Retigabine Efficacy and Safety Trial for Partial Onset Refractory Seizures in Epilepsy
- Registration Number
- NCT00235755
- Lead Sponsor
- GlaxoSmithKline
- Brief Summary
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).
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 539
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Retigabine 600 mg Retigabine - Retigabine 900 mg Retigabine - Placebo Placebo -
- Primary Outcome Measures
Name Time Method Number of Participants Classified as Responders and Non-responders During the Maintenance Phase Week 5 through Week 16 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.
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), DB Phase (Week 1 through Week 16) 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.
- Secondary Outcome Measures
Name Time Method Number of Participants Who Were Responders and Non-responders During the DB Phase Week 1 through Week 16 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 5 through Week 16 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 16 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.
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 Baseline (Week -7 through Week 0), Week 1 through Week 16 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.
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 5 through Week 16 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 5 through Week 16 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 16 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 16 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.
Patient Global Impression (PGI) Score at the End of the Maintenance Phase Week 16/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.
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 Weeks 2 and 4 of Titration Phase and Weeks 6, 8, 12, and 16 of Maintenance Phase The number of participants with recorded weight gain of \>=7% over their baseline weight was measured.
Number of Participants Who Were Seizure-free During the Maintenance Phase Week 5 through Week 16 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 16 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 5 through Week 16 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%.
Clinical Global Impression-Improvement (CGI-I) Score at the End of the Maintenance Phase Week 16/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.
Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm) Week 1 through Week 16 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.
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 End of Baseline (Week 0), 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.
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 16 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 8 and 16 of the Maintenance Phase Baseline (Week -7 through 0), Weeks 8 and 16 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.
Trial Locations
- Locations (70)
Royal Prince Alfred Hospital
🇦🇺Camperdown, New South Wales, Australia
Neurological Clinic-Texas
🇺🇸Dallas, Texas, United States
University of Bonn -- Department for Epileptplogy
🇩🇪Bonn, Germany
Universitaetsklinik Mainz Neurologische Klinik
🇩🇪Mainz, Germany
Rambam Medical Center
🇮🇱Haifa, Israel
Specjalistyczna Przychodnia Lekarska Medikard
🇵🇱Padlewskiego 4, Plock, Poland
Katedra i Klinika Neurologii Slaskiej Akademii Medycznej
🇵🇱Katowice, Poland
Wojewodzki Szpital Specjalistyczny im.Mikolaja Kopernika
🇵🇱Gdansk, Poland
Instytut Psychiatrii i Neurologii II Oddzial Neurologii
🇵🇱Warsaw, Poland
City Hospital # 1
🇷🇺Moscow, Russian Federation
District Antiepileptic Centre City Clinical Hospital # 71
🇷🇺Moscow, Russian Federation
Triple M Research
🇿🇦Port Elizabeth, East Cape, South Africa
Military Medical Academy n.a. S.M.Kirov
🇷🇺St. Petersburg, Russian Federation
St.Petersburg State Medical University n.a. I.P.Pavlov
🇷🇺St. Petersburg, Russian Federation
Wilgers MR & Medical Centre
🇿🇦Pretoria, Gauteng, South Africa
University of the Free State
🇿🇦Bloemfontein, Gauteng, South Africa
Carl Bremer Hospital
🇿🇦Belville, West Cape, South Africa
Panorama Medi-Clinic
🇿🇦Cape Town, South Africa
Hospital de La Santa Creu i Sant Pau
🇪🇸Barcelona, Spain
Hospital de Cruces
🇪🇸Bilbao, Spain
Groote Schuur Hospital
🇿🇦Cape Town, Western Cape, South Africa
Hosp. Virgen de las Nieves
🇪🇸Granada, Spain
Hosp de Donostia
🇪🇸San Sebastian, Spain
Hospital Ruber Internacional de Madrid
🇪🇸Madrid, Spain
Kharkiv State Medical University
🇺🇦Kharkiv, Ukraine
Institute of Neurology, Psychiatry and Narcology of AMS, Ukr
🇺🇦Kharkov, Ukraine
Odessa Regional Clinical Hospital
🇺🇦Odessa, Ukraine
Epilepsy Center of Municipal Clinical Psychoneurological Hospital
🇺🇦Kiev, Ukraine
The James Cook University Hospital
🇬🇧Middlesbrough, Mersyd, United Kingdom
Western Infirmary (Epilepsy)
🇬🇧Glasgow, United Kingdom
Fylde Coast Hospital
🇬🇧Blackpool, United Kingdom
Inkosi Albert Luthuli Central Hospital
🇿🇦Durban, KwaZulu-Natal, South Africa
AZ Sint-Jan
🇧🇪Brugge, Belgium
Theatinerstrasse 44
🇩🇪Munich, Germany
Royal Melbourne Hospital
🇦🇺Parkville, Victoria, Australia
Hopital Neurologique Pierre Wertheimer
🇫🇷Lyon, Lyonnais, France
Centre Medical de La Teppe
🇫🇷Tain L'Hermitage, France
Universitaetsklinikum Ulm
🇩🇪Ulm, Germany
Tel-Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Orszagos Idegsebeszeti Tudomanyos Intezet
🇭🇺Budapest, Hungary
Prywatna Wielospecjalistyczna Lecznica Medyczna "Zycie"
🇵🇱Warsaw, Poland
Clinic of Nervous Diseases of Sechenov's Moscow Med. Academy
🇷🇺Moscow, Russian Federation
Walton Centre for Neurology & Neurosurgery
🇬🇧Liverpool, United Kingdom
Royal London Hospital
🇬🇧London, United Kingdom
Hosp. Clinico Univ. Lozano Blesa
🇪🇸Zaragoza, Spain
Centre Neurologique William Lennox
🇧🇪Ottignies, Belgium
Mid-Atlantic Epilepsy and Sleep Center
🇺🇸Bethesda, Maryland, United States
Zentrum Epilepsie Erlangen (ZEE) der Universitaet Erlangen
🇩🇪Erlangen, Germany
Wolfson Medical Center
🇮🇱Holon, Israel
Western Galilee Hospital
🇮🇱Nahariya, Israel
Interregional Clinical Diagnostic Centre
🇷🇺Kazan, Russian Federation
Austin & Repatriation Medical Centre
🇦🇺West Heidelberg, Victoria, Australia
A. Z. Middelheim -- Department of Neurology
🇧🇪Antwerp, Belgium
Hopital Civil de Strasbourg
🇫🇷Strasbourg, France
Universitaet Giessen / Marburg Neurologie
🇩🇪Marburg, Germany
Assaf Harofeh Medical Center
🇮🇱Beer Yaakov, Israel
Kaplan Medical Center
🇮🇱Rechovot, Israel
Sunninghill & Kopano Clinical Trials
🇿🇦Sunninghill, Gauteng, South Africa
Johannesburg Hospital
🇿🇦Johannesburg, Gauten, South Africa
Psychosomatic Center of Dnepropetr. Regional Clinic
🇺🇦Dnepropetrovsk, Ukraine
Natl. Inst. of Psychiatry and Neurology
🇭🇺Budapest, Hungary
Universitaire Ziekenhuizen Gasthuisberg -- Department Neurology
🇧🇪Leuven, Belgium
CHU Pontchaillou
🇫🇷Rennes Cedex, France
Georg-August-Universitaet Goettingen
🇩🇪Goettingen, Germany
Barzilai Medical Center
🇮🇱Ashkelon, Israel
Chaim Sheba Medical Center
🇮🇱Ramat Gan, Israel
North Coast Neurology Centre
🇦🇺Maroochydore, Queensland, Australia
Monash Medical Centre
🇦🇺Clayton, Victoria, Australia
NZOZ Przychodnia Internistyczno - Stomatologiczna "Kendron"
🇵🇱Bialystok, Poland
WSS im.Kardynala S. Wyszynskiego
🇵🇱Lublin, Poland