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. GSK Medicine: Lamotrigine Study Number: LAM115376 Title: A multi-center, uncontrolled, open-label, evaluation of lamotrigine monotherapy in subjects with newly diagnosed epilepsy or recurrent epilepsy (currently untreated) Rationale: Since current lamotrigine s indications are limited to adjunctive treatment of partial seizures (including secondary generalized seizures), tonic-clonic seizures and generalized seizures of Lennox-Gastaut syndrome in patients who have not responded to other antiepileptic drugs (AEDs) in Japan, this study was intended to evaluate the efficacy and safety of lamotrigine monotherapy in patients with newly diagnosed epilepsy and those with recurrent epilepsy (currently untreated). Phase: III in Japan, IV in South Korea Study Period: 20 September 2011-24 October 2014 Study Design: This study was planned and conducted as a multi-centre, uncontrolled, open-label study and consisted of the Escalation phase (6 weeks), Maintenance phase (24 weeks), Taper phase (2 weeks or more), and Post study examination was conducted within 1-4 weeks after the last dose of lamotrigine, and also only in Japan the Extension phase was conducted until either approval of this indication or after 24 months after LSLV (Last Subject s Last Visit) in the Maintenance phase, whichever came first. Centres: 13 medical institutions (11 in Japan and 2 in South Korea). Indication: Monotherapy for partial seizures (including secondary generalized seizures) and generalized tonic-clonic seizures Treatment: Lamotrigine tablets were administered once daily in the evening. If a tolerability issue occurred with evening dosing, it was possible to administer lamotrigine tablets in the morning. Also the dose, when exceeding 200 milligram per day (mg/day), might be administered in two divided doses (in the morning and evening). Details of the dosage regimens for the Escalation and Maintenance phases were shown below. Phase Week Daily dose Number of tablets Dose regimen b Escalation 1-2 25 mg 25 mg 1 3-4 50 mg 25 mg 2 5-6 100 mg 100 mg 1 Once daily in the evening Maintenance 7-30 a 200 mg 100 mg 2 a. After Week 7, if there were safety concerns at 200 mg/day, the dose could be decreased to 100 mg/day by the investigator s (or subinvestigator s) judgment. Also, if seizures could not be controlled at the dose of 200 mg/day, the dose could be gradually increased up to 400 mg/day by 50-100 mg/day at intervals of at least 1 week. b. When the dose exceeded 200 mg/day during the Maintenance phase, lamotrigine could be administered in two divided doses (in the morning and evening). Taper phase: When the study was completed or discontinued, the dose was gradually tapered by about one half over a period of 2 weeks or longer. Extension phase (only in Japan): The investigational product was administered at 100-400 mg/day considering the subject s seizure status and safety. If the dose lower than 100 mg/day or higher than 400 mg/day was judged to be necessary, the subject was withdrawn from the study. Objectives: To evaluate the efficacy and safety of lamotrigine monotherapy in subjects with newly diagnosed partial seizures (including secondarily generalized seizures) or tonic-clonic seizures (primary generalized tonic-clonic seizures), or those with recurrent epilepsy (currently untreated) in Japan and South Korea. Primary Outcome (Endpoints)/Efficacy: Seizure free rate in the Maintenance phase (across seizure types and by seizure type within 6 months prior to the start of the study): [Number of subjects who complete the study and who have not experienced seizures in the Maintenance phase / Number of subjects who receive the investigational product]. Secondary Outcome (Endpoints)/Efficacy : Time to withdrawal/dropout from the study (across seizure types and by seizure type within 6 months prior to the start of the study) Time to first seizure in the Maintenance phase (across seizure types and by seizure type within 6 months prior to the start of the study) Statistical Methods: 1
The result from overseas study UK106 suggested a seizure free rate of 0.60 under treatment with 200 mg/day of lamotrigine. A sample size of 55 will produce a 95% confidence interval with the lower limit exceeding the threshold value of 0.40 with a probability greater than 80%. Based on this consideration, the target number of partial seizure subjects for analysis was set at 55. The threshold value was set based on PMDA s advice given at PMDA consultation. For generalized tonic-clonic seizure, the target number of subjects for analysis was set at 5 based on the feasibility. The Safety Population (SP) consists of all subjects who have taken at least one dose of investigational product. The Extension Safety Population (Ext-SP) consists of all subjects who entered Extension phase and have taken at least one dose of investigational product in the Extension phase. The Full Analysis Set (FAS), i.e., the population for efficacy analysis, consists of all subjects in the SP who have provided at least one efficacy data that were evaluable with respect to occurrence of seizure after the first dosing of investigational product. The PK Population was defined as a population of subjects whose pharmacokinetic sample (plasma) was obtained to be analyzed. No formal statistical comparisons were conducted because this study contains only a single treatment group. The planned first interim analysis was conducted after all subjects completed Maintenance phase. For the first interim analysis, data from the Escalation and Maintenance phases were analyzed, as one of the planned analyses. For this study, the planned analysis was conducted using data of the Escalation and Maintenance phases. The second interim analysis was conducted after all subjects complete Week 24 of the Extension phase or withdraw, using data up to Week 24 of Extension phase. Furthermore, the final analysis covered all data. The primary endpoint for this study is seizure free rate in the Maintenance phase (i.e., Number of subjects who complete the study and who have not experienced seizures in the Maintenance phase / Number of subjects who receive the investigational product), which was summarized along with associated 95% confidence intervals. Furthermore, the secondary endpoints time to withdrawal/dropout from the study and time from entering the Maintenance phase to first seizure in Maintenance phase were estimated, and the survival function for each endpoint was plotted using Kaplan-Meier method. The quartiles and associated 95% confidence intervals were estimated if calculable. Similar analyses by seizure type [ABC, partial seizure (including secondarily generalized seizure); AB, partial seizure (excluding secondarily generalized seizure); C, secondarily generalized seizure; D5, generalized tonicclonic seizure.] were also performed for these efficacy endpoints. Study Population: Subjects with newly diagnosed epilepsy or recurrent epilepsy which is untreated, having partial seizures (including secondarily generalization) or generalized tonic-clonic seizures; subjects having a confident diagnosis of epilepsy uncomplicated by pseudoseizures (psychogenic nonepileptic seizures); subjects having had at least 2 seizures in the previous 6 months with at least 1 seizure in the previous 3 months; outpatients aged 16 years at the time of obtaining consent who are able to write a seizure diary; subjects having no other seizure types than partial seizures or generalized tonic-clonic seizures with or without myoclonus; subjects having no status epilepticus within the 6 months prior to the start of study treatment; subjects without a history of treatment with antiepileptic drugs ( 2 weeks) during 6 months before the start of treatment with the investigational product; and subjects without a history of treatment with lamotrigine. Number of Subjects: Subjects Planned, N 60 65 Subjects Enrolled, N 67 Escalation phase Escalation + Maintenance phases n, (%) Subjects who completed Week 30 (Maintenance phase) 52 (78) 42 (63) Subjects withdrawn from the study by Week 30 15 (22) a 25 (37) a Main reasons for withdrawal Adverse events 11 (16) 16 (24) Lack of efficacy 1 (1) 5 (7) Deviations from protocol 1 (1) 1 (1) Meeting withdrawal criteria defined by protocol 0 1 (1) Discontinuation of study 0 0 Lost to follow-up 0 0 Investigator's judgment 0 0 Withdrawal of consent 2 (3) 2 (3) a. Includes subjects withdrawn from the study before the Escalation phase. Subjects who entered the Extension phase, N 22 n (%) Subjects who completed Week 24 of the Extension phase 19 (86) Subjects withdrawn from the study by Week 24 of the Extension phase 3 (14) Extension phase 2
Main reasons for withdrawal Adverse events 1 (5) Lack of efficacy 1 (5) Meeting withdrawal criteria defined by protocol 1 (5) Subjects Enrolled, N 67 n, (%) End of the Study Subjects who completed study 32 (48) Subjects withdrawn from the study 35 (52) Main reasons for withdrawal Adverse events 18 (27) Lack of efficacy 7 (10) Deviations from protocol 1 (1) Meeting withdrawal criteria defined by protocol 2 (3) Discontinuation of study 0 Lost to follow-up 0 Investigator's judgment 4 (6) Withdrawal of consent 3 (4) Demographics and Other Baseline Characteristics (SP) Sex, n (%) Female 26 (40) Male 39 (60) Age, n Mean (Standard Deviation [SD]) 37.3 (20.20) Median (min-max) 30.0 (16-85) Height (cm) Mean (SD) 165.1 (9.05) Median (min-max) 166.2 (147-185) Body weight (kg) Mean (SD) 63.01 (13.395) Median (min-max) 63.20 (37.5-105.0) Race, n (%) Asia-Japanese 39 (60) Asia-East Asians 26 (40) History of seizures, n (%) Subjects with newly diagnosed epilepsy 59 (91) Subjects with recurrent epilepsy 6 (9) Number of seizures during 6 months before initiation of study Seizure type ABC n 55 Mean (SD) 45.3 (99.78) Median (min-max) 5.0 (2-585) Seizure type D5 n 10 Mean (SD) 3.3 (1.57) Median (min-max) 3.0 (2-7) Primary Outcome Results: The seizure free rate (95%CI) in the Maintenance phase across seizure types N Subjects who completed the study without experiencing Seizure free rate seizures in the Maintenance phase (%) 95%CI 65 28 43.1 (30.85, 55.96) The seizure free rate (95%CI) in the Maintenance phase by seizure types Subjects who completed the study N Seizure type n without experiencing seizures in the Maintenance phase Seizure free rate (%) 95%CI 65 ABC 55 22 40.0 (27.02, 54.09) AB 42 17 40.5 (25.63, 56.72) C 33 23 69.7 (51.29, 84.41) D5 10 8 80.0 (44.39, 97.48) Secondary Outcome Results: Time to withdrawal/dropout from the study (across seizure types) Number of subjects withdrawal/dropout from the study 23 3
Time to withdrawal/dropout from the study Median (95%CI) - (-, -) 25% point (95%CI) 107.0 (30.0, -) Mean time (SE) 150.0 (8.99) Time to first seizure in the Maintenance phase (across seizure types) Lamotrigine (N=52) Subjects who had first seizure 20 Time to first seizure Median (95%CI) - (146.0, -) 25% point (95%CI) 19.0 (3.0, 151.0) Mean time (SE) 103.0 (9.43) Safety Results 1st Interim (Escalation + Maintenance phases): An on therapy adverse event (AE) was defined as an AE with onset on or after the start date of study medication but not later than the last date of the Maintenance phase (in case of withdrawal, the last date of study medication). An on therapy serious adverse event (SAE) was defined as a SAE with onset on or after the start date of study medication and up to the date of the Post study examination. Most Frequent Adverse Events On-Therapy: The most frequent events in total are shown as below. Subjects with any AEs, n(%) 53 (82) Headache 14 (22) Nasopharyngitis 12 (18) Rash 7 (11) Nausea 6 (9) Dizziness 4 (6) Cough 3 (5) Drug eruption 3 (5) Dyspepsia 3 (5) Insomnia 3 (5) Memory impairment 3 (5) Rhinitis allergic 3 (5) Tinnitus 3 (5) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] n (%) [related] Subjects with non-fatal SAEs, n (%) 7 (11) [2] Gastrooesophageal reflux disease 1 (2) [0] Haemorrhoids 1 (2) [0] Intestinal obstruction 1 (2) [1] Sick sinus syndrome 1 (2) [0] Post procedural haemorrhage 1 (2) [0] Electrocardiogram QT prolonged 1 (2) [0] Decreased appetite 1 (2) [0] Epilepsy 1 (2) [0] Stevens-Johnson syndrome 1 (2) [1] Subjects with fatal SAEs, n (%) 0 Safety Results 2nd Interim (Extension phase): An on therapy AE was defined as an AE with onset on or after the start date of the Extension phase but not later than the last date of Week 24 of Extension phase (in case of withdrawal, the last date of study medication). An on therapy SAE was defined as a SAE with onset on or after the start date of Extension phase and up to the date of the Post study examination. Most Frequent Adverse Events On-Therapy: The most frequent events in total are shown as below. Lamotrigine (N=22) Subjects with any AEs, n (%) 10 (45) Nasopharyngitis 4 (18) Abdominal pain upper 2 (9) Contusion 2 (9) Headache 2 (9) 4
Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Lamotrigine (N=22) n (%) [related] Subjects with non-fatal SAEs, n (%) 1 (5) [0] Pulmonary contusion 1 (5) [0] Epilepsy 1 (5) [0] Subjects with fatal SAEs, n (%) 0 Safety Results - Final: An on therapy adverse event (AE) was defined as an AE with onset on or after the start date of study medication but not later than the last date of the Taper phase (in case of withdrawal, the last date of study medication). An on therapy serious adverse event (SAE) was defined as a SAE with onset on or after the start date of study medication and up to the date of the Post study examination. Most Frequent Adverse Events On-Therapy: The most frequent events in total are shown as below. Subjects with any AEs, n(%) 53 (82) Headache 14 (22) Nasopharyngitis 14 (22) Rash 8 (12) Nausea 6 (9) Abdominal pain upper 4 (6) Dizziness 4 (6) Drug eruption 4 (6) Contusion 3 (5) Cough 3 (5) Dyspepsia 3 (5) Epilepsy 3 (5) Insomnia 3 (5) Memory impairment 3 (5) Rhinitis allergic 3 (5) Tinnitus 3 (5) Toothache 3 (5) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] n (%) [related] Subjects with non-fatal SAEs, n (%) 8 (12) [2] Epilepsy 2 (3) [0] Gastrooesophageal reflux disease 1 (2) [0] Haemorrhoids 1 (2) [0] Intestinal obstruction 1 (2) [1] Post procedural haemorrhage 1 (2) [0] Pulmonary contusion 1 (2) [0] Sick sinus syndrome 1 (2) [0] Electrocardiogram QT prolonged 1 (2) [0] Decreased appetite 1 (2) [0] Stevens-Johnson syndrome 1 (2) [1] Subjects with fatal SAEs, n (%) 0 Pharmacokinetic Results (plasma concentration of lamotrigine): Time since the nearest Investigational Product Dose Number of Subjects in each Category n Mean 95%CI SD Median Min Max Overall (N=65) 0< 24 hour (h) 53 53 4.55 (3.83, 5.27) 2.600 4.06 0.3 13.3 24< 48 h 6 6 1.92 (-0.08, 3.92) 1.906 1.13 0.5 5.5 5
48< 72 h 2 2 1.30 (-11.88, 14.47) 1.467 1.30 0.3 2.3 72< 96 h 1 1 0.99 - - 0.99 1.0 1.0 96< 120 h 1 1 0.28 - - 0.28 0.3 0.3 168< 192 h 1 0 a - - - - - - 600< 624 h 1 0 a - - - - - - a: The concentration of 2 subjects categorized in 168< 192 h and 600< 624 h was <0.050 μg/ml. Conclusion: The seizure free rate (95%CI) in the Maintenance phase for all seizure types was 43.1% (30.85-55.96). During the Escalation and Maintenance phases, 53 subjects reported AEs with the most frequently reported being headache (22%) and nasopharyngitis (18%). Non-fatal SAEs were reported in 7 subjects included gastrooesophageal reflux disease haemorrhoids, intestinal obstruction, sick sinus syndrome, post procedural haemorrhage, electrocardiogram QT prolonged, decreased appetite, epilepsy and Stevens-Johnson syndrome. During the Extension phase, 10 subjects reported AEs with the most frequently reported being nasopharyngitis (18%). Non-fatal SAEs were reported in 1 subject included pulmonary contusion and epilepsy. A total of 53 subjects reported AEs in this study. The most frequently reported AEs were headache (22%) and nasopharyngitis (22%). Non-fatal SAEs were reported in 8 subjects included epilepsy, gastrooesophageal reflux disease, haemorrhoids, intestinal obstruction, sick sinus syndrome, post procedural haemorrhage, electrocardiogram QT prolonged, decreased appetite, pulmonary contusion and Stevens-Johnson syndrome. There were no fatalities reported up to the Post study examination. 6