Retigabine (Adjunctive Therapy) Efficacy and Safety Study for Partial Onset Refractory Seizures in Epilepsy (RESTORE1)

• 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) [ Time Frame: Baseline (Week -7 through Week 0), Week 1 through Week 18 ] [ Designated as safety issue: No ]
  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 values indicate a reduction in seizure frequency.
• Number of Participants Who Were Responders and Non-responders in the Maintenance Phase [ Time Frame: Week 7 through Week 18 ] [ Designated as safety issue: No ]
  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.

• Number of Participants Who Were Responders and Non-responders in the DB Phase [ Time Frame: Week 1 through Week 18 ] [ Designated as safety issue: No ]
  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.
• Percent Change From Baseline (BL) in the 28-day Total Partial Seizure Frequency During the Maintenance Phase [ Time Frame: Baseline (Week -7 through Week 0), Week 7 through Week 18 ] [ Designated as safety issue: No ]
  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.
• 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 [ Time Frame: Baseline (Week -7 through Week 0), Week 1 through Week 18 ] [ Designated as safety issue: No ]
  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 were included in the "No reduction" category.
• Number of Participants With a Reduction in the 28-day Total Partial Seizure Frequency From Baseline to the End of the DB Phase (Titration and Maintenance Phases) by Indicated Decile Reduction and Increase Categories [ Time Frame: Baseline (Week -7 through Week 0), Week 1 through Week 18 ] [ Designated as safety issue: No ]
  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 0-10% increase category.
• Number of Participants With the Indicated Reduction From Baseline in the 28-day Total Partial Seizure Frequency During the Maintenance Phase [ Time Frame: Baseline (Week -7 through Week 0), Week 7 through Week 18 ] [ Designated as safety issue: No ]
  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).
• 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 [ Time Frame: Baseline (Week -7 through Week 0), Week 7 through Week 18 ] [ Designated as safety issue: No ]
  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.
• 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 [ Time Frame: Baseline (Week -7 through Week 0), Week 1 through Week 18 ] [ Designated as safety issue: No ]
  New seizure types included those seizures which were not reported by any participant at Baseline.
• Number of Participants Who Were Seizure-free During the DB Phase (Titration and Maintenance Phases) [ Time Frame: Week 1 through Week 18 ] [ Designated as safety issue: No ]
  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.
• Number of Participants Who Were Seizure-free During the Maintenance Phase [ Time Frame: Week 7 through Week 18 ] [ Designated as safety issue: No ]
  Participants were considered to be seizure-free if they had not reported any seizures during the Maintenance Phase.
• Percentage of Seizure-free Days During the DB Phase (Titration and Maintenance Phases) [ Time Frame: Week 1 through Week 18 ] [ Designated as safety issue: No ]
  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%.
• Percentage of Seizure-free Days During the Maintenance Phase [ Time Frame: Week 7 through Week 18 ] [ Designated as safety issue: No ]
  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 DB period divided by the number of days in the DB period x 100%.
• Clinical Global Impression-Improvement (CGI-I) Score at the End of the Maintenance Phase [ Time Frame: Week 18/end of treatment phase ] [ Designated as safety issue: No ]
  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.
• Patient Global Impression (PGI) Score at the End of the Maintenance Phase [ Time Frame: Week 18/end of treatment phase ] [ Designated as safety issue: No ]
  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.
• Quality of Life (QOL) Assessed by QOL in Epilepsy-Problems Questionnaire (QOLIE-31-P) at Baseline (Week 0) and Weeks 6, 10, and 18 [ Time Frame: End of Baseline (Week 0), Weeks 6, 10, and 18 ] [ Designated as safety issue: No ]
  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.
• Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) [ Time Frame: Week 1 through Week 24 ] [ Designated as safety issue: No ]
  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.
• Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) [ Time Frame: Week 1 through Week 24 ] [ Designated as safety issue: No ]
  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.
• Change From Baseline in Post-void Residual Urine Volume at Weeks 10 and 18 of the DB Treatment Phase [ Time Frame: Baseline (Week -7 through Week 0), Weeks 10 and 18 ] [ Designated as safety issue: No ]
  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 18 minus the value at Baseline.
• Number of Participants With a >=7% Increase in Body Weight During Weeks 2, 4, and 6 of theTitration Phase and Weeks 7, 8, 10, 14, and 18 of the Maintenance Phase [ Time Frame: Weeks 2, 4, 6 of Titration Phase and Weeks 7, 8, 10, 14, and 18 of Maintenance Phase ] [ Designated as safety issue: No ]
  The number of participants with recorded weight gain of >=7% over their baseline weight was measured.

• - Proportion of responders defined as 50% or more reduction in total partial seizure frequency
• - Change in distribution of seizure frequency
• - Change in incidence of new seizure types
• - Clinical Global Impression (CGI)
• - Incidence of Adverse Events as well as Safety Labs and Assessments
• - Quality of Life Using the QOLIE-31-P Scale

This Phase 3 study is being conducted to evaluate the efficacy and safety of retigabine dosed at 1200 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 North America, Argentina, and Brazil to evaluate the efficacy and safety of retigabine dosed at 1200 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 total partial seizure frequency for four weeks from baseline to the double-blind period) will also be evaluated.

• Drug: Retigabine
  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 7, patients will enter a 12 week maintenance phase
  Other Names:

  • D-23129
  • GKE-841
• Drug: Placebo
  Oral tablet.

• Placebo Comparator: Placebo
  Intervention: Drug: Placebo
• Experimental: Retigabine
  Intervention: Drug: Retigabine

Inclusion Criteria:

• Diagnosis of refractory epilepsy with simple or complex partial onset seizures with or without secondary generalization
• 28-day partial seizure frequency rate of four or more partial seizures over the 8-week baseline phase
• Currently treated with up to three established AEDs
• Vagal Nerve Stimulator may be included

Exclusion Criteria:

• Existing medical or psychiatric condition which could affect patient's health or compromise ability to participate in the study
• Clinically significant abnormalities on physical exam, vital signs, ECG, or liver function tests
• Impaired renal function (creatinine clearance less than 50 mL/minute)
• Evidence of progressive central nervous disease, lesion, or encephalopathy
• History of primary generalized seizures
• History of clustering or flurries or status epilepticus within 12 months of study entry