SP0993: Trial Comparing the Efficacy and Safety of Lacosamide (LCM) to Carbamazepine Controlled-Release (CBZ-CR); Initial Monotherapy in Epilepsy; Subjects Aged 16 and Older

• Sponsor: UCB BIOSCIENCES GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01243177
• Collaborator: Eden Sarl (Industry)
• Enrollment: 888
• Locations: 184
• Arms: 2
• Duration (Months): 52
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Compare efficacy and safety of Lacosamide (LCM) to Carbamazepine Controlled-Release (CBZ-CR) as monotherapy in newly or recently newly diagnosed subjects with a primary efficacy endpoint of 6-month seizure freedom. Noninferiority design to show a similar risk/benefit balance between Lacosamide (LCM) and Carbamazepine-CR (CBZ-CR).

Condition or Disease	Intervention/Treatment	Phase
Epilepsy; Monotherapy	Drug: Lacosamide; Drug: Carbamazepine-Controlled Release	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 888 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Double-blind, Double-dummy, Randomized, Positive- Controlled Study Comparing the Efficacy and Safety of Lacosamide (200 to 600 mg/Day) to Controlled Release Carbamazepine (400 to 1200 mg/Day), Used as Monotherapy in Subjects (≥ 16 Years) Newly or Recently Diagnosed With Epilepsy and Experiencing Partial-onset or Generalized Tonic-clonic Seizures.
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lacosamide	Drug: Lacosamide; Lacosamide: Strengths: 50 mg / 100 mg Form: tablets Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose Duration: up to 118 weeks; Other Names: Vimpat®
Active Comparator: Carbamazepine-Controlled Release (CBZ-CR)	Drug: Carbamazepine-Controlled Release; Carbamazepine-CR: Strengths: 200 mg Form: tablets Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose Duration: up to 118 weeks; Other Names: Tegretol® Retard Tablets 200 mg

Outcome Measures

Primary Outcome Measures

1. Proportion of Subjects in the Full Analysis Set (FAS) Remaining Seizure Free for 6 Consecutive Months (26 Consecutive Weeks) of Treatment Following Stabilization at the Last Evaluated Dose for Each Subject [6 consecutive months (26 consecutive weeks) of treatment following stabilization at the last evaluated dose for each subject]

   The proportion of subjects remaining seizure free for 6 months (26 weeks) was estimated using Kaplan-Meier methods.

2. Proportion of Subjects in the Per Protocol Set (PPS) Remaining Seizure Free for 6 Consecutive Months (26 Consecutive Weeks) of Treatment Following Stabilization at the Last Evaluated Dose for Each Subject [6 consecutive months (26 consecutive weeks) of treatment]

   The proportion of subjects remaining seizure free for 6 months (26 weeks) was estimated using Kaplan-Meier methods.

3. Number of Subjects With at Least One Treatment-emergent Adverse Event (AE) During the Treatment Phase (up to 113 Weeks) [Duration of the Treatment Phase (up to 113 weeks)]

   An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose.

4. Number of Subjects Who Withdraw From the Study Due to a Treatment-emergent Adverse Event (AE) During the Treatment Phase (up to 113 Weeks) [Duration of the Treatment Phase (up to 113 weeks)]

   An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose.

5. Number of Subjects With at Least One Treatment-emergent Serious Adverse Event (SAE) During the Treatment Phase (up to 113 Weeks) [Duration of the Treatment Phase (up to 113 weeks)]

   An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A Serious Adverse Event must meet 1 or more predefined criteria like death, life-threatening, etc. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose.

Secondary Outcome Measures

1. Proportion of Subjects Remaining Seizure Free for 12 Consecutive Months (52 Consecutive Weeks) Following Stabilization at the Last Evaluated Dose for Each Subject [12 consecutive months of treatment following stabilization at the last evaluated dose for each subject]

   The proportion of subjects remaining seizure free for 12 months (52 weeks) was estimated using Kaplan-Meier methods.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject able to comply with study requirements

• Subject is 16 years and older (female; male). Minors will be included in countries only if legally permitted

• Subject has newly or recently diagnosed Epilepsy experiencing partial onset seizures (POS) or generalized tonic-clonic seizures with at least 2 unprovoked seizures separated by 48 hours in the 12 months preceding Visit 1 out of which at least 1 seizure occured 3 months preceding Visit 1

• Subject has had an Electroencephalogram (EEG) and a brain Computed Tomography (CT) scan or Magnetic Resonance Imaging (MRI) exam of the brain within the past 12 months. If the EEG and brain CT scan or MRI exam were not performed prior to Visit 1, they need to be completed and results must be available prior to randomization at Visit 2

Exclusion Criteria:

• Subject has a history or presence of seizures of other types than partial-onset (IA, IB, IC with clear focal origin) and generalized tonic-clonic (without clear focal origin) seizures (eg, myoclonic, absence)

• Subject has a history or presence of seizures occurring only in clustered patterns, defined as repeated seizures occurring over a short period of time (ie, < 20 minutes) with or without function regained between 2 ictal events

• Subject has a history, clinical, or Electroencephalogram (EEG) finding suggestive of Idiopathic Generalized Epilepsy (IGE) at randomization

• Subject has current or previous diagnosis of pseudoseizures, conversion disorders, or other nonepileptic ictal events that could be confused with seizures based on expert opinion and/or EEG evidence

• Subject has any medical or psychiatric condition

• Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response (Yes) to either Question 4 or Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening

• Subject has received treatment with Phenobarbital or Primidone within 28 days prior to Visit 1

• Subject is taking Benzodiazepines for a nonepilepsy indication

• Subject has been treated for Epilepsy with any Antiepileptic Drug (AED) (including Benzodiazepines) in the last 6 months before Visit. However, acute and subacute seizure treatment is accepted with a maximum of 2 weeks duration and if treatment was stopped at least 3 days prior to randomization

• Prior use of Felbamate or Vigabatrin is not allowed

• Benzodiazepines as rescue therapy for Epilepsy may have been used as needed in this time period, but not more frequently than once per week

• Subject has a medical condition that could reasonably be expected to interfere with drug absorption, distribution, metabolism, or excretion, has a history of alcohol or drug abuse within the previous 2 years

• Asian ancestry and tests positive for HLA-B*1502 allele

• Asian ancestry and tests positive for HLA-A*3101 allele

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	786	Alabaster	Alabama	United States
2	799	Huntsville	Alabama	United States
3	780	Phoenix	Arizona	United States
4	777	Little Rock	Arkansas	United States
5	795	Ocala	Florida	United States
6	789	Panama City	Florida	United States
7	776	Port Charlotte	Florida	United States
8	779	Manhattan	Kansas	United States
9	874	Charlotte	North Carolina	United States
10	876	Hickory	North Carolina	United States
11	873	Raleigh	North Carolina	United States
12	794	Oklahoma City	Oklahoma	United States
13	881	Mansfield	Texas	United States
14	790	Madison	Wisconsin	United States
15	798	Casper	Wyoming	United States
16	106	East Gosford	New South Wales	Australia
17	109	Randwick	New South Wales	Australia
18	102	Westmead	New South Wales	Australia
19	103	Herston	Queensland	Australia
20	100	Woodville	South Australia	Australia
21	101	Fitzroy	Victoria	Australia
22	108	Heidelberg	Victoria	Australia
23	104	Chatswood		Australia
24	105	Clayton		Australia
25	127	Brugge		Belgium
26	134	Brugge		Belgium
27	128	Hasselt		Belgium
28	126	Leuven		Belgium
29	805	Blagoevgrad		Bulgaria
30	807	Panagyurishte		Bulgaria
31	803	Pleven		Bulgaria
32	810	Russe		Bulgaria
33	806	Sofia		Bulgaria
34	808	Sofia		Bulgaria
35	811	Sofia		Bulgaria
36	809	Veliko Tarnovo		Bulgaria
37	153	St John's	Newfoundland and Labrador	Canada
38	152	Greenfield Park	Quebec	Canada
39	155	Calgary		Canada
40	158	Halifax Nova Scotia		Canada
41	156	Hamilton		Canada
42	159	Veilleux		Canada
43	185	Brno		Czechia
44	190	Ostrava - Vitkovice		Czechia
45	189	Prague		Czechia
46	184	Praha 5		Czechia
47	180	Zlin		Czechia
48	205	Helsinki		Finland
49	207	Kuopio		Finland
50	236	Nancy		France
51	233	Paris		France
52	231	Strasbourg		France
53	235	Toulouse Cedex 9		France
54	263	Altenburg		Germany
55	258	Aschaffenburg		Germany
56	265	Bad Neustadt		Germany
57	257	Berlin		Germany
58	262	Berlin		Germany
59	270	Berlin		Germany
60	260	Göttingen		Germany
61	271	Köln		Germany
62	269	Leipzig		Germany
63	256	Marburg		Germany
64	264	Muenchen		Germany
65	261	Münster		Germany
66	259	Osnabruck		Germany
67	496	Alexandroupoli		Greece
68	495	Ioannina		Greece
69	490	Thessalonikis		Greece
70	493	Thessaloníki		Greece
71	289	Balassagyarmat		Hungary
72	283	Budapest		Hungary
73	284	Budapest		Hungary
74	286	Debrecen		Hungary
75	282	Gyor		Hungary
76	288	Pecs		Hungary
77	285	Szeged		Hungary
78	290	Szekszárd		Hungary
79	291	Szombathely		Hungary
80	310	Bari		Italy
81	309	Modena		Italy
82	308	Padova		Italy
83	314	Prato		Italy
84	311	Roma		Italy
85	831	Asaka-shi		Japan
86	833	Hamamatsu-shi		Japan
87	834	Kagoshima-shi		Japan
88	844	Kamakura-shi		Japan
89	846	Kawasaki-shi		Japan
90	829	Kokubunji-shi		Japan
91	843	Miyakonojo		Japan
92	835	Nagoya-shi		Japan
93	830	Nara-shi		Japan
94	837	Okayama-shi		Japan
95	828	Saitama-shi		Japan
96	836	Sapporo-shi		Japan
97	847	Sapporo		Japan
98	832	Shizuoka-shi		Japan
99	525	Busan		Korea, Republic of
100	521	Daegu		Korea, Republic of
101	518	Dajeon		Korea, Republic of
102	516	Seoul		Korea, Republic of
103	517	Seoul		Korea, Republic of
104	519	Seoul		Korea, Republic of
105	520	Seoul		Korea, Republic of
106	523	Seoul		Korea, Republic of
107	524	Seoul		Korea, Republic of
108	751	Riga		Latvia
109	727	Alytus		Lithuania
110	724	Kaunas		Lithuania
111	728	Vilnius		Lithuania
112	547	San Luis Potosí		Mexico
113	673	Manila		Philippines
114	672	Pasig City		Philippines
115	676	Quezon City		Philippines
116	336	Gdańsk		Poland
117	334	Katowice		Poland
118	340	Katowice		Poland
119	342	Lublin		Poland
120	341	Poznan		Poland
121	338	Szczecin		Poland
122	343	Warsaw		Poland
123	360	Coimbra		Portugal
124	362	Lisboa		Portugal
125	365	Lisboa		Portugal
126	366	Porto		Portugal
127	361	Santa Maria da Feira		Portugal
128	576	Bucuresti		Romania
129	569	Cluj-Napoca		Romania
130	578	Craiova		Romania
131	570	Iasi		Romania
132	579	Iasi		Romania
133	571	Sibiu		Romania
134	577	Sibiu		Romania
135	572	Targu Mures		Romania
136	387	Kazan		Russian Federation
137	389	Kazan		Russian Federation
138	396	Kirov		Russian Federation
139	394	Moscow		Russian Federation
140	401	Moscow		Russian Federation
141	390	Nizhny Novgorod		Russian Federation
142	392	Novosibirsk		Russian Federation
143	397	Saint Petersburg		Russian Federation
144	400	Saint-Petersburg		Russian Federation
145	386	Smolensk		Russian Federation
146	399	Yaroslavl		Russian Federation
147	594	Dolni Kubin		Slovakia
148	598	Dubnica nad Vahom		Slovakia
149	596	Hlohovec		Slovakia
150	600	Krompachy		Slovakia
151	595	Levoca		Slovakia
152	599	Tornala		Slovakia
153	601	Žilina		Slovakia
154	422	Badalona		Spain
155	413	Barcelona		Spain
156	419	La Laguna		Spain
157	416	Madrid		Spain
158	425	Madrid		Spain
159	426	Madrid		Spain
160	421	Murcia (El Palmar)		Spain
161	418	San Sebastian		Spain
162	414	Santiago de Compostela		Spain
163	424	Sevilla		Spain
164	440	Göteborg		Sweden
165	438	Stockholm		Sweden
166	442	Umea		Sweden
167	651	Aarau		Switzerland
168	654	Biel		Switzerland
169	653	Lugano		Switzerland
170	647	St. Gallen		Switzerland
171	699	Bangkok		Thailand
172	702	Bangkok		Thailand
173	703	Bangkok		Thailand
174	698	Khon Kaen		Thailand
175	622	Chernihiv		Ukraine
176	628	Dnipropetrovsk		Ukraine
177	626	Kharkov		Ukraine
178	621	Luhansk		Ukraine
179	625	Odesa		Ukraine
180	632	Simferopol		Ukraine
181	633	Vinnytsa		Ukraine
182	466	Birmingham		United Kingdom
183	472	Glasgow		United Kingdom
184	471	Stoke-on-Trent		United Kingdom

Sponsors and Collaborators

• UCB BIOSCIENCES GmbH
• Eden Sarl

Investigators

• Study Director: UCB Cares, [phone] (UCB)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• FDA Safety Alerts and Recalls
• Product Information

Publications

None provided.

• Responsible Party: UCB BIOSCIENCES GmbH
• ClinicalTrials.gov Identifier: NCT01243177
• Other Study ID Numbers: SP0993; 2010-019765-28
• First Posted: Nov 18, 2010
• Last Update Posted: Feb 2, 2021
• Last Verified: Jan 1, 2021

• Keywords provided by UCB BIOSCIENCES GmbH: Lacosamide; Vimpat®; Epilepsy; Monotherapy; Velocity
• Additional relevant MeSH terms: Epilepsy; Lacosamide; Carbamazepine

Study Results

Participant Flow

Recruitment Details	This study started to enroll in April 2011 and concluded in August 2015.
Pre-assignment Detail	Participant Flow refers to the Safety Analysis Set which is defined as all randomized subjects who took at least 1 dose of study medication and is identical with the Full Analysis Set.

Arm/Group Title	Lacosamide	Carbamazepine-Controlled Release (CBZ-CR)
Arm/Group Description	Strengths: 50 mg / 100 mg Form: tablets Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose Duration: up to 118 weeks	Strengths: 200 mg Form: tablets Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose Duration: up to 118 weeks
Period Title: Overall Study
STARTED	444	442
COMPLETED	266	264
NOT COMPLETED	178	178

Baseline Characteristics

Arm/Group Title	Lacosamide	Carbamazepine-Controlled Release (CBZ-CR)	Total Title
Arm/Group Description	Strengths: 50 mg / 100 mg Form: tablets Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose Duration: up to 118 weeks	Strengths: 200 mg Form: tablets Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose Duration: up to 118 weeks
Overall Participants	444	442	886
Age (Count of Participants)
<=18 years	27 6.1%	19 4.3%	46 5.2%
Between 18 and 65 years	355 80%	366 82.8%	721 81.4%
>=65 years	62 14%	57 12.9%	119 13.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.9 (17.9)	41.8 (17.2)	41.8 (17.6)
Sex: Female, Male (Count of Participants)
Female	201 45.3%	210 47.5%	411 46.4%
Male	243 54.7%	232 52.5%	475 53.6%

Outcome Measures

1. Primary Outcome

Title	Proportion of Subjects in the Full Analysis Set (FAS) Remaining Seizure Free for 6 Consecutive Months (26 Consecutive Weeks) of Treatment Following Stabilization at the Last Evaluated Dose for Each Subject
Description	The proportion of subjects remaining seizure free for 6 months (26 weeks) was estimated using Kaplan-Meier methods.
Time Frame	6 consecutive months (26 consecutive weeks) of treatment following stabilization at the last evaluated dose for each subject

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), consisting of all randomized subjects who took at least 1 dose of study medication.

Arm/Group Title	Lacosamide	Carbamazepine-Controlled Release (CBZ-CR)
Arm/Group Description	Strengths: 50 mg / 100 mg Form: tablets Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose Duration: up to 118 weeks	Strengths: 200 mg Form: tablets Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose Duration: up to 118 weeks
Measure Participants	444	442
Number (95% Confidence Interval) [percentage of subjects]	89.8	91.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lacosamide, Carbamazepine-Controlled Release (CBZ-CR)
	Comments	This was a noninferiority assessment of Lacosamide versus Carbamazepine-CR for the proportion of subjects remaining seizure free for 6 months at the last evaluated dose.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	The hypothesis was as follows: H0: [S(t)LCM] - [S(t)CBZ-CR] ≤ -12 % versus HA: [S(t)LCM] - [S(t)CBZ-CR] > -12 %, where S(t) (t= 182 days) is the cumulative rate of subjects remaining seizure free for 6 months following stabilization at the last evaluated dose (also known as the survivorship function), and -12 % represents the noninferiority margin based on absolute difference.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95%; -5.5 to 2.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	The lower limit of the confidence interval was >-12 %, noninferiority of LCM to CBZ-CR was demonstrated. Additionally, the lower confidence limit relative to the CBZ-CR seizure freedom rate was >- 20 %.

2. Primary Outcome

Title	Proportion of Subjects in the Per Protocol Set (PPS) Remaining Seizure Free for 6 Consecutive Months (26 Consecutive Weeks) of Treatment Following Stabilization at the Last Evaluated Dose for Each Subject
Description	The proportion of subjects remaining seizure free for 6 months (26 weeks) was estimated using Kaplan-Meier methods.
Time Frame	6 consecutive months (26 consecutive weeks) of treatment

Outcome Measure Data

Analysis Population Description

The Per Protocol Set (PPS) was defined as containing all subjects in the Full Analysis Set (FAS) who did not have any important protocol deviations determined to impact the interpretation of primary efficacy.

Arm/Group Title	Lacosamide	Carbamazepine-Controlled Release (CBZ-CR)
Arm/Group Description	Strengths: 50 mg / 100 mg Form: tablets Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose Duration: up to 118 weeks	Strengths: 200 mg Form: tablets Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose Duration: up to 118 weeks
Measure Participants	408	397
Number (95% Confidence Interval) [percentage of subjects]	91.4	92.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lacosamide, Carbamazepine-Controlled Release (CBZ-CR)
	Comments	This was a noninferiority assessment of Lacosamide versus Carbamazepine-CR for the proportion of subjects remaining seizure free for 6 months at the last evaluated dose.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	The hypothesis was as follows: H0: [S(t)LCM] - [S(t)CBZ-CR] ≤ -12 % versus HA: [S(t)LCM] - [S(t)CBZ-CR] > -12 %, where S(t) (t= 182 days) is the cumulative rate of subjects remaining seizure free for 6 months following stabilization at the last evaluated dose (also known as the survivorship function), and -12 % represents the noninferiority margin based on absolute difference.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95%; -5.3 to 2.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	The lower limit of the confidence interval was >-12 %, noninferiority of LCM to CBZ-CR was demonstrated. Additionally, the lower confidence limit relative to the CBZ-CR seizure freedom rate was >- 20 %.

3. Primary Outcome

Title	Number of Subjects With at Least One Treatment-emergent Adverse Event (AE) During the Treatment Phase (up to 113 Weeks)
Description	An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose.
Time Frame	Duration of the Treatment Phase (up to 113 weeks)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set consisting of all randomized subjects who took at least 1 dose of study medication.

Arm/Group Title	Lacosamide	Carbamazepine-Controlled Release (CBZ-CR)
Arm/Group Description	Strengths: 50 mg / 100 mg Form: tablets Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose Duration: up to 118 weeks	Strengths: 200 mg Form: tablets Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose Duration: up to 118 weeks
Measure Participants	444	442
Number [Participants]	328 73.9%	332 75.1%

4. Primary Outcome

Title	Number of Subjects Who Withdraw From the Study Due to a Treatment-emergent Adverse Event (AE) During the Treatment Phase (up to 113 Weeks)
Description	An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose.
Time Frame	Duration of the Treatment Phase (up to 113 weeks)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set consisting of all randomized subjects who took at least 1 dose of study medication.

Arm/Group Title	Lacosamide	Carbamazepine-Controlled Release (CBZ-CR)
Arm/Group Description	Strengths: 50 mg / 100 mg Form: tablets Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose Duration: up to 118 weeks	Strengths: 200 mg Form: tablets Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose Duration: up to 118 weeks
Measure Participants	444	442
Number [Participants]	47 10.6%	69 15.6%

5. Secondary Outcome

Title	Proportion of Subjects Remaining Seizure Free for 12 Consecutive Months (52 Consecutive Weeks) Following Stabilization at the Last Evaluated Dose for Each Subject
Description	The proportion of subjects remaining seizure free for 12 months (52 weeks) was estimated using Kaplan-Meier methods.
Time Frame	12 consecutive months of treatment following stabilization at the last evaluated dose for each subject

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS), consisting of all randomized subjects who took at least 1 dose of study medication.

Arm/Group Title	Lacosamide	Carbamazepine-Controlled Release (CBZ-CR)
Arm/Group Description	Strengths: 50 mg / 100 mg Form: tablets Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose Duration: up to 118 weeks	Strengths: 200 mg Form: tablets Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose Duration: up to 118 weeks
Measure Participants	444	442
Number (95% Confidence Interval) [percentage of subjects]	77.8	82.7

6. Primary Outcome

Title	Number of Subjects With at Least One Treatment-emergent Serious Adverse Event (SAE) During the Treatment Phase (up to 113 Weeks)
Description	An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A Serious Adverse Event must meet 1 or more predefined criteria like death, life-threatening, etc. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose.
Time Frame	Duration of the Treatment Phase (up to 113 weeks)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set consisting of all randomized subjects who took at least 1 dose of study medication.

Arm/Group Title	Lacosamide	Carbamazepine-Controlled Release (CBZ-CR)
Arm/Group Description	Strengths: 50 mg / 100 mg Form: tablets Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose Duration: up to 118 weeks	Strengths: 200 mg Form: tablets Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose Duration: up to 118 weeks
Measure Participants	444	442
Number [Participants]	32 7.2%	43 9.7%

Adverse Events

Time Frame	Adverse Events were collected during the whole study from Screening Phase (Week 0) over Evaluation, Maintenance and End of Study Phase up to 121 weeks.
Adverse Event Reporting Description	Adverse Events refer to the Safety Analysis Set consisting of all randomized subjects who took at least 1 dose of study medication.
Arm/Group Title	Lacosamide		Carbamazepine-Controlled Release (CBZ-CR)
Arm/Group Description	Strengths: 50 mg / 100 mg Form: tablets Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose Duration: up to 118 weeks		Strengths: 200 mg Form: tablets Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose Duration: up to 118 weeks
All Cause Mortality
	Lacosamide		Carbamazepine-Controlled Release (CBZ-CR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lacosamide		Carbamazepine-Controlled Release (CBZ-CR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/444 (8.1%)		46/442 (10.4%)
Blood and lymphatic system disorders
Antiphospholipid syndrome	1/444 (0.2%)	1	0/442 (0%)	0
Aplastic anaemia	0/444 (0%)	0	1/442 (0.2%)	1
Cardiac disorders
Atrial fibrillation	1/444 (0.2%)	1	1/442 (0.2%)	1
Angina pectoris	1/444 (0.2%)	1	0/442 (0%)	0
Cardiac failure	1/444 (0.2%)	1	0/442 (0%)	0
Sinus tachycardia	1/444 (0.2%)	1	0/442 (0%)	0
Ventricular extrasystoles	1/444 (0.2%)	2	0/442 (0%)	0
Atrioventricular block first degree	0/444 (0%)	0	1/442 (0.2%)	1
Pericardial haemorrhage	0/444 (0%)	0	1/442 (0.2%)	1
Ear and labyrinth disorders
Deafness unilateral	1/444 (0.2%)	1	0/442 (0%)	0
Endocrine disorders
Addison's disease	0/444 (0%)	0	1/442 (0.2%)	1
Hyperthyroidism	0/444 (0%)	0	1/442 (0.2%)	1
Gastrointestinal disorders
Hernial eventration	1/444 (0.2%)	1	0/442 (0%)	0
Dyspepsia	0/444 (0%)	0	1/442 (0.2%)	1
Inguinal hernia	0/444 (0%)	0	1/442 (0.2%)	1
General disorders
Gait disturbance	2/444 (0.5%)	2	0/442 (0%)	0
Oedema peripheral	1/444 (0.2%)	1	1/442 (0.2%)	1
Fatigue	1/444 (0.2%)	1	0/442 (0%)	0
Inflammation	1/444 (0.2%)	1	0/442 (0%)	0
Pyrexia	1/444 (0.2%)	1	0/442 (0%)	0
Hepatobiliary disorders
Cholelithiasis	1/444 (0.2%)	1	1/442 (0.2%)	1
Cholecystitis acute	1/444 (0.2%)	1	0/442 (0%)	0
Immune system disorders
Hypersensitivity	0/444 (0%)	0	1/442 (0.2%)	1
Infections and infestations
Pneumonia	1/444 (0.2%)	1	1/442 (0.2%)	1
Appendicitis	1/444 (0.2%)	1	0/442 (0%)	0
Bronchitis	0/444 (0%)	0	1/442 (0.2%)	1
Dengue fever	0/444 (0%)	0	1/442 (0.2%)	1
Gastroenteritis	0/444 (0%)	0	1/442 (0.2%)	1
Peritonsillar abscess	0/444 (0%)	0	1/442 (0.2%)	1
Pyelonephritis acute	0/444 (0%)	0	1/442 (0.2%)	1
Sinusitis	0/444 (0%)	0	1/442 (0.2%)	1
Tuberculous pleurisy	0/444 (0%)	0	1/442 (0.2%)	1
Vestibular neuronitis	0/444 (0%)	0	1/442 (0.2%)	1
Injury, poisoning and procedural complications
Tendon rupture	2/444 (0.5%)	2	0/442 (0%)	0
Fall	1/444 (0.2%)	1	1/442 (0.2%)	1
Post procedural complication	1/444 (0.2%)	1	0/442 (0%)	0
Road traffic accident	1/444 (0.2%)	1	0/442 (0%)	0
Skin injury	1/444 (0.2%)	1	0/442 (0%)	0
Skull fracture	1/444 (0.2%)	1	0/442 (0%)	0
Ulna fracture	1/444 (0.2%)	1	0/442 (0%)	0
Accident	0/444 (0%)	0	1/442 (0.2%)	1
Alcohol poisoning	0/444 (0%)	0	1/442 (0.2%)	1
Craniocerebral injury	0/444 (0%)	0	1/442 (0.2%)	1
Femur fracture	0/444 (0%)	0	1/442 (0.2%)	1
Rib fracture	0/444 (0%)	0	1/442 (0.2%)	2
Thoracic vertebral fracture	0/444 (0%)	0	1/442 (0.2%)	1
Upper limb fracture	0/444 (0%)	0	1/442 (0.2%)	1
Investigations
Smear cervix abnormal	1/444 (0.2%)	1	0/442 (0%)	0
Urine albumin/creatinine ratio increased	1/444 (0.2%)	1	0/442 (0%)	0
Alanine aminotransferase increased	0/444 (0%)	0	1/442 (0.2%)	1
Aspartate aminotransferase increased	0/444 (0%)	0	1/442 (0.2%)	1
Gamma-glutamyltransferase increased	0/444 (0%)	0	1/442 (0.2%)	1
Musculoskeletal and connective tissue disorders
Lumbar spinal stenosis	0/444 (0%)	0	1/442 (0.2%)	1
Osteoarthritis	0/444 (0%)	0	1/442 (0.2%)	1
Rotator cuff syndrome	0/444 (0%)	0	1/442 (0.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acoustic neuroma	1/444 (0.2%)	1	0/442 (0%)	0
Anaplastic astrocytoma	1/444 (0.2%)	1	0/442 (0%)	0
Bladder cancer	0/444 (0%)	0	1/442 (0.2%)	1
Nervous system disorders
Convulsion	4/444 (0.9%)	4	2/442 (0.5%)	3
Complex partial seizures	2/444 (0.5%)	2	1/442 (0.2%)	1
Epilepsy	2/444 (0.5%)	3	0/442 (0%)	0
Headache	1/444 (0.2%)	1	1/442 (0.2%)	1
Dyskinesia	1/444 (0.2%)	1	0/442 (0%)	0
Motor neurone disease	1/444 (0.2%)	1	0/442 (0%)	0
Orthostatic intolerance	1/444 (0.2%)	1	0/442 (0%)	0
Preictal state	1/444 (0.2%)	1	0/442 (0%)	0
Subarachnoid haemorrhage	1/444 (0.2%)	1	0/442 (0%)	0
Syncope	1/444 (0.2%)	1	0/442 (0%)	0
Partial seizures with secondary generalisation	0/444 (0%)	0	3/442 (0.7%)	3
Cerebrovascular accident	0/444 (0%)	0	2/442 (0.5%)	2
Grand mal convulsion	0/444 (0%)	0	2/442 (0.5%)	2
Ischaemic stroke	0/444 (0%)	0	2/442 (0.5%)	2
Psychomotor hyperactivity	0/444 (0%)	0	1/442 (0.2%)	1
Transient ischaemic attack	0/444 (0%)	0	1/442 (0.2%)	1
Trigeminal nerve disorder	0/444 (0%)	0	1/442 (0.2%)	1
Psychiatric disorders
Aggression	1/444 (0.2%)	1	0/442 (0%)	0
Agitation	1/444 (0.2%)	1	0/442 (0%)	0
Suicidal ideation	1/444 (0.2%)	1	0/442 (0%)	0
Suicide attempt	1/444 (0.2%)	1	0/442 (0%)	0
Renal and urinary disorders
Urinary incontinence	1/444 (0.2%)	1	0/442 (0%)	0
Stress urinary incontinence	0/444 (0%)	0	1/442 (0.2%)	1
Reproductive system and breast disorders
Metrorrhagia	1/444 (0.2%)	1	0/442 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/444 (0.2%)	1	0/442 (0%)	0
Dyspnoea exertional	0/444 (0%)	0	1/442 (0.2%)	1
Dyspnoea paroxysmal nocturnal	0/444 (0%)	0	1/442 (0.2%)	1
Skin and subcutaneous tissue disorders
Rash macular	1/444 (0.2%)	1	0/442 (0%)	0
Drug reaction with eosinophilia and systemic symptoms	0/444 (0%)	0	2/442 (0.5%)	2
Dermatitis allergic	0/444 (0%)	0	1/442 (0.2%)	1
Rash generalised	0/444 (0%)	0	1/442 (0.2%)	1
Vascular disorders
Hypertension	0/444 (0%)	0	1/442 (0.2%)	2
Other (Not Including Serious) Adverse Events
	Lacosamide		Carbamazepine-Controlled Release (CBZ-CR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	165/444 (37.2%)		181/442 (41%)
Gastrointestinal disorders
Nausea	26/444 (5.9%)	32	23/442 (5.2%)	30
General disorders
Fatigue	34/444 (7.7%)	38	49/442 (11.1%)	55
Infections and infestations
Nasopharyngitis	29/444 (6.5%)	42	29/442 (6.6%)	37
Investigations
Gamma-glutamyltransferase increased	7/444 (1.6%)	8	35/442 (7.9%)	36
Nervous system disorders
Headache	60/444 (13.5%)	82	58/442 (13.1%)	78
Dizziness	53/444 (11.9%)	61	41/442 (9.3%)	52
Somnolence	27/444 (6.1%)	28	41/442 (9.3%)	47

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.