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

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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:
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
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
Hide 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
Arm/Group Title Placebo Levetiracetam Total
Hide 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
Hide 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
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)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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
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
Hide 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   --/--      --/--    
Show Serious Adverse Events Hide 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)
Show Other (Not Including Serious) Adverse Events Hide 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)
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
Layout table for Results Point of Contact information
Name/Title: UCB Clinical Trial Call Center
Organization: UCB
Phone: +1 877 822 9493 (UCB)
Layout table for additonal information
Responsible Party: UCB Pharma ( UCB Japan Co. Ltd. )
ClinicalTrials.gov Identifier: NCT01228747     History of Changes
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