ALEX-MT: Trial to Demonstrate the Efficacy and Safety of Conversion to Lacosamide Monotherapy for Partial-onset Seizures

• Sponsor: UCB BIOSCIENCES, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00520741
• Collaborator: (none)
• Enrollment: 426
• Locations: 158
• Arms: 2
• Duration (Months): 64
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The objective of this historical-controlled trial is to demonstrate the efficacy and safety of conversion to Lacosamide monotherapy in subjects with Partial-onset Seizures who are withdrawn from 1 to 2 marketed antiepileptic drugs.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: Lacosamide; Drug: Lacosamide	Phase 3

Detailed Description

Sudden unexplained death in epilepsy have been reported in epilepsy patients. A causal relationship with the administration of antiepileptic drugs has not been established. The most important known risk factor for sudden unexplained death in epilepsy (SUDEP) is the occurrence and frequency of generalized tonic-clonic seizures (GTCS). Twenty-seven patients with only GTCS were enrolled in the conversion to monotherapy study. In this study, two patients with only GTCS had SUDEP. Due to the potential increased risk of SUDEP in patients with only GTCS in a trial setting, the 1 remaining patient with only GTCS was withdrawn from this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 426 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Historical-controlled, Multicenter, Double-blind, Randomized Trial to Assess the Efficacy and Safety of Conversion to Lacosamide 400 mg/Day Monotherapy in Subjects With Partial-onset Seizures
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lacosamide 400 mg/day Lacosamide 400 mg/day	Drug: Lacosamide; 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks.; Other Names: Vimpat
Active Comparator: Lacosamide 300 mg/day Lacosamide 300 mg/day	Drug: Lacosamide; 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks.; Other Names: Vimpat

Outcome Measures

Primary Outcome Measures

1. Percentage of Subjects (Using Kaplan-Meier) Who Are Identified As Meeting At Least 1 Pre-defined Exit Criteria By Day 112 Relative To The Start of Withdrawal of Background Antiepileptic Drug(s) [16 Weeks Maintenance Period (approximately 112 days)]

   Pre-defined exit criteria: A 2-fold or greater increase in average monthly (28-day) partial seizure frequency (motor and non-motor) compared to average monthly partial seizure frequency (motor and non-motor) during the Baseline Phase A 2-fold or greater increase in consecutive 2-day partial seizure frequency (motor and non-motor) versus the highest consecutive 2-day partial seizure frequency (motor and non-motor) that occurred during the Baseline Phase. Note: if the highest consecutive 2-day partial seizure frequency during the Baseline Phase is 1, a 2-day partial seizure frequency of ≥3 is required to meet this exit criterion Occurrence of a single generalized tonic-clonic seizure if none had occurred in the 6 months prior to randomization A prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator as serious enough to warrant trial discontinuation Status epilepticus, or new onset of serial/cluster seizures

Secondary Outcome Measures

1. Time to First Occurrence of Any Exit Event During The Maintenance Period [16 Weeks Maintenance Period (approximately 112 days)]

   The time to first occurrence (days) of any exit event was estimated using Kaplan-Meier methods and was based on the time from the start of the Maintenance Phase to the earliest date a subject met an exit criterion. Subjects who discontinued during the Maintenance Phase due to non-exit criteria reasons or who completed the Maintenance Phase before 112 days and did not meet an exit criterion were censored as of the last Maintenance Phase dose date. Subjects completing 112 days in the Maintenance Phase were censored as of Day 112.

2. Percentage of Subjects (Using Kaplan-Meier) Who Are Identified as Meeting at Least 1 Pre-defined Exit Criteria by Day 112, Withdrew Due to Adverse Event (AE) or Withdrew Due to Lack of Efficacy During The Maintenance Period [16 Weeks Maintenance Period (approximately 112 days)]

   Subjects were classified as having an exit event if they experienced at least 1 of the following events during the Maintenance Phase as of Day 112: Met at least 1 exit criterion based on the calculations applied for the Primary Efficacy Analysis Withdrawal due to AE with onset during the Maintenance Phase Withdrew prematurely due to lack of efficacy during the Maintenance Phase The date the subject experienced the event was set to the earliest date the subject met an exit criterion or the date of the last Maintenance Phase dose for subjects not meeting an exit criterion but withdrawing due to an AE or lack of efficacy. The secondary analysis is only conducted on the Lacosamide 400 mg/day group.

3. Duration of Monotherapy Treatment During the Monotherapy Phase of The Maintenance Period (Visit 9 - Visit 12) [Visit 9 - Visit 12 (approximately 10 weeks)]

   Days on Monotherapy Treatment were defined as the number of days during the Monotherapy Phase when the subject took Lacosamide (LCM) only (ie, the total number of days exposed to LCM during the Monotherapy Phase minus any days where a concomitant or rescue Anti-epileptic Drug (AED) was taken by the subject). The days on Monotherapy Treatment did not need to be consecutive.

4. Clinical Global Impression of Change (CGIC) From Baseline To Last Visit [Baseline; Last Visit (approximately 27 weeks)]

   For the assessment of the Clinical Global Impression of Change (CGIC), the investigator should provide his/her assessment of the subject's clinical status, compared to Baseline, including an evaluation of seizure frequency and intensity, the occurrence of AEs, and subject's functional status. He was asked the following:Please check the number that best describes the subject's condition over the past 4 weeks compared to Baseline: Very much improved Much improved Minimally improved No change Minimally worse Much worse Very much worse

5. Patient's Global Impression of Change (PGIC) From Baseline To Last Visit [Baseline; Last Visit (approximately 27 weeks)]

   For the assessment of the Patient's Global Impression of Change, the subject should provide his/her assessment of his/her own clinical status, compared to Baseline, including an evaluation of seizure frequency and intensity, the occurrence of AEs, and subject's functional status.The subject was asked to answer the following: Over the past 4 weeks, how have you felt compared to before you entered this clinical trial? (Please check the number that best describes your condition.) Very much improved Much improved Minimally improved No change Minimally worse Much worse Very much worse

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject has a diagnosis of Epilepsy with Simple Partial Seizures (motor component) and or Complex Partial Seizures (with or without secondary generalization)

• Must be experiencing 2 to 40 seizures per 28-day period

• Stable dose of 1 or 2 marketed antiepileptic drugs

• Second Antiepileptic Drug (AED) must be less than or equal to 50 % of the minimum recommended maintenance dose per USA product label at screening

Exclusion Criteria:

• Subject has a history of primary generalized or unclassified seizures

• Seizure disorder primarily characterized by isolated auras

• History of status epilepticus

• Seizures that are uncountable due to clustering

• Has greater than 5 seizures/day

• Subjects taking Benzodiazepines, Phenobarbital or Primidone

• Subject has Vagus Nerve Stimulation (VNS)

• Significant medical or psychiatric condition

• History of alcohol or drug abuse

• History of Ethosuximide use, Felbamate use after 1994 or Vigabatrin use after 1997

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	48	Alabaster	Alabama	United States
2	10	Birmingham	Alabama	United States
3	18	Huntsville	Alabama	United States
4	42	Northport	Alabama	United States
5	14	Phoenix	Arizona	United States
6	151	Phoenix	Arizona	United States
7	9	Phoenix	Arizona	United States
8	150	Sun City	Arizona	United States
9	103	Tucson	Arizona	United States
10	102	Jonesboro	Arkansas	United States
11	7	Little Rock	Arkansas	United States
12	86	Little Rock	Arkansas	United States
13	120	La Habra	California	United States
14	156	Loma Linda	California	United States
15	59	Los Angeles	California	United States
16	76	Los Angeles	California	United States
17	45	Newport Beach	California	United States
18	21	Santa Monica	California	United States
19	107	Torrance	California	United States
20	60	Aurora	Colorado	United States
21	25	Fairfield	Connecticut	United States
22	133	Dover	Delaware	United States
23	37	Washington	District of Columbia	United States
24	94	Doral	Florida	United States
25	108	Gainesville	Florida	United States
26	130	Gulf Breeze	Florida	United States
27	55	Maitland	Florida	United States
28	123	Miami	Florida	United States
29	132	Miami	Florida	United States
30	77	Orlando	Florida	United States
31	49	Panama City	Florida	United States
32	109	Pinellas Park	Florida	United States
33	129	Port Charlotte	Florida	United States
34	50	Sarasota	Florida	United States
35	81	Sarasota	Florida	United States
36	4	Tallahassee	Florida	United States
37	163	Tampa	Florida	United States
38	79	Atlanta	Georgia	United States
39	72	Canton	Georgia	United States
40	40	Savannah	Georgia	United States
41	58	Boise	Idaho	United States
42	131	Hines	Illinois	United States
43	146	Peoria	Illinois	United States
44	11	Springfield	Illinois	United States
45	78	Indianapolis	Indiana	United States
46	73	Ames	Iowa	United States
47	124	Manhattan	Kansas	United States
48	160	Wichita	Kansas	United States
49	23	Wichita	Kansas	United States
50	119	Lexington	Kentucky	United States
51	164	Lexington	Kentucky	United States
52	62	Louisville	Kentucky	United States
53	29	Scarborough	Maine	United States
54	20	Baltimore	Maryland	United States
55	34	Baltimore	Maryland	United States
56	19	Bethesda	Maryland	United States
57	65	Pikesville	Maryland	United States
58	137	Waldorf	Maryland	United States
59	41	Detroit	Michigan	United States
60	30	Golden Valley	Minnesota	United States
61	71	Hattiesburg	Mississippi	United States
62	31	Chesterfield	Missouri	United States
63	105	Columbia	Missouri	United States
64	66	Saint Louis	Missouri	United States
65	174	Omaha	Nebraska	United States
66	17	Lebanon	New Hampshire	United States
67	43	Edison	New Jersey	United States
68	67	Voorhees	New Jersey	United States
69	36	Albany	New York	United States
70	83	Buffalo	New York	United States
71	69	Cedarhurst	New York	United States
72	154	Mineola	New York	United States
73	122	New York	New York	United States
74	27	New York	New York	United States
75	175	Schenectady	New York	United States
76	3	Asheville	North Carolina	United States
77	63	Durham	North Carolina	United States
78	152	Rocky Mount	North Carolina	United States
79	117	Wilmington	North Carolina	United States
80	47	Winston-Salem	North Carolina	United States
81	15	Cleveland	Ohio	United States
82	61	Columbus	Ohio	United States
83	2	Toledo	Ohio	United States
84	147	Oklahoma City	Oklahoma	United States
85	8	Medford	Oregon	United States
86	157	Portland	Oregon	United States
87	100	Greensburg	Pennsylvania	United States
88	32	Philadelphia	Pennsylvania	United States
89	26	Tarentum	Pennsylvania	United States
90	24	Beaufort	South Carolina	United States
91	114	Chattanooga	Tennessee	United States
92	1	Nashville	Tennessee	United States
93	138	Austin	Texas	United States
94	111	Dallas	Texas	United States
95	22	Dallas	Texas	United States
96	46	El Paso	Texas	United States
97	51	Houston	Texas	United States
98	53	Houston	Texas	United States
99	98	San Antonio	Texas	United States
100	82	Temple	Texas	United States
101	136	Layton	Utah	United States
102	161	Alexandria	Virginia	United States
103	16	Charlottesville	Virginia	United States
104	106	Richmond	Virginia	United States
105	125	Winchester	Virginia	United States
106	74	Renton	Washington	United States
107	80	Madison	Wisconsin	United States
108	28	Milwaukee	Wisconsin	United States
109	421	Capmerdown	New South Wales	Australia
110	425	Chatswood	New South Wales	Australia
111	423	Herston	Queensland	Australia
112	422	Maroochydore	Queensland	Australia
113	420	Adelaide	South Australia	Australia
114	429	Clayton	Victoria	Australia
115	427	Parkville	Victoria	Australia
116	204	Innsbruck		Austria
117	127	Calgary	Alberta	Canada
118	140	Halifax	Nova Scotia	Canada
119	116	Hamilton	Ontario	Canada
120	93	London	Ontario	Canada
121	91	Greenfield Park	Quebec	Canada
122	110	Montreal	Quebec	Canada
123	113	Montreal	Quebec	Canada
124	223	Aarhus		Denmark
125	220	Copenhagen		Denmark
126	402	Bron		France
127	404	Dijon		France
128	405	Ramonville Saint Agne		France
129	465	Berlin		Germany
130	461	Mainz		Germany
131	240	Dublin		Ireland
132	442	Bologna		Italy
133	449	Catanzaro		Italy
134	443	Ferrara		Italy
135	441	Milano		Italy
136	450	Perugia		Italy
137	448	Pisa		Italy
138	445	Reggio Calabria		Italy
139	447	Torrette Di Ancona		Italy
140	284	Czestochowa		Poland
141	286	Gdansk		Poland
142	282	Gdynia		Poland
143	280	Krakow		Poland
144	283	Lublin		Poland
145	290	Lublin		Poland
146	289	Szczecin		Poland
147	281	Warszawa		Poland
148	287	Warszawa		Poland
149	158	San Juan		Puerto Rico
150	323	Granada		Spain
151	324	Santa Cruz De Tenerife		Spain
152	360	Blackpool		United Kingdom
153	364	London		United Kingdom
154	369	London		United Kingdom
155	361	Manchester		United Kingdom
156	363	Middlesborough		United Kingdom
157	368	Stoke on Trent		United Kingdom
158	367	Truro		United Kingdom

Sponsors and Collaborators

• UCB BIOSCIENCES, Inc.

Investigators

• Study Director: UCB Clinical Trial Call Center, [phone] (UCB)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Product information
• FDA safety Alerts and Recalls

Publications

None provided.

• Responsible Party: UCB BIOSCIENCES, Inc.
• ClinicalTrials.gov Identifier: NCT00520741
• Other Study ID Numbers: SP0902; 2007-005439-27; NCT01058954
• First Posted: Aug 27, 2007
• Last Update Posted: Jul 19, 2018
• Last Verified: Jul 1, 2017

• Keywords provided by UCB BIOSCIENCES, Inc.: Epilepsy; Partial Onset Seizures; Lacosamide; Monotherapy; Vimpat
• Additional relevant MeSH terms: Epilepsy; Seizures; Lacosamide

Study Results

Participant Flow

Recruitment Details	The study was conducted at 160 sites in the United States of America (USA), Canada, Europe, and Australia.The maximum duration of a subject's trial participation is 30 weeks. The Participant Flow refers to the Safety Set (SS) population which consists of all patients who received at least one dose of study medication.
Pre-assignment Detail	Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.

Arm/Group Title	Lacosamide 300 mg/Day	Lacosamide 400 mg/Day
Arm/Group Description	Lacosamide 300 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.	Lacosamide 400 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.
Period Title: Overall Study
STARTED	106	319
COMPLETED	69	194
NOT COMPLETED	37	125

Baseline Characteristics

Arm/Group Title	Lacosamide 300 mg/Day	Lacosamide 400 mg/Day	Total
Arm/Group Description	Lacosamide 300 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.	Lacosamide 400 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.	Total of all reporting groups
Overall Participants	106	319	425
Age (Count of Participants)
<=18 years	3 2.8%	7 2.2%	10 2.4%
Between 18 and 65 years	99 93.4%	303 95%	402 94.6%
>=65 years	4 3.8%	9 2.8%	13 3.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.4 (14.3)	40.4 (12.5)	40.6 (13.0)
Sex: Female, Male (Count of Participants)
Female	50 47.2%	169 53%	219 51.5%
Male	56 52.8%	150 47%	206 48.5%
Race/Ethnicity, Customized (participants) [Number]
White	91 85.8%	246 77.1%	337 79.3%
Black	9 8.5%	53 16.6%	62 14.6%
Asian	0 0%	1 0.3%	1 0.2%
Other	6 5.7%	19 6%	25 5.9%
Height (centimeter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter]	169.72 (10.69)	169.01 (10.87)	169.19 (10.82)
Weight (kilogram) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram]	81.62 (19.53)	82.13 (21.30)	82.00 (20.85)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	28.22 (5.74)	28.67 (6.64)	28.56 (6.42)
Average Baseline Seizure Frequency per 28 days (seizures/28 days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [seizures/28 days]	10.10 (8.82)	10.22 (8.88)	10.19 (8.86)

Outcome Measures

1. Primary Outcome

Title	Percentage of Subjects (Using Kaplan-Meier) Who Are Identified As Meeting At Least 1 Pre-defined Exit Criteria By Day 112 Relative To The Start of Withdrawal of Background Antiepileptic Drug(s)
Description	Pre-defined exit criteria: A 2-fold or greater increase in average monthly (28-day) partial seizure frequency (motor and non-motor) compared to average monthly partial seizure frequency (motor and non-motor) during the Baseline Phase A 2-fold or greater increase in consecutive 2-day partial seizure frequency (motor and non-motor) versus the highest consecutive 2-day partial seizure frequency (motor and non-motor) that occurred during the Baseline Phase. Note: if the highest consecutive 2-day partial seizure frequency during the Baseline Phase is 1, a 2-day partial seizure frequency of ≥3 is required to meet this exit criterion Occurrence of a single generalized tonic-clonic seizure if none had occurred in the 6 months prior to randomization A prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator as serious enough to warrant trial discontinuation Status epilepticus, or new onset of serial/cluster seizures
Time Frame	16 Weeks Maintenance Period (approximately 112 days)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included subjects who completed the Titration Phase and started withdrawing background Anti-epileptic Drugs (AEDs) (ie, entered the Maintenance Phase and took at least 1 dose of Maintenance medication). The primary analysis is only conducted on the Lacosamide 400 mg/day group.

Arm/Group Title	Lacosamide 300 mg/Day	Lacosamide 400 mg/Day
Arm/Group Description	Lacosamide (LCM) 300 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.	Lacosamide (LCM) 400 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks. This study had a single inferential test of the primary efficacy variable for the LCM 400 mg/day treatment arm which was to be compared to an external historical control. As such, no adjustment for multiplicity was required. Additional analyses of the primary efficacy variable for the LCM 400 mg/day and LCM 300 mg/day treatment arms was for exploratory or supportive purposes only. The analysis of the LCM 300 mg/day arm is exploratory due to the 3:1 randomization ratio. Therefore the LCM 300 mg/day arm is not reported for this Outcome Measure.
Measure Participants	0	284
Number [percentage of subjects]	30.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lacosamide 400 mg/Day
	Comments	The upper limit of the Confidence Interval for the estimate of the Lacosamide (LCM) 400 mg/day exit rate was compared with the lower bound of the 95 % prediction interval for the historical-control of 0.653; hereafter referred to as the historical-control exit rate. The LCM 400 mg/day dose group would be declared an effective conversion to monotherapy treatment if the upper 95 % confidence limit for the estimate of the exit rate was less than 0.653.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Predicted exit rate at 112 days
	Estimated Value	0.300
	Confidence Interval	(2-Sided) 95%; 0.246 to 0.355
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time to First Occurrence of Any Exit Event During The Maintenance Period
Description	The time to first occurrence (days) of any exit event was estimated using Kaplan-Meier methods and was based on the time from the start of the Maintenance Phase to the earliest date a subject met an exit criterion. Subjects who discontinued during the Maintenance Phase due to non-exit criteria reasons or who completed the Maintenance Phase before 112 days and did not meet an exit criterion were censored as of the last Maintenance Phase dose date. Subjects completing 112 days in the Maintenance Phase were censored as of Day 112.
Time Frame	16 Weeks Maintenance Period (approximately 112 days)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to a subset of the Full Analysis Set (FAS). The FAS included subjects who completed the Titration Phase and started withdrawing background Anti-epileptic Drugs (AEDs). In addition to being a member of FAS, subjects also met at least one of the exit criterion noted under the Primary Outcome Measure.

Arm/Group Title	Lacosamide 300 mg/Day	Lacosamide 400 mg/Day
Arm/Group Description	Lacosamide (LCM) 300 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.	Lacosamide (LCM) 400 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.
Measure Participants	26	82
Median (Full Range) [days]	39 (21.2)	45.0 (24.3)

3. Secondary Outcome

Title	Percentage of Subjects (Using Kaplan-Meier) Who Are Identified as Meeting at Least 1 Pre-defined Exit Criteria by Day 112, Withdrew Due to Adverse Event (AE) or Withdrew Due to Lack of Efficacy During The Maintenance Period
Description	Subjects were classified as having an exit event if they experienced at least 1 of the following events during the Maintenance Phase as of Day 112: Met at least 1 exit criterion based on the calculations applied for the Primary Efficacy Analysis Withdrawal due to AE with onset during the Maintenance Phase Withdrew prematurely due to lack of efficacy during the Maintenance Phase The date the subject experienced the event was set to the earliest date the subject met an exit criterion or the date of the last Maintenance Phase dose for subjects not meeting an exit criterion but withdrawing due to an AE or lack of efficacy. The secondary analysis is only conducted on the Lacosamide 400 mg/day group.
Time Frame	16 Weeks Maintenance Period (approximately 112 days)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included subjects who completed the Titration Phase and started withdrawing background Anti-epileptic Drugs (AEDs) (eg, entered the Maintenance Phase and took at least 1 dose of Maintenance medication).

Arm/Group Title	Lacosamide 300 mg/Day	Lacosamide 400 mg/Day
Arm/Group Description	Lacosamide (LCM) 300 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.	Lacosamide (LCM) 400 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks. This study had a single inferential test of the primary efficacy variable for the LCM 400 mg/day treatment arm which was to be compared to an external historical control. As such, no adjustment for multiplicity was required. Additional analyses of the primary efficacy variable for the LCM 400 mg/day and LCM 300mg/day treatment arms was for exploratory or supportive purposes only. The analysis of the LCM 300 mg/day arm is exploratory due to the 3 :1 randomization ratio. Therefore the LCM 300 mg/day arm is not reported for this Outcome Measure.
Measure Participants	0	284
Number [percentage of subjects]	32.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lacosamide 400 mg/Day
	Comments	The upper limit of the Confidence Interval for the estimate of the Lacosamide (LCM) 400 mg/day exit rate was compared with the historical-control exit rate. The LCM 400 mg/day dose group would be declared an effective conversion to monotherapy treatment if the upper 95 % confidence limit for the estimate of the exit rate was less than 0.653.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	predicted exit rate at 112 days
	Estimated Value	0.323
	Confidence Interval	(2-Sided) 95%; 0.268 to 0.378
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Duration of Monotherapy Treatment During the Monotherapy Phase of The Maintenance Period (Visit 9 - Visit 12)
Description	Days on Monotherapy Treatment were defined as the number of days during the Monotherapy Phase when the subject took Lacosamide (LCM) only (ie, the total number of days exposed to LCM during the Monotherapy Phase minus any days where a concomitant or rescue Anti-epileptic Drug (AED) was taken by the subject). The days on Monotherapy Treatment did not need to be consecutive.
Time Frame	Visit 9 - Visit 12 (approximately 10 weeks)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to a subset of the Full Analysis Set (FAS). The FAS included subjects who completed the Titration Phase and started withdrawing background Anti-epileptic Drugs (AEDs).This subset of the FAS included subjects who entered the Maintenance Phase but who never achieved Lacosamide (LCM) monotherapy.

Arm/Group Title	Lacosamide 300 mg/Day	Lacosamide 400 mg/Day
Arm/Group Description	Lacosamide (LCM) 300 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.	Lacosamide (LCM) 400 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.
Measure Participants	86	254
Median (Full Range) [days]	71 (22.0)	71 (20.3)

5. Secondary Outcome

Title	Clinical Global Impression of Change (CGIC) From Baseline To Last Visit
Description	For the assessment of the Clinical Global Impression of Change (CGIC), the investigator should provide his/her assessment of the subject's clinical status, compared to Baseline, including an evaluation of seizure frequency and intensity, the occurrence of AEs, and subject's functional status. He was asked the following:Please check the number that best describes the subject's condition over the past 4 weeks compared to Baseline: Very much improved Much improved Minimally improved No change Minimally worse Much worse Very much worse
Time Frame	Baseline; Last Visit (approximately 27 weeks)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included subjects who completed the Titration Phase and started withdrawing background Anti-epileptic Drugs (AEDs) (eg, entered the Maintenance Phase and took at least 1 dose of Maintenance medication).

Arm/Group Title	Lacosamide 300 mg/Day	Lacosamide 400 mg/Day
Arm/Group Description	Lacosamide (LCM) 300 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.	Lacosamide (LCM) 400 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.
Measure Participants	99	284
Very much improved	21 19.8%	56 17.6%
Much improved	33 31.1%	116 36.4%
Minimally improved	18 17%	42 13.2%
No change	8 7.5%	18 5.6%
Minimally worse	6 5.7%	16 5%
Much worse	8 7.5%	23 7.2%
Very much worse	1 0.9%	1 0.3%
Not done	4 3.8%	12 3.8%

6. Secondary Outcome

Title	Patient's Global Impression of Change (PGIC) From Baseline To Last Visit
Description	For the assessment of the Patient's Global Impression of Change, the subject should provide his/her assessment of his/her own clinical status, compared to Baseline, including an evaluation of seizure frequency and intensity, the occurrence of AEs, and subject's functional status.The subject was asked to answer the following: Over the past 4 weeks, how have you felt compared to before you entered this clinical trial? (Please check the number that best describes your condition.) Very much improved Much improved Minimally improved No change Minimally worse Much worse Very much worse
Time Frame	Baseline; Last Visit (approximately 27 weeks)

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS). The FAS included subjects who completed the Titration Phase and started withdrawing background Anti-epileptic Drugs (AEDs) (eg, entered the Maintenance Phase and took at least 1 dose of Maintenance medication).

Arm/Group Title	Lacosamide 300 mg/Day	Lacosamide 400 mg/Day
Arm/Group Description	Lacosamide (LCM) 300 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.	Lacosamide (LCM) 400 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.
Measure Participants	99	284
Very much improved	24 22.6%	81 25.4%
Much improved	33 31.1%	93 29.2%
Minimally improved	15 14.2%	37 11.6%
No change	10 9.4%	15 4.7%
Minimally worse	3 2.8%	19 6%
Much worse	7 6.6%	22 6.9%
Very much worse	3 2.8%	3 0.9%
Not done	4 3.8%	14 4.4%

Adverse Events

Time Frame	Adverse Events (AEs) were collected from Baseline (week -8) up to the end of the study (week 22). Only Treatment-Emergent Adverse Events (TEAEs) are presented.
Adverse Event Reporting Description	Further detailed information about Sudden Unexplained Death in Epilepsy (SUDEP) is reported in the "Detailed Description" section.
Arm/Group Title	Lacosamide 300 mg/Day		Lacosamide 400 mg/Day
Arm/Group Description	Lacosamide 300 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.		Lacosamide 400 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.
All Cause Mortality
	Lacosamide 300 mg/Day		Lacosamide 400 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lacosamide 300 mg/Day		Lacosamide 400 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/106 (3.8%)		21/319 (6.6%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion	0/106 (0%)	0	1/319 (0.3%)	1
Gastrointestinal disorders
Food poisoning	0/106 (0%)	0	1/319 (0.3%)	1
Gastrointestinal haemorrhage	0/106 (0%)	0	1/319 (0.3%)	1
Glossitis	0/106 (0%)	0	1/319 (0.3%)	1
General disorders
Sudden unexplained death in epilepsy	0/106 (0%)	0	2/319 (0.6%)	2
Immune system disorders
Hypersensitivity	0/106 (0%)	0	1/319 (0.3%)	1
Injury, poisoning and procedural complications
Limb injury	0/106 (0%)	0	1/319 (0.3%)	1
Polytraumatism	0/106 (0%)	0	1/319 (0.3%)	1
Subdural haematoma	1/106 (0.9%)	1	0/319 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/106 (0%)	0	1/319 (0.3%)	1
Nervous system disorders
Convulsion	1/106 (0.9%)	1	6/319 (1.9%)	6
Epilepsy	0/106 (0%)	0	1/319 (0.3%)	1
Headache	0/106 (0%)	0	1/319 (0.3%)	1
Status epilepticus	0/106 (0%)	0	1/319 (0.3%)	1
Subarachnoid haemorrhage	0/106 (0%)	0	1/319 (0.3%)	1
Toxic induced encephalopathy	0/106 (0%)	0	1/319 (0.3%)	1
Psychiatric disorders
Abnormal behaviour	0/106 (0%)	0	1/319 (0.3%)	1
Conversion disorder	1/106 (0.9%)	1	0/319 (0%)	0
Hallucination, auditory	1/106 (0.9%)	1	0/319 (0%)	0
Hallucination, visual	1/106 (0.9%)	1	0/319 (0%)	0
Psychotic disorder	1/106 (0.9%)	1	0/319 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory acidosis	0/106 (0%)	0	1/319 (0.3%)	1
Respiratory failure	0/106 (0%)	0	1/319 (0.3%)	2
Skin and subcutaneous tissue disorders
Drug eruption	0/106 (0%)	0	1/319 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Lacosamide 300 mg/Day		Lacosamide 400 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/106 (69.8%)		215/319 (67.4%)
Eye disorders
Vision blurred	6/106 (5.7%)	6	19/319 (6%)	25
Gastrointestinal disorders
Nausea	13/106 (12.3%)	16	46/319 (14.4%)	57
Diarrhoea	7/106 (6.6%)	9	21/319 (6.6%)	22
Vomiting	2/106 (1.9%)	2	23/319 (7.2%)	27
General disorders
Fatigue	12/106 (11.3%)	14	32/319 (10%)	37
Infections and infestations
Nasopharyngitis	7/106 (6.6%)	8	28/319 (8.8%)	30
Upper respiratory tract infection	5/106 (4.7%)	6	16/319 (5%)	19
Musculoskeletal and connective tissue disorders
Back pain	9/106 (8.5%)	9	11/319 (3.4%)	13
Nervous system disorders
Dizziness	19/106 (17.9%)	26	86/319 (27%)	121
Headache	21/106 (19.8%)	32	45/319 (14.1%)	58
Convulsion	17/106 (16%)	22	29/319 (9.1%)	36
Somnolence	15/106 (14.2%)	19	29/319 (9.1%)	35
Tremor	8/106 (7.5%)	8	23/319 (7.2%)	23
Cognitive disorder	7/106 (6.6%)	8	6/319 (1.9%)	6
Psychiatric disorders
Insomnia	8/106 (7.5%)	10	17/319 (5.3%)	17
Anxiety	7/106 (6.6%)	8	11/319 (3.4%)	13
Skin and subcutaneous tissue disorders
Rash	4/106 (3.8%)	5	16/319 (5%)	20

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.