Protocol Amendment 1, dated 21 Jul 2015, provided the following key changes. The primary purpose of this substantial amendment was to provide further clarification regarding the design of the study, the definition of the clinical situation in which a study participant was qualified for enrollment in this study, and the pharmacokinetic(s) (PK) assessments in accordance with the United States (US) Food and Drug Administration (FDA) request. It was clarified that this study enrolls approximately 75 study participants ≥4 to <17 years of age and that another Phase 2/3 study was planned to investigate the use of intravenous (iv) lacosamide (LCM) in study participants with epilepsy ≥1 month to <4 years of age. EP0060 initially enrolled older pediatric study participants (Cohort 1), which includes at least 20 study participants ≥12 to <17 years of age. After the first 10 study participants in each cohort completed their iv LCM treatment over infusion durations of 30 to 60 minutes, the enrollment was temporarily put on hold for the Independent Data Monitoring Committee (IDMC) to review the available safety and tolerability data. Additional changes were implemented for consistency with other protocols in the LCM pediatric program. Furthermore, administrative changes including the update of the study team and update of the Sponsor Declaration were made. At the time of approval of this amendment, no study participants were enrolled in EP0060.

Protocol Amendment 2, dated 30 Nov 2016, provided the following key changes. The primary purpose of this substantial amendment was to maximize the patient pool used in the evaluation of the safety of iv LCM in pediatric study participants. Thus, enrollment was opened to include open-label lacosamide (OLL) and prescribed lacosamide (RxL) study participants who are on a stable dose of oral LCM and elect to receive iv LCM as well as initiating intravenous lacosamide (IIL) study participants who are not currently taking LCM and initiate adjunctive LCM treatment using iv LCM. This amendment also included the option for RxL and IIL study participants to continue oral LCM treatment in SP848, if clinically appropriate, after completion of iv LCM in EP0060. Given this option for RxL and IIL study participants, 2 visits were added to the study design. If required, a Transition Visit was added for RxL and IIL study participants transitioning to SP848 and requiring up to 7 days for scheduling of additional assessments to be performed during EP0060. If not transitioning to SP848, an additional Safety Follow-Up (SFU) Telephone Contact Visit was added approximately 30 days after last infusion to collect final safety data. In order to provide treatment continuity, a short-term oral LCM solution may have been dispensed to RxL and IIL study participants eligible for SP848 enrollment in the event that additional time was needed to schedule the Transition Visit. Enrollment from EP0012 was removed as well as enrollment from future pediatric studies.

- Continuation 1 - The study design was changed to merge the previous Cohort 1 (≥12 to <17 years of age) and Cohort 2 (≥8 to <12 years of age) into 1 cohort spanning the age range of ≥8 to <17 years of age while maintaining the combined planned enrollment for this age group. The decision to combine these 2 age groups was supported by the following 3 considerations: PK modeling, growth chart information, postmarketing safety assessment of iv LCM use, and a recent publication (Arkilo, et al 2016). • In the oral and iv LCM PK pediatric modeling CL0266, simulations of iv LCM infused over durations of 15 to 60 minutes suggested that exposure was similar to oral administration. These results were consistent with the LCM PK profile and bioequivalence of iv and oral LCM established in adults. Thus, using the weight-based dosing adaptations for LCM adjunctive therapy, it was predicted that the LCM concentration at steady-state in pediatric study participants with partial-onset seizures would be similar to that in adults for both oral and iv LCM. Based on the PK modeling, the use of iv LCM was expected to be safe in the pediatric patient population down to 4 years of age. • Based on the Centers for Disease Control and Prevention (CDC) growth charts for weight-for-age percentiles (2 years to 20 years of age), the ages at which a child reaches the 50th percentile at a weight of 50kg are 13.82 years for boys and 14.21 years for girls (http://www.cdc.gov/growthcharts, 2000). Therefore, average pediatric patients weighing 50kg are approximately 2 to 3 years younger than the currently approved lower limit for age for VIMPAT (16 years [EU] or 17 years [US]). Based on PK modeling, LCM exposure in pediatric study participants weighing 50kg or more was predicted to be the same as exposure observed in adults. 

- Continuation 2 - • Postmarketing data were evaluated for the period from 01 Aug 2008 to 30 Nov 2015, and 49 cases were identified for iv LCM formulation use in the pediatric population (in patients 4 to <16 years of age). Based on review of these cases, no new safety concerns were identified. • Arkilo and colleagues examined use of iv LCM in 47 infants and children from 4 months to <12 years of age, and this study included use in nonapproved indications (ie, status epilepticus) (Arkilo, et al 2016). Evaluation of adverse effects was not possible for the 11 study participants in status epilepticus. Five of remaining 36 study participants experienced sedation, and no new safety concerns were noted in this evaluation. Taken together, along with current knowledge of the safety of oral LCM in children down to 4 years of age, enrollment of children ≥8 to <17 years of age within the same cohort were expected not to present a significant safety risk and to allow earlier benefit of access to the iv LCM option of treatment for those study participants who were ≥8 to <12 years of age. Initiation of the assessment of safety in patients ≥4 to <8 year olds remained dependent on review of safety data from Cohort 1 by the IDMC. To accommodate these changes, revisions were made to the inclusion/exclusion criteria, schedule of assessments, LCM dosing, and statistical analyses. Additional changes were implemented for consistency with other protocols in the LCM pediatric program and updated language in protocol template regarding monitoring for potential drug-induced liver injury (PDILI) events. Furthermore, administrative changes including the update of the study team were made. At the time of approval of this amendment, no study participants were enrolled in EP0060.

Protocol Amendment 3, dated 30 Apr 2018, provided the following key changes. The primary purpose of this substantial amendment was to lower the age of study participants from ≥4 years to ≥1 month in an effort to maximize the study participant pool in the evaluation of iv LCM, to include age stratification within Cohort 2 to be most informative with regard to safety and PK, and to increase study enrollment from 75 to 100 study participants to reflect the inclusion of study participants down to 1 month of age. Since the initial conception of the study, substantial new safety and efficacy information on the lowest age group (≥1 month to <4 years of age) was published. The available safety information consisted of postmarketing data (n=27 patient cases), data from internal studies (n=15 patient cases), as well as from 2 published reports (n=15 and n=22 patient cases) (Arkilo et al, 2016; Welsh et al, 2017, respectively). These reports covered the age range from ≥1 month to <4 years of age and also covered the clinical spectrum from an open-label extension study with oral treatment to critical care patients receiving iv treatment. This data pointed to no specific risks in the age group after administration of VIMPAT and UCB, therefore, believed it was justified to open Cohort 2 to the lowest age group in agreement with the IDMC outcome on safety of Cohort 1. To accommodate these changes, revisions were made to the inclusion/exclusion criteria, schedule of assessments, LCM dosing, and statistical analyses. Additional changes included the following: • Study contact information was updated as applicable. • Additional region to maximize enrollment was included. • Number of study participants included in the IDMC process in Cohort 2 was modified. • The timing of the End-of-Study/Final Visit was clarified. • Wording regarding the taper of LCM for IIL study participants who discontinue use was removed. • US and EU regulatory authority approvals of LCM were updated.

- Continuation 1 - • Pharmacokinetic variables were further defined as “Other”. • Bicarbonate testing was optional for study participants weighing less than 8kg. • New inclusion criterion was added for all study participants. • New exclusion criterion was added for RxL and IIL study participants. • Oral LCM was to be administered approximately 12 hours after the final iv LCM infusion was clarified. • Potential drug-induced liver injury language was updated to most current UCB template. • List of hematology PDILI laboratory measurements was updated. • List of chemistry PDILI laboratory measurements was updated. • Clarification was added regarding the reading of 12-lead electrocardiogram (ECG). • Definitions of analysis sets were modified. • Data presentations for planned PK and safety analyses were revised. • Minor typographical errors and clarifications were made and are not listed in the summary of changes.