A Trial to Evaluate the Efficacy and Safety of Adjunctive Therapy With Lacosamide in Adults With Partial-Onset Seizures

• ClinicalTrials.gov Identifier: NCT01710657
• Recruitment Status: Completed
• First Posted: October 19, 2012
• Results First Posted: February 9, 2015
• Last Update Posted: August 25, 2017
• Sponsor: UCB Pharma SA
• Collaborator: UCB Japan Co. Ltd.
• Information provided by (Responsible Party): UCB Pharma ( UCB Pharma SA )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Epilepsy; Partial Onset Seizures
• Interventions: Drug: Lacosamide 50 mg; Drug: Lacosamide 100 mg; Drug: Placebo
• Enrollment: 548

Participant Flow

Recruitment Details	A total of 676 subjects with uncontrolled partial-onset seizures (of the 676 subjects, the number of Chinese subjects and Japanese subjects was planned to be 507 and 169, respectively) was planned to be screened and 540 subjects were planned to be enrolled in all regions of Japan and China.
Pre-assignment Details	Overall, 692 subjects were screened and 548 subjects were enrolled. The Participant Flow refers to the Safety Set (SS) which was defined as all enrolled subjects who took at least 1 dose of Lacosamide. Reasons for discontinuation were only calculated for the SS. 547 subjects were included in the Safety Set.

Arm/Group Title	Placebo	Lacosamide 200 mg/Day	Lacosamide 400 mg/Day
Arm/Group Description	Matching Placebo for 16 weeks. Placebo: Matching oral Placebo tablets twice daily for 16 weeks.	Lacosamide Treatment of 200 mg/day (100 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use	Lacosamide Treatment of 400 mg/day (200 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use
Period Title: Overall Study
Started	184	183	180
Titration Period (4 Weeks)	184	183	180
Maintenance Period (12 Weeks)	176	175	168
Completed	166	171	148
Not Completed	18	12	32
Reason Not Completed
Lost to Follow-up	2	0	1
Protocol Violation	2	2	0
Adverse Event	14	8	28
Withdrawal by Subject	0	1	2
Lack of Efficacy	0	1	1

Baseline Characteristics

Arm/Group Title		Placebo	Lacosamide 200 mg/Day	Lacosamide 400 mg/Day	Total
Arm/Group Description		Matching Placebo for 16 weeks. Placebo: Matching oral Placebo tablets twice daily for 16 weeks.	Lacosamide Treatment of 200 mg/day (100 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use	Lacosamide Treatment of 400 mg/day (200 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use	Total of all reporting groups
Overall Number of Baseline Participants		184	183	180	547
Baseline Analysis Population Description		The Baseline Characteristics refer to the Safety Set (SS) which was defined as all enrolled subjects who took at least 1 dose of Lacosamide.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	184 participants	183 participants	180 participants	547 participants
	<=18 years	20 10.9%	18 9.8%	15 8.3%	53 9.7%
	Between 18 and 65 years	164 89.1%	163 89.1%	164 91.1%	491 89.8%
	>=65 years	0 0.0%	2 1.1%	1 0.6%	3 0.5%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	184 participants	183 participants	180 participants	547 participants
		31.8 (12.0)	33.2 (12.2)	32.3 (11.9)	32.4 (12.0)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	184 participants	183 participants	180 participants	547 participants
	Female	82 44.6%	89 48.6%	76 42.2%	247 45.2%
	Male	102 55.4%	94 51.4%	104 57.8%	300 54.8%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	184 participants	183 participants	180 participants	547 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	184 100.0%	183 100.0%	180 100.0%	547 100.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	White	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	184 participants	183 participants	180 participants	547 participants
Chinese		136	136	133	405
Japanese		48	47	47	142

Outcome Measures

1. Primary Outcome

Title	Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Maintenance Period
Description	Partial-onset seizure (POS) frequency per 28 days was calculated as: POS frequency = (Number of POS over the specified time interval) / (Number of days in the interval with available diary data) x 28. A negative value in Change in Partial-onset seizure frequency indicates a reduction of Partial-onset seizure frequency from Baseline to the Maintenance Period.
Time Frame	8-week Baseline Period (Visit 1 to 3) and 12-week Maintenance Period (Visit 5 to 8)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set consists of all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 post-baseline efficacy assessment.

Arm/Group Title	Placebo	Lacosamide 200 mg/Day	Lacosamide 400 mg/Day
Arm/Group Description:	Matching Placebo for 16 weeks. Placebo: Matching oral Placebo tablets twice daily for 16 weeks.	Lacosamide Treatment of 200 mg/day (100 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use	Lacosamide Treatment of 400 mg/day (200 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use
Overall Number of Participants Analyzed	183	182	179
Median (Full Range); Unit of Measure: Seizures per 28 days
	-1.22; (-93.0 to 39.8)	-3.33; (-754.3 to 165.2)	-4.50; (-97.5 to 28.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lacosamide 400 mg/Day
	Comments	To avoid inflation of Type I error, hypothesis testing followed predefined hierarchical procedure starting LCM 400 mg/day treatment group versus the placebo group. If the test was not statistically significant, the procedure stopped and no Groups were declared different from placebo. If the test was statistically significant, the treatment group was considered different from placebo and the procedure continued with the LCM 200 mg/day treatment group.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	Significant at the 0.05 level. This testing procedure is considered a closed testing procedure and no adjustment of the significance level was necessary.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	% Reduction over Placebo
	Estimated Value	39.6
	Confidence Interval	(2-Sided) 95%; 30.5 to 47.6
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lacosamide 200 mg/Day
	Comments	To avoid inflation of Type I error, hypothesis testing followed predefined hierarchical procedure starting LCM 400 mg/day treatment group versus the placebo group. If the test was not statistically significant, the procedure stopped and no Groups were declared different from placebo. If the test was statistically significant, the treatment group was considered different from placebo and the procedure continued with the LCM 200 mg/day treatment group.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	Significant at the 0.05 level. This testing procedure is considered a closed testing procedure and no adjustment of the significance level was necessary.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	% Reduction over Placebo
	Estimated Value	29.4
	Confidence Interval	(2-Sided) 95%; 18.7 to 38.7
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	The Proportion of Individual Patients Who Experience a 50 % or Greater Reduction in Seizure Frequency From Baseline to the Maintenance Period (50 % Responder Rate)
Description	[Not Specified]
Time Frame	8-week Baseline Period (Visit 1 to 3) to the 12-week Maintenance Period (Visit 5 to 8)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set consists of all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 post-baseline efficacy assessment.

Arm/Group Title	Placebo	Lacosamide 200 mg/Day	Lacosamide 400 mg/Day
Arm/Group Description:	Matching Placebo for 16 weeks. Placebo: Matching oral Placebo tablets twice daily for 16 weeks.	Lacosamide Treatment of 200 mg/day (100 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use	Lacosamide Treatment of 400 mg/day (200 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use
Overall Number of Participants Analyzed	183	182	179
Measure Type: Number; Unit of Measure: participants
	36	70	88

3. Secondary Outcome

Title	Percent Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Maintenance Period
Description	Calculates as 28-day seizure frequency during the Maintenance Period - 28-day seizure frequency during the Baseline Period, divided by the 28-day seizure frequency during the Baseline Period with this quantity multiplied by 100. A negative value in percent change from Baseline indicates a decrease in Partial-Onset Seizure frequency from Baseline to the Maintenance Period.
Time Frame	8-week Baseline Period (Visit 1 to 3) to the 12-week Maintenance Period (Visit 5 to 8)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set consists of all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 post-baseline efficacy assessment.

Arm/Group Title	Placebo	Lacosamide 200 mg/Day	Lacosamide 400 mg/Day
Arm/Group Description:	Matching Placebo for 16 weeks. Placebo: Matching oral Placebo tablets twice daily for 16 weeks.	Lacosamide Treatment of 200 mg/day (100 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use	Lacosamide Treatment of 400 mg/day (200 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use
Overall Number of Participants Analyzed	183	182	179
Median (Full Range); Unit of Measure: percentage change
	-10.10; (-97.6 to 233.5)	-36.75; (-100.0 to 185.5)	-48.78; (-100.0 to 346.4)

4. Secondary Outcome

Title	Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Treatment Period (i.e., Titration + Maintenance Period)
Description	Partial-onset seizure (POS) frequency per 28 days was calculated as: POS frequency = (Number of POS over the specified time interval) / (Number of days in the interval with available diary data) x 28. A negative value in Change in Partial-onset seizure frequency indicates a reduction of Partial-onset seizure frequency from Baseline to the Treatment Period.
Time Frame	8-week Baseline Period (Visit 1 to 3) to the 16-week Treatment Period (Visit 3 to 8)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set consists of all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 post-baseline efficacy assessment.

Arm/Group Title	Placebo	Lacosamide 200 mg/Day	Lacosamide 400 mg/Day
Arm/Group Description:	Matching Placebo for 16 weeks. Placebo: Matching oral Placebo tablets twice daily for 16 weeks.	Lacosamide Treatment of 200 mg/day (100 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use	Lacosamide Treatment of 400 mg/day (200 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use
Overall Number of Participants Analyzed	183	182	179
Median (Full Range); Unit of Measure: Seizures per 28 days
	-1.10; (-102.4 to 102.5)	-3.39; (-670.0 to 138.9)	-4.00; (-92.4 to 34.2)

Adverse Events

Time Frame	Adverse Events (AEs) were collected from Baseline to the end of the study (up to Week 19).
Adverse Event Reporting Description	Treatment Emergent Adverse Events (TEAEs) refer to the Safety Set (SS). The SS includes all randomized subjects who took at least 1 dose of study drug.
Arm/Group Title	Placebo		Lacosamide 200 mg/Day		Lacosamide 400 mg/Day
Arm/Group Description	Matching Placebo for 16 weeks. Placebo: Matching oral Placebo tablets twice daily for 16 weeks.		Lacosamide Treatment of 200 mg/day (100 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use		Lacosamide Treatment of 400 mg/day (200 mg bid) for 16 weeks. Lacosamide 50 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 50 mg; Route of Administration: Oral use Lacosamide 100 mg: - Active Substance: Lacosamide; Pharmaceutical Form: Film-coated tablet; Concentration: 100 mg; Route of Administration: Oral use
All-Cause Mortality
	Placebo		Lacosamide 200 mg/Day		Lacosamide 400 mg/Day
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--
Serious Adverse Events
	Placebo		Lacosamide 200 mg/Day		Lacosamide 400 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/184 (2.17%)		2/183 (1.09%)		9/180 (5.00%)
Ear and labyrinth disorders
Vertigo * 1	1/184 (0.54%)	1	0/183 (0.00%)	0	0/180 (0.00%)	0
Gastrointestinal disorders
Upper gastrointestinal haemorrhage * 1	0/184 (0.00%)	0	0/183 (0.00%)	0	1/180 (0.56%)	1
Hepatobiliary disorders
Drug-induced liver injury * 1	0/184 (0.00%)	0	0/183 (0.00%)	0	1/180 (0.56%)	1
Infections and infestations
Bronchitis * 1	0/184 (0.00%)	0	0/183 (0.00%)	0	1/180 (0.56%)	1
Pneumonia * 1	1/184 (0.54%)	1	0/183 (0.00%)	0	1/180 (0.56%)	1
Injury, poisoning and procedural complications
Comminuted fracture * 1	0/184 (0.00%)	0	0/183 (0.00%)	0	1/180 (0.56%)	1
Hand fracture * 1	0/184 (0.00%)	0	0/183 (0.00%)	0	1/180 (0.56%)	1
Subdural haematoma * 1	0/184 (0.00%)	0	0/183 (0.00%)	0	1/180 (0.56%)	1
Metabolism and nutrition disorders
Diabetes mellitus * 1	0/184 (0.00%)	0	0/183 (0.00%)	0	1/180 (0.56%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer * 1	0/184 (0.00%)	0	1/183 (0.55%)	1	0/180 (0.00%)	0
Nervous system disorders
Dizziness * 1	0/184 (0.00%)	0	0/183 (0.00%)	0	1/180 (0.56%)	1
Grand mal convulsion * 1	0/184 (0.00%)	0	0/183 (0.00%)	0	1/180 (0.56%)	1
Status epilepticus * 1	2/184 (1.09%)	2	0/183 (0.00%)	0	0/180 (0.00%)	0
Psychiatric disorders
Epileptic psychosis * 1	0/184 (0.00%)	0	0/183 (0.00%)	0	1/180 (0.56%)	1
Suicide attempt * 1	0/184 (0.00%)	0	1/183 (0.55%)	1	0/180 (0.00%)	0
Surgical and medical procedures
Abortion induced * 1	0/184 (0.00%)	0	0/183 (0.00%)	0	1/180 (0.56%)	1
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 16.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Lacosamide 200 mg/Day		Lacosamide 400 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/184 (41.85%)		87/183 (47.54%)		112/180 (62.22%)
Eye disorders
Diplopia * 1	4/184 (2.17%)	5	4/183 (2.19%)	8	13/180 (7.22%)	15
Gastrointestinal disorders
Vomiting * 1	4/184 (2.17%)	4	5/183 (2.73%)	6	14/180 (7.78%)	18
Nausea * 1	9/184 (4.89%)	10	7/183 (3.83%)	8	10/180 (5.56%)	11
Infections and infestations
Nasopharyngitis * 1	24/184 (13.04%)	41	28/183 (15.30%)	40	29/180 (16.11%)	36
Upper respiratory tract infection * 1	22/184 (11.96%)	31	10/183 (5.46%)	14	19/180 (10.56%)	28
Investigations
White blood cell count decreased * 1	2/184 (1.09%)	2	8/183 (4.37%)	14	10/180 (5.56%)	12
Nervous system disorders
Dizziness * 1	24/184 (13.04%)	32	33/183 (18.03%)	57	63/180 (35.00%)	118
Somnolence * 1	9/184 (4.89%)	10	18/183 (9.84%)	26	19/180 (10.56%)	21
Headache * 1	11/184 (5.98%)	21	16/183 (8.74%)	18	19/180 (10.56%)	32
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 16.1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: UCB Clinical Trial Call Center
• Organization: UCB
• Phone: +1 877 822 9493 (UCB)

Publications of Results:

Doty P, Hebert D, Mathy FX, Byrnes W, Zackheim J, Simontacchi K. Development of lacosamide for the treatment of partial-onset seizures. Ann N Y Acad Sci. 2013 Jul;1291(1):56-68. doi: 10.1111/nyas.12213.

• Responsible Party: UCB Pharma ( UCB Pharma SA )
• ClinicalTrials.gov Identifier: NCT01710657
• Other Study ID Numbers: EP0008; 2014-003622-41 ( EudraCT Number ); JapicCTI-121988 ( Registry Identifier: JAPIC )
• First Submitted: October 17, 2012
• First Posted: October 19, 2012
• Results First Submitted: January 22, 2015
• Results First Posted: February 9, 2015
• Last Update Posted: August 25, 2017