A Double-blind, Placebo-controlled Study of Levetiracetam in Epilepsy Patients With Generalized Tonic-clonic Seizures (Except Partial Seizures Evolving to Secondarily Generalized Seizures)

• ClinicalTrials.gov Identifier: NCT01228747
• Recruitment Status: Completed
• First Posted: October 26, 2010
• Results First Posted: May 13, 2015
• Last Update Posted: January 15, 2019
• Sponsor: UCB Japan Co. Ltd.
• Information provided by (Responsible Party): UCB Pharma ( UCB Japan Co. Ltd. )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Epilepsy; Generalized Tonic-Clonic Seizures
• Interventions: Drug: Levetiracetam; Drug: Placebo
• Enrollment: 361

Participant Flow

Recruitment Details	This study started to enroll subjects in Japan and China in October 2010.
Pre-assignment Details	Participant Flow refers to the Randomized Set consisting of all screened subjects who signed the Informed Consent form, participated in the prospective Baseline Period and were randomized at Visit 2.

Arm/Group Title	Placebo	Levetiracetam
Arm/Group Description	Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily for 28 weeks	Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily
Period Title: Overall Study
Started	125	126
Completed	60	81
Not Completed	65	45
Reason Not Completed
Adverse Event	8	4
Lack of Efficacy	40	27
Protocol Violation	6	5
Lost to Follow-up	4	3
Withdrawal by Subject	5	1
Other Reason	2	5

Baseline Characteristics

Arm/Group Title		Placebo	Levetiracetam	Total
Arm/Group Description		Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily	Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily	Total of all reporting groups
Overall Number of Baseline Participants		125	126	251
Baseline Analysis Population Description		Baseline Characteristics refer to the Safety Set (SS), which is a subset of the Randomized Set and consisted of all subjects who received at least 1 dose of study medication after randomization, either Placebo or Levetiracetam.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	125 participants	126 participants	251 participants
	<=18 years	11 8.8%	10 7.9%	21 8.4%
	Between 18 and 65 years	113 90.4%	115 91.3%	228 90.8%
	>=65 years	1 0.8%	1 0.8%	2 0.8%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	125 participants	126 participants	251 participants
		32.8 (12.5)	31.5 (11.3)	32.2 (11.9)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	125 participants	126 participants	251 participants
	Female	49 39.2%	47 37.3%	96 38.2%
	Male	76 60.8%	79 62.7%	155 61.8%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	125 participants	126 participants	251 participants
China		104	104	208
Japan		21	22	43

Outcome Measures

1. Primary Outcome

Title	Percentage Change From the Combined Baseline in the Generalized Tonic-clonic Seizure Frequency Per Week Over the 28-week Treatment Period (Dose Adjustment + Evaluation Periods)
Description	Percentage change in generalized tonic-clonic (GTC) seizure frequency per week from Combined Baseline B over the Treatment Period A is calculated using the equation: Percentage change from Baseline = ((A-B)/B)*100. Percentage change from baseline is not defined for subjects whose baseline information is missing / unknown or equal to zero, or whose seizure frequency per week is missing / unknown. A negative value in change in generalized tonic-clonic (GTC) seizure frequency indicates a reduction of generalized tonic-clonic (GTC) seizure frequency over the 28-week treatment Period. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline
Time Frame	From Baseline to Week 28

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all subjects in the SS who had an evaluable Baseline and at least 1 post-Baseline GTC seizure count data point for the primary efficacy analysis excluding those who had seriously violated GCP. Evaluable Baseline for the primary efficacy analysis: at least 1 GTC seizure was documented for the Combined Baseline.

Arm/Group Title	Placebo	Levetiracetam
Arm/Group Description:	Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily for 28 weeks	Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily
Overall Number of Participants Analyzed	109	117
Mean (Standard Deviation); Unit of Measure: Percentage Change
	-13.19 (55.54)	-68.22 (34.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Levetiracetam
	Comments	The statistical hypotheses, null hypothesis (H0) and alternate hypothesis (H1), are stated below: H0: μLEV = μPBO vs. H1: μLEV ≠ μPBO ANCOVA on the endpoint "percentage change from Combined Baseline of GTC seizures per week" using "treatment" and "country" as factors (categorical predictors) and "Combined Baseline GTC seizure frequency per week" as a covariate (a continuous predictor) where μLEV and μPBO are adjusted means for LEV and PBO, respectively.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Statistical testing was 2-sided, and was performed using a significance (α) level of 0.05.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	- 56.13
	Confidence Interval	(2-Sided) 95%; - 68.24 to - 44.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.15
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	The Percentage Change in Generalized Tonic-clonic Seizure Frequency Per Week From the Combined Baseline Over the Evaluation Period
Description	Percentage change in generalized tonic-clonic (GTC) seizure frequency per week from combined baseline B over the Evaluation Period A is calculated using the equation: Percentage change from Baseline = ((A-B)/B)*100. Percentage change from baseline is not defined for subjects whose baseline Information is missing / unknown or equal to zero, or whose seizure frequency per week is missing / unknown. A negative value in change in generalized tonic-clonic (GTC) seizure frequency indicates a reduction of generalized tonic-clonic (GTC) seizure frequency. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline.
Time Frame	From Baseline to Evaluation Period (Week 12 to Week 28)

Outcome Measure Data

Analysis Population Description

Of the 226 subjects in the Full Analysis Set (FAS), 205 are included in the analysis of this Outcome Measure in Evaluation Period.

Arm/Group Title	Placebo	Levetiracetam
Arm/Group Description:	Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily for 28 weeks	Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily
Overall Number of Participants Analyzed	97	108
Mean (Standard Deviation); Unit of Measure: Percentage Change
	-4.44 (153.82)	-68.27 (42.63)

3. Secondary Outcome

Title	Generalized Tonic-clonic Seizures 50 % Responder Rate (the Proportion of Subjects With 50 % or More Reduction From the Combined Baseline in the Frequency of Generalized Tonic-clonic Seizures) During the Treatment Period
Description	A subject with an at least 50 % reduction in weekly generalized tonic-clonic (GTC) seizure frequency from Combined Baseline Period to the Treatment Period is considered a GTC 50 % responder. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline
Time Frame	From Baseline to Week 28

Outcome Measure Data

Analysis Population Description

Full Analysis Set consisted of all subjects in the SS who had an evaluable Baseline and at least 1 post-Baseline GTC seizure count data point for the primary efficacy analysis excluding those who had seriously violated GCP. Evaluable Baseline for the primary efficacy analysis: at least 1 GTC seizure was documented for the Combined Baseline.

Arm/Group Title	Placebo	Levetiracetam
Arm/Group Description:	Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily for 28 weeks	Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily
Overall Number of Participants Analyzed	109	117
Measure Type: Number; Unit of Measure: participants
	31	91

4. Secondary Outcome

Title	Generalized Tonic-clonic Seizures 50 % Responder Rate (the Proportion of Subjects With 50 % or More Reduction From the Combined Baseline in the Frequency of Generalized Tonic-clonic Seizures) During the Evaluation Period
Description	A subject with an at least 50 % reduction in weekly generalized tonic-clonic (GTC) seizure frequency from Combined Baseline Period to the Evaluation Period is considered a GTC 50 % responder. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline
Time Frame	From Baseline to Evaluation Period (Week 12 to Week 28)

Outcome Measure Data

Analysis Population Description

Of the 226 subjects in the Full Analysis Set (FAS), 205 are included in the analysis of this Outcome Measure.

Arm/Group Title	Placebo	Levetiracetam
Arm/Group Description:	Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily for 28 weeks	Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily
Overall Number of Participants Analyzed	97	108
Measure Type: Number; Unit of Measure: participants
	33	82

5. Secondary Outcome

Title	Generalized Tonic-clonic Seizure Freedom Over the Evaluation Period
Description	A subject with a non-missing weekly generalized tonic-clonic (GTC) baseline seizure frequency and a weekly GTC seizure frequency of zero throughout the Evaluation Period, is considered as a GTC seizure-free subject on the Evaluation Period.
Time Frame	Evaluation Period (Week 12 to Week 28)

Outcome Measure Data

Analysis Population Description

Of the 226 subjects in the Full Analysis Set (FAS), 205 are included in the analysis of this Outcome Measure.

Arm/Group Title	Placebo	Levetiracetam
Arm/Group Description:	Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily for 28 weeks	Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily
Overall Number of Participants Analyzed	97	108
Measure Type: Number; Unit of Measure: participants
	3	32

Adverse Events

Time Frame	Adverse Events were collected from the Prospective Baseline Period ( Week -8 to Week 0) over Dose Adjustment (12 weeks) and Evaluation Period (16 weeks) until Conversion or Withdrawal Period (4-6 weeks).
Adverse Event Reporting Description	Adverse Events refer to the Safety Set (SS), which is a subset of the Randomized Set and consisted of all subjects who received at least 1 dose of study medication after randomization, either Placebo or Levetiracetam. Adverse Events were presented for the Dose Adjustment and Evaluation Period.
Arm/Group Title	Placebo		Levetiracetam
Arm/Group Description	Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily for 28 weeks		Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily
All-Cause Mortality
	Placebo		Levetiracetam
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Placebo		Levetiracetam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/125 (3.20%)		1/126 (0.79%)
General disorders
Drowning * 1	2/125 (1.60%)	2	0/126 (0.00%)	0
Sudden unexplained death in epilepsy * 1	1/125 (0.80%)	1	0/126 (0.00%)	0
Infections and infestations
Pneumonia * 1	0/125 (0.00%)	0	1/126 (0.79%)	1
Nervous system disorders
Epilepsy * 1	1/125 (0.80%)	1	0/126 (0.00%)	0
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (17.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Levetiracetam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/125 (25.60%)		40/126 (31.75%)
General disorders
Pyrexia * 1	5/125 (4.00%)	5	7/126 (5.56%)	8
Infections and infestations
Nasopharyngitis * 1	20/125 (16.00%)	36	24/126 (19.05%)	33
Investigations
Platelet count decreased * 1	4/125 (3.20%)	4	7/126 (5.56%)	8
Protein urine present * 1	1/125 (0.80%)	1	10/126 (7.94%)	11
Nervous system disorders
Dizziness * 1	9/125 (7.20%)	14	4/126 (3.17%)	7
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (17.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: UCB Clinical Trial Call Center
• Organization: UCB
• Phone: +1 877 822 9493 (UCB)

Publications of Results:

Wu L, Yagi K, Hong Z, Liao W, Wang X, Zhou D, Inoue Y, Ohtsuka Y, Sasagawa M, Terada K, Du X, Muramoto Y, Sano T. Adjunctive levetiracetam in the treatment of Chinese and Japanese adults with generalized tonic-clonic seizures: A double-blind, randomized, placebo-controlled trial. Epilepsia Open. 2018 Sep 29;3(4):474-484. doi: 10.1002/epi4.12255. eCollection 2018 Dec.

• Responsible Party: UCB Pharma ( UCB Japan Co. Ltd. )
• ClinicalTrials.gov Identifier: NCT01228747
• Other Study ID Numbers: N01159; 2014-004401-32 ( EudraCT Number )
• First Submitted: October 22, 2010
• First Posted: October 26, 2010
• Results First Submitted: April 27, 2015
• Results First Posted: May 13, 2015
• Last Update Posted: January 15, 2019