Global Protocol Amendment 1 dated 13 Dec 2010 provided the following primary and other key revisions. No subjects were randomized prior to the date of this amendment. The primary purpose of this substantial protocol amendment was to add an exclusion criterion for known sodium channelopathy and revise withdrawal criteria and follow-up recommendations for abnormal liver function tests (LFTs). The rationales for these changes are described below. The decision to exclude subjects with known channelopathies, such as Brugada syndrome, from clinical studies with Lacosamide (LCM) was based on a recommendation from the US FDA (17 Aug 2010). The basis for this request was a theoretical concern that enhanced slow inactivation of sodium channels by LCM may be proarrhythmic in subjects with sodium channelopathies. 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 US 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 have been identified, LFT abnormal has been added as a postmarketing adverse drug reaction in the LCM Company Core Data Sheet (CCDS) and the EU Summary of Product Characteristics (SmPC). Therefore, LCM protocols are being 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.

Other key revisions included the following: - Clarification that minors were included in some countries if legally permitted - Addition of language with regard to male contraception - Clarification of the guidance followed in the analysis of the primary efficacy variable - Change of the Screening Phase from 7 days ±2 days to 7 days ±5 days - Removal of the desmethyl metabolite of LCM from bioanalytical analysis - Clarification that the fasting period prior to blood sample collection for additional laboratory tests (fasting serum lipid levels and thyroid and sex hormone concentrations) should be 8 hours - Further clarification for the sites The remainder of the changes in this amendment were minor or administrative in nature.

Global Protocol Amendment 2, dated 18 Nov 2011 provided the following key revisions. A total of 61 subjects (32 subjects and 29 subjects in the LCM and CBZ-CR treatment groups, respectively) were randomized prior to the date of this amendment. The primary purposes of this substantial protocol amendment were to revise the exclusion criteria related to a history of suicidality and to add withdrawal criteria related to suicidality. The rationale for these changes is described below. As required 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, 2010). The sponsor’s name was also changed to UCB BIOSCIENCES GmbH, and specific Sponsor contact information was updated. The remainder of the changes in this amendment were minor or administrative in nature.

Global Protocol Amendment 3, dated 01 Aug 2012 provided the following key revisions. A total of 206 subjects (103 subjects and 103 subjects in the LCM and CBZ-CR treatment groups, respectively) were randomized prior to the date of this amendment. The primary purpose of this substantial protocol amendment was to provide clarification for the efficacy variables, withdrawal criteria (eg, following a seizure that occurred after dose reduction), and the use of concomitant medications that may have interacted with study medication. The remainder of the changes in this amendment were minor or administrative in nature.

Global Protocol Amendment 4, dated 27 Nov 2012 provided the following key revisions. A total of 313 subjects (156 subjects and 157 subjects in the LCM and CBZ-CR treatment groups, respectively) were randomized prior to the date of this amendment. With the expansion of SP0993 to investigational sites in the US, and based on a request from the US FDA, a primary purpose of this substantial protocol amendment was to include language that reflected the FDA’s requirements. Exclusion criterion 11 (regarding prior treatment of epilepsy with any antiepileptic drug (AED)) was modified to indicate that acute and subacute seizure treatment was accepted with a maximum of 2 weeks duration and if treatment was stopped “at least 3 days prior to randomization” formerly “at least 1 week before Visit 1”). This change decreased the duration of time during which subjects could potentially go untreated before initiating study medication in SP0993, therefore increasing subject safety. Most withdrawal seizures were expected to occur within 72 hours of AED withdrawal, and most AEDs (including benzodiazepines) were expected to be cleared within this time period with little potential for drug interactions. A withdrawal criterion was clarified for situations in which a subject experienced a seizure during the Evaluation Phase at the maximum dosage of study medication. Section 7.8.3.4 of the protocol (Permitted agents whose plasma levels may be affected by CBZ) was updated with the addition of alprazolam and the deletion of amitriptyline (amitriptyline use as an antidepressant is disallowed in Section 7.8.2 of the Protocol). The remainder of the changes in this amendment were minor or administrative in nature.

Global Protocol Amendment 5, dated 14 Mar 2013 provided the following key revisions. This amendment was submitted only to local ethic committees in Spain and was not implemented by any site, therefore, no subjects were randomized under this amendment. Human leukocyte antigen (HLA)-A*3101 is associated with an increased risk of CBZ-induced cutaneous adverse drug reactions in people of European descent and the Japanese. Although there are insufficient data supporting a recommendation for HLA-A*3101 screening before starting CBZ treatment (Tegretol Prolonged Release 200mg, SmPC of Carbamazepine-United Kingdom; Drug Safety Update Dec 2012, vol 6, issue 5: A1), the protocol was updated based on a recommendation from the Japanese regulatory authorities (Pharmaceuticals and Medical Devices Agency [PMDA]) to exclude subjects of Asian ancestry who tested positive for the HLA-A*3101 allele. This was in addition to the exclusion of subjects of Asian ancestry who tested positive for the HLA-B*1502 allele. Screening of subjects of Asian ancestry for the HLA-A*3101 allele was previously included in a country-specific protocol amendment (Protocol Amendment 4.2 [Japan]) and was then incorporated with the global Protocol Amendment 5.

Contraceptive measures for male participants (exclusion criterion 30) were deleted because preclinical studies did not find any LCM-related findings at any dose level on male reproductive function. Lacosamide did not show any effects on reproductive function in male rats and no abnormalities in the F1 offspring of male rats were observed in peri-postnatal study. Female contraception requirements (exclusion criterion 27) were adjusted based on World Health Organization (WHO) guidance on highly effective methods of contraception for women of childbearing potential taking enzyme-inducing AEDs (WHO, 2010). In Section 7.8.2 of the protocol (Concomitant non-AED treatments), text regarding antidepressant and neuroleptic use was modified to permit the introduction of antidepressants (eg, serotonin-selective reuptake inhibitors [SSRIs]) that do not cause drug interaction issues and do not interfere with epilepsy therapy. In Section 7.8.3.4 of the protocol (Permitted agents whose plasma levels may be affected by CBZ), alprazolam was removed as a permitted medication. This change was made in order to be consistent with other sections of the protocol that limit the use of benzodiazepines. The remainder of the changes in this amendment were minor or administrative in nature.

Global Protocol Amendment 6 dated 20 May 2013 included all of the changes in Protocol Amendment 5 and also provided the following key revisions. A total of 476 subjects (239 subjects and 237 subjects in the LCM and CBZ-CR treatment groups, respectively) were randomized prior to the date of this amendment. In Section 7.8.2 of the protocol (Concomitant non-AED treatments), the following sentence was deleted in this amendment: “Oral contraceptive use is allowed if ethinylestradiol dosage is at least 50 μg per intake.” This correction was made to be consistent with exclusion criterion 27 that no longer required a minimum dosage of ethinylestradiol (modification in global Protocol Amendment 5).