Efficacy and Safety of Lacosamide as Adjunctive Therapy in Subjects ≥1 Month to <4 Years With Partial-onset Seizures

Phase 3

Completed

Conditions: Epilepsy With Partial-onset Seizures

Interventions: Drug: Lacosamide
Other: Placebo

Registration Number: NCT02477839

Lead Sponsor: UCB BIOSCIENCES, Inc.

Brief Summary: The purpose of this trial is to assess the efficacy, safety and tolerability of lacosamide administered as add-on therapy with 1 to 3 anti-seizure medications. This trial is for children aged 1 month to less than 4 years with epilepsy who currently have uncontrolled partial-onset seizures.

Detailed Description: The trial consists of a 7-day Baseline Period, a 20-day Titration Period, a 7-day Maintenance Period, and a 12-day Transition Period for subjects who complete the study and choose to enter the extension study. Subjects who will not enter the extension study will continue after the Maintenance Period with a 16-day Taper Period followed by a 30-day Safety Follow-Up Period. The Taper Period and Safety Follow-Up are also applicable for subjects not eligible for continuation and therefore ending the study earlier.

If subjects meet the eligibility criteria, they will be randomized to receive either lacosamide 8 mg/kg/day to 12 mg/kg/day, or placebo during the Maintenance Phase. The dose of lacosamide will be titrated from 4 mg/kg/day at study start to maximum of 12 mg/kg/day at 4-day intervals of 1-2 mg/kg/day.

All subjects who complete the 20-day Titration Period will enter the 7-day Maintenance Period. No dose adjustment is allowed during the Maintenance Phase. The Treatment Phase is defined as the combined Titration and Maintenance Phases.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 255

Inclusion Criteria

Subject is male or female from >=1 month (ie, 4 weeks after full term [37 weeks gestational age]) to <4 years of age
Subject has a diagnosis of epilepsy with partial-onset seizures. The results of >=1 prior EEG and >=1 magnetic resonance imaging/computerized tomography scan should be consistent with this diagnosis
Subject weighs >=4 kg to <30 kg at Visit 1
Subject has experienced >=2 partial-onset seizures with or without secondary generalization during each consecutive 7-day period during the 2 weeks prior to Visit 1
Subject has >=2 partial-onset seizures with or without secondary generalization during the End-of-Baseline video-EEG. Electrographic seizures are defined as recognizable ictal patterns on an EEG involving >=2 contiguous electrodes. The seizures are initiated as a unilateral or strongly asymmetric abnormal epileptiform discharge lasting a total of >10 seconds
Subject is on a stable (concurrently or sequentially) dosage regimen of 1 to 3 AEDs. The dosage regimen of concomitant AED therapy must be kept constant for a period of >=2 weeks prior to Visit 1. A stable daily dosage regimen of a concomitant benzodiazepine (BZD) will be considered as a concomitant AED
Vagus nerve stimulation (VNS) is allowed and will not be counted as a concomitant AED. The VNS device must have been implanted for >=6 months prior to Visit 1; device settings must be kept stable for >=2 weeks prior to Visit 1 and kept stable during the Baseline, Treatment, and Transition Periods. Use of the VNS device magnet is allowed
Subject is an acceptable candidate for venipuncture

Exclusion Criteria

Subject has experienced febrile seizures exclusively. The occurrence of febrile seizures in addition to partial-onset seizures is not exclusionary
Subject is on a ketogenic diet that has either changed within the 4 weeks prior to Visit 1 or is expected to change during the study
Subject has creatinine clearance <30 mL/minute
Subject has a clinically relevant ECG abnormality, in the opinion of the investigator (eg, second or third degree heart block at rest or a corrected QT interval [QTc] >=450 ms)
Subject has a hemodynamically significant congenital heart disease
Subject has an arrhythmic heart condition requiring medical therapy
Subject has a known history of severe anaphylactic reaction secondary to medication intake or serious blood dyscrasias
Subject has nonepileptic events that could be confused with seizures. Subjects may be included if epileptic events can be clearly distinguished and the frequency meets the study inclusion criteria
Subject has a current diagnosis of Lennox-Gastaut syndrome, epilepsia partialis continua, primary generalized epilepsy, Dravet Syndrome, or seizures that are not of partial-onset origin
Subject has a history of generalized convulsive status epilepticus <=2 months prior to Screening (Visit 1)
Subject has been treated with felbamate and has experienced any serious toxicity issues (defined as liver failure, aplastic anemia) with this treatment. Subjects treated with felbamate for <12 months are excluded. Subjects treated with felbamate for >=12 months prior to Visit 1 and who have not experienced serious toxicity issues are eligible
Subject has an acute or subacutely progressive central nervous system disease. Subject has epilepsy secondary to a progressing cerebral disease or any other progressively neurodegenerative disease (malignant brain tumor or Rasmussen Syndrome)
Subject has a known cardiac sodium channelopathy, such as Brugada syndrome

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lacosamide	Lacosamide	Lacosamide syrup 8 mg/kg/day to 12 mg/kg/day
Placebo	Placebo	Matching placebo syrup

Primary Outcome Measures

Name	Time	Method
Change in Average Daily Frequency (ADF) of Electrographic Partial-onset Seizures From End-of-Baseline (EOB) Period Video-EEG to End-of-Maintenance (EOM) Period Video-EEG	End-of-Baseline Period (Day -3 to Day 1) to End-of-Maintenance Period (Day 24 to Day 27)	The change in ADF of electrographic partial-onset seizures as measured on the End-of-Maintenance Period video-electroencephalogram (EEG) compared to the End-of-Baseline Period video-EEG. Seizure frequency was analyzed using an analysis of covariance (ANCOVA) with terms for treatment, pooled randomized age stratum, pooled center, and Baseline seizure ADF. Seizure ADF was log transformed using the transformation of ln(X+1), where X is the seizure ADF. Baseline seizure ADF was log transformed. Least squares means were based on log-transformed data of the full ANCOVA model.
Participant Withdrawals Due to Adverse Events (AEs) During the Study	From the Baseline Period (Day -7) to the End of Study Visit (up to 93 days)	An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study medication, whether or not considered related to the study medication. An AE could, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study medication.
Percentage of Participants With Adverse Events Reported Spontaneously by the Participant's Parent(s) and/or Legal Representative(s)/Caregiver(s) (in Accordance With Local Regulation) or Observed by the Investigator	From the Baseline Period (Day -7) to the End of Study Visit (up to 93 days)	An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study medication, whether or not considered related to the study medication. An AE could, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study medication.

Secondary Outcome Measures

Name	Time	Method
Absolute Change in Average Daily Frequency (ADF) of Electrographic Partial-onset Seizures From End-of-Baseline (EOB) Period Video-EEG to End-of-Maintenance (EOM) Period Video-EEG	End-of-Baseline Period (Day -3 to Day 1) to End-of-Maintenance Period (Day 24 to Day 27)	The absolute change in ADF of electrographic partial-onset seizures as measured on the End-of-Maintenance Period video-EEG compared to the End-of-Baseline Period video-EEG.
Percent Change in Average Daily Frequency (ADF) of Electrographic Partial-onset Seizures From End-of-Baseline (EOB) Period Video-EEG to End-of-Maintenance (EOM) Period Video-EEG	End-of-Baseline Period (Day -3 to Day 1) to End-of-Maintenance Period (Day 24 to Day 27)	The percent change in ADF of electrographic partial-onset seizures as measured on the End-of-Maintenance Period video-EEG compared to the End-of-Baseline Period video-EEG.
Percentage of Participants Who Achieved 'Seizure-free' Status From All Seizure Types During the End-of-Maintenance (EOM) Period Video-EEG	During the End-of-Maintenance Period (Day 24 to Day 27)	A study participant was considered seizure-free from all seizures if the End-of-Maintenance (EOM) Period video-EEG had zero seizures reported from all seizure types (not just partial-onset seizures (POS)).
Percentage of Participants Who Achieved 'Seizure-free' Status From Partial-onset Seizure Types Only During the End-of-Maintenance (EOM) Period Video-EEG	During the End-of-Maintenance Period (Day 24 to Day 27)	A study participant was considered seizure free from partial-onset seizures (POS) if the End-of-Maintenance (EOM) Period video-EEG had zero POS reported.
Percentage of Participants Experiencing a >=25% to <50% Reduction in Average Daily Frequency (ADF) of Electrographic Partial-onset Seizures From End-of-Baseline (EOB) Period Video-EEG to End-of-Maintenance (EOM) Period Video-EEG	End-of-Baseline Period (Day -3 to Day 1) to End-of-Maintenance Period (Day 24 to Day 27)	A ≥25% to \<50% response was defined as ≥25% to \<50% reduction in ADF of electrographic partial-onset seizures (POS) from the End-of-Baseline (EOB) video-EEG to the End-of-Maintenance (EOM) video-EEG.
Percentage of Participants Experiencing a 50% to 75% Reduction in Average Daily Frequency (ADF) of Electrographic Partial-onset Seizures From End-of-Baseline (EOB) Period Video-EEG to End-of-Maintenance (EOM) Period Video-EEG	End-of-Baseline Period (Day -3 to Day 1) to End-of-Maintenance Period (Day 24 to Day 27)	A ≥50% to ≤75% response was defined as ≥50% to ≤75% reduction in ADF of electrographic partial-onset seizures (POS) from the End-of-Baseline (EOB) video-EEG to the End-of-Maintenance (EOM) video-EEG.
Percentage of Participants Experiencing a >75% Reduction in Average Daily Frequency (ADF) of Electrographic Partial-onset Seizures From End-of-Baseline (EOB) Period Video-EEG to End-of-Maintenance (EOM) Period Video-EEG	End-of-Baseline Period (Day -3 to Day 1) to End-of-Maintenance Period (Day 24 to Day 27)	A \>75% response was defined as \>75% reduction in ADF of electrographic partial-onset seizures (POS) from the End-of-Baseline (EOB) video-EEG to the End-of-Maintenance (EOM) video-EEG.
Percentage of Participants Experiencing no Change in Average Daily Frequency (ADF) of Electrographic Partial-onset Seizures (Between <25% Reduction and <25% Increase) From EOB Period Video-EEG to EOM Period Video-EEG	End-of-Baseline Period (Day -3 to Day 1) to End-of-Maintenance Period (Day 24 to Day 27)	No change was defined as between \<25% reduction and \<25% increase in ADF of electrographic partial-onset seizures (POS) from the End-of-Baseline (EOB) video-EEG to the End-of-Maintenance (EOM) video-EEG.
Percentage of Participants Experiencing an Increase in Average Daily Frequency (ADF) of Electrographic Partial-onset Seizures of >=25% From End-of-Baseline (EOB) Period Video-EEG to End-of-Maintenance (EOM) Period Video-EEG	End-of-Baseline Period (Day -3 to Day 1) to End-of-Maintenance Period (Day 24 to Day 27)	An increase was defined as ≥25% increase in ADF of electrographic partial-onset seizures (POS) from the End-of-Baseline (EOB) video-EEG to the End-of-Maintenance (EOM) video-EEG.

Trial Locations

Locations (88): Sp0967 537
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Shenzhen, China
Sp0967 542
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Athens, Greece
Sp0967 456
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Nizhny Novgorod, Russian Federation
Sp0967 452
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Novosibirsk, Russian Federation
Sp0967 730
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Smolensk, Russian Federation
Sp0967 581
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Bucuresti, Romania
Sp0967 577
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Timişoara, Romania
Sp0967 621
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Tbilisi, Georgia
Sp0967 561
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Chihuahua, Mexico
Sp0967 727
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Quezon City, Philippines
Sp0967 454
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Kemerovo, Russian Federation
Sp0967 474
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Bratislava, Slovakia
Sp0967 609
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Dnipro, Ukraine
Sp0967 682
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Uzhgorod, Ukraine
Sp0967 603
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Vinnytsia, Ukraine
Sp0967 361
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Budapest, Hungary
Sp0967 368
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Budapest, Hungary
Sp0967 620
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Tbilisi, Georgia
Sp0967 724
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Cebu, Philippines
Sp0967 461
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Belgrade, Serbia
Sp0967 235
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Pathum Wan, Thailand
Sp0967 681
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Ivano-Frankivs'k, Ukraine
Sp0967 224
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Taipei, Taiwan
Sp0967 694
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Aguascalientes, Mexico
Sp0967 450
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Yekaterinburg, Russian Federation
Sp0967 463
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Novi Sad, Serbia
Sp0967 237
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Bangkok, Thailand
Sp0967 602
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Dnipropetrovs'k, Ukraine
Sp0967 606
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Kiev, Ukraine
Sp0967 363
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Budapest, Hungary
Sp0967 569
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Culiacán, Mexico
Sp0967 692
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Monterrey, Mexico
Sp0967 453
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Omsk, Russian Federation
Sp0967 458
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Tomsk, Russian Federation
Sp0967 459
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Ulyanovsk, Russian Federation
Sp0967 532
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Chongqing, China
Sp0967 158
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Passo Fundo, Brazil
Sp0967 154
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São Paulo, Brazil
Sp0967 310
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Plovdiv, Bulgaria
Sp0967 150
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São Paulo, Brazil
Sp0967 349
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Marseille, France
Sp0967 346
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Rennes, France
Sp0967 344
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Strasbourg, France
Sp0967 613
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Osijek, Croatia
Sp0967 612
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Zagreb, Croatia
Sp0967 320
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Ostrava-Poruba, Czechia
Sp0967 536
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Nanchang, China
Sp0967 531
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Shanghai, China
Sp0967 362
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Budapest, Hungary
Sp0967 623
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Tbilisi, Georgia
Sp0967 398
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Messina, Italy
Sp0967 374
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Petah tikva, Israel
Sp0967 397
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Genova, Italy
Sp0967 422
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Kraków, Poland
Sp0967 383
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Roma, Italy
Sp0967 364
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Budapest, Hungary
Sp0967 610
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Rijeka, Croatia
Sp0967 129
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Dallas, Texas, United States
Sp0967 638
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Birmingham, Alabama, United States
Sp0967 117
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Tampa, Florida, United States
Sp0967 120
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Lebanon, New Hampshire, United States
Sp0967 115
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Henderson, Nevada, United States
Sp0967 630
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San Antonio, Texas, United States
Sp0967 643
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San Antonio, Texas, United States
Sp0967 142
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Córdoba, Argentina
Sp0967 152
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Porto Alegre, Brazil
Sp0967 530
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Beijing, China
Sp0967 535
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Changchun, China
Sp0967 622
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Tbilisi, Georgia
Sp0967 381
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Milano, Italy
Sp0967 700
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Napoli, Italy
Sp0967 395
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Roma, Italy
Sp0967 212
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Seoul, Korea, Republic of
Sp0967 693
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Culiacán, Mexico
Sp0967 215
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Seoul, Korea, Republic of
Sp0967 564
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Mexico, Mexico
Sp0967 563
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Guadalajara, Mexico
Sp0967 568
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Monterrey, Mexico
Sp0967 650
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Chisinau, Moldova, Republic of
Sp0967 723
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Manila, Philippines
Sp0967 720
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Cebu, Philippines
Sp0967 721
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Manila, Philippines
Sp0967 750
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Lisbon, Portugal
Sp0967 573
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Sibiu, Romania
Sp0967 582
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Iaşi, Romania
Sp0967 455
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Perm, Russian Federation
Sp0967 464
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Belgrade, Serbia
Sp0967 600
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Kiev, Ukraine