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Clinical Trial Results:
An Open-Lable, 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

Summary
EudraCT number	2021-003372-13
Trial protocol	Outside EU/EEA
Global end of trial date	28 Jul 2023

Results information
Results version number	v1
This version publication date	19 Jan 2024
First version publication date	19 Jan 2024
Other versions	v2

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

EP0100

ISRCTN number

US NCT number

NCT03340064

WHO universal trial number (UTN)

Sponsor organisation name

UCB Japan Co. Ltd.

Sponsor organisation address

Shinjuku Grand Tower, 8-17-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, Japan, 160-0023

Public contact

Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com

Scientific contact

Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

29 Aug 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Jun 2021

Global end of trial reached?

Yes

Global end of trial date

28 Jul 2023

Was the trial ended prematurely?

Main objective of the trial

To confirm the efficacy of Levetiracetam (LEV) in reducing seizure frequency in the First Period compared to historical control as adjunctive treatment in pediatric epilepsy subjects aged 1 month to <4 years with partial seizures.

Protection of trial subjects

During the conduct of the study all participants were closely monitored.

Background therapy

Adjunctive therapy must be on a stable maximum of two AED regimens, and Monotherapy must not receive AED treatment.

Evidence for comparator

Not applicable.

Actual start date of recruitment

30 Nov 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Japan: 38

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study started to enroll participants in November 2017 and concluded in July 2023.

Screening details

Participant Flow refers to the Safety Set Adjunctive therapy (SS_A) and Safety Set Monotherapy (SS_M).

Period 1 title

First Period

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Levetiracetam: Adjunctive Therapy

Arm description

Participants aged 1 month to less than (<) 6 months received LEV 14 milligram per kilogram per day (mg/kg/day) as adjunctive therapy at Visit 3 (Week 0) of First Period and dose up titrated up to 42 mg/kg/day. Participants aged 6 months to <4 years received LEV 20 mg/kg/day at Visit 3(Week 0) of first period and dose up titrated up to maximum of 60 mg/kg/day up to 6 weeks. Dose increased by 2 weeks interval per Investigator’s discretion. At Visit 6 (Week 6), dose of participants either down-titrated during 4 weeks interval or they entered in second period and continued LEV 14 to 42 mg/kg/day in participants aged 1 month to <6 months or LEV 20 to 60 mg/kg/day for participants aged greater than or equal to (≥) 6 months <4 years. Participants visited every 4 weeks for first 6 months of administration and then every 12 weeks thereafter until approval or till program discontinued. Dose down-titrated during 4 weeks Interval at discretion of Investigator.

Arm type

Experimental

Investigational medicinal product name

Levetiracetam

Investigational medicinal product code

LEV

Other name

Keppra and E-Keppra

Pharmaceutical forms

Syrup

Routes of administration

Oral use

Dosage and administration details

Participants received LEV as prespecified.

Levetiracetam: Monotherapy

Arm description

Participants aged 1 month to < 6 months received LEV 14 mg/kg/day as monotherapy at Visit 3 (Week 0) of First Period and dose up titrated up to 42 mg/kg/day. Participants aged 6 months to <4 years received LEV 20 mg/kg/day at Visit 3 (Week 0) of first period and dose up titrated up to a maximum of 60 mg/kg/day up to 6 weeks. The dose was increased by 2 weeks interval as per Investigator’s discretion. At Visit 6 (Week 6), dose of participants either down-titrated during 4 weeks interval or they entered in second period and continued LEV 14 to 42 mg/kg/day in participants aged 1 month to <6 months or LEV 20 to 60 mg/kg/day for participants aged ≥ 6 months <4 years at the discretion of the Investigator. Participants visited every 4 weeks for the first 6 months of administration and then every 12 weeks thereafter until approval or till the program discontinued. The dose down-titrated during 4 weeks Interval at the discretion of Investigator.

Arm type

Experimental

Investigational medicinal product name

Levetiracetam

Investigational medicinal product code

LEV

Other name

Keppra and E-Keppra

Pharmaceutical forms

Syrup

Routes of administration

Oral use

Dosage and administration details

Participants received LEV as prespecified.

Number of subjects in period 1	Levetiracetam: Adjunctive Therapy	Levetiracetam: Monotherapy
Started	32	6
Completed	27	6
Not completed	5	0
Adverse Event, non-fatal	2	-
Lack of efficacy	3	-

Period 2 title

Second Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Levetiracetam: Adjunctive Therapy

Arm description

Arm type

Experimental

Investigational medicinal product name

Levetiracetam

Investigational medicinal product code

Other name

Pharmaceutical forms

Syrup

Routes of administration

Oral use

Dosage and administration details

Participants received LEV as prespecified.

Levetiracetam: Monotherapy

Arm description

Arm type

Experimental

Investigational medicinal product name

Levetiracetam

Investigational medicinal product code

Other name

Pharmaceutical forms

Syrup

Routes of administration

Oral use

Dosage and administration details

Participants received LEV as prespecified.

Number of subjects in period 2	Levetiracetam: Adjunctive Therapy	Levetiracetam: Monotherapy
Started	27	6
Completed	8	4
Not completed	19	2
Physician decision	3	-
Consent withdrawn by subject	2	1
Adverse Event, non-fatal	1	1
Approved Drug Available For Indication	1	-
Protocol-Specified Withdrawal Criterion Met	1	-
Lack of efficacy	11	-

Baseline characteristics

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Reporting group title

Levetiracetam: Adjunctive Therapy

Reporting group description

Reporting group title

Levetiracetam: Monotherapy

Reporting group description

Reporting group values	Levetiracetam: Adjunctive Therapy	Levetiracetam: Monotherapy	Total
Number of subjects	32	6	38
Age Categorical
Units: Participants
28 days - <24 months	26	3	29
24 months - <12 years	6	3	9
Age Continuous
Units: Years
arithmetic mean (standard deviation)	14.7 ( 10.7 )	32.4 ( 13.2 )	-
Sex: Female, Male
Units: Participants
Female	15	5	20
Male	17	1	18

End points

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Reporting group title

Levetiracetam: Adjunctive Therapy

Reporting group description

Reporting group title

Levetiracetam: Monotherapy

Reporting group description

Reporting group title

Levetiracetam: Adjunctive Therapy

Reporting group description

Reporting group title

Levetiracetam: Monotherapy

Reporting group description

Primary: Percent change in partial seizure frequency per week from Baseline to Visit 6

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End point title

Percent change in partial seizure frequency per week from Baseline to Visit 6 ^[1] ^[2]

End point description

The percent difference in partial seizure frequency per week at Baseline and Study Visit 6 (Week 6) was computed as: {[(Number of partial seizures per week at Baseline) minus (Number of partial seizures per week at Study Visit 6)] divided by (Number of partial seizures per week at Baseline)} multiplied by 100. A positive value in percent difference from Baseline indicates a reduction in partial seizure frequency from Baseline. The Full Analysis Set Adjunctive therapy (FAS_A) consisted of all participants in the SS_A who had at least 1 post-Baseline efficacy assessment. Number of participants analyzed included those participants who were evaluable for the assessment.

End point type

Primary

End point timeframe

From Baseline (Week 0) to Visit 6 (up to Week 6)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Results were summarized and reported as descriptive statistics only for the single arm.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Inferential statistics are reported as descriptive statistics because the study is a single arm study.

End point values	Levetiracetam: Adjunctive Therapy
Number of subjects analysed	28
Units: percent change
median (confidence interval 95%)	24.24 (-25.48 to 51.85)

No statistical analyses for this end point

Secondary: Percent change in partial seizure frequency per week from Baseline to Visit 4

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End point title

Percent change in partial seizure frequency per week from Baseline to Visit 4 ^[3]

End point description

The percent difference in partial seizure frequency per week at Baseline and Study Visit 4 (Week 2) was computed as: {[(Number of partial seizures per week at Baseline) minus (Number of partial seizures per week at Study Visit 4)] divided by (Number of partial seizures per week at Baseline)} multiplied by 100. A positive value in percent difference from Baseline indicates a reduction in partial seizure frequency from Baseline. The FAS_A consisted of all participants in the SS_A who had at least 1 post-Baseline efficacy assessment.

End point type

Secondary

End point timeframe

From Baseline (Week 0) to Visit 4 (up to Week 2)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data of this outcome measure was analyzed and reported for participants on adjunctive therapy.

End point values	Levetiracetam: Adjunctive Therapy
Number of subjects analysed	32
Units: percent change
median (full range (min-max))	8.62 (-343.1 to 100.0)

No statistical analyses for this end point

Secondary: Percent change in partial seizure frequency per week from Baseline to Visit 5

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End point title

Percent change in partial seizure frequency per week from Baseline to Visit 5 ^[4]

End point description

The percent difference in partial seizure frequency per week at Baseline and Study Visit 5 (Week 4) was computed as: {[(Number of partial seizures per week at Baseline) minus (Number of partial seizures per week at Study Visit 5)] divided by (Number of partial seizures per week at Baseline)} multiplied by 100. A positive value in percent difference from Baseline indicates a reduction in partial seizure frequency from Baseline. The FAS_A consisted of all participants in the SS_A who had at least 1 post-Baseline efficacy assessment.

End point type

Secondary

End point timeframe

From Baseline (Week 0) to Visit 5 (up to Week 4)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data of this outcome measure was analyzed and reported for participants on adjunctive therapy.

End point values	Levetiracetam: Adjunctive Therapy
Number of subjects analysed	32
Units: percent change
median (full range (min-max))	16.79 (-414.3 to 100.0)

No statistical analyses for this end point

Secondary: Percent change from baseline for each analysis visit in partial seizure frequency per week on adjunctive therapy

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End point title

Percent change from baseline for each analysis visit in partial seizure frequency per week on adjunctive therapy ^[5]

End point description

Percent difference in partial seizure frequency (PSF) per week at each Analysis Visit: {[(Number of partial seizures per week at Baseline [BL]) - (Number of partial seizures per week at analysis visit X)]/(Number of partial seizures per week at BL)}*100. Positive value indicates reduction in PSF from BL. End of study (EOS)/early discontinuation visit (EDV) was based on last EDV and calculation of number of partial seizure per week were based on period from previous EDV visit. Mapping of seizure data to Analysis Visits was based on target dates of the visits. A seizure date after that of target date of an Analysis Visit n and up to that of target date of next Analysis Visit n+1 was mapped to next Analysis Visit (n+1). Data for one participant assessed within study duration was mapped to Analysis Visit 35/Week 300 based on statistical plan. Analysis set: FAS_A. Here, N = participants evaluable for this outcome measure. 'n' = participants evaluable at specified time points.

End point type

Secondary

End point timeframe

From Baseline (Week 0), Week 8, 10, 12, 15, 18, 21, 24, 27, 30, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, EOS/ED (up to Week 295), and Safety follow-up (up to Week 295)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data of this outcome measure was analyzed and reported for participants on adjunctive therapy.

End point values	Levetiracetam: Adjunctive Therapy
Number of subjects analysed	25
Units: percent change
median (full range (min-max))
Week 8 (n = 25)	35.53 (-137.9 to 100.0)
Week 10 (n = 24)	59.39 (-138.2 to 100.0)
Week 12 (n = 22)	50.90 (-167.8 to 100.0)
Week 15 (n = 22)	60.29 (-129.4 to 100.0)
Week 18 (n = 20)	82.74 (-22.3 to 100.0)
Week 21 (n = 20)	80.33 (-44.1 to 100.0)
Week 24 (n = 19)	88.44 (-97.8 to 100.0)
Week 27 (n = 18)	93.84 (-4.8 to 100.0)
Week 30 (n = 17)	98.05 (-4.8 to 100.0)
Week 36 (n = 16)	100.00 (-94.5 to 100.0)
Week 48 (n = 16)	98.70 (-28.4 to 100.0)
Week 60 (n = 13)	100.00 (44.7 to 100.0)
Week 72 (n = 13)	100.00 (32.0 to 100.0)
Week 84 (n = 13)	100.00 (62.9 to 100.0)
Week 96 (n = 12)	99.57 (78.2 to 100.0)
Week 108 (n = 11)	100.00 (-48.0 to 100.0)
Week 120 (n = 10)	100.00 (80.4 to 100.0)
Week 132 (n = 8)	100.00 (50.7 to 100.0)
Week 144 (n = 7)	100.00 (93.4 to 100.0)
Week 156 (n = 6)	99.76 (93.5 to 100.0)
Week 168 (n = 6)	99.74 (90.7 to 100.0)
Week 180 (n = 6)	99.02 (86.1 to 100.0)
Week 192 (n = 6)	99.76 (85.5 to 100.0)
Week 204 (n = 5)	97.94 (78.3 to 100.0)
Week 216 (n = 5)	96.58 (81.4 to 100.0)
Week 228 (n = 3)	97.12 (96.6 to 100.0)
Week 240 (n = 3)	96.36 (86.8 to 100.0)
Week 252 (n = 2)	91.12 (85.3 to 96.9)
Week 264 (n = 2)	96.91 (95.8 to 98.0)
Week 276 (n = 2)	96.40 (95.2 to 97.6)
Week 288 (n = 2)	96.14 (94.2 to 98.0)
Week 300 (n = 1)	89.7 (89.7 to 89.7)
EOS/EDV (n = 10)	21.86 (-120.1 to 100.0)
Safety Follow Up (n = 24)	39.82 (-267.8 to 100.0)

No statistical analyses for this end point

Secondary: Percent change in partial seizure frequency per week grouped into 6 categories on adjunctive therapy

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End point title

Percent change in partial seizure frequency per week grouped into 6 categories on adjunctive therapy ^[6]

End point description

Percent difference in PSF per week on adjunctive therapy at BL and each analysis visit:{[(Number of partial seizures per week at BL)-(Number of partial seizures per week at analysis visit X)]/(Number of partial seizures per week at BL)}*100. Percent difference in PSF per week from BL for each analysis visit reported into 6 categories:<0%, 0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100%. Positive value indicates reduction in PSF from BL. Outcome categories “≥50%”, “≥75%” and “100%” are overlapping, so that percentages of categories of this outcome measure can add up to more than 100%. Mapping of seizure data to Analysis Visits was based on target dates of visits. Seizure date after that of target date of Analysis Visit n and up to that of target date of next Visit n+1 was mapped to next Visit (n+1). Data for one participant assessed within study duration mapped to Analysis Visit 35/Week 300 based on statistical plan. FAS_M. 'n'=participants at risk at each previous analysis visit (X-1).

End point type

Secondary

End point timeframe

From Baseline (Week 0), Week 2, 4, 6, 8, 10, 12, 15, 18, 21, 24, 27, 30, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, EOS/EDV Week 2, EOS/EDV Week 4, and Safety follow-up (up to Week 295)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data of this outcome measure was analyzed and reported for participants on adjunctive therapy.

End point values	Levetiracetam: Adjunctive Therapy
Number of subjects analysed	32
Units: percent change
number (not applicable)
Week 2: <0% (n = 32)	43.8
Week 2: 0% - <25% (n = 32)	18.8
Week 2: 25% - <50% (n = 32)	9.4
Week 2: ≥ 50% (n = 32)	28.1
Week 2: ≥ 75% (n = 32)	12.5
Week 2: 100% (n = 32)	9.4
Week 4: <0% (n = 32)	37.5
Week 4: 0% - <25% (n = 32)	18.8
Week 4: 25% - <50% (n = 32)	15.6
Week 4: ≥ 50% (n = 32)	28.1
Week 4: ≥ 75% (n = 32)	18.8
Week 4: 100% (n = 32)	9.4
Week 6: <0% (n = 32)	31.3
Week 6: 0% - <25% (n = 32)	15.6
Week 6: 25% - <50% (n = 32)	12.5
Week 6: ≥ 50% (n = 32)	28.1
Week 6: ≥ 75% (n = 32)	18.8
Week 6: 100% (n = 32)	15.6
Week 8: <0% (n = 28)	21.4
Week 8: 0% - <25% (n = 28)	14.3
Week 8: 25% - <50% (n = 28)	17.9
Week 8: ≥ 50% (n = 28)	35.7
Week 8: ≥ 75% (n = 28)	25.0
Week 8: 100% (n = 28)	17.9
Week 10: <0% (n = 25)	24.0
Week 10: 0% - <25% (n = 25)	12.0
Week 10: 25% - <50% (n = 25)	8.0
Week 10: ≥ 50% (n = 25)	52.0
Week 10: ≥ 75% (n = 25)	28.0
Week 10: 100% (n = 25)	20.0
Week 12: <0% (n = 24)	20.8
Week 12: 0% - <25% (n = 24)	4.2
Week 12: 25% - <50% (n = 24)	20.8
Week 12: ≥ 50% (n = 24)	45.8
Week 12: ≥ 75% (n = 24)	37.5
Week 12: 100% (n = 24)	25.0
Week 15: <0% (n = 22)	13.6
Week 15: 0% - <25% (n = 22)	9.1
Week 15: 25% - <50% (n = 22)	13.6
Week 15: ≥ 50% (n = 22)	63.6
Week 15: ≥ 75% (n = 22)	36.4
Week 15: 100% (n = 22)	27.3
Week 18: <0% (n = 22)	9.1
Week 18: 0% - <25% (n = 22)	4.5
Week 18: 25% - <50% (n = 22)	9.1
Week 18: ≥ 50% (n = 22)	68.2
Week 18: ≥ 75% (n = 22)	54.5
Week 18: 100% (n = 22)	31.8
Week 21: <0% (n = 20)	10.0
Week 21: 0% - <25% (n = 20)	5.0
Week 21: 25% - <50% (n = 20)	5.0
Week 21: ≥ 50% (n = 20)	80.0
Week 21: ≥ 75% (n = 20)	55.0
Week 21: 100% (n = 20)	30.0
Week 24: <0% (n = 20)	10.0
Week 24: 0% - <25% (n = 20)	10.0
Week 24: 25% - <50% (n = 20)	5.0
Week 24: ≥ 50% (n = 20)	70.0
Week 24: ≥ 75% (n = 20)	55.0
Week 24: 100% (n = 20)	40.0
Week 27: <0% (n = 19)	5.3
Week 27: 0% - <25% (n = 19)	5.3
Week 27: 25% - <50% (n = 19)	10.5
Week 27: ≥ 50% (n = 19)	73.7
Week 27: ≥ 75% (n = 19)	52.6
Week 27: 100% (n = 19)	36.8
Week 30: <0% (n = 18)	5.6
Week 30: 0% - <25% (n = 18)	11.1
Week 30: 25% - <50% (n = 18)	5.6
Week 30: ≥ 50% (n = 18)	72.2
Week 30: ≥ 75% (n = 18)	55.6
Week 30: 100% (n = 18)	44.4
Week 36: <0% (n = 17)	11.8
Week 36: 0% - <25% (n = 17)	5.9
Week 36: 25% - <50% (n = 17)	0
Week 36: ≥ 50% (n = 17)	76.5
Week 36: ≥ 75% (n = 17)	70.6
Week 36: 100% (n = 17)	52.9
Week 48: <0% (n = 16)	6.3
Week 48: 0% - <25% (n = 16)	12.5
Week 48: 25% - <50% (n = 16)	6.3
Week 48: ≥ 50% (n = 16)	75.0
Week 48: ≥ 75% (n = 16)	75.0
Week 48:100% (n = 16)	43.8
Week 60: <0% (n = 16)	0
Week 60: 0% - <25% (n = 16)	0
Week 60: 25% - <50% (n = 16)	6.3
Week 60: ≥ 50% (n = 16)	75.0
Week 60: ≥ 75% (n = 16)	68.8
Week 60: 100% (n = 16)	43.8
Week 72: <0% (n = 13)	0
Week 72: 0% - <25% (n = 13)	0
Week 72: 25% - <50% (n = 13)	7.7
Week 72: ≥ 50% (n = 13)	92.3
Week 72: ≥ 75% (n = 13)	76.9
Week 72: 100% (n = 13)	53.8
Week 84: <0% (n = 13)	0
Week 84: 0% - <25% (n = 13)	0
Week 84: 25% - <50% (n = 13)	0
Week 84: ≥ 50% (n = 13)	100
Week 84: ≥ 75% (n = 13)	84.6
Week 84: 100% (n = 13)	53.8
Week 96: <0% (n = 13)	0
Week 96: 0% - <25% (n = 13)	0
Week 96: 25% - <50% (n = 13)	0
Week 96: ≥ 50% (n = 13)	92.3
Week 96: ≥ 75% (n = 13)	92.3
Week 96: 100% (n = 13)	46.2
Week 108: <0% (n = 12)	8.3
Week 108: 0% - <25% (n = 12)	0
Week 108: 25% - <50% (n = 12)	0
Week 108: ≥ 50% (n = 12)	83.3
Week 108: ≥ 75% (n = 12)	75.0
Week 108: 100% (n = 12)	50.0
Week 120: <0% (n = 11)	0
Week 120: 0% - <25% (n = 11)	0
Week 120: 25% - <50% (n = 11)	0
Week 120: ≥ 50% (n = 11)	90.9
Week 120: ≥ 75% (n = 11)	90.9
Week 120: 100% (n = 11)	63.6
Week 132: <0% (n = 10)	0
Week 132: 0% - <25% (n = 10)	0
Week 132: 25% - <50% (n = 10)	0
Week 132: ≥ 50% (n = 10)	80.0
Week 132: ≥ 75% (n = 10)	70.0
Week 132: 100% (n = 10)	50.0
Week 144: <0% (n = 8)	0
Week 144: 0% - <25% (n = 8)	0
Week 144: 25% - <50% (n = 8)	0
Week 144: ≥ 50% (n = 8)	87.5
Week 144: ≥ 75% (n = 8)	87.5
Week 144: 100% (n = 8)	50.0
Week 156: <0% (n = 7)	0
Week 156: 0% - <25% (n = 7)	0
Week 156: 25% - <50% (n = 7)	0
Week 156: ≥ 50% (n = 7)	85.7
Week 156: ≥ 75% (n = 7)	85.7
Week 156: 100% (n = 7)	42.9
Week 168: <0% (n = 6)	0
Week 168: 0% - <25% (n = 6)	0
Week 168: 25% - <50% (n = 6)	0
Week 168: ≥ 50% (n = 6)	100
Week 168: ≥ 75% (n = 6)	100
Week 168: 100% (n = 6)	50.0
Week 180: <0% (n = 6)	0
Week 180: 0% - <25% (n = 6)	0
Week 180: 25% - <50% (n = 6)	0
Week 180: ≥ 50% (n = 6)	100
Week 180: ≥ 75% (n = 6)	100
Week 180: 100% (n = 6)	50.0
Week 192: <0% (n = 6)	0
Week 192: 0% - <25% (n = 6)	0
Week 192: 25% - <50% (n = 6)	0
Week 192: ≥ 50% (n = 6)	100
Week 192: ≥ 75% (n = 6)	100
Week 192: 100% (n = 6)	50.0
Week 204: <0% (n = 6)	0
Week 204: 0% - <25% (n = 6)	0
Week 204: 25% - <50% (n = 6)	0
Week 204: ≥ 50% (n = 6)	83.3
Week 204: ≥ 75% (n = 6)	83.3
Week 204: 100% (n = 6)	16.7
Week 216: <0% (n = 5)	0
Week 216: 0% - <25% (n = 5)	0
Week 216: 25% - <50% (n = 5)	0
Week 216: ≥ 50% (n = 5)	100
Week 216: ≥ 75% (n = 5)	100
Week 216: 100% (n = 5)	20.0
Week 228: <0% (n = 5)	0
Week 228: 0% - <25% (n = 5)	0
Week 228: 25% - <50% (n = 5)	0
Week 228: ≥ 50% (n = 5)	60.0
Week 228: ≥ 75% (n = 5)	60.0
Week 228: 100% (n = 5)	20.0
Week 240: <0% (n = 3)	0
Week 240: 0% - <25% (n = 3)	0
Week 240: 25% - <50% (n = 3)	0
Week 240: ≥ 50% (n = 3)	100
Week 240: ≥ 75% (n = 3)	100
Week 240: 100% (n = 3)	33.3
Week 252: <0% (n = 3)	0
Week 252: 0% - <25% (n = 3)	0
Week 252: 25% - <50% (n = 3)	0
Week 252: ≥ 50% (n = 3)	66.7
Week 252: ≥ 75% (n = 3)	66.7
Week 252: 100% (n = 3)	0
Week 264: <0% (n = 2)	0
Week 264: 0% - <25% (n = 2)	0
Week 264: 25% - <50% (n = 2)	0
Week 264: ≥ 50% (n = 2)	100
Week 264: ≥ 75% (n = 2)	100
Week 264: 100% (n = 2)	0
Week 276: <0% (n = 2)	0
Week 276: 0% - <25% (n = 2)	0
Week 276: 25% - <50% (n = 2)	0
Week 276: ≥ 50% (n = 2)	100
Week 276: ≥ 75% (n = 2)	100
Week 276: 100% (n = 2)	0
Week 288: <0% (n = 2)	0
Week 288: 0% - <25% (n = 2)	0
Week 288: 25% - <50% (n = 2)	0
Week 288: ≥ 50% (n = 2)	100
Week 288: ≥ 75% (n = 2)	100
Week 288: 100% (n = 2)	0
Week 300: <0% (n = 2)	0
Week 300: 0% - <25% (n = 2)	0
Week 300: 25% - <50% (n = 2)	0
Week 300: ≥ 50% (n = 2)	50.0
Week 300: ≥ 75% (n = 2)	50.0
Week 300: 100% (n = 2)	0
EOS/EDV, Week 2: <0% (n = 32)	3.1
EOS/EDV, Week 2: 0% - <25% (n = 32)	3.1
EOS/EDV, Week 2: 25% - <50% (n = 32)	0
EOS/EDV, Week 2: ≥ 50% (n = 32)	3.1
EOS/EDV, Week 2: ≥ 75% (n = 32)	3.1
EOS/EDV, Week 2: 100% (n = 32)	3.1
EOS/EDV, Week 4: <0% (n = 10)	20.0
EOS/EDV, Week 4: 0% - <25% (n = 10)	10.0
EOS/EDV, Week 4: 25% - <50% (n = 10)	20.0
EOS/EDV, Week 4: ≥ 50% (n = 10)	20.0
EOS/EDV, Week 4: ≥ 75% (n = 10)	10.0
EOS/EDV, Week 4: 100% (n = 10)	0
Safety Follow Up: <0% (n = 24)	37.5
Safety Follow Up: 0% - <25% (n = 24)	4.2
Safety Follow Up: 25% - <50% (n = 24)	12.5
Safety Follow Up: ≥ 50% (n = 24)	45.8
Safety Follow Up: ≥ 75% (n = 24)	29.2
Safety Follow Up: 100% (n = 24)	20.8

No statistical analyses for this end point

Secondary: Percent change from baseline for each analysis visit in partial seizure frequency per week on monotherapy

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End point title

Percent change from baseline for each analysis visit in partial seizure frequency per week on monotherapy ^[7]

End point description

The percent difference in partial seizure frequency per week on monotherapy at Baseline and each analysis visit was computed as: {[(Number of partial seizures per week at Baseline) minus (Number of partial seizures per week at analysis visit X)] divided by (Number of partial seizures per week at Baseline)} multiplied by 100. A positive value in percent difference from Baseline indicates a reduction in partial seizure frequency from Baseline. The maximum duration of study participation in monotherapy participants was shorter than in adjunctive therapy. Therefore, data at Week 288 and 300 is not reported for Monotherapy. The FAS_M consisted of all participants in the SS_M who had at least 1 post-Baseline efficacy assessment. 'n' signifies participants who were evaluable at specified time points.

End point type

Secondary

End point timeframe

From Baseline (Week 0), Week 2, 4, 6, 8, 10, 12, 15, 18, 21, 24, 27, 30, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, and Safety follow-up (up to Week 295)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data of this outcome measure was analyzed and reported for participants on monotherapy.

End point values	Levetiracetam: Monotherapy
Number of subjects analysed	6
Units: percent change
median (full range (min-max))
Week 2 (n = 6)	-51.87 (-731.6 to 100.0)
Week 4 (n = 6)	4.88 (-115.9 to 100.0)
Week 6 (n = 6)	51.10 (-325.0 to 100.0)
Week 8 (n = 5)	100.00 (-1.1 to 100.0)
Week 10 (n = 5)	100.00 (-277.1 to 100.0)
Week 12 (n = 5)	76.92 (-10.0 to 100.0)
Week 15 (n = 5)	100.00 (-78.1 to 100.0)
Week 18 (n = 5)	91.58 (58.1 to 100.0)
Week 21 (n = 5)	100.00 (76.9 to 100.0)
Week 24 (n = 5)	100.00 (92.3 to 100.0)
Week 27 (n = 5)	100.00 (26.7 to 100.0)
Week 30 (n = 5)	100.00 (37.1 to 100.0)
Week 36 (n = 5)	100.00 (16.2 to 100.0)
Week 48 (n = 5)	98.08 (-138.3 to 100.0)
Week 60 (n = 5)	94.23 (-41.4 to 100.0)
Week 72 (n = 5)	92.31 (-36.2 to 100.0)
Week 84 (n = 5)	95.79 (-86.0 to 100.0)
Week 96 (n = 5)	98.08 (-65.0 to 100.0)
Week 108 (n = 5)	96.15 (-44.0 to 100.0)
Week 120 (n = 5)	93.68 (-46.7 to 100.0)
Week 132 (n = 4)	92.63 (-138.3 to 100.0)
Week 144 (n = 4)	92.63 (-106.9 to 100.0)
Week 156 (n = 4)	94.73 (8.3 to 100.0)
Week 168 (n = 4)	100.00 (-70.2 to 100.0)
Week 180 (n = 3)	100.00 (-274.5 to 100.0)
Week 192 (n = 3)	100.00 (-223.0 to 100.0)
Week 204 (n = 2)	100.00 (100.0 to 100.0)
Week 216 (n = 2)	100.00 (100.0 to 100.0)
Week 228 (n = 1)	100.00 (100.0 to 100.0)
Week 240 (n =1)	100.00 (100.0 to 100.0)
Week 252 (n = 1)	100.00 (100.0 to 100.0)
Week 264 (n = 1)	100.00 (100.0 to 100.0)
Week 276 (n =1)	100.00 (100.0 to 100.0)
Safety Follow Up (n = 2)	100.00 (100.0 to 100.0)

No statistical analyses for this end point

Secondary: Percent change in partial seizure frequency per week grouped into 6 categories on monotherapy

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End point title

Percent change in partial seizure frequency per week grouped into 6 categories on monotherapy ^[8]

End point description

Percent difference in partial seizure frequency per week on monotherapy at Baseline and each analysis visit computed as:{[(Number of partial seizures per week at Baseline)-(Number of partial seizures per week at analysis visit X)]/(Number of partial seizures per week at Baseline)}*100. Positive value in percent difference from Baseline indicates reduction in partial seizure frequency from Baseline. Percent difference in partial seizure frequency per week from Baseline for each analysis visit was reported into 6 categories:<0%,0% to <25%, 25% to <50%, ≥50%, ≥75%, and 100%. Outcome categories “≥50%”, “≥75%” and “100%” are overlapping, so that percentages of categories of this outcome measure can add up to more than 100%. Maximum duration of study participation in monotherapy participants was shorter than in adjunctive therapy. Therefore, data at Week 288 and 300 is not reported for Monotherapy. Analysis set:FAS_M. 'n' signifies participants at risk at each previous analysis visit(X-1).

End point type

Secondary

End point timeframe

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data of this outcome measure was analyzed and reported for participants on monotherapy.

End point values	Levetiracetam: Monotherapy
Number of subjects analysed	6
Units: percent change
number (not applicable)
Week 2: <0% (n = 5)	60.0
Week 2: 0% - <25% (n = 5)	0
Week 2: 25% - <50% (n = 5)	20.0
Week 2: ≥ 50% (n = 5)	40.0
Week 2: ≥ 75% (n = 5)	20.0
Week 2: 100% (n = 5)	20.0
Week 4: <0% (n = 6)	50.0
Week 4: 0% - <25% (n = 6)	0
Week 4: 25% - <50% (n = 6)	16.7
Week 4: ≥ 50% (n = 6)	33.3
Week 4: ≥ 75% (n = 6)	33.3
Week 4: 100% (n = 6)	33.3
Week 6: <0% (n = 6)	33.3
Week 6: 0% - <25% (n = 6)	0
Week 6: 25% - <50% (n = 6)	16.7
Week 6: ≥ 50% (n = 6)	50.0
Week 6: ≥ 75% (n = 6)	33.3
Week 6: 100% (n = 6)	16.7
Week 8: <0% (n = 6)	16.7
Week 8: 0% - <25% (n = 6)	16.7
Week 8: 25% - <50% (n = 6)	0
Week 8: ≥ 50% (n = 6)	50.0
Week 8: ≥ 75% (n = 6)	50.0
Week 8: 100% (n = 6)	50.0
Week 10: <0% (n = 5)	20.0
Week 10: 0% - <25% (n = 5)	0
Week 10: 25% - <50% (n = 5)	0
Week 10: ≥ 50% (n = 5)	80.0
Week 10: ≥ 75% (n = 5)	80.0
Week 10: 100% (n = 5)	60.0
Week 12: <0% (n = 5)	20.0
Week 12: 0% - <25% (n = 5)	0
Week 12: 25% - <50% (n = 5)	20.0
Week 12: ≥ 50% (n = 5)	60.0
Week 12: ≥ 75% (n = 5)	60.0
Week 12: 100% (n = 5)	40.0
Week 15: <0% (n = 5)	20.0
Week 15: 0% - <25% (n = 5)	0
Week 15: 25% - <50% (n = 5)	20.0
Week 15: ≥ 50% (n = 5)	60.0
Week 15: ≥ 75% (n = 5)	60.0
Week 15: 100% (n = 5)	60.0
Week 18: <0% (n = 5)	0
Week 18: 0% - <25% (n = 5)	0
Week 18: 25% - <50% (n = 5)	0
Week 18: ≥ 50% (n = 5)	100
Week 18: ≥ 75% (n = 5)	80.0
Week 18: 100% (n = 5)	40.0
Week 21: <0% (n = 5)	0
Week 21: 0% - <25% (n = 5)	0
Week 21: 25% - <50% (n = 5)	0
Week 21: ≥ 50% (n = 5)	100
Week 21: ≥ 75% (n = 5)	100
Week 21: 100% (n = 5)	60.0
Week 24: <0% (n = 5)	0
Week 24: 0% - <25% (n = 5)	0
Week 24: 25% - <50% (n = 5)	0
Week 24: ≥ 50% (n = 5)	100
Week 24: ≥ 75% (n = 5)	100
Week 24: 100% (n = 5)	80.0
Week 27: <0% (n = 5)	0
Week 27: 0% - <25% (n = 5)	0
Week 27: 25% - <50% (n = 5)	20.0
Week 27: ≥ 50% (n = 5)	80.0
Week 27: ≥ 75% (n = 5)	80.0
Week 27: 100% (n = 5)	80.0
Week 30: <0% (n = 5)	0
Week 30: 0% - <25% (n = 5)	0
Week 30: 25% - <50% (n = 5)	20.0
Week 30: ≥ 50% (n = 5)	80.0
Week 30: ≥ 75% (n = 5)	60.0
Week 30: 100% (n = 5)	60.0
Week 36: <0% (n = 5)	0
Week 36: 0% - <25% (n = 5)	20.0
Week 36: 25% - <50% (n = 5)	0
Week 36: ≥ 50% (n = 5)	80.0
Week 36: ≥ 75% (n = 5)	80.0
Week 36: 100% (n = 5)	60.0
Week 48: <0% (n = 5)	20.0
Week 48: 0% - <25% (n = 5)	0
Week 48: 25% - <50% (n = 5)	0
Week 48: ≥ 50% (n = 5)	80.0
Week 48: ≥ 75% (n = 5)	80.0
Week 48:100% (n = 5)	40.0
Week 60: <0% (n = 5)	20.0
Week 60: 0% - <25% (n = 5)	0
Week 60: 25% - <50% (n = 5)	0
Week 60: ≥ 50% (n = 5)	80.0
Week 60: ≥ 75% (n = 5)	80.0
Week 60: 100% (n = 5)	40.0
Week 72: <0% (n = 5)	20.0
Week 72: 0% - <25% (n = 5)	0
Week 72: 25% - <50% (n = 5)	0
Week 72: ≥ 50% (n = 5)	80.0
Week 72: ≥ 75% (n = 5)	80.0
Week 72: 100% (n = 5)	40.0
Week 84: <0% (n = 5)	20.0
Week 84: 0% - <25% (n = 5)	0
Week 84: 25% - <50% (n = 5)	0
Week 84: ≥ 50% (n = 5)	80.0
Week 84: ≥ 75% (n = 5)	80.0
Week 84: 100% (n = 5)	40.0
Week 96: <0% (n = 5)	20.0
Week 96: 0% - <25% (n = 5)	0
Week 96: 25% - <50% (n = 5)	0
Week 96: ≥ 50% (n = 5)	80.0
Week 96: ≥ 75% (n = 5)	80.0
Week 96: 100% (n = 5)	40.0
Week 108: <0% (n = 5)	20.0
Week 108: 0% - <25% (n = 5)	0
Week 108: 25% - <50% (n = 5)	0
Week 108: ≥ 50% (n = 5)	80.0
Week 108: ≥ 75% (n = 5)	80.0
Week 108: 100% (n = 5)	40.0
Week 120: <0% (n = 5)	20.0
Week 120: 0% - <25% (n = 5)	0
Week 120: 25% - <50% (n = 5)	0
Week 120: ≥ 50% (n = 5)	80.0
Week 120: ≥ 75% (n = 5)	80.0
Week 120: 100% (n = 5)	40.0
Week 132: <0% (n = 5)	20.0
Week 132: 0% - <25% (n = 5)	0
Week 132: 25% - <50% (n = 5)	0
Week 132: ≥ 50% (n = 5)	60.0
Week 132: ≥ 75% (n = 5)	60.0
Week 132: 100% (n = 5)	40.0
Week 144: <0% (n = 4)	25.0
Week 144: 0% - <25% (n = 4)	0
Week 144: 25% - <50% (n = 4)	0
Week 144: ≥ 50% (n = 4)	75.0
Week 144: ≥ 75% (n = 4)	75.0
Week 144: 100% (n = 4)	50.0
Week 156: <0% (n = 4)	0
Week 156: 0% - <25% (n = 4)	25.0
Week 156: 25% - <50% (n = 4)	0
Week 156: ≥ 50% (n = 4)	75.0
Week 156: ≥ 75% (n = 4)	75.0
Week 156: 100% (n = 4)	50.0
Week 168: <0% (n = 4)	25.0
Week 168: 0% - <25% (n = 4)	0
Week 168: 25% - <50% (n = 4)	0
Week 168: ≥ 50% (n = 4)	75.0
Week 168: ≥ 75% (n = 4)	75.0
Week 168: 100% (n = 4)	75.0
Week 180: <0% (n = 4)	25.0
Week 180: 0% - <25% (n = 4)	0
Week 180: 25% - <50% (n = 4)	0
Week 180: ≥ 50% (n = 4)	50.0
Week 180: ≥ 75% (n = 4)	50.0
Week 180: 100% (n = 4)	50.0
Week 192: <0% (n = 3)	33.3
Week 192: 0% - <25% (n = 3)	0
Week 192: 25% - <50% (n = 3)	0
Week 192: ≥ 50% (n = 3)	66.7
Week 192: ≥ 75% (n = 3)	66.7
Week 192: 100% (n = 3)	66.7
Week 204: <0% (n = 3)	0
Week 204: 0% - <25% (n = 3)	0
Week 204: 25% - <50% (n = 3)	0
Week 204: ≥ 50% (n = 3)	66.7
Week 204: ≥ 75% (n = 3)	66.7
Week 204: 100% (n = 3)	66.7
Week 216: <0% (n = 2)	0
Week 216: 0% - <25% (n = 2)	0
Week 216: 25% - <50% (n = 2)	0
Week 216: ≥ 50% (n = 2)	100
Week 216: ≥ 75% (n = 2)	100
Week 216: 100% (n = 2)	100
Week 228: <0% (n = 2)	0
Week 228: 0% - <25% (n = 2)	0
Week 228: 25% - <50% (n = 2)	0
Week 228: ≥ 50% (n = 2)	50.0
Week 228: ≥ 75% (n = 2)	50.0
Week 228: 100% (n = 2)	50.0
Week 240: <0% (n = 1)	0
Week 240: 0% - <25% (n = 1)	0
Week 240: 25% - <50% (n = 1)	0
Week 240: ≥ 50% (n = 1)	100
Week 240: ≥ 75% (n = 1)	100
Week 240: 100% (n = 1)	100
Week 252: <0% (n = 1)	0
Week 252: 0% - <25% (n = 1)	0
Week 252: 25% - <50% (n = 1)	0
Week 252: ≥ 50% (n = 1)	100
Week 252: ≥ 75% (n = 1)	100
Week 252: 100% (n = 1)	100
Week 264: <0% (n = 1)	0
Week 264: 0% - <25% (n = 1)	0
Week 264: 25% - <50% (n = 1)	0
Week 264: ≥ 50% (n = 1)	100
Week 264: ≥ 75% (n = 1)	100
Week 264: 100% (n = 1)	100
Week 276: <0% (n = 1)	0
Week 276: 0% - <25% (n = 1)	0
Week 276: 25% - <50% (n = 1)	0
Week 276: ≥ 50% (n = 1)	100
Week 276: ≥ 75% (n = 1)	100
Week 276: 100% (n = 1)	100
Safety Follow Up: <0% (n = 2)	0
Safety Follow Up: 0% - <25% (n = 2)	0
Safety Follow Up: 25% - <50% (n = 2)	0
Safety Follow Up: ≥ 50% (n = 2)	100
Safety Follow Up: ≥ 75% (n = 2)	100
Safety Follow Up: 100% (n = 2)	100

No statistical analyses for this end point

Secondary: Percentage of Participants with treatment-emergent adverse events (TEAEs) during the First Period

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End point title

Percentage of Participants with treatment-emergent adverse events (TEAEs) during the First Period

End point description

An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation Participant administered a pharmaceutical product that does not necessarily have a causal relationship treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. The TEAEs were defined as those events that started on or after the date (and time) of first dose of study medication, or adverse events whose intensity worsened on or after the date (and time) of first dose of study medication. The SS_A consisted of all enrolled participants on adjunctive therapy who received at least 1 dose of study medication in the evaluation period. The SS_M consisted of all enrolled participants on monotherapy who received at least 1 dose of study medication in the evaluation period.

End point type

Secondary

End point timeframe

From Baseline (Week 0) to Visit 6 (up to Week 6)

End point values	Levetiracetam: Adjunctive Therapy	Levetiracetam: Monotherapy
Number of subjects analysed	32	6
Units: percentage of participants
number (not applicable)	62.5	0

No statistical analyses for this end point

Secondary: Percentage of Participants with treatment-emergent serious adverse events (SAEs) during the First Period

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End point title

Percentage of Participants with treatment-emergent serious adverse events (SAEs) during the First Period

End point description

Serious adverse event (SAE) is defined any untoward medical occurrence at any dose results in: Death; Life-threatening; Significant or persistent disability/incapacity; Congenital anomaly/birth defect (including that occurring in fetus); Important medical event that, based upon appropriate medical judgment, may jeopardize patient or participant and may require medical or surgical intervention to prevent 1 of other outcomes listed in definition of serious; Initial inpatient hospitalization or prolongation of hospitalization. TEAEs were defined as those events that started on or after date (and time) of first dose of study medication, or adverse events whose intensity worsened on or after date (and time) of first dose of study medication. SS_A: all enrolled participants on adjunctive therapy who received at least 1 dose of study medication in the evaluation period. SS_M: all enrolled participants on monotherapy who received at least 1 dose of study medication in the evaluation period.

End point type

Secondary

End point timeframe

From Baseline (Week 0) to Visit 6 (up to Week 6)

End point values	Levetiracetam: Adjunctive Therapy	Levetiracetam: Monotherapy
Number of subjects analysed	32	6
Units: percentage of participants
number (not applicable)	9.4	0

No statistical analyses for this end point

Secondary: Percentage of Participants with TEAEs leading to discontinuation from study medication during the First Period

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End point title

Percentage of Participants with TEAEs leading to discontinuation from study medication during the First Period

End point description

AE is any untoward medical occurrence in patient or clinical investigation participant administered pharmaceutical product that does not necessarily have causal relationship treatment. AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of medicinal (investigational) product, whether or not related to medicinal (investigational) product. TEAEs were defined as those events that started on or after the date (and time) of first dose of study medication, or adverse events whose intensity worsened on or after date (and time) of first dose of study medication. TEAEs leading to discontinuation from study medication are reported. SS_A: participants on adjunctive therapy who received at least 1 dose of study medication in the evaluation period. SS_M consisted of all enrolled participants on monotherapy who received at least 1 dose of study medication in the evaluation period.

End point type

Secondary

End point timeframe

From Baseline (Week 0) to Visit 6 (up to Week 6)

End point values	Levetiracetam: Adjunctive Therapy	Levetiracetam: Monotherapy
Number of subjects analysed	32	6
Units: percentage of participants
number (not applicable)	6.3	0

No statistical analyses for this end point

Secondary: Percentage of Participants with TEAEs during the Combined First and Second Period

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End point title

Percentage of Participants with TEAEs during the Combined First and Second Period

End point description

An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. The TEAEs were defined as those events that started on or after the date (and time) of first dose of study medication, or adverse events whose intensity worsened on or after the date (and time) of first dose of study medication. The SS_A consisted of all enrolled participants on adjunctive therapy who received at least 1 dose of study medication in the evaluation period. The SS_M consisted of all enrolled participants on monotherapy who received at least 1 dose of study medication in the evaluation period.

End point type

Secondary

End point timeframe

From Baseline (Week 0) to the End of Safety Follow-up (up to Week 295)

End point values	Levetiracetam: Adjunctive Therapy	Levetiracetam: Monotherapy
Number of subjects analysed	32	6
Units: percentage of participants
number (not applicable)	96.9	100

No statistical analyses for this end point

Secondary: Percentage of Participants with treatment-emergent SAEs during the Combined First and Second Period

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End point title

Percentage of Participants with treatment-emergent SAEs during the Combined First and Second Period

End point description

A SAE is defined as any untoward medical occurrence at any dose results in: Death; Life-threatening; Significant or persistent disability/incapacity; Congenital anomaly/birth defect (including that occurring in fetus); Important medical event that, based upon appropriate medical judgment, may jeopardize patient or participant and may require medical or surgical intervention to prevent 1 of other outcomes listed in definition of serious; Initial inpatient hospitalization or prolongation of hospitalization. TEAEs were defined as those events that started on or after date (and time) of first dose of study medication, or adverse events whose intensity worsened on or after date (and time) of first dose of study medication. SS_A: all enrolled participants on adjunctive therapy who received at least 1 dose of study medication in the evaluation period. SS_M: all enrolled participants on monotherapy who received at least 1 dose of study medication in the evaluation period.

End point type

Secondary

End point timeframe

From Baseline (Week 0) to the End of Safety Follow-up (up to Week 295)

End point values	Levetiracetam: Adjunctive Therapy	Levetiracetam: Monotherapy
Number of subjects analysed	32	6
Units: percentage of participants
number (not applicable)	56.3	33.3

No statistical analyses for this end point

Secondary: Percentage of Participants with TEAEs leading to discontinuation from study medication during the Combined First and Second Period

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End point title

Percentage of Participants with TEAEs leading to discontinuation from study medication during the Combined First and Second Period

End point description

End point type

Secondary

End point timeframe

From Baseline (Week 0) to the End of Safety Follow-up (up to Week 295)

End point values	Levetiracetam: Adjunctive Therapy	Levetiracetam: Monotherapy
Number of subjects analysed	32	6
Units: percentage of participants
number (not applicable)	9.4	16.7

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Baseline (Week 0) to the End of Safety Follow-up (up to Week 295)

Adverse event reporting additional description

The TEAEs were defined as those events that started on or after the date (and time) of first dose of study medication, or adverse events whose intensity worsened on or after the date (and time) of first dose of study medication. TEAEs were analyzed and reported for SS_A and SS_M.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Levetiracetam: Monotherapy

Reporting group description

Reporting group title

Levetiracetam: Adjunctive Therapy

Reporting group description

Serious adverse events	Levetiracetam: Monotherapy	Levetiracetam: Adjunctive Therapy
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 6 (33.33%)	18 / 32 (56.25%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Investigations
Blood pressure increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Post procedural fistula
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Cryptorchism
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Epilepsy surgery
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Somnolence
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure cluster
subjects affected / exposed	1 / 6 (16.67%)	2 / 32 (6.25%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 6 (16.67%)	2 / 32 (6.25%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infantile spasms
subjects affected / exposed	0 / 6 (0.00%)	3 / 32 (9.38%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 6 (0.00%)	3 / 32 (9.38%)
occurrences causally related to treatment / all	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Selective eating disorder
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia viral
subjects affected / exposed	0 / 6 (0.00%)	3 / 32 (9.38%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory syncytial virus bronchitis
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coronavirus infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis viral
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 6 (16.67%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Levetiracetam: Monotherapy	Levetiracetam: Adjunctive Therapy
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	28 / 32 (87.50%)
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	2 / 6 (33.33%)	12 / 32 (37.50%)
occurrences all number	3	51
Immune system disorders
Food allergy
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	2
Reproductive system and breast disorders
Balanoposthitis
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	2
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract inflammation
subjects affected / exposed	2 / 6 (33.33%)	3 / 32 (9.38%)
occurrences all number	2	8
Cough
subjects affected / exposed	0 / 6 (0.00%)	3 / 32 (9.38%)
occurrences all number	0	7
Rhinitis allergic
subjects affected / exposed	2 / 6 (33.33%)	3 / 32 (9.38%)
occurrences all number	2	4
Rhinorrhoea
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	2
Allergic bronchitis
subjects affected / exposed	1 / 6 (16.67%)	1 / 32 (3.13%)
occurrences all number	1	1
Epistaxis
subjects affected / exposed	3 / 6 (50.00%)	1 / 32 (3.13%)
occurrences all number	4	1
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 6 (16.67%)	2 / 32 (6.25%)
occurrences all number	1	2
Irritability
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	2
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences all number	1	0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences all number	1	0
Glucose urine present
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences all number	1	0
Injury, poisoning and procedural complications
Skin abrasion
subjects affected / exposed	0 / 6 (0.00%)	3 / 32 (9.38%)
occurrences all number	0	3
Arthropod bite
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	3
Fall
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	2
Contusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences all number	1	0
Lip injury
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences all number	2	0
Oral contusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences all number	1	0
Thermal burn
subjects affected / exposed	1 / 6 (16.67%)	1 / 32 (3.13%)
occurrences all number	1	1
Nervous system disorders
Somnolence
subjects affected / exposed	0 / 6 (0.00%)	6 / 32 (18.75%)
occurrences all number	0	7
Eye disorders
Conjunctivitis allergic
subjects affected / exposed	2 / 6 (33.33%)	3 / 32 (9.38%)
occurrences all number	2	4
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 6 (16.67%)	6 / 32 (18.75%)
occurrences all number	1	10
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	8 / 32 (25.00%)
occurrences all number	0	10
Abdominal pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences all number	1	0
Dental caries
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	2
Nausea
subjects affected / exposed	0 / 6 (0.00%)	3 / 32 (9.38%)
occurrences all number	0	3
Vomiting
subjects affected / exposed	1 / 6 (16.67%)	4 / 32 (12.50%)
occurrences all number	1	4
Skin and subcutaneous tissue disorders
Urticaria thermal
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences all number	1	0
Eczema
subjects affected / exposed	1 / 6 (16.67%)	9 / 32 (28.13%)
occurrences all number	1	16
Dermatitis diaper
subjects affected / exposed	0 / 6 (0.00%)	4 / 32 (12.50%)
occurrences all number	0	9
Dry skin
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	3
Miliaria
subjects affected / exposed	1 / 6 (16.67%)	2 / 32 (6.25%)
occurrences all number	1	2
Rash
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	2
Dermatitis
subjects affected / exposed	1 / 6 (16.67%)	1 / 32 (3.13%)
occurrences all number	1	1
Dermatitis atopic
subjects affected / exposed	1 / 6 (16.67%)	1 / 32 (3.13%)
occurrences all number	1	1
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences all number	1	0
Infections and infestations
COVID-19
subjects affected / exposed	1 / 6 (16.67%)	3 / 32 (9.38%)
occurrences all number	1	3
Hand-foot-and-mouth disease
subjects affected / exposed	3 / 6 (50.00%)	3 / 32 (9.38%)
occurrences all number	3	3
Hordeolum
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	4
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	3
Coronavirus infection
subjects affected / exposed	0 / 6 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	2
Molluscum contagiosum
subjects affected / exposed	1 / 6 (16.67%)	2 / 32 (6.25%)
occurrences all number	1	2
Impetigo
subjects affected / exposed	1 / 6 (16.67%)	1 / 32 (3.13%)
occurrences all number	1	1
Pharyngitis
subjects affected / exposed	1 / 6 (16.67%)	1 / 32 (3.13%)
occurrences all number	1	1
Tonsillitis
subjects affected / exposed	1 / 6 (16.67%)	1 / 32 (3.13%)
occurrences all number	1	1
Cystitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences all number	1	0
Pharyngitis streptococcal
subjects affected / exposed	1 / 6 (16.67%)	0 / 32 (0.00%)
occurrences all number	1	0
Otitis media
subjects affected / exposed	0 / 6 (0.00%)	3 / 32 (9.38%)
occurrences all number	0	5
Respiratory syncytial virus infection
subjects affected / exposed	1 / 6 (16.67%)	4 / 32 (12.50%)
occurrences all number	1	5
Exanthema subitum
subjects affected / exposed	0 / 6 (0.00%)	5 / 32 (15.63%)
occurrences all number	0	5
Influenza
subjects affected / exposed	1 / 6 (16.67%)	5 / 32 (15.63%)
occurrences all number	1	6
Conjunctivitis
subjects affected / exposed	0 / 6 (0.00%)	6 / 32 (18.75%)
occurrences all number	0	16
Gastroenteritis
subjects affected / exposed	2 / 6 (33.33%)	7 / 32 (21.88%)
occurrences all number	4	11
Nasopharyngitis
subjects affected / exposed	5 / 6 (83.33%)	17 / 32 (53.13%)
occurrences all number	21	108

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Were there any global substantial amendments to the protocol? Yes

28 Jun 2018

Protocol Amendment 2, dated 28 Jun 2018, provided the following changes: • The long-term efficacy and safety assessments were updated so that they were more appropriate, taking into account 48h video-electroencephalogram (EEG) failures. − The secondary objectives to be evaluated during the Second Period were changed to be evaluated during the combined First and Second Periods. − Efficacy variables, safety variables, the schedule of assessments for study participants who were 48h video-EEG failures, the study schematic, and the planned analyses and analysis sets were updated. • Minor administrative edits, including typographical changes for formatting, were made.

29 Jun 2020

Protocol Amendment 3, dated 29 Jan 2020, provided the following changes: • The primary efficacy variable was changed from daily partial seizure frequency monitored by 48h video-EEG to partial seizure frequency per week from Baseline to Visit 6 as agreed with Pharmaceuticals and Medical Devices Agency (PMDA). Text was revised throughout to reflect the change from 48h video-EEG to patient diary (ie, Daily Record Card [DRC]). • Study participants who were directly enrolled in the Second Period based on the protocol prior to Amendment 3 were to be included in the efficacy and safety analyses, with remapping of visit numbers to correspond to those for study participants who enrolled in the First Period. • Minor administrative edits were made.

22 Feb 2023

Protocol Amendment 4, dated 22 Feb 2023, provided the following changes: • The summary was updated to comply with regulations in Japan for the conduct of postmarketing clinical studies: − EP0100 was to be conducted as a clinical study (Phase 3) until approval was obtained for the indication of levetiracetam (LEV) as monotherapy or adjunctive treatment in study participants aged 1 month to <4 years with partial seizures, and continued as a postmarketing clinical study (Phase 4) after the date of approval until the study participant was switched to commercial LEV as soon as possible, or until LEV was discontinued after a period of dose reduction. In Japan, the meaning and expressions related to "clinical study" shall automatically be read as "postmarketing clinical study" after the date of approval in Japan. • Minor administrative edits were made.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: An Open-Lable, 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent change in partial seizure frequency per week from Baseline to Visit 6

Primary: Percent change in partial seizure frequency per week from Baseline to Visit 6

Secondary: Percent change in partial seizure frequency per week from Baseline to Visit 4

Secondary: Percent change in partial seizure frequency per week from Baseline to Visit 4

Secondary: Percent change in partial seizure frequency per week from Baseline to Visit 5

Secondary: Percent change in partial seizure frequency per week from Baseline to Visit 5

Secondary: Percent change from baseline for each analysis visit in partial seizure frequency per week on adjunctive therapy

Secondary: Percent change from baseline for each analysis visit in partial seizure frequency per week on adjunctive therapy

Secondary: Percent change in partial seizure frequency per week grouped into 6 categories on adjunctive therapy

Secondary: Percent change in partial seizure frequency per week grouped into 6 categories on adjunctive therapy

Secondary: Percent change from baseline for each analysis visit in partial seizure frequency per week on monotherapy

Secondary: Percent change from baseline for each analysis visit in partial seizure frequency per week on monotherapy

Secondary: Percent change in partial seizure frequency per week grouped into 6 categories on monotherapy

Secondary: Percent change in partial seizure frequency per week grouped into 6 categories on monotherapy

Secondary: Percentage of Participants with treatment-emergent adverse events (TEAEs) during the First Period

Secondary: Percentage of Participants with treatment-emergent adverse events (TEAEs) during the First Period

Secondary: Percentage of Participants with treatment-emergent serious adverse events (SAEs) during the First Period

Secondary: Percentage of Participants with treatment-emergent serious adverse events (SAEs) during the First Period

Secondary: Percentage of Participants with TEAEs leading to discontinuation from study medication during the First Period

Secondary: Percentage of Participants with TEAEs leading to discontinuation from study medication during the First Period

Secondary: Percentage of Participants with TEAEs during the Combined First and Second Period

Secondary: Percentage of Participants with TEAEs during the Combined First and Second Period

Secondary: Percentage of Participants with treatment-emergent SAEs during the Combined First and Second Period

Secondary: Percentage of Participants with treatment-emergent SAEs during the Combined First and Second Period

Secondary: Percentage of Participants with TEAEs leading to discontinuation from study medication during the Combined First and Second Period

Secondary: Percentage of Participants with TEAEs leading to discontinuation from study medication during the Combined First and Second Period

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
An Open-Lable, 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