Protocol Amendment 1 dated 18 Oct 2007 provided the following key changes. Based on the date of the amendment, 1 subject was randomized prior to this amendment. The wording “post-Baseline” was removed from the definitions of exit criteria 1 and 2 to avoid confusion since all exit criteria were defined relative to the start of the withdrawal of Background AEDs. In addition, the wording “the highest” was removed from the definition of exit criterion 2 because the assessment of exit criterion 2 was based on the earliest occurrence of a doubling in the 2-day seizure frequency during the Maintenance Phase. A sentence was added describing a calculation worksheet that was provided to site personnel to assist with the calculation of average seizure frequency for determination of whether a subject had met exit criterion 1, 2, 3, or 5 (refer to Section 6.2.1 of the protocol). Eight inclusion and exclusion criteria (inclusion criteria #6, #7, #8, and #9, and exclusion criteria #3, #6, #8, and #22) were revised to improve clarity or further define the criteria, based on the original intent. Two exclusion criteria (#11 and #12) were modified to correct omissions in the original criteria. Five exclusion criteria (#9, #10, #11, #14, and #29) were modified and two exclusion criteria (#31 and #32) were added to further exclude specific populations considered inappropriate for a conversion to monotherapy study. The criteria for withdrawal of a subject requiring a modification to the AED dose(s) between Visit 1 and Visit 5 was changed to between Visit 1 and Visit 6.

If concomitant narcotic use became necessary, the investigator was instructed to contact the medical monitor; restrictions in concomitant AED or benzodiazepine use were clarified (refer to Section 4.6 of the protocol). A revision was made to clarify that 1 dose reduction was allowed once the subject had taken at least 1 dose of Maintenance Phase study medication (refer to Section 8.1.1 of the protocol). A clarification was made regarding the prediction interval for an estimate of the combined pseudo-placebo exit rate (the lower 95% prediction interval was changed to the lower limit of a 2-sided 95% prediction interval), and the statement that the 95% prediction interval for the historical control provides 95% confidence that a single repeated study would yield a pseudo-placebo exit rate of 67.8% or higher was changed to a 97.5% confidence level (refer to Section 11.1.2 of the protocol). The remainder of the changes in this amendment were minor or administrative.

Protocol Amendment 2 dated 26 Sep 2008 provided the following key changes. Based on the date of the amendment, 44 subjects were randomized prior to this amendment. The secondary efficacy parameter, “duration of monotherapy treatment,” was changed to “during the Monotherapy Phase.” The statement regarding the Taper Phase (refer to Section 4.2 and Section 4.4.1 of the protocol) was modified to permit flexibility in the length of taper, based on discussion between the investigator and the medical monitor. Select inclusion, exclusion, and withdrawal criteria were revised (refer to Section 4.3 of the protocol). Exclusion criteria based on previous and current drug use (ie, ethosuximide, felbamate, vigabatrin) were detailed. The withdrawal criteria were differentiated into those that required subject discontinuation and those that may have resulted in subject discontinuation. The criterion for withdrawal of a subject requiring a modification to the AED dose(s) was changed from between Visit 1 and Visit 6 to between Visit 3 and Visit 6. The section on withdrawal of background AEDs was revised to allow for a slower taper of the primary background AED to ensure adequate safety for the subjects (refer to Section 4.6.1 of the protocol). The allowable window for Visit 12 was clarified to be at least 112 days between Visit 6 and Visit 12. Description of the Transition Phase was revised to clarify when reintroduction/initiation of background AEDs may begin (refer to Section 5.7 of the protocol).

Text was added to indicate details regarding calculations required for the assessment of exit criteria 1 and 2 (primary variables) in the statistical analysis plan (SAP) (refer to Section 11.1.2 of the protocol). Evaluation of explanatory variables was revised to clearly specify pre-planned analyses for evaluating the influence of potential differences in Baseline demographics between the LCM 400mg/day group and the historical-control population (refer to Section 11.1.3.2 of the protocol). In the statistical analysis of secondary variables, text was revised to clarify the duration of monotherapy treatment was during the Monotherapy Phase and treatment-emergent adverse events (TEAEs) would be tabulated by Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC; refer to Section 11.1.4 of the protocol). A statement was added regarding the evaluation of the impact of missing values on the assessment of Primary efficacy using sensitivity analyses (refer to Section 11.1.7 of the protocol). The remainder of the changes in this amendment were minor or administrative.

Protocol Amendment 3 dated 21 Jan 2010 provided the following key changes. Based on the date of the amendment, 144 subjects were randomized prior to this amendment. Text associated with primary efficacy exit criterion 1 was deleted as recommended by the Food and Drug Administration (FDA) through review of the SAP for this study. Detail was added to the protocol to allow subjects who, in consultation with the investigator, choose to initiate treatment with commercially available LCM upon completion of or withdrawal from the study, to do so without taper. The ECG- and cardiac-related exclusion and withdrawal criteria, and liver function test (LFT) withdrawal criteria were revised across LCM studies to reflect the sponsor’s current understanding of the safety profile of LCM based on a comprehensive review of the data from clinical studies. Exclusion criteria regarding past use of LCM, past or current use of VNS, and suicidality were also revised to include subjects deemed appropriate for enrollment. 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 statistical methods were updated to clarify the evaluation of efficacy data for subjects who discontinue from the study due to non-exit criteria reasons. The remainder of the changes in this amendment was minor or administrative.

Protocol Amendment 4 dated 04 Aug 2010 provided the following key changes. Based on the date of the amendment, 203 subjects were randomized prior to this amendment. Based on the recent publication of French et al (2010) noting a revised historical-control exit rate (0.653) relative to the French et al (2005) draft of the White Paper (0.678), the historical-control exit rate and sample size were updated. The remainder of the changes in this amendment were minor or administrative.

Protocol Amendment 5 dated 07 Jan 2011 provided the following key changes. Based on the date of the amendment, 258 subjects were randomized prior to this amendment. The primary purposes of this protocol amendment were to modify an exclusion criterion regarding prior use of LCM, to add an exclusion criterion for known sodium channelopathy, and to revise withdrawal criteria and follow-up recommendations for abnormal LFTs. The rationales for these changes are described below. The decision to exclude subjects with prior use of LCM beyond a single iv administration for acute treatment was based on an FDA recommendation (16 Dec 2010). The decision to exclude subjects with known channelopathies, such as Brugada syndrome, from clinical studies with LCM was based on an 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. The decision to reinsert additional withdrawal criteria and follow-up recommendations for abnormal LFTs was based on the following: Newly adopted FDA Guidance on Drug-Induced Liver Injury (Jul 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.

Although no new liver-related safety issues with LCM were identified, LFT abnormality was 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. The remainder of the changes in this amendment were minor or administrative.

Protocol Amendment 6 dated 22 Jul 2011 provided the following key changes. Based on the date of the amendment, 320 subjects were randomized prior to this amendment. The primary purposes of this protocol amendment were to revise the exclusion criterion related to a history of suicidality, add a withdrawal criterion related to suicidality, add a list of anticipated serious adverse events (SAEs), and to add a third category of AEs to be reported immediately on occurrence. The rationale for these changes is described below. As recommended by the US FDA, the Columbia-Suicide Severity Rating Scale (C-SSRS) was added to evaluate and identify subjects at risk for suicide while participating in a clinical study of a drug with central nervous system (CNS) activity (FDA, Guidance for Industry and Investigators, 2010). A list of anticipated SAEs was included in this amendment in compliance with the recent US FDA guidance on safety reporting requirements for studies conducted under an open IND (effective 28 Mar 2011; FDA, Guidance for Industry and Investigators, 2010). To meet the requirements of safety reporting and for consistency with the safety reporting currently being done for LCM “suspected transmission of an infectious agent via a medicinal product” was included as a further category of AEs to be reported immediately on occurrence. The remainder of the changes in this amendment were minor or administrative.