 (<1) [0] Breast cancer 0 (0) [0] 1 (<1) [0] Malignant lung neoplasm 1 (<1) [0] 0 (0) [0] Malignant neoplasm 0 (0) [0] 1 (<1) [0] Balance disorder 0 (0) [0] 1 (<1) [0] Convulsion 0 (0) [0] 1 (<1) [0] Abdominal pain 1 (<1) [0] 0 (0) [0] Nausea 1 (<1) [0] 0 (0) [0] Vomiting 1 (<1) [0] 0 (0) [0] Pneumonia 0 (0) [0] 1 (<1) [0] Uncontrolled diabetes mellitus 0 (0) [0] 1 (<1) [0] Confusional state 1 (<1) [0] 0 (0) [0] Dyspnea 1 (<1) [0] 0 (0) [0] Subjects with fatal serious adverse events, n (%) [drug-related] 1 (<1) [0] 0 (0) [0] Injury- Asphyxiation 1 (<1) [0] 0 (0) [0] Conclusion: Subjects receiving lamotrigine had a statistically significant improvement relative to levetiracetam as measured by the Anger-Hostility subscale score of the Profile of Mood States (POMS). In the lamotrigine group 108 subjects reported adverse events with the most frequently reported being headache and dizziness. In the levetiracetam group 115 subjects reported adverse events with the most frequently reported being headache and dizziness. Three subjects reported serious adverse events in the lamotrigine group and one subject experienced a fatal serious adverse event (reported by investigator to not be drug-related). Nine subjects reported serious adverse events in the levetiracetam group, none was fatal. 8

9 Publications: No Publication Date Updated: 08-May