臨床研究等提出・公開システム

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

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

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The overall mean age of adjunctive therapy study participants (N=32) was 14.7 months, and the proportion of female participants (46.9%) was similar to the proportion of male participants (53.1%). The overall mean weight, height, and BMI for study participants were 9.00kg, 73.23cm, and 16.46kg/m2, respectively. In keeping with the study design, 100% of study participants were of Japanese descent. The overall mean age of monotherapy study participants (N=6) was 32.4 months. There was a greater proportion of female study participants (83.3%) compared with male study participants (16.7%). The overall mean weight, height, and BMI for study participants were 12.27kg, 84.88cm, and 16.84kg/m2, respectively. In keeping with the study design, 100% of study participants were of Japanese descent. Overall, the mean age at onset of epilepsy in adjunctive therapy study participants was 7.860 months, and the mean duration of epilepsy at study entry was 6.890 months. As required by study inclusion criteria, all adjunctive therapy study participants (100%) had a history of partial seizures. Overall, the most frequently observed subtype of partial seizures was IB (71.9% of adjunctive therapy study participants). A total of 9.4% and 12.5% of adjunctive therapy study participants had a history of generalized seizures or unclassified epileptic seizures, respectively. The majority of adjunctive therapy study participants (96.9%) had epileptic syndromes that were classified as cryptogenic or symptomatic. Overall, adjunctive therapy study participants had a median of 34.0 partial seizures during the Retrospective Baseline Period. The median numbers of type IA, IB, and IC partial seizures were 0.0, 14.0, and 0.0, respectively. As expected, all adjunctive therapy study participants (100%) received concomitant AEDs on the date of Study Visit 1. By PT, the AEDs most frequently used at Study Visit 1 by adjunctive therapy study participants overall were carbamazepine (34.4%), phenobarbital (21.9%), and valproate sodium (21.9%) Overall, the mean age at onset of epilepsy in monotherapy study participants was 31.962 months, and the mean duration of epilepsy at study entry was 0.630 months. As required by study inclusion criteria, all monotherapy study participants (100%) had a history of partial seizures. Overall, the most frequently observed subtype of partial seizures was IB (83.3% of monotherapy study participants). A total of 16.7% of monotherapy study participants had a history of generalized seizures, and none had unclassified epileptic seizures. All monotherapy study participants (100%) had epileptic syndromes that were classified as cryptogenic or symptomatic. Overall, monotherapy study participants had a median of 10.0 partial seizures during the Retrospective Baseline Period. The median numbers of type IA, IB, and IC partial seizures were 0.0, 8.0, and 0.0, respectively.

A total of 32 adjunctive therapy participants received LEV in the study and were included in the SS_A, FAS_A, and PK-PPS_A. Eight participants (25.0%) who received adjunctive therapy completed the study. Twenty-four participants (75.0%) discontinued from the study. The primary reasons for discontinuation were lack of efficacy in 14 participants (43.8%), "Other" in 5 participants (15.6%), AEs in 3 participants (9.4%), and withdrawal by participant (ie, consent withdrawal) in 2 participants (6.3%). A total of 6 monotherapy participants received LEV in the study and were included in the SS_M, FAS_M, and PK-PPS_M. Four participants (66.7%) who received monotherapy completed the study. Two participants (33.3%) discontinued from the study; one participant discontinued due to the primary reason of AE and one participant discontinued due to withdrawal by participant (ie, consent withdrawal).

Overall, LEV was generally well tolerated in study participants aged 1 month to <4 years with partial seizures, both as adjunctive therapy and monotherapy. A total of 32 adjunctive therapy participants and 6 monotherapy participants received at least 1 LEV dose, with median LEV exposure durations of 241.00 days and 1202.50 days, respectively. A total of 31 study participants (96.9%) in the adjunctive therapy group and all study participants (100%) in the monotherapy group had TEAEs during the study. Across both treatment groups (adjunctive therapy and monotherapy), the majority of TEAEs were mild or moderate in severity. By preferred term (PT), the most frequently reported TEAEs in adjunctive therapy study participants were nasopharyngitis (17 study participants [53.1%]), pyrexia (12 study participants [37.5%]), eczema (9 study participants [28.1%]), diarrhoea (8 study participants [25.0%]), and gastroenteritis and somnolence (7 study participants [21.9%] each). By PT, the most frequently reported TEAEs in monotherapy study participants were nasopharyngitis (5 study participants [83.3%]), epistaxis, gastroenteritis, hand-foot-and-mouth disease, and pyrexia (3 study participants [50.0%] each), and conjunctivitis allergic, rhinitis allergic, upper respiratory tract inflammation (2 study participants [33.3%] each). Across both treatment groups (adjunctive therapy and monotherapy), the majority of TEAEs were not considered related to study medication. By PT, the only TEAEs considered related to study medication that occurred in >1 adjunctive therapy study participant were somnolence (7 study participants [21.9%]) and agitation (2 study participants [6.3%]). By PT, no TEAEs considered related to study medication occurred in >1 monotherapy study participant. No deaths occurred in the study. A total of 18 study participants (56.3%) in the adjunctive therapy group and 2 study participants (33.3%) in the monotherapy group had serious TEAEs during the study. Across both treatment groups (adjunctive therapy and monotherapy), the majority of serious TEAEs were not considered related to study medication. By PT, the only serious TEAEs that were reported in >1 adjunctive therapy study participant infantile spasms, pneumonia viral, and status epilepticus (3 study participants [9.4%] each), bronchitis, epilepsy, pneumonia aspiration, respiratory syncytial virus bronchitis, respiratory syncytial virus infection, and seizure cluster (2 study participants [6.3%] each). A total of 3 adjunctive therapy study participants (9.4%) had serious TEAEs that were considered related to study medication: related serious TEAEs of dehydration, epilepsy, and somnolence were each reported in 1 study participant (3.1%). By PT, no serious TEAEs were reported in >1 monotherapy study participant, and no serious TEAEs were considered related to study medication. A total of 3 study participants (9.4%) in the adjunctive therapy group and 1 study participant (16.7%) in the monotherapy group had TEAEs leading to discontinuation of study medication. Serious TEAEs of infantile spasms and epilepsy that were not considered related to study medication and a nonserious TEAE of somnolence that was considered related to study medication led to discontinuation of study medication in adjunctive therapy study participants. A serious TEAE of seizure cluster that was not considered related to study medication led to discontinuation of study medication in a monotherapy study participant. No consistent or clinically relevant trends in mean changes from Baseline were observed in hematology or clinical chemistry parameters in adjunctive therapy or monotherapy study participants. Shifts to possibly clinically significant (PCS) hematology or clinical chemistry values were observed but did not occur in the majority of participants, with the exception of shifts to "too high" in alkaline phosphatase, which occurred in 50.0% of monotherapy study participants. No TEAEs associated with abnormal hematology values were reported. Treatment emergent AEs associated with abnormal clinical chemistry values included hypernatremia and hyperphosphatasemia in adjunctive therapy study participants and alanine aminotransferase increased and aspartate aminotransferase increased, and glucose urine present in monotherapy study participants; these TEAEs occurred in 1 participant each. As expected, mean height and weight generally increased over time in adjunctive therapy and monotherapy study participants, and the majority of study participants did not have shifts to PCS values. No consistent or clinically relevant trends were observed in vital signs or electrocardiogram (ECG) findings in adjunctive therapy or monotherapy study participants. Treatment emergent PCS vital sign or ECG findings were observed but did not occur in the majority of study participants, with the exception of PCS low diastolic blood pressure, which occurred in 66.7% of monotherapy study participants. The only reported TEAEs associated with abnormal vital signs or ECG findings were blood pressure increased and ventricular extrasystoles in adjunctive therapy study participants; both TEAEs by PT occurred in 1 participant each.

For the primary efficacy variable, the median percent reduction in partial seizure frequency per week from Baseline to Visit 6 for study participants on adjunctive therapy was 24.24% with a 95% CI of 25.48% to 51.85%. Because the lower limit of the 95% CI was less than the predefined threshold of 15%, these results did not confirm the efficacy of LEV.

During the First Period, the median partial seizure frequencies per week were lower at Visit 4 (Analysis Visit 1) and at Visit 5 (Analysis Visit 2) than at Baseline for study participants on adjunctive therapy, with median percent reductions of 8.62% (95% CI: 20.72% to 41.96%) and 16.79% (95% CI: -7.64% to 43.83%), respectively. During the combined First and Second Periods, the median percent reductions from Baseline in partial seizure frequency per week for adjunctive therapy study participants were all positive and ranged from 8.62% at Analysis Visit 1 (Week 2) to 100.00% at Analysis Visit 13 (Week 36). For the long-term follow-up, the median percent reductions from Baseline ranged from 89.74% at Analysis Visit 35 (Week 300) to 100% at Analysis Visit 15 (Week 60) through Analysis Visit 17 (Week 84) and Analysis Visit 19 (Week 108) through Analysis Visit 22 (Week 144). The median percent reductions from Baseline at the End of Study (EOS)/Early Discontinuation Visit (EDV) and SFU Visits were 21.86% and 39.82%, respectively. For monotherapy study participants, the change in partial seizure frequency per week by analysis visit ranged from a median increase of 51.87% at Analysis Visit 1 (Week 2) to a median decrease of 100.00% at Analysis Visit 4 (Week 8), Analysis Visit 5 (Week 10), Analysis Visit 7 (Week 15), and Analysis Visit 9 (Week 21) through Analysis Visit 13 (Week 36). For the long term follow-up, the median percent reductions from Baseline ranged from 92.31% at Analysis Visit 16 (Week 72) to 100% at Analysis Visit 24 (Week 168) through Analysis Visit 33 (Week 276). The median percent reduction from Baseline at the SFU Visit was 100%. The percentages of both adjunctive therapy and monotherapy study participants in the >=50%, >=75%, and 100% categories for percent reduction in partial seizure frequency per week had a general tendency to increase from Baseline over time for study participants who had reached each visit, including for the long-term follow-up data. During the First Period, for ADF of partial seizures monitored by 48h video-EEG in adjunctive therapy study participants, the median percent reductions from Baseline were 31.20% at Analysis Visit 1 (Week 2) and 39.91% at Analysis Visit 3 (Week 6). The percentages of adjunctive therapy study participants with >=50%, >=75%, or 100% reductions in ADF of partial seizures monitored by 48h video EEG were 46.7%, 40.0%, and 26.7%, respectively, at Analysis Visit 1 (Week 2) and 38.5%, 38.5%, and 30.8%, respectively, at Analysis Visit 3 (Week 6). In monotherapy study participants, no results for percent reduction from Baseline in ADF of partial seizures monitored by 48h video-EEG at Analysis Visit 1 or Analysis Visit 3 were applicable. During the combined First and Second Periods, for all types of seizure frequency per week in adjunctive therapy study participants, the median percent reductions from Baseline were all positive ranged and from 8.62% at Analysis Visit 1 (Week 2) to 100.00% at Analysis Visit 13 (Week 36). The long-term follow-up median percent reduction ranged from 89.74% at Analysis Visit 35 (Week 300) to 100% at Analysis Visit 20 (Week 120) through Analysis Visit 22 (Week 144). The change from Baseline in all types of seizure frequency at EOS/EDV indicated a median reduction of 2.03% and at the SFU Visit indicated a median increase of 10.25%. In monotherapy study participants, the change in all types of seizure frequency per week by analysis visit ranged from a median increase of 51.87% at Analysis Visit 1 (Week 2) to a median decrease of 100.00% at Analysis Visit 4 (Week 8), Analysis Visit 5 (Week 10), Analysis Visit 7 (Week 15), and Analysis Visit 9 (Week 21) through Analysis Visit 13 (Week 36). The long-term follow-up median percent reduction ranged from 92.31% at Analysis Visit 16 (Week 72) to 100% at Analysis Visit 24 (Week 168) through Analysis Visit 33 (Week 276). In monotherapy study participants, the change from Baseline in all types of seizure frequency at the SFU Visit indicated a median reduction of 100%. The percentages of both adjunctive therapy and monotherapy study participants in the >=50%, >=75%, and 100% categories for percent reduction in all types of seizure frequency per week had a general tendency to increase from Baseline over time for study participants who had reached each visit, including for the long-term follow-up data. A total of 2 monotherapy study participants (33.3%) were continuously 6-months seizure free as monitored by the DRC during the Evaluation and Maintenance Periods.

As assessed by percent reduction in partial seizure frequency per week from Baseline to Visit 6, did not confirm the efficacy of LEV compared to historical control in Japanese pediatric epilepsy study participants aged 1 month to <4 years on adjunctive therapy. However, numerical reductions at the entire period were observed for both adjunctive and monotherapy. LEV was generally well tolerated and demonstrated an acceptable safety profile. The safety findings were consistent with the known and expected.

Aug. 07, 2024

No

Matsuo Tetsuo

UCB Japan Co., Ltd.

8-17-1 Nishi-shinjuku, Shinjuku-ku, Tokyo

CTR-JRCT.UCBJapan@ucb.com

Global Clinical Science & Operation

UCB Japan Co., Ltd.

8-17-1 Nishi-shinjuku, Shinjuku-ku, Tokyo

+81-3-6864-7587

CTR_SCC_UCBJapan@UCB.com

completed

Nov. 30, 2017

Interventional

OPEN-LABEL, SINGLE-ARM, MULTICENTER STUDY

treatment purpose

3

- 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 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

- 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 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 < 1 year 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 (>= 1.5 x ULN total bilirubin if known Gilbert's syndrome). If subject has elevations only in total bilirubin that are > ULN and < 1.5 x ULN, fractionate bilirubin to identify possible undiagnosed Gilbert's syndrome (ie, direct bilirubin < 35%)

Both

Epilepsy and epilepsy syndrome

investigational material(s)
Generic name etc : L059IV, L059
INN of investigational material : Levetiracetam
Therapeutic category code : 113 Antiepileptics
Dosage and Administration for Investigational material : Oral administration, Intravenous infusion (14mg/kg/day to 42mg/kg/day for subjects aged at 1 month to <6 months, 20mg/kg/day to 60mg/kg/day for subjects aged at 6 months to <4 years)

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : -

efficacy
The primary efficacy variable for the First Period for subjects on adjunctive therapy is the percent reduction in partial seizure frequency per week from Baseline to Visit 6.

safety
efficacy
Efficacy, Safety

+81-11-706-7061

June. 20, 2017