A Single-dose Reduction and Early Termination Protocol Clarification document was attached as a supplement to the protocol. In general, this attachment clarified that if a subject had a dose reduction, he/she would have been terminated early from the study after sufficient PK data were collected. The AEs of special interest were revised to reflect the Sponsor’s current understanding of the potential risks of LCM based on a comprehensive review of the data from clinical studies and commitments to regulatory agencies. The liver function test (LFT) withdrawal criteria were revised to reflect the Sponsor’s current understanding of the safety profile of LCM based on a comprehensive review of the data from clinical studies.

The study was expanded to include approximately 25 investigational sites in the USA and Mexico, with the possibility to extend to other countries if deemed necessary. The clinic visit at Day 6 (including the overnight hospitalization) was made optional for additional subjects in Cohort 1 and for all subjects in Cohorts 2, 3, and 4; subjects in these cohorts were permitted to have all Visit 3 procedures performed during a clinic visit on Day 7. The clinic visit (including the overnight hospitalization) at Day 27 (Visit 5, if the maximum recommended dose did not exceed LCM 8mg/kg/day), Day 34 (Visit 6, if the maximum recommended dose was LCM 10mg/kg/day), or Day 41 (Visit 7, if the maximum recommended dose was LCM 12mg/kg/day) was also optional for those subjects in Cohort 1 (additional subjects), Cohorts 2, 3, and 4 who were not expected to provide urine samples for pharmacokinetic (PK) analysis (eg, subjects aged <5 years); these subjects were permitted to have all Visit 5, Visit 6, or Visit 7 procedures performed during a clinic visit on the second day of each of these scheduled visits (ie, Day 28, Day 35, or Day 42). The analysis of PK data from Cohort 1 was clarified. Subjects in Cohort 1 who did not achieve a maximum dose of LCM 8mg/kg/day because of tolerability issues, but did complete the Treatment Period (ie, the collection of blood samples for PK analysis during Visit 3 and Visit 5 [or the Early Termination Visit]) contributed toward the 6 subjects needed for the determination of the maximum recommended dose for subsequent cohorts. Completion of the Treatment Period was defined as any subject who achieved steady-state at LCM ≥4mg/kg/day and completed the Early Termination Visit or Visit 5 procedures.

The primary purposes of this protocol amendment were to include an additional cohort (now designated as Cohort 5) of subjects aged ≥1 month to <2 years, to define an absolute maximum dose of LCM 600 mg/day to be received by subjects in the study, to add an exclusion criterion for known sodium channelopathy, and to revise withdrawal criteria and follow-up recommendations for abnormal Liver Function Tests (LFTs). The rationales for these changes are described below. An additional cohort (now designated as Cohort 5) of 12 subjects aged ≥1 month to <2 years was included in the study. The addition of the younger subjects in Cohort 4 (previously planned for a separate clinical study of similar design) was to permit an earlier assessment of LCM PK and determination of dosing in pediatric subjects before initiating Phase 3 pediatric studies. Based on the analysis of SP847 Cohort 1 (subjects aged ≥5 to 11 years) safety and PK data, the maximum permitted LCM dose in SP847 Cohorts 2 to 5 was LCM 12 mg/kg/day (for subjects weighing up to 50 kg) or LCM 600 mg/day (for subjects weighing >50 kg). The decision to exclude subjects with known channelopathies, such as Brugada syndrome, from clinical studies with LCM was based on a Food and Drug Administration (FDA) recommendation (17 Aug 2010). The basis for this recommendation was a theoretical concern that enhanced slow inactivation of sodium channels by LCM may be proarrhythmic in subjects with sodium channelopathies.

- Text was added or modified to make it clear that the maximum permitted dose in SP847 was LCM 12 mg/kg/day or LCM 600 mg/day, whichever was lower. - Columbia-Suicide Severity Rating Scale was added to evaluate and identify subjects at risk for suicide while participating in a clinical study of a drug with central nervous system activity. - Changed from LCM oral solution 15 mg/mL to LCM oral (syrup) solution 10 mg/mL due to a quality defect related to the formation of a flake-like precipitate of LCM in the 15 mg/mL syrup. - Beginning with Visit 5 (the visit at which subject had been on LCM 8 mg/kg/day for 6 to 7 days) and for subsequent visits, the remaining subjects enrolled into SP847 were required to arrive at the clinic prior to taking their morning dose of LCM. Subjects were administered their morning LCM dose by study personnel at the clinic so that an ECG could be performed 30 minutes to 1 hour after the administration of LCM. - A list of anticipated serious adverse events was included in this amendment in compliance with the USA FDA guidance on safety reporting requirements for studies conducted under an open Investigational New Drug Application. - The exclusion criterion limiting subjects who had a history of suicide attempt, had received professional counseling for suicidal ideation, or those who were currently experiencing suicidal ideation, was deleted.

The primary purpose of this protocol amendment was to reduce from 2 to 1 the required minimum total number of AEDs (current or past) to have been taken by subjects in Cohort 5 (subjects 1 month to <2 years of age). This change may have increased the number of subjects in Cohort 5 who were eligible for the study. It is possible that subjects in this youngest age range may not have received AEDs for a period of time long enough for >1 AED to have been used. In addition, the exclusion criterion limiting eligible subjects to those who were able to swallow or take food by mouth was deleted (Exclusion criterion 21). A result of this change is that subjects who had a feeding tube may have been eligible for enrollment in the study and may have received LCM oral solution via a feeding tube. Previous tests have demonstrated that the LCM oral solution is compatible with administration via a feeding tube.

In the FDA’s 06 Aug 2012 Request for Information regarding SP847 Protocol Amendment 5, the Agency recommended that UCB BIOSCIENCES revise inclusion criterion 6 to require the use of >1 AED as monotherapy before initiating adjunctive LCM therapy in SP847. In accordance with UCB BIOSCIENCES 29 Aug 2012 Response to Request for Information, the primary purpose of this protocol amendment was to modify inclusion criterion 6 to require for all subjects a minimum total of 2 antiepileptic drugs (AEDs) (current or past) before initiation of adjunctive treatment with LCM in SP847.

The primary purposes of this protocol amendment were to update the use of the Safety Set (SS), Full Analysis Set (FAS), Evaluable Set (EVS), and Pharmacokinetic Per-Protocol Set (PK-PPS) analysis sets for evaluation of safety, efficacy, and PK variables such that they reflect the planned analyses included in the Statistical Analysis Plan (SAP). Additional changes were made to clarify study procedures and variables for consistency across the protocol, SAP, and Pediatric Investigational Plan Final Opinion. The changes included in this amendment were administrative in nature and did not impact the treatment of subjects during the course of the study.