Seizures
Conditions
Keywords
Partial Seizures, Anticonvulsant, Complex Partial Seizures, Potassium Channels, Epilepsy
Brief summary
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).
Detailed description
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.
Interventions
DRUGRetigabine
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
DRUGPlacebo
Oral tablet.
Sponsors
Bausch Health Americas, Inc.
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Baseline (Week -7 through Week 0), Week 1 through Week 18 | 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 | Week 7 through Week 18 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Were Responders and Non-responders in the DB Phase | Week 1 through Week 18 | 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 | Baseline (Week -7 through Week 0), Week 7 through Week 18 | 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 | Baseline (Week -7 through Week 0), Week 1 through Week 18 | 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 | Baseline (Week -7 through Week 0), Week 1 through Week 18 | 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 | Baseline (Week -7 through Week 0), Week 7 through Week 18 | 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 | Baseline (Week -7 through Week 0), Week 7 through Week 18 | 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 | Baseline (Week -7 through Week 0), Week 1 through Week 18 | 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) | Week 1 through Week 18 | 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 | Week 7 through Week 18 | 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) | Week 1 through Week 18 | 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 | Week 7 through Week 18 | 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 | Week 18/end of treatment 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. |
| Patient Global Impression (PGI) Score at the End of the Maintenance Phase | Week 18/end of treatment 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. |
| Quality of Life (QOL) Assessed by QOL in Epilepsy-Problems Questionnaire (QOLIE-31-P) at Baseline (Week 0) and Weeks 6, 10, and 18 | End of Baseline (Week 0), Weeks 6, 10, and 18 | 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) | Week 1 through Week 24 | 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) | Week 1 through Week 24 | 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 | Baseline (Week -7 through Week 0), Weeks 10 and 18 | 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 | Weeks 2, 4, 6 of Titration Phase and Weeks 7, 8, 10, 14, and 18 of Maintenance Phase | The number of participants with recorded weight gain of \>=7% over their baseline weight was measured. |
Countries
Argentina, Brazil, Canada, Mexico, United States
Participant flow
Pre-assignment details
Participants who completed the Double-blind Phase (Titration plus Maintenance Phases) who elected to continue in the Open-Label Extension Study (OLE-S) entered the Transition Phase, for titration, if on placebo, or to maintain the blind if on retigabine. Participants who did not enter the Titration Phase entered a Taper Phase.
Participants by arm
| Arm | Count |
|---|---|
| Placebo - Double-blind (DB) Phase (Titration + Maintenance) Matching placebo tablets of dummy strengths of 50 milligrams (mg), 100 mg, and 300 mg administered orally thrice a day (TID) for 18 weeks (6 weeks of Titration Phase and 12 weeks of Maintenance Phase) | 152 |
| Retigabine - DB Phase (Titration + Maintenance) Retigabine tablets of strengths 50 mg, 100 mg, and 300 mg administered orally TID for a target daily dose of 1200 mg/day (400 mg TID) for 18 weeks (6 weeks of Titration Phase, with dosage increase from 300 mg/day to 1200 mg/day \[weekly increase of 150 mg/day\], and 12 weeks of Maintenance Phase, with 1200 mg/day or 1050 mg/day \[for participants who could not tolerate 1200 mg/day\]) | 153 |
| Total | 305 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 12-Week Maintenance Phase | Adverse Event | 7 | 22 |
| 12-Week Maintenance Phase | Other | 1 | 3 |
| 12-Week Maintenance Phase | Protocol Violation | 3 | 1 |
| 12-Week Maintenance Phase | Unsatisfactory Response -Efficacy | 1 | 2 |
| 6-Week Titration Phase | Adverse Event | 6 | 19 |
| 6-Week Titration Phase | Failed to Return | 2 | 1 |
| 6-Week Titration Phase | Other | 3 | 3 |
| 6-Week Titration Phase | Participant Did Not Receive Study Drug | 0 | 1 |
| 6-Week Titration Phase | Participant Request Unrelated to Study | 1 | 0 |
| 6-Week Titration Phase | Protocol Violation | 1 | 3 |
| 6-Week Titration Phase | Unsatisfactory Response - Efficacy | 1 | 2 |
Baseline characteristics
| Characteristic | Retigabine - DB Phase (Titration + Maintenance) | Placebo - Double-blind (DB) Phase (Titration + Maintenance) | Total |
|---|---|---|---|
| Age, Continuous | 37.7 Years STANDARD_DEVIATION 12.55 | 36.7 Years STANDARD_DEVIATION 11.63 | 37.2 Years STANDARD_DEVIATION 12.09 |
| Gender Female | 85 Participants | 80 Participants | 165 Participants |
| Gender Male | 68 Participants | 72 Participants | 140 Participants |
| Race/Ethnicity, Customized African - American (Black) | 15 participants | 15 participants | 30 participants |
| Race/Ethnicity, Customized American Indian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Caucasian | 90 participants | 78 participants | 168 participants |
| Race/Ethnicity, Customized Hispanic | 39 participants | 48 participants | 87 participants |
| Race/Ethnicity, Customized Mestizo | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Mixed Race | 8 participants | 8 participants | 16 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 91 / 152 | 64 / 123 | 121 / 153 | 35 / 92 |
| serious Total, serious adverse events | 8 / 152 | 6 / 123 | 19 / 153 | 5 / 92 |
Outcome results
Primary
Number of Participants Who Were Responders and Non-responders in 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 7 through Week 18
Population: Intent-to-Treat (ITT) Population for European Medicines Agency (EMEA) review: all randomized participants who received at least one dose of study drug in the Maintenance Phase and had at least one seizure measurement (whether or not they had a seizure) recorded in the Maintenance Phase
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Were Responders and Non-responders in the Maintenance Phase | Responders | 31 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Were Responders and Non-responders in the Maintenance Phase | Non-responders | 106 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Were Responders and Non-responders in the Maintenance Phase | Responders | 66 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Were Responders and Non-responders in the Maintenance Phase | Non-responders | 53 participants |
p-value: <0.001Fisher Exact
Primary
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 values indicate a reduction in seizure frequency.
Time frame: Baseline (Week -7 through Week 0), Week 1 through Week 18
Population: Intent-to-Treat (ITT) Population for Food and Drug Administration (FDA) review: all randomized participants (par.) who received at least one dose of the study drug. Only par. with baseline and post-baseline measures were analyzed. Two par. in each treatment arm did not have post-baseline measures and were thus not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | 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) | -17.5 percent change in seizure frequency |
| Retigabine - DB Phase (Titration + Maintenance) | 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) | -44.3 percent change in seizure frequency |
p-value: <0.001Non-parametric rank ANCOVA
Secondary
Change From Baseline in Post-void Residual Urine Volume at Weeks 10 and 18 of the DB Treatment 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 18 minus the value at Baseline.
Time frame: Baseline (Week -7 through Week 0), Weeks 10 and 18
Population: Safety Population. Only participants who remained in the study at the indicated week and who also had a PVR assessment were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Change From Baseline in Post-void Residual Urine Volume at Weeks 10 and 18 of the DB Treatment Phase | Week 10, n=111, 100 | -1.0 milliliters |
| Placebo - DB Phase (Titration + Maintenance) | Change From Baseline in Post-void Residual Urine Volume at Weeks 10 and 18 of the DB Treatment Phase | Week 18, n=95, 76 | -3.0 milliliters |
| Retigabine - DB Phase (Titration + Maintenance) | Change From Baseline in Post-void Residual Urine Volume at Weeks 10 and 18 of the DB Treatment Phase | Week 10, n=111, 100 | 0.0 milliliters |
| Retigabine - DB Phase (Titration + Maintenance) | Change From Baseline in Post-void Residual Urine Volume at Weeks 10 and 18 of the DB Treatment Phase | Week 18, n=95, 76 | 0.0 milliliters |
Secondary
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 18/end of treatment phase
Population: ITT Population for EMEA review. Only participants who had CGI-I scores were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Clinical Global Impression-Improvement (CGI-I) Score at the End of the Maintenance Phase | 3.2 scores on a scale | Standard Deviation 1.11 |
| Retigabine - DB Phase (Titration + Maintenance) | Clinical Global Impression-Improvement (CGI-I) Score at the End of the Maintenance Phase | 2.7 scores on a scale | Standard Deviation 1.3 |
Secondary
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 18
Population: ITT Population for FDA review
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | 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 | No new seizure type | 33 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Partial seizures without motor signs | 12 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Partial evolving to secondarily generalized | 7 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Complex partial seizures | 5 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Partial seizures with motor signs | 11 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Flurries | 3 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Tonic-clonic seizures | 0 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Atonic seizures | 1 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Atonic seizures | 0 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | No new seizure type | 42 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Partial seizures with motor signs | 7 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Partial seizures without motor signs | 17 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Tonic-clonic seizures | 1 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Partial evolving to secondarily generalized | 12 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Flurries | 1 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Complex partial seizures | 11 participants |
Secondary
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 7 through Week 18
Population: ITT Population for EMEA review.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | 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 | 0% to 25% increase | 20 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | >=25% increase | 21 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | >0% reduction | 96 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | 0% to 25% increase | 4 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | >=25% increase | 16 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | >0% reduction | 99 participants |
Secondary
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 24
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Urinary hesitation | 1 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Hematuria | 1 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Nephrolithiasis | 0 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Dysuria | 2 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Urinary retention | 2 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Chromaturia | 0 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Polyuria | 1 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Hematuria | 2 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Polyuria | 0 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Chromaturia | 0 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Nephrolithiasis | 0 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Urinary retention | 2 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Dysuria | 2 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Urinary hesitation | 2 participants |
| Retigabine - DB Phase (Titration and Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Polyuria | 4 participants |
| Retigabine - DB Phase (Titration and Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Urinary hesitation | 9 participants |
| Retigabine - DB Phase (Titration and Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Dysuria | 8 participants |
| Retigabine - DB Phase (Titration and Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Chromaturia | 7 participants |
| Retigabine - DB Phase (Titration and Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Nephrolithiasis | 4 participants |
| Retigabine - DB Phase (Titration and Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Hematuria | 2 participants |
| Retigabine - DB Phase (Titration and Maintenance) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Urinary retention | 1 participants |
| Retigabine (DB Phase) and Retigabine (Transition Phase) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Chromaturia | 0 participants |
| Retigabine (DB Phase) and Retigabine (Transition Phase) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Urinary retention | 0 participants |
| Retigabine (DB Phase) and Retigabine (Transition Phase) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Hematuria | 0 participants |
| Retigabine (DB Phase) and Retigabine (Transition Phase) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Dysuria | 1 participants |
| Retigabine (DB Phase) and Retigabine (Transition Phase) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Urinary hesitation | 0 participants |
| Retigabine (DB Phase) and Retigabine (Transition Phase) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Nephrolithiasis | 0 participants |
| Retigabine (DB Phase) and Retigabine (Transition Phase) | Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm) | Polyuria | 0 participants |
Secondary
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 24
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Urine analysis abnormal | 3 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Bacteria urine | 1 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Hematology test abnormal | 0 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Urinary sediment present | 1 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Bacteria urine | 0 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Hematology test abnormal | 0 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Urinary sediment present | 0 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Urine analysis abnormal | 3 participants |
| Retigabine - DB Phase (Titration and Maintenance) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Hematology test abnormal | 1 participants |
| Retigabine - DB Phase (Titration and Maintenance) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Bacteria urine | 1 participants |
| Retigabine - DB Phase (Titration and Maintenance) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Urinary sediment present | 0 participants |
| Retigabine - DB Phase (Titration and Maintenance) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Urine analysis abnormal | 4 participants |
| Retigabine (DB Phase) and Retigabine (Transition Phase) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Urinary sediment present | 2 participants |
| Retigabine (DB Phase) and Retigabine (Transition Phase) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Bacteria urine | 2 participants |
| Retigabine (DB Phase) and Retigabine (Transition Phase) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Urine analysis abnormal | 2 participants |
| Retigabine (DB Phase) and Retigabine (Transition Phase) | Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) | Hematology test abnormal | 2 participants |
Secondary
Number of Participants Who Were Responders and Non-responders in 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 18
Population: ITT Population for FDA review
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Were Responders and Non-responders in the DB Phase | Responders | 27 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Were Responders and Non-responders in the DB Phase | Non-responders | 125 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Were Responders and Non-responders in the DB Phase | Responders | 68 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Were Responders and Non-responders in the DB Phase | Non-responders | 85 participants |
Secondary
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 18
Population: ITT Population for FDA review. Only participants who had post-baseline seizure data were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Were Seizure-free During the DB Phase (Titration and Maintenance Phases) | Seizure free | 0 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Were Seizure-free During the DB Phase (Titration and Maintenance Phases) | Not seizure free | 150 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Were Seizure-free During the DB Phase (Titration and Maintenance Phases) | Not seizure free | 148 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Were Seizure-free During the DB Phase (Titration and Maintenance Phases) | Seizure free | 3 participants |
Secondary
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 7 through Week 18
Population: ITT Population for EMEA review
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Were Seizure-free During the Maintenance Phase | Seizure free | 2 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants Who Were Seizure-free During the Maintenance Phase | Not seizure free | 135 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Were Seizure-free During the Maintenance Phase | Seizure free | 9 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants Who Were Seizure-free During the Maintenance Phase | Not seizure free | 110 participants |
Secondary
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
The number of participants with recorded weight gain of \>=7% over their baseline weight was measured.
Time frame: Weeks 2, 4, 6 of Titration Phase and Weeks 7, 8, 10, 14, and 18 of Maintenance Phase
Population: Safety Population. Only participants who remained in the study at the indicated week and who also had a body weight assessment were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | 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 | Maintenance Phase, Week 8, n=135, 128 | 1 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Titration Phase, Week 2, n=149, 150 | 0 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Maintenance Phase, Week 10, n=136, 119 | 3 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Titration Phase, Week 6, n=146, 129 | 1 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Maintenance Phase, Week 14, n=137, 109 | 3 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Maintenance Phase, Week 7, n=130, 121 | 2 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Maintenance Phase, Week 18, n=127, 92 | 4 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Titration Phase, Week 4, n=145, 144 | 0 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Maintenance Phase, Week 18, n=127, 92 | 17 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Titration Phase, Week 2, n=149, 150 | 5 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Titration Phase, Week 4, n=145, 144 | 5 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Maintenance Phase, Week 7, n=130, 121 | 9 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Maintenance Phase, Week 8, n=135, 128 | 10 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Maintenance Phase, Week 10, n=136, 119 | 15 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Maintenance Phase, Week 14, n=137, 109 | 18 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Titration Phase, Week 6, n=146, 129 | 6 participants |
Secondary
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 were included in the No reduction category.
Time frame: Baseline (Week -7 through Week 0), Week 1 through Week 18
Population: ITT Population for FDA review
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | 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 | 50% to <75% reduction | 21 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | >0 to <25% reduction | 33 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | 25% to <50% reduction | 37 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | No reduction | 55 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | 75% to 100% reduction | 6 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | No reduction | 39 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | 75% to 100% reduction | 27 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | 50% to <75% reduction | 41 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | 25% to <50% reduction | 20 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | >0 to <25% reduction | 26 participants |
Secondary
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
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.
Time frame: Baseline (Week -7 through Week 0), Week 1 through Week 18
Population: ITT Population for FDA review
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | 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 | Reduction: 90% to 100% | 0 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Reduction: 80% to <90% | 5 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Reduction: 70% to <80% | 4 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Reduction: 60% to <70% | 7 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Reduction: 50% to <60% | 11 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Reduction: 40% to <50% | 11 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Reduction: 30% to <40% | 13 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Reduction: 20% to <30% | 19 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Reduction: 10% to <20% | 13 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Reduction: >0% to <10% | 14 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Increase: 0% to 10% | 14 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Increase: >10% to 20% | 12 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Increase: >20% to 30% | 4 participants |
| Placebo - DB Phase (Titration + Maintenance) | 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 | Increase: >30% | 25 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Increase: 0% to 10% | 10 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Reduction: 90% to 100% | 12 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Reduction: 20% to <30% | 12 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Reduction: 80% to <90% | 11 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Increase: >20% to 30% | 4 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Reduction: 70% to <80% | 10 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Reduction: 10% to <20% | 10 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Reduction: 60% to <70% | 20 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Increase: >10% to 20% | 5 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Reduction: 50% to <60% | 15 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Reduction: >0% to <10% | 8 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Reduction: 40% to <50% | 10 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Increase: >30% | 20 participants |
| Retigabine - DB Phase (Titration + Maintenance) | 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 | Reduction: 30% to <40% | 6 participants |
Secondary
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 7 through Week 18
Population: ITT Population for EMEA review
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants With the Indicated Reduction From Baseline in the 28-day Total Partial Seizure Frequency During the Maintenance Phase | >75% reduction | 13 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants With the Indicated Reduction From Baseline in the 28-day Total Partial Seizure Frequency During the Maintenance Phase | 50% to 75% reduction | 18 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants With the Indicated Reduction From Baseline in the 28-day Total Partial Seizure Frequency During the Maintenance Phase | >0 to <50% reduction | 65 participants |
| Placebo - DB Phase (Titration + Maintenance) | Number of Participants With the Indicated Reduction From Baseline in the 28-day Total Partial Seizure Frequency During the Maintenance Phase | No reduction | 41 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants With the Indicated Reduction From Baseline in the 28-day Total Partial Seizure Frequency During the Maintenance Phase | No reduction | 20 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants With the Indicated Reduction From Baseline in the 28-day Total Partial Seizure Frequency During the Maintenance Phase | >75% reduction | 37 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants With the Indicated Reduction From Baseline in the 28-day Total Partial Seizure Frequency During the Maintenance Phase | >0 to <50% reduction | 33 participants |
| Retigabine - DB Phase (Titration + Maintenance) | Number of Participants With the Indicated Reduction From Baseline in the 28-day Total Partial Seizure Frequency During the Maintenance Phase | 50% to 75% reduction | 29 participants |
Secondary
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 18/end of treatment phase
Population: ITT Population for EMEA review. Only participants who had a PGI score were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Patient Global Impression (PGI) Score at the End of the Maintenance Phase | 2.9 scores on a scale | Standard Deviation 1.16 |
| Retigabine - DB Phase (Titration + Maintenance) | Patient Global Impression (PGI) Score at the End of the Maintenance Phase | 2.9 scores on a scale | Standard Deviation 1.23 |
Secondary
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 18
Population: ITT Population for FDA review. Only participants who had post-baseline seizure data were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Percentage of Seizure-free Days During the DB Phase (Titration and Maintenance Phases) | 77.3 percentage of days |
| Retigabine - DB Phase (Titration + Maintenance) | Percentage of Seizure-free Days During the DB Phase (Titration and Maintenance Phases) | 84.1 percentage of days |
Secondary
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 DB period divided by the number of days in the DB period x 100%.
Time frame: Week 7 through Week 18
Population: ITT Population for EMEA review
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Percentage of Seizure-free Days During the Maintenance Phase | 78.2 percentage of days |
| Retigabine - DB Phase (Titration + Maintenance) | Percentage of Seizure-free Days During the Maintenance Phase | 86.9 percentage of days |
Secondary
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.
Time frame: Baseline (Week -7 through Week 0), Week 7 through Week 18
Population: ITT Population for EMEA review
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Percent Change From Baseline (BL) in the 28-day Total Partial Seizure Frequency During the Maintenance Phase | -18.9 percent change in seizure frequency |
| Retigabine - DB Phase (Titration + Maintenance) | Percent Change From Baseline (BL) in the 28-day Total Partial Seizure Frequency During the Maintenance Phase | -54.5 percent change in seizure frequency |
Secondary
Quality of Life (QOL) Assessed by QOL in Epilepsy-Problems Questionnaire (QOLIE-31-P) at Baseline (Week 0) and Weeks 6, 10, and 18
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 6, 10, and 18
Population: Safety Population: all randomized participants who received at least 1 dose of retigabine or placebo. Participants who were cognitively impaired and could not complete the QOLIE-31-P assessment were not analyzed. The number of participants analyzed differs by week because not all participants completed the questionnaire at the indicated weeks.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo - DB Phase (Titration + Maintenance) | Quality of Life (QOL) Assessed by QOL in Epilepsy-Problems Questionnaire (QOLIE-31-P) at Baseline (Week 0) and Weeks 6, 10, and 18 | Baseline (Week -7 through Week 0), n=139, 137 | 52.6 scores on a scale | Standard Deviation 15.55 |
| Placebo - DB Phase (Titration + Maintenance) | Quality of Life (QOL) Assessed by QOL in Epilepsy-Problems Questionnaire (QOLIE-31-P) at Baseline (Week 0) and Weeks 6, 10, and 18 | Week 6 (Titration Phase), n=127, 108 | 55.2 scores on a scale | Standard Deviation 16.71 |
| Placebo - DB Phase (Titration + Maintenance) | Quality of Life (QOL) Assessed by QOL in Epilepsy-Problems Questionnaire (QOLIE-31-P) at Baseline (Week 0) and Weeks 6, 10, and 18 | Week 10 (Maintenance Phase), n=121, 102 | 57.9 scores on a scale | Standard Deviation 15.57 |
| Placebo - DB Phase (Titration + Maintenance) | Quality of Life (QOL) Assessed by QOL in Epilepsy-Problems Questionnaire (QOLIE-31-P) at Baseline (Week 0) and Weeks 6, 10, and 18 | Week 18 (Maintenance Phase), n=116, 85 | 57.3 scores on a scale | Standard Deviation 15.56 |
| Retigabine - DB Phase (Titration + Maintenance) | Quality of Life (QOL) Assessed by QOL in Epilepsy-Problems Questionnaire (QOLIE-31-P) at Baseline (Week 0) and Weeks 6, 10, and 18 | Week 18 (Maintenance Phase), n=116, 85 | 53.8 scores on a scale | Standard Deviation 17.79 |
| Retigabine - DB Phase (Titration + Maintenance) | Quality of Life (QOL) Assessed by QOL in Epilepsy-Problems Questionnaire (QOLIE-31-P) at Baseline (Week 0) and Weeks 6, 10, and 18 | Baseline (Week -7 through Week 0), n=139, 137 | 55.6 scores on a scale | Standard Deviation 17.95 |
| Retigabine - DB Phase (Titration + Maintenance) | Quality of Life (QOL) Assessed by QOL in Epilepsy-Problems Questionnaire (QOLIE-31-P) at Baseline (Week 0) and Weeks 6, 10, and 18 | Week 10 (Maintenance Phase), n=121, 102 | 56.2 scores on a scale | Standard Deviation 18.04 |
| Retigabine - DB Phase (Titration + Maintenance) | Quality of Life (QOL) Assessed by QOL in Epilepsy-Problems Questionnaire (QOLIE-31-P) at Baseline (Week 0) and Weeks 6, 10, and 18 | Week 6 (Titration Phase), n=127, 108 | 55.7 scores on a scale | Standard Deviation 19.18 |