A Study of Levetiracetam as Monotherapy or Adjunctive Treatment of Partial Seizures in Pediatric Epileptic Subjects Ranging From 1 Month to Less Than 4 Years of Age

Study Overview
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Brief Summary
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This is a study to confirm the efficacy of levetiracetam as adjunctive treatment or as monotherapy in pediatric epilepsy subjects aged 1 month to less than 4 years of age with partial seizures.

Detailed Description
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The study will consist of 2 periods. The First Period (6 weeks drug treatment) is designed to confirm efficacy of levetiracetam (LEV), and the Second Period is designed to evaluate the long-term efficacy and safety of LEV.

Official Title
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An Open-Label, Single-Arm, Multicenter Study of Levetiracetam as Monotherapy or Adjunctive Treatment of Partial Seizures in Pediatric Epileptic Subjects Ranging From 1 Month to Less Than 4 Years of Age

Conditions
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Partial Seizures

Intervention / Treatment
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* Drug: Levetiracetam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have a diagnosis of epilepsy with partial onset seizures whether or not secondarily generalized Male or female from 1 month to <4 years of age. Pre-term infants aged <1 year are to be stratified into an appropriate age category using the best estimate of their corrected gestational age For subjects on adjunctive therapy, subject must be on a stable antiepileptic drug (AED) regimen for the Selection and Evaluation Periods of the study. Minor adjustments to the dose of current AEDs are allowed only prior to Visit 1. Monotherapy subjects must not receive AED treatment, receive temporary AED treatment, or switch an AED prior to Visit 1 Subject weighs >=3.0 kg Subject may have Vagal Nerve Stimulation (VNS) which has been implanted for at least 6 months prior to Visit 1; the settings must be stable for at least 2 months prior to Visit 1. Activated VNS must be counted as 1 of the 2 AEDs Subject must have experienced at least 2 observable partial seizures, with or without secondary generalization during each 7-day period during the 2 weeks prior to Visit 1. This time period (the 2 weeks prior to Visit 1) will be referred to as the Retrospective Baseline Period. This seizure information (including type, frequency, and date) must have been recorded on a daily record card (DRC) in order to be acceptable If epilepsy surgery has been performed prior to study entry, subjects must have a documented failed epilepsy surgery outcome at least 4 weeks prior to Visit 1 The use of intermittent benzodiazepines, phenobarbitals, and phenytoins is allowed as long as the frequency is not greater than 1 single administration per week for at least 2 weeks prior to Visit 1 and throughout study participation. If benzodiazepines are used more than once a week, they must be considered as 1 of the AEDs Exclusion Criteria: Subject has been taking any medication (other than their concomitant AEDs) that influences the central nervous system (CNS) for which they had not been on a stable regimen for at least 1 month prior to Visit 1 Subject is taking any medication that may interfere with the absorption, distribution, metabolism, or excretion of the concomitant AEDs or levetiracetam (LEV) during the course of the study Subject has received any investigational medication or device within 30 days prior to Visit 1 Subject has taken LEV prior to the study Subjects using felbamate who have presented with clinically significant abnormalities and/or hepatic function during felbamate treatment, and subjects who are taking felbamate <1year from the date of Visit 1 History of status epilepticus requiring hospitalization during the 30 days prior to Visit 1, except for status epilepticus occurring during the first 10 days of life Subject has a treatable seizure etiology Subject is on a ketogenic diet (concomitantly or within 30 days prior to Visit 1) Subject has epilepsy secondary to progressing cerebral diseases Subject has a current diagnosis of Rasmussen's syndrome, Landau-Kleffner disease or Lennox-Gastaut syndrome Clinically significant deviations from reference range values for renal function or any of the other laboratory parameters required for this study, as determined by the Investigator Clinically significant acute or chronic illness (as determined during the physical examination or from other information available to the Investigator) Allergy to pyrrolidine derivatives or a history of multiple drug allergies Subject is known to have a terminal illness Subject has a disorder or condition that may interfere with the absorption, distribution, metabolism, or excretion of medications Subject has a history of or presence of pseudoseizures Subject has any medical condition that might interfere with the subject's study participation Subject has ≥3x upper limit of normal (ULN) of any of the following: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or >ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert's syndrome). If subject has elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate bilirubin to identify possible undiagnosed Gilbert's syndrome (ie, direct bilirubin <35%)

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 3 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Levetiracetam<br>Subjects aged 1 month to <6 months will be started on levetiracetam (LEV) 14 mg/kg/day at Visit 3. The dose may be increased by LEV 14 mg/kg/day for subjects aged 1 month to <6 months at 2-week intervals to a maximum dose of 42 mg/kg/day. Subjects aged 6 months to <4 years will be started on LEV 20 mg/kg/day at Visit 3. The dose may be increased by LEV 20 mg/kg/day at 2-week intervals to a maximum dose of 60 mg/kg/day. At Visit 6, subjects may enter the Second Period or enter the Down-Titration Period followed by a Safety Follow-Up Period. Subjects who do not enter the Second Period will be down-titrated. The dose will be decreased by LEV 14 mg/kg/day for subjects aged 1 month to <6 months or by LEV 20 mg/kg/day for subjects aged 6 months to <4 years at 2-week intervals to 0 mg/kg/day. | Drug: Levetiracetam<br>* levetiracetam dry syrup 50% for oral administration and levetiracetam solution for infusion (100 mg/mL)<br>* Other names: LEV;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in partial seizure frequency per week from Baseline to Visit 6 | This Variable will be tested in the First Period for subjects on adjunctive therapy. The efficacy variables are based on the partial seizure frequency per week as measured by patient diary. | From Baseline (Week 0) to Visit 6 (up to Week 6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in partial seizure frequency per week from Baseline to Visit 4 | This Variable will be tested in the First Period for subjects on adjunctive therapy. | From Baseline (Week 0) to Visit 4 (up to Week 2) | 
| Percent change in partial seizure frequency per week from Baseline to Visit 5 | This Variable will be tested in the First Period for subjects on adjunctive therapy. | From Baseline (Week 0) to Visit 5 (up to Week 4) | 
| Percent change in partial seizure frequency per week on adjunctive therapy | This Variable will be tested in the Combined First and Second Period for subjects on adjunctive therapy. The change of seizure frequency per week will be monitored for each Analysis Visit at Week 2, 4, 6, 10, 14, 18, 22, 26 and then every 12 weeks. | From Baseline (Week 0) for each Visit (up to Week 312) | 
| Percent change in partial seizure frequency per week grouped into 6 categories on adjunctive therapy | This Variable will be tested in the Combined First and Second Period for subjects on adjunctive therapy. The change of seizure frequency will be presented in following categories: <0%, 0% to <25%, 25% to <50%, >=50%, >=75%, and 100% The change of seizure frequency per week will be monitored for each Analysis Visit at Week 2, 4, 6, 10, 14, 18, 22, 26 and then every 12 weeks. | From Baseline (Week 0) for each Visit (up to Week 312) | 
| Percent change in partial seizure frequency per week on monotherapy | This Variable will be tested in the Combined First and Second Period for subjects on monotherapy. The change of seizure frequency per week will be monitored for each Analysis Visit at Week 2, 4, 6, 10, 14, 18, 22, 26 and then every 12 weeks. | From Baseline (Week 0) for each Visit (up to Week 312) | 
| Percent change in partial seizure frequency per week grouped into 6 categories on monotherapy | This Variable will be tested in the Combined First and Second Period for subjects on monotherapy. The change of seizure frequency will be presented in following categories: <0%, 0% to <25%, 25% to <50%, >=50%, >=75%, and 100% The change of seizure frequency per week will be monitored for each Analysis Visit at Week 2, 4, 6, 10, 14, 18, 22, 26 and then every 12 weeks. | From Baseline (Week 0) for each Visit (up to Week 312) | 
| Incidence of treatment-emergent adverse events (TEAEs) during the First Period | 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. | From Baseline (Week 0) to Visit 6 (up to Week 6) | 
| Incidence of treatment-emergent serious adverse events (SAEs) during the First Period | A serious adverse event (SAE) is any untoward medical occurrence at any dose that must meet 1 or more of the following criteria: Death Life-threatening Significant or persistent disability/incapacity Congenital anomaly/birth defect (including that occurring in a fetus) Important medical event that, based upon appropriate medical judgment, may jeopardize the patient or subject and may require medical or surgical intervention to prevent 1 of the other outcomes listed in the definition of serious Initial inpatient hospitalization or prolongation of hospitalization | From Baseline (Week 0) to Visit 6 (up to Week 6) | 
| Incidence of TEAEs leading to discontinuation from study medication during the First Period | 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. | From Baseline (Week 0) to Visit 6 (up to Week 6) | 
| Incidence of TEAEs during the Combined First and Second Period | 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. | From Baseline (Week 0) to the End of Safety Follow-up (up to Week 314) | 
| Incidence of treatment-emergent SAEs during the Combined First and Second Period | A serious adverse event (SAE) is any untoward medical occurrence at any dose that must meet 1 or more of the following criteria: Death Life-threatening Significant or persistent disability/incapacity Congenital anomaly/birth defect (including that occurring in a fetus) Important medical event that, based upon appropriate medical judgment, may jeopardize the patient or subject and may require medical or surgical intervention to prevent 1 of the other outcomes listed in the definition of serious Initial inpatient hospitalization or prolongation of hospitalization | From Baseline (Week 0) to the End of Safety Follow-up (up to Week 314) | 
| Incidence of TEAEs leading to discontinuation from study medication during the Combined First and Second Period | 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. | From Baseline (Week 0) to the End of Safety Follow-up (up to Week 314) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epilepsy, Partial Seizures, Levetiracetam, Monotherapy, Adjunctive Treatment