This Phase 3 study is being conducted to evaluate the efficacy and safety of retigabine dosed at 900 mg/day and 600 mg/day, in three equally divided doses, compared with placebo in patients with epilepsy who are receiving up to three established antiepileptic drugs (AEDs).
This Phase 3 study is being conducted in Europe, Israel, Australia, and South Africa to evaluate the efficacy and safety of retigabine dosed at 900 mg/day and 600 mg/day, in three equally divided doses, compared with placebo in patients with epilepsy who are receiving up to three established antiepileptic drugs (AEDs). The primary objective is to demonstrate a superior change in total partial seizure frequency for four weeks from baseline to the double-blind period. The proportion of responders (greater than or equal to 50% reduction in seizure frequency for four weeks from baseline to the double-blind period) will also be evaluated.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
539
Oral tablet. The starting daily dose will be 300 mg/day administered orally in three equally divided doses. This dosage will be increased by 150 mg/day (50 mg/dose) at 1-week intervals (titration phase). At the beginning of Week 3, patients will enter a 12 week maintenance phase.
Oral tablet. The starting daily dose will be 300 mg/day administered orally in three equally divided doses. This dosage will be increased by 150 mg/day (50 mg/dose) at 1-week intervals (titration phase). At the beginning of Week 5, patients will enter a 12 week maintenance phase.
Oral tablet.
Percent Change in the 28-day Total Partial Seizure (PS) Frequency From Baseline (BL) to the End of the Double-blind (DB) Phase (Titration and Maintenance Phases)
28-day total PS (PSs \[also called focal seizures\] are seizures limited to a specific area of the brain) frequency in the BL period = (Number \[No.\] of total PSs reported in the BL period divided by the No. of days of available total PS data in the BL period) x 28 days. 28-day total PS frequency in the DB period = (No. of total PSs reported in the DB period divided by the No. of days of available total PS data in the DB period) x 28 days. Percent change = (\[value in the DB period minus value at BL\] divided by the BL value) x 100%. Negative valu es indicate a reduction in seizure frequency.
Time frame: Baseline (Week -7 through Week 0), DB Phase (Week 1 through Week 16)
Number of Participants Classified as Responders and Non-responders During the Maintenance Phase
Responders were participants with at least a 50% reduction in the 28-day total partial seizure frequency in the Maintenance Phase as compared to the Baseline period.
Time frame: Week 5 through Week 16
Number of Participants Who Were Responders and Non-responders During the DB Phase
Responders were participants with at least a 50% reduction in the 28-day total partial seizure frequency in the DB Phase as compared to the Baseline period. Participants without any post-baseline data were considered non-responders.
Time frame: Week 1 through Week 16
Percent Change From Baseline (BL) in the 28-day Total Partial Seizure Frequency During the Maintenance Phase
28-day total partial seizure frequency in the BL period = (No. of total partial seizures reported in the BL period divided by the No. of days of available total partial seizure data in the BL period) x 28 days. 28-day total partial seizure frequency in the Maintenance Phase = (No. of total partial seizures reported in the Maintenance Phase divided by the No. of days of available total partial seizure data in the same phase) x 28 days. Percent change = (value in the Maintenance Phase minus value at BL divided by the BL value) x 100%. Negative values indicate a reduction in seizure frequency.
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Mid-Atlantic Epilepsy and Sleep Center
Bethesda, Maryland, United States
Neurological Clinic-Texas
Dallas, Texas, United States
Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia
North Coast Neurology Centre
Maroochydore, Queensland, Australia
Monash Medical Centre
Clayton, Victoria, Australia
Royal Melbourne Hospital
Parkville, Victoria, Australia
Austin & Repatriation Medical Centre
West Heidelberg, Victoria, Australia
A. Z. Middelheim -- Department of Neurology
Antwerp, Belgium
AZ Sint-Jan
Bruges, Belgium
Universitaire Ziekenhuizen Gasthuisberg -- Department Neurology
Leuven, Belgium
...and 60 more locations
Time frame: Baseline (Week -7 through Week 0), Week 5 through Week 16
Number of Participants With a Reduction in the 28-day Total Partial Seizure Frequency From Baseline to the End of DB Phase (Titration and Maintenance Phases) by Indicated Quartile Reduction Categories
Participants who experienced a reduction from Baseline in the 28-day total partial seizure frequency were categorized as having a reduction of 75-100%, 50-\<75%, 25-\<50%, or \<25%, in addition to having no reduction. This quartile cutting was specified in the study protocol. Participants without any post-baseline data are included in the "No reduction" category.
Time frame: Baseline (Week -7 through Week 0), Week 1 through Week 16
Number of Participants With a Reduction in the 28-day Total Partial Seizure Frequency From Baseline to the DB Phase (Titration and Maintenance Phases) by Indicated Decile Reduction and Increase Categories
Participants who experienced a reduction from Baseline in the 28-day total partial seizure frequency were categorized in decile cutting, i.e., reduction categories of 90-100%, 80-\<90%, 70-\<80%, 60-\<70%, 50-\<60%, 40-\<50%, 30-\<40%, 20-\<30%, 10-\<20%, \>0-\<10%, and increase categories of 0-10%, \>10-20%, \>20-30%, \>30% (FDA endpoint). Participants without any post-baseline data were included in the category 0-10% increase category.
Time frame: Baseline (Week -7 through Week 0), Week 1 through Week 16
Number of Participants With the Indicated Reduction From Baseline in the 28-day Total Partial Seizure Frequency During the Maintenance Phase
Participants who experienced a reduction from Baseline in the 28-day total partial seizure frequency were categorized as having a \>75%, a 50-75%, or a \<50% reduction, in addition to having no reduction (EMEA endpoint).
Time frame: Baseline (Week -7 through Week 0), Week 5 through Week 16
Number of Participants Who Experienced the Indicated Level of Exacerbation and Reduction in the 28-day Total Partial Seizure Frequency From Baseline During the Maintenance Phase
Participants who experienced an exacerbation from Baseline in the 28-day total partial seizure frequency were categorized as having a 0-25% or a \>25% increase (EMEA endpoint). The number of participants experiencing a \>0% reduction from Baseline in the 28-day total partial seizure frequency are also presented.
Time frame: Baseline (Week -7 through Week 0), Week 5 through Week 16
Number of Participants Reporting New Seizure Types in the Indicated Categories During the DB Phase (Titration and Maintenance Phases) That Were Not Reported at Baseline
New seizure types included those seizures which were not reported by any participant at Baseline.
Time frame: Baseline (Week -7 through Week 0), Week 1 through Week 16
Number of Participants Who Were Seizure-free During the DB Phase (Titration and Maintenance Phases)
Participants were considered to be seizure-free if they had not reported any seizures during the DB treatment period (Weeks 1-18). For a participant to be seizure free during the DB Phase, the participant had to be seizure free both Week 7 to Week 18 and Week 1 to Week 6. A participant could be seizure free Week 7 to Week 18 (during the Maintenance Phase), but not seizure free Week 1 to Week 6. Hence, there are fewer participants being reported as seizure free from Week 1 to Week 18 than from Week 7 to Week 18.
Time frame: Week 1 through Week 16
Number of Participants Who Were Seizure-free During the Maintenance Phase
Participants were considered to be seizure-free if they had not reported any seizures during the Maintenance Phase.
Time frame: Week 5 through Week 16
Percentage of Seizure-free Days During the DB Phase (Titration and Maintenance Phases)
A seizure-free day was a day without any seizures. For a participant to be seizure free during the DB Phase, the participant had to be seizure free both Week 7 to Week 18 and Week 1 to Week 6. A participant could be seizure free Week 7 to Week 18 (during the Maintenance Phase), but not seizure free Week 1 to Week 6. Hence, there are fewer participants being reported as seizure free from Week 1 to Week 18 than from Week 7 to Week 18. The percentage of seizure-free days was calculated as the total number of days without seizures in the DB period divided by the number of days in DB period x 100%.
Time frame: Week 1 through Week 16
Percentage of Seizure-free Days During the Maintenance Phase
A seizure-free day was a day without any seizures. The percentage of seizure-free days was calculated as the total number of days without seizures in the Maintenance Phase divided by the number of days in the Maintenance Phase x 100%.
Time frame: Week 5 through Week 16
Clinical Global Impression-Improvement (CGI-I) Score at the End of the Maintenance Phase
Clinical Global Impression of Improvement (CGI-I) is a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the treatment. Scores on the scale are rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.
Time frame: Week 16/end of treatment phase
Patient Global Impression (PGI) Score at the End of the Maintenance Phase
PGI is a participant-rated scale of improvement that was administered at the end of the Maintenance Phase in order to assess the participant's impression of his or her own improvement. PGI assessments were scored using a 7-point scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.
Time frame: Week 16/end of treatment phase
Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) at BL (Week 0) and Weeks 4, 8, and 16
The QOLIE-31-P is a 31-item questionnaire evaluating a participant's QOL perception in 7 domains: seizure worry, emotional well being, energy/fatigue, cognitive functioning, medication effects, social functioning, overall QOL. Precoded numeric values for some domains are such that a higher number reflects a more favorable health state; others are such that a higher number reflects a less favorable state. Precoded values are first converted to 0-100 point scores; higher converted scores always reflect better QOL. The overall score is derived by weighting and then summing the 7 domain scores.
Time frame: End of Baseline (Week 0), Weeks 4, 8, and 16
Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm)
Clinically important changes in laboratory values were to be reported as an adverse event if they met one of the following criteria: (1) intervention required; (2) change in dose of study drug required; (3) other treatment/therapy required; (4) association with other diagnoses.
Time frame: Week 1 through Week 16
Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm)
A summary of the adverse events classified as renal or urinary disorders and in which at least 2% (rounded to an integer) of participants in any treatment arm reported during the study is presented.
Time frame: Week 1 through Week 16
Change From Baseline in Post-void Residual Urine Volume at Weeks 8 and 16 of the Maintenance Phase
Post-void residual (PVR) urine refers to the amount of urine remaining in the bladder after normal urination. To investigate the possible effects of retigabine on bladder function, all participants underwent post-void residual bladder ultrasound at Baseline and during the Maintenance Phase. The PVR bladder ultrasound was performed by a urologist, a qualified ultrasound technician, or a qualified study nurse who was certified to do PVR bladder ultrasound. Change from Baseline in PVR residual volume was calculated as the values at Week 10 and Week 16 minus the value at Baseline.
Time frame: Baseline (Week -7 through 0), Weeks 8 and 16
Number of Participants With a >=7% Increase in Body Weight During Weeks 2 and 4 of theTitration Phase and Weeks 6, 8, 12, and 16 of the Maintenance Phase
The number of participants with recorded weight gain of \>=7% over their baseline weight was measured.
Time frame: Weeks 2 and 4 of Titration Phase and Weeks 6, 8, 12, and 16 of Maintenance Phase