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

A Double-blind, Multicenter, Randomized, Placebo-controlled Study to Evaluate the Efficacy and Safety of Adjunctive Treatment With Oral Levetiracetam, in Epilepsy Patients Aged ≥16 Years, With Generalized Tonic-clonic (GTC) Seizures

The purpose of this study is to evaluate the efficacy, safety and tolerability of levetiracetam treatment used as adjunctive therapy in Japanese and Chinese epilepsy patients aged ≥16 years and with uncontrolled Generalized Tonic-Clonic seizures despite treatment with 1 or 2 anti-epileptic drugs.

Study Overview

• Status: Completed
• Conditions: Epilepsy; Generalized Tonic-Clonic Seizures
• Intervention / Treatment: Drug: Placebo; Drug: Levetiracetam

• Study Type: Interventional
• Enrollment (Actual): 361
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • 1
  • Beijing, China
    • 9
  • Changchun, China
    • 12
  • Chengdu, China
    • 19
  • Chengdu, China
    • 6
  • Chongqing, China
    • 10
  • Guangzhou, China
    • 16
  • Guangzhou, China
    • 5
  • Harbin, China
    • 18
  • Kunming, China
    • 13
  • Nanjing, China
    • 22
  • Qingdao, China
    • 14
  • Shanghai, China
    • 2
  • Shanghai, China
    • 3
  • Shenyang, China
    • 17
  • Taiyuan, China
    • 15
  • Wuhan, China
    • 8
  • Xi'an, China
    • 7
  • Xian, China
    • 20
• Japan
  • Fujisawa, Japan
    • 152
  • Fukuoka, Japan
    • 112
  • Fukuoka, Japan
    • 113
  • Fukuoka, Japan
    • 166
  • Fukushima, Japan
    • 187
  • Hamamatsu, Japan
    • 124
  • Higashiosaka, Japan
    • 175
  • Himeji, Japan
    • 162
  • Hiroshima, Japan
    • 110
  • Hiroshima, Japan
    • 177
  • Iizuka, Japan
    • 165
  • Kagoshima, Japan
    • 143
  • Kagoshima, Japan
    • 156
  • Kameda, Japan
    • 176
  • Kashihara, Japan
    • 150
  • Kashiwakazi, Japan
    • 153
  • Kokubunji, Japan
    • 105
  • Miyakonojo, Japan
    • 172
  • Miyazaki, Japan
    • 179
  • Miyazaki, Japan
    • 186
  • Nagoya, Japan
    • 189
  • Niigata, Japan
    • 106
  • Okayama, Japan
    • 158
  • Osaka, Japan
    • 157
  • Osaka, Japan
    • 174
  • Osaka-sayama, Japan
    • 129
  • Otaru, Japan
    • 130
  • Saito, Japan
    • 170
  • Sakai, Japan
    • 147
  • Sakai, Japan
    • 194
  • Sapporo, Japan
    • 117
  • Sapporo, Japan
    • 131
  • Sapporo, Japan
    • 304
  • Sendai, Japan
    • 103
  • Shimajiri, Japan
    • 168
  • Shimotsuke, Japan
    • 138
  • Shizuoka, Japan
    • 121
  • Tokyo, Japan
    • 120
  • Ube, Japan
    • 111

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• An epilepsy patient with generalized tonic-clonic seizures that are classifiable according to the ILAE classification of epileptic seizures (Epilepsia, 1981)
• A patient on a stable dose of 1 or 2 anti-epileptic drugs for the last 4 weeks (potassium bromide and sodium bromide for the last 12 weeks) prior to and during the combined baseline period

Exclusion Criteria:

• Presence of any sign (clinical or imaging procedures) suggesting a progressive brain lesion/disease, in particular, progressive disorder with epileptic seizures
• Diagnosis of Lennox-Gastaut Syndrome
• Confirmed focal epilepsy based on clinical signs (seizure types), with consistent electroencephalogram and magnetic resonance imagining features
• A history of convulsive or non-convulsive status epilepticus while taking concomitant anti-epileptic drugs for the last 3 months prior to Visit 1

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching placebo for 28 weeks	Drug: Placebo; Matching oral placebo tablets twice daily for 28 weeks
Experimental: Levetiracetam; Levetiracetam treatment with flexible dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks	Drug: Levetiracetam; Oral dose at flexible increase doses: 1000 mg/day or 2000 mg/day or 3000 mg/day, twice daily, 28 weeks; Other Names: Keppra®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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	From Baseline to Week 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percentage Change in Generalized Tonic-clonic Seizure Frequency Per Week From the Combined Baseline Over the Evaluation Period	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.	From Baseline to Evaluation Period (Week 12 to Week 28)
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	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	From Baseline to Week 28
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	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	From Baseline to Evaluation Period (Week 12 to Week 28)
Generalized Tonic-clonic Seizure Freedom Over the Evaluation Period	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.	Evaluation Period (Week 12 to Week 28)

Collaborators and Investigators

• Sponsor: UCB Japan Co. Ltd.

Publications and helpful links

General Publications

• 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.

Helpful Links

• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: October 22, 2010
• First Submitted That Met QC Criteria: October 25, 2010
• First Posted (Estimate): October 26, 2010

Study Record Updates

• Last Update Posted (Actual): January 15, 2019
• Last Update Submitted That Met QC Criteria: January 3, 2019
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: epilepsy; Levetiracetam; generalized tonic-clonic
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Epilepsy; Seizures; Anticonvulsants; Nootropic Agents; Levetiracetam
• Other Study ID Numbers: N01159; 2014-004401-32 (EudraCT Number)