Protocol Amendment 1 dated 18 Oct 2007 provided the following key changes. Based on the date of the amendment, 26 subjects were enrolled at the time of the amendment. A clinic visit (scheduled or unscheduled) was added as a requirement for all LCM dose increases. This requirement was added because it was expected that a number of subjects entering SP904 would have been titrating to find their optimal LCM dose based on having recently met an exit criterion for SP902, and it would have been important for these subjects to increase their dose at clinic visits so that LCM tolerability was appropriately assessed. Text was added to Section 4.6 to clarify that if concomitant narcotic use became necessary, the investigator should have contacted the medical monitor to determine whether the subject should have continued participation in the study. A sentence was added to Section 4.6 stating that the use of vigabatrin, felbamate, and ethosuximide was prohibited throughout the study. This sentence was added because subjects taking vigabatrin, felbamate, and ethosuximide do not reflect an appropriate population for this study. 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, 66 subjects were enrolled at the time of the amendment. Throughout the clinical study protocol, information on the maximum duration of a subject’s study participation was clarified to be 2 years after Visit 1 in SP904, and if LCM was not available (eg, commercially) in a subject’s country 2 years after Visit 1 in SP904, access to LCM was to be ensured according to local laws. Criteria for withdrawal (Section 4.3.3) were differentiated into those requiring discontinuation and those that may have required discontinuation. Section 4.6 was modified to clarify when concomitant benzodiazepine use was permitted. 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, 23 subjects were enrolled at the time of the amendment. 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 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. Vagus nerve stimulation was added as a permitted concomitant treatment; subjects receiving VNS were deemed appropriate to include in the study. 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. Lacosamide has been classified as a controlled substance in the USA; thus, it was necessary to add a statement that the LCM label indicated class scheduling as a controlled substance. The remainder of the changes in this amendment were minor or administrative.

Protocol Amendment 4 dated 04 Aug 2010 provided the following key changes. Based on the date of the amendment, 43 subjects were enrolled at the time of the 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 change. Based on the date of the amendment, 42 subjects were enrolled at the time of the amendment. The primary purpose of this protocol amendment was to revise withdrawal criteria and follow-up recommendations for abnormal LFTs. The rationale for this change is described below. The decision to reinsert additional withdrawal criteria and follow-up recommendations for abnormal LFTs was based on the following: 1. Newly adopted Food and Drug Administration (FDA) Guidance on Drug Induced Liver Injury (Jul 2009) and a recommendation from the US FDA to reinsert 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 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 20 Jul 2011 provided the following key changes. Based on the date of the amendment, 122 subjects were enrolled at the time of the 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 AEs (SAEs), and 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 activity (FDA, Guidance for Industry and Investigator, 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 Investigational New Drug application (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.