A Trial to Evaluate the Long Term Safety and Tolerability of Lacosamide Taken as Monotherapy in Adults With Partial-onset Seizures

• Sponsor: UCB Japan Co. Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02124564
• Collaborator: (none)
• Enrollment: 19
• Locations: 11
• Arm: 1
• Actual Duration (Months): 43.7
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study is to evaluate the long-term safety and tolerability of Lacosamide (LCM) 200 mg/day to LCM 600 mg/day taken in monotherapy in Japanese subjects who currently have partial-onset seizures with or without secondary generalization and who are treated with a single Anti-Epileptic Drug (AED) with marketing approval in Japan.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy; Partial-onset Seizures	Drug: Lacosamide	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicenter, Open-Label, Long-Term Study to Investigate the Safety of Conversion to Lacosamide at Doses up to 600 mg/Day as Monotherapy in Japanese Adults With Partial-Onset Seizures With or Without Secondary Generalization
• Actual Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Nov 21, 2017
• Actual Study Completion Date: Nov 21, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Lacosamide Open-label, single-arm

Drug: Lacosamide; Lacosamide (LCM) immediate-release, film-coated tablets at a strength of 50 mg orally administered twice daily in two equally divided doses. 4-week Titration Period: Starting on LCM 100 mg/day increased by 100 mg/day each week until 400 mg/day dose reached at the beginning of Week 4 . The AED Withdrawal Period and Monotherapy Period (52- week Evaluation Period plus a Follow Up Period): During the AED Withdrawal and Monotherapy Period, the investigator may increase or decrease the dose of LCM to optimize tolerability and seizure control. The LCM dose may be decreased no lower than 200 mg/day or increased, no faster than 100 mg/day per week, up to 600 mg/day.; Other Names: Vimpat

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With at Least One Incidence of Treatment-Emergent Adverse Events (TEAEs) During the Study [From the Titration Period (investigational product is taken) to the End of Study Visit (up to 3.5 years)]

   An Adverse Event (AE) 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 could 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.

2. Number of Subjects Who Withdraw Due to Adverse Events (AEs) During the Study [From the Titration Period (investigational product is taken) to the End of Study Visit (up to 3.5 years)]

   An Adverse Event (AE) 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 could 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.

3. Number of Subjects With at Least One Incidence of Serious Adverse Events (SAEs) During the Study [From the Titration Period (investigational product is taken) to the End of Study Visit (up to 3.5 years)]

   A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: Results in death Is life-threatening Requires in patient hospitalization or prolongation of existing hospitalization Is a congenital anomaly or birth defect Is as infection that requires treatment parenteral antibiotics Other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above

Secondary Outcome Measures

1. Number of Subjects Remaining Seizure Free for 6 Consecutive Months During the Monotherapy Period [From the beginning of the Monotherapy Period to the end of the Follow-Up Period (up to 3.1 years until the time of approval granted)]

   Subjects were considered seizure free if their seizure counts for every day over the entire Treatment Period was zero and if they completed the Treatment Period. A subject was considered seizure free, if no seizure occurred during the 6 consecutive months in the Evaluation Period. If one of the following occurred, the subject was not considered seizure free: A documented seizure during 6 consecutive months of the Evaluation Analysis Period Subject discontinued the study prematurely during the Evaluation Analysis Period Missing Seizure Count Case Report Forms (CRFs) prior to completing the Evaluation Analysis Period

2. Number of Subjects Remaining Seizure Free for 12 Consecutive Months During the Monotherapy Period [From the beginning of the Monotherapy Period to the end of the Follow-Up Period (up to 3.1 years until the time of approval granted)]

   Subjects were considered seizure free if their seizure counts for every day over the entire Treatment Period was zero and if they completed the Treatment Period. A subject was considered seizure free, if no seizure occurred during the 12 consecutive months in the Evaluation Period. If one of the following occurred, the subject was not considered seizure free: A documented seizure during 6 consecutive months of the Evaluation Analysis Period Subject discontinued the study prematurely during the Evaluation Analysis Period Missing Seizure Count Case Report Forms (CRFs) prior to completing the Evaluation Analysis Period. Subjects who discontinued before the end date of 6 consecutive months were included in this analysis.

3. Percentage of Participants in the Monotherapy Period Without Discontinuation Due to Adverse Events (AE) or Lack of Efficacy (LOE) [From the beginning of the Monotherapy Period to the end of the Follow-Up Period (up to 3.1 years until the time of approval granted)]

   For Time to discontinuation (event), Retention rate and 95% CI was calculated using the Kaplan-Meier method. Retention rate is indicated in Percent and 95% confidence intervals (CI) with respect to the Time to discontinuation.

4. Plasma Concentrations of Lacosamide Versus Time Postdose [From Titration Period up to Week 94]

   Dose-normalized lacosamide Plasma Concentration (µg/mL) by Visit and Dose during the Evaluation Period.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subject is male or female and ≥16 years of age

• Subject has a diagnosis of epilepsy, having experienced unprovoked partial-onset seizures (IA, IB, or IC with clear focal origin) that are classifiable according to the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures, 1981

• Subject experiences partial-onset seizures despite appropriately chosen and adequately tried treatment with 1 antiepileptic drug (AED)

• Subject has been treated for epilepsy with a stable dose of 1 marketed AED The use of benzodiazepines is permitted as rescue therapy for epilepsy. Benzodiazepines may have been used as needed but not more frequently than once per week.

Exclusion Criteria:

• Subject has a history or presence of seizures of other types than partial onset (IA, IB, or IC with clear focal origin)

• Subject is taking benzodiazepines for a nonepilepsy indication (Exception: Concomitant use of benzodiazepines is allowed if the subject is taking them on a regular basis, has been on a stable dose for at least 1 month prior to Visit 1, and does not require changes in the dosage and administration throughout the study period. However, concomitant use of benzodiazepines on an as needed basis is not permitted.)

• Female subject who is pregnant or nursing, and/or a woman of childbearing potential who is not surgically sterile, 2 years postmenopausal or does not practice 1 highly effective method of contraception, unless sexually abstinent, for the duration of the study

• Female subject of childbearing potential taking enzyme-inducing antiepileptic drugs (EI-AEDs: CBZ, phenytoin, barbiturates, primidone, topiramate) who is not surgically sterile, 2 years postmenopausal or does not practice 1 highly effective method of contraception according to the World Health Organization (WHO) recommendation (ie, depot medroxyprogesterone acetate, norethisterone enantate, intrauterine devices, combined injectables, and progestogen implants) with administration of EI-AEDs or does not practice 2 combined methods of contraception (ie, combined hormonal contraception plus barrier method with spermicidal agent), unless sexually abstinent, for the duration of the study

• Subject has sick sinus syndrome without a pacemaker, or a second or third degree atrioventricular (AV) block, or subject has any other clinically relevant electrocardiogram (ECG) abnormalities

• Subject has a history of convulsive status epilepticus within the last 12 months prior to Visit 1

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	5	Asaka		Japan
2	1	Hamamatsu		Japan
3	11	Itami		Japan
4	6	Kagoshima		Japan
5	7	Kamakura		Japan
6	10	Nagoya		Japan
7	12	Saitama		Japan
8	8	Sapporo		Japan
9	13	Shinagawa		Japan
10	4	Shizuoka		Japan
11	9	Toyonaka		Japan

Sponsors and Collaborators

• UCB Japan Co. Ltd.

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Oct 9, 2013
• Statistical Analysis Plan - Apr 21, 2016

More Information

Publications

None provided.

• Responsible Party: UCB Japan Co. Ltd.
• ClinicalTrials.gov Identifier: NCT02124564
• Other Study ID Numbers: EP0057
• First Posted: Apr 28, 2014
• Last Update Posted: Oct 28, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by UCB Japan Co. Ltd.: Lacosamide; Epilepsy; Focal, Partial-Onset Seizures with or without secondary generalization; Monotherapy
• Additional relevant MeSH terms: Epilepsy; Seizures; Lacosamide

Study Results

Participant Flow

Recruitment Details	The study started to enroll patients in April 2014 and concluded in November 2017.
Pre-assignment Detail	Participant flow refers to Safety Set including all subjects which took at least one dose of study medication.

Arm/Group Title	Lacosamide
Arm/Group Description	Subjects randomized in this arm received lacosamide from 200 mg/day to 600 mg/day, from the Titration to the End of Study Visit (up to 3.5 years).
Period Title: Treatment Period
STARTED	19
Started Treatment Period	19
Started Titration Period	19
Started AED Withdrawal Period	19
Started Monotherapy Period	17
Started Evaluation Period	17
Started Follow-Up Period	13
COMPLETED	12
NOT COMPLETED	7
Period Title: Treatment Period
STARTED	2
COMPLETED	2
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Lacosamide
Arm/Group Description	Subjects randomized in this arm received lacosamide from 200 mg/day to 600 mg/day, from the Titration to the End of Study Visit (up to 3.5 years).
Overall Participants	19
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	17 89.5%
>=65 years	2 10.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.2 (15.8)
Sex: Female, Male (Count of Participants)
Female	8 42.1%
Male	11 57.9%
Race/Ethnicity, Customized (Count of Participants)
Asian (Japanese)	19 100%
Other	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With at Least One Incidence of Treatment-Emergent Adverse Events (TEAEs) During the Study
Description	An Adverse Event (AE) 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 could 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.
Time Frame	From the Titration Period (investigational product is taken) to the End of Study Visit (up to 3.5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lacosamide (Safety Set)
Arm/Group Description	Subjects randomized in this arm received lacosamide from 200 mg/day to 600 g/day, from the Titration to the End of Study Visit (up to 3.5 years).
Measure Participants	19
Count of Participants [Participants]	19 100%

2. Primary Outcome

Title	Number of Subjects Who Withdraw Due to Adverse Events (AEs) During the Study
Description	An Adverse Event (AE) 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 could 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.
Time Frame	From the Titration Period (investigational product is taken) to the End of Study Visit (up to 3.5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lacosamide (Safety Set)
Arm/Group Description	Subjects randomized in this arm received lacosamide from 200 mg/day to 600 g/day, from the Titration to the End of Study Visit (up to 3.5 years).
Measure Participants	19
Count of Participants [Participants]	2 10.5%

3. Primary Outcome

Title	Number of Subjects With at Least One Incidence of Serious Adverse Events (SAEs) During the Study
Description	A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: Results in death Is life-threatening Requires in patient hospitalization or prolongation of existing hospitalization Is a congenital anomaly or birth defect Is as infection that requires treatment parenteral antibiotics Other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above
Time Frame	From the Titration Period (investigational product is taken) to the End of Study Visit (up to 3.5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lacosamide (Safety Set)
Arm/Group Description	Subjects randomized in this arm received lacosamide from 200 mg/day to 600 g/day, from the Titration to the End of Study Visit (up to 3.5 years).
Measure Participants	19
Count of Participants [Participants]	2 10.5%

4. Secondary Outcome

Title	Number of Subjects Remaining Seizure Free for 6 Consecutive Months During the Monotherapy Period
Description	Subjects were considered seizure free if their seizure counts for every day over the entire Treatment Period was zero and if they completed the Treatment Period. A subject was considered seizure free, if no seizure occurred during the 6 consecutive months in the Evaluation Period. If one of the following occurred, the subject was not considered seizure free: A documented seizure during 6 consecutive months of the Evaluation Analysis Period Subject discontinued the study prematurely during the Evaluation Analysis Period Missing Seizure Count Case Report Forms (CRFs) prior to completing the Evaluation Analysis Period
Time Frame	From the beginning of the Monotherapy Period to the end of the Follow-Up Period (up to 3.1 years until the time of approval granted)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of subjects in the Safety Set (SS) who had at least 1 seizure diary assessment. Subjects who discontinued before the end date of 6 consecutive months were included in this analysis.

Arm/Group Title	Lacosamide (FAS)
Arm/Group Description	Subjects randomized in this arm received lacosamide from 200 mg/day to 600 mg/day, from the Titration to the End of Study Visit (up to 3.5 years).
Measure Participants	13
Count of Participants [Participants]	6 31.6%

5. Secondary Outcome

Title	Number of Subjects Remaining Seizure Free for 12 Consecutive Months During the Monotherapy Period
Description	Subjects were considered seizure free if their seizure counts for every day over the entire Treatment Period was zero and if they completed the Treatment Period. A subject was considered seizure free, if no seizure occurred during the 12 consecutive months in the Evaluation Period. If one of the following occurred, the subject was not considered seizure free: A documented seizure during 6 consecutive months of the Evaluation Analysis Period Subject discontinued the study prematurely during the Evaluation Analysis Period Missing Seizure Count Case Report Forms (CRFs) prior to completing the Evaluation Analysis Period. Subjects who discontinued before the end date of 6 consecutive months were included in this analysis.
Time Frame	From the beginning of the Monotherapy Period to the end of the Follow-Up Period (up to 3.1 years until the time of approval granted)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of subjects in the SS who had at least 1 seizure diary assessment. Subjects who discontinued before the end date of 12 consecutive months were included in this Analysis.

Arm/Group Title	Lacosamide (FAS)
Arm/Group Description	Subjects randomized in this arm received lacosamide from 200 mg/day to 600 mg/day, from the Titration to the End of Study Visit (up to 3.5 years).
Measure Participants	13
Count of Participants [Participants]	6 31.6%

6. Secondary Outcome

Title	Percentage of Participants in the Monotherapy Period Without Discontinuation Due to Adverse Events (AE) or Lack of Efficacy (LOE)
Description	For Time to discontinuation (event), Retention rate and 95% CI was calculated using the Kaplan-Meier method. Retention rate is indicated in Percent and 95% confidence intervals (CI) with respect to the Time to discontinuation.
Time Frame	From the beginning of the Monotherapy Period to the end of the Follow-Up Period (up to 3.1 years until the time of approval granted)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) consisted of subjects in the Safety Set (SS) who had at least 1 seizure diary assessment. Subjects who discontinued before Monotherapy Period were not included in this Analysis.

Arm/Group Title	Lacosamide (FAS)
Arm/Group Description	Subjects randomized in this arm received lacosamide from 200 mg/day to 600 mg/day, from the Titration to the End of Study Visit (up to 3.5 years).
Measure Participants	17
Retention Rate after 6-months	81.3
Retention Rate after 12-months	81.3
Retention Rate after 18-months	81.3
Retention Rate after 24-months	81.3

7. Secondary Outcome

Title	Plasma Concentrations of Lacosamide Versus Time Postdose
Description	Dose-normalized lacosamide Plasma Concentration (µg/mL) by Visit and Dose during the Evaluation Period.
Time Frame	From Titration Period up to Week 94

Outcome Measure Data

Analysis Population Description

Two Subjects withdrew during the AED Withdrawal Period (prior to the Evaluation Period).

Arm/Group Title	Lacosamide (Safety Set)
Arm/Group Description	Subjects randomized in this arm received lacosamide from 200 mg/day to 600 g/day, from the Titration to the End of Study Visit (up to 3.5 years).
Measure Participants	17
Concentration at First Visit	0.028 (0.016)
Concentration at Last Visit	0.034 (0.010)

Adverse Events

Time Frame	Adverse Events were collected from Visit 1 until Safety Follow-Up Visit (up to week 2 after last dose), for approximately 3.5 years
Arm/Group Title	Lacosamide
Arm/Group Description	Subjects randomized in this arm received lacosamide from 200 mg/day to 600 mg/day, from the Titration to the End of Study Visit (up to 3.5 years).
All Cause Mortality
	Lacosamide
	Affected / at Risk (%)	# Events
Total	0/19 (0%)
Serious Adverse Events
	Lacosamide
	Affected / at Risk (%)	# Events
Total	2/19 (10.5%)
Nervous system disorders
Convulsion	1/19 (5.3%)	1
Vascular disorders
Varicose vein	1/19 (5.3%)	2
Other (Not Including Serious) Adverse Events
	Lacosamide
	Affected / at Risk (%)	# Events
Total	19/19 (100%)
Blood and lymphatic system disorders
Leukopenia	1/19 (5.3%)	1
Ear and labyrinth disorders
Vertigo	4/19 (21.1%)	5
Eye disorders
Dry eye	1/19 (5.3%)	1
Gastrointestinal disorders
Abdominal pain	2/19 (10.5%)	3
Abdominal pain upper	2/19 (10.5%)	3
Diarrhoea	2/19 (10.5%)	2
Nausea	2/19 (10.5%)	2
Aphthous stomatitis	1/19 (5.3%)	1
Constipation	1/19 (5.3%)	1
Dry mouth	1/19 (5.3%)	1
Dyspepsia	1/19 (5.3%)	1
Gastritis	1/19 (5.3%)	1
Gastrointestinal disorder	1/19 (5.3%)	1
Paraesthesia oral	1/19 (5.3%)	1
General disorders
Chest pain	1/19 (5.3%)	1
Irritability	1/19 (5.3%)	1
Malaise	1/19 (5.3%)	1
Pyrexia	1/19 (5.3%)	1
Hepatobiliary disorders
Hepatic steatosis	1/19 (5.3%)	1
Infections and infestations
Nasopharyngitis	7/19 (36.8%)	13
Influenza	2/19 (10.5%)	2
Acute tonsillitis	1/19 (5.3%)	2
Bronchitis	1/16 (6.3%)	1
Cystitis	1/19 (5.3%)	2
Herpes virus infection	1/19 (5.3%)	1
Infected dermal cyst	1/19 (5.3%)	1
Laryngitis	1/19 (5.3%)	1
Periodontitis	1/19 (5.3%)	1
Pharyngitis	1/19 (5.3%)	1
Tinea pedis	1/19 (5.3%)	1
Injury, poisoning and procedural complications
Arthropod bite	2/19 (10.5%)	4
Contusion	1/19 (5.3%)	1
Head injury	1/19 (5.3%)	1
Heat illness	1/19 (5.3%)	1
Injury	1/19 (5.3%)	1
Ligament sprain	1/19 (5.3%)	1
Tooth fracture	1/19 (5.3%)	1
Investigations
Blood growth hormone increased	1/19 (5.3%)	1
Crystal urine present	1/19 (5.3%)	1
Gamma-glutamyltransferase increased	1/19 (5.3%)	2
White blood cell count decreased	1/19 (5.3%)	1
Metabolism and nutrition disorders
Decreased appetite	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/19 (5.3%)	2
Pubic pain	1/19 (5.3%)	1
Tenosynovitis	1/19 (5.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Fibrous histiocytoma	1/19 (5.3%)	1
Nervous system disorders
Dizziness	10/19 (52.6%)	13
Somnolence	8/19 (42.1%)	9
Headache	3/19 (15.8%)	5
Tremor	2/19 (10.5%)	2
Cerebellar ataxia	1/19 (5.3%)	1
Complex partial seizures	1/19 (5.3%)	1
Hypoaesthesia	1/19 (5.3%)	1
Simple partial seizures	1/19 (5.3%)	1
Sudden onset of sleep	1/19 (5.3%)	1
Psychiatric disorders
Depressed mood	1/19 (5.3%)	1
Insomnia	1/19 (5.3%)	1
Reproductive system and breast disorders
Uterine polyp	1/19 (5.3%)	1
Respiratory, thoracic and mediastinal disorders
Vocal cord inflammation	1/19 (5.3%)	1
Skin and subcutaneous tissue disorders
Eczema	3/19 (15.8%)	3
Chloasma	1/19 (5.3%)	1
Dermatitis allergic	1/19 (5.3%)	1
Eczema asteatotic	1/19 (5.3%)	1
Pustular psoriasis	1/19 (5.3%)	1
Urticaria	1/19 (5.3%)	1

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.