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 trials 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 trials.

Based on the analysis of SP847 Cohort 1 (study participants aged 5 to 11 years) safety and PK data, the maximum permitted LCM dose in SP848 was 12mg/kg/day (for study participants weighing up to 50kg) or 600mg/day (for study participants weighing >50kg). The decision to re-insert additional withdrawal criteria and follow-up recommendations for abnormal LFTs was based on the following: 1. Newly adopted FDA Guidance on Drug-Induced Liver Injury (July 2009) and a recommendation from the FDA to re-insert previously included wording regarding additional withdrawal criteria and follow-up recommendations for abnormal LFTs in LCM protocols. 2. Although no new liver-related safety issues with LCM had been identified, LFT abnormal had been added as a postmarketing adverse drug reaction in the LCM Company Core Data Sheet and the EU Summary of Product Characteristics. Therefore, LCM protocols were amended to reflect this addition. With these revisions, liver-related safety signals continued to be detected via protocol-directed monitoring and additional follow up in ongoing and future LCM clinical studies. In addition, the protocol was revised to allow enrollment of study participants who had participated in other future LCM pediatric clinical studies in epilepsy (ie, in addition to SP847) to provide the opportunity to continue receiving LCM treatment in SP848.

The sponsor’s name was changed from SCHWARZ to UCB BIOSCIENCES, INC. Specific sponsor contact information was updated. As recommended by FDA, text was added or modified to make it clear that maximum permitted LCM dose in SP848 was 12mg/kg/day or 600mg/day, whichever was lower. As recommended by FDA, Columbia-Suicide Severity Rating Scale (C-SSRS) was added to evaluate and identify study participants at risk for suicide while participating in a clinical study of a drug with CNS activity. Oral solution formulation of LCM used in this study was revised to contain 10mg/mL of drug substance (formerly containing 15mg/mL of drug substance). UCB, in agreement with the Committee for Medicinal Products for Human Use, initiated the recall of VIMPAT syrup 15mg/mL due to a quality defect related to the formation of a flake-like precipitate of LCM in the syrup. UCB received approval for a 10mg/mL syrup; thus, all study participants in study were transitioned to LCM 10mg/mL. Also, UCB did not receive any reports from investigative sites of the appearance of these flake-like precipitants in the clinical trial supplies of LCM 15mg/mL syrup formulation used in SP848. All study participants were required to have a 12-lead ECG conducted at LCM maximum plasma concentration (Cmax) 1 week after an initial LCM dose increase. This ECG could have been conducted at an unscheduled visit, if necessary. These participants were required to arrive at the clinic prior to taking their morning dose of LCM. Participants were administered their morning LCM dose by study personnel at the clinic so that an ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to vital signs assessment) could be performed 30 minutes to 1 hour after administration of LCM (ie, at LCM steady state Cmax). A list of SAEs was included in this amendment in compliance with recent US FDA guidance on safety reporting requirements for studies conducted under an open Investigational New Drug Application.

Selected sites were permitted to directly enroll in SP848 up to approximately 100 eligible pediatric study participants ≥4 to ≤17 years of age with POS (deemed appropriate for treatment with adjunctive LCM) who had not previously participated in a LCM clinical study. The purpose of enrolling these study participants directly into SP848 was to obtain sufficient long-term safety exposures in the age range of ≥4 to ≤17 years of age; the additional long-term safety data were to be included in planned regulatory submissions for LCM as adjunctive therapy for POS in pediatric study participants aged 4 years and above with epilepsy. Based on regulatory agency recommendations to include scales to measure development and cognition, the Achenbach Child Behavior Checklist (CBCL); Bayley Scales of Infant and Toddler Development®, Third Edition (Bayley®-III); and Tanner Scale were selected by UCB and added as assessments in SP848. In addition, a LCM palatability and ease of use questionnaire was added to the study assessments.

In the FDA Division of Neurology Products’ 06 Aug 2012 Request for Information regarding SP847 Protocol Amendment 5, the Agency recommended that UCB revise an inclusion criterion to require the use of more than 1 AED as monotherapy before initiating adjunctive LCM therapy in SP847. UCB made this recommended change in the SP847 protocol (Amendment 6). In alignment with SP847, Inclusion Criterion 7 was modified to require that each study participant in SP848 have had uncontrolled POS after an adequate course of treatment (in the opinion of the investigator) with at least 2 AEDs (concurrently or sequentially). Inclusion Criterion 7 applied only to study participants who enrolled directly into SP848 without previous participation in a LCM clinical study. The Behavior Rating Inventory of Executive Function® (BRIEF®)/Behavior Rating Inventory of Executive Function®-Preschool Version (BRIEF®-P), Pediatric Quality of Life Inventory (PedsQL™), and health care resource use were added as assessments in SP848.

The primary purpose of this protocol amendment was to permit enrollment of up to approximately 75 eligible pediatric study participants ≥4 to <17 years of age with POS (deemed appropriate for treatment with LCM) who had previously participated in the iv LCM clinical study EP0060. The purpose of enrolling these study participants was to obtain additional long-term safety exposures in the age range of ≥4 to <17 years of age; the additional long-term safety data were submitted on 30 Apr 2020 and 15 May 2020 to the LCM iv and tablet New Drug Applications, respectively. Of note, EP0060 was further amended (Protocol Amendment 3; 30 Apr 2018) to allow enrollment of up to 100 study participants ≥1 month to <17 years of age, all of whom could rollover into SP848. Sponsor language for monitoring of PDILI events was added to increase clarity for the sites and to align across programs. Addition of this language was to align with FDA guidance regarding monitoring of PDILI events and did not reflect a change in the liver safety signal for LCM. In addition, Exclusion Criterion 16, which excluded use of vigabatrin or felbamate, was removed.

This administrative amendment fixed the numbering of the exclusion criteria that resulted from the removal of Exclusion Criterion 16 in Protocol Amendment 6.

The primary purpose of this protocol amendment was to align with modifications made to the Paediatric Investigation Plan. Changes included: • A new categorization for main primary and secondary endpoints key binding element was proposed to ensure reporting compliance with registries (European Union Drug Regulating Authorities Clinical Trials Database, clinicaltrials.gov). This categorization did not affect the type or processing of data collected and reported in the study report, which were assessed as initially planned. • Further clarification was provided for the study duration as well as the wording and categorization of the primary, secondary, and other variables. In addition, language specifying applicable study conduct modifications due to the coronavirus disease 2019 (COVID-19) pandemic was added.