Retigabine Efficacy and Safety Trial for Partial Onset Refractory Seizures in Epilepsy (RESTORE2)

Randomized, Double-Blind, Placebo-Controlled, Multicenter, Parallel-Group Phase 3 Study - Determine Efficacy and Safety of Two Doses of Retigabine (900 Mg/Day and 600 Mg/Day) Used as Adjunctive Therapy in Refractory Epilepsy Patients With Partial-Onset Seizures

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).

Study Overview

• Status: Completed
• Conditions: Seizures
• Intervention / Treatment: Drug: Placebo; Drug: Retigabine; Drug: Retigabine

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.

• Study Type: Interventional
• Enrollment (Actual): 539
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
  • Queensland
    • Maroochydore, Queensland, Australia, 4558
      • North Coast Neurology Centre
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
    • West Heidelberg, Victoria, Australia, 3084
      • Austin & Repatriation Medical Centre
• Belgium
  • Antwerp, Belgium, 2020
    • A. Z. Middelheim -- Department of Neurology
  • Brugge, Belgium, 8000
    • AZ Sint-Jan
  • Leuven, Belgium, 3000
    • Universitaire Ziekenhuizen Gasthuisberg -- Department Neurology
  • Ottignies, Belgium, 1340
    • Centre Neurologique William Lennox
• France
  • Rennes Cedex, France, 35033
    • CHU Pontchaillou
  • Strasbourg, France, 67 67091
    • Hopital Civil de strasbourg
  • Tain L'Hermitage, France, 26 26600
    • Centre Medical de La Teppe
  • Lyonnais
    • Lyon, Lyonnais, France, 69003
      • Hôpital Neurologique Pierre Wertheimer
• Germany
  • Bonn, Germany, D-53105
    • University of Bonn -- Department for Epileptplogy
  • Erlangen, Germany, BY 91054
    • Zentrum Epilepsie Erlangen (ZEE) der Universitaet Erlangen
  • Goettingen, Germany, NI 37075
    • Georg-August-Universitaet Goettingen
  • Mainz, Germany, RP 55101
    • Universitaetsklinik Mainz Neurologische Klinik
  • Marburg, Germany, HE 35033
    • Universitaet Giessen / Marburg Neurologie
  • Munich, Germany, BY 80333
    • Theatinerstrasse 44
  • Ulm, Germany, BW 89081
    • Universitaetsklinikum Ulm
• Hungary
  • Budapest, Hungary, 1145
    • Országos Idegsebészeti Tudományos Intézet
  • Budapest, Hungary, 1021
    • Natl. Inst. of Psychiatry and Neurology
• Israel
  • Ashkelon, Israel, 78306
    • Barzilai Medical Center
  • Beer Yaakov, Israel, 70300
    • Assaf Harofeh Medical Center
  • Haifa, Israel, 31096
    • Rambam Medical Center
  • Holon, Israel, 58100
    • Wolfson Medical Center
  • Nahariya, Israel, 22100
    • Western Galilee Hospital
  • Ramat Gan, Israel, 52621
    • Chaim Sheba Medical Center
  • Rechovot, Israel, 76100
    • Kaplan Medical Center
  • Tel Aviv, Israel, 64239
    • Tel-Aviv Sourasky Medical Center
• Poland
  • Bialystok, Poland, 15-420
    • NZOZ Przychodnia Internistyczno - Stomatologiczna "Kendron"
  • Gdansk, Poland, 80-803
    • Wojewodzki Szpital Specjalistyczny im.Mikolaja Kopernika
  • Katowice, Poland, 40-752
    • Katedra i Klinika Neurologii Slaskiej Akademii Medycznej
  • Lublin, Poland, 20-718
    • WSS im.Kardynala S. Wyszynskiego
  • Warsaw, Poland, 02-957
    • Instytut Psychiatrii i Neurologii II Oddzial Neurologii
  • Warsaw, Poland, 03-464
    • Prywatna Wielospecjalistyczna Lecznica Medyczna "Zycie"
  • Plock
    • Padlewskiego 4, Plock, Poland, 09-402
      • Specjalistyczna Przychodnia Lekarska Medikard
• Russian Federation
  • Kazan, Russian Federation, 420048
    • Interregional Clinical Diagnostic Centre
  • Moscow, Russian Federation, 117049
    • City hospital # 1
  • Moscow, Russian Federation, 119021
    • Clinic of Nervous Diseases of Sechenov's Moscow Med. Academy
  • Moscow, Russian Federation, 121374
    • District Antiepileptic Centre City Clinical Hospital # 71
  • St. Petersburg, Russian Federation, 194044
    • Military Medical Academy n.a. S.M.Kirov
  • St. Petersburg, Russian Federation, 197022
    • St.Petersburg State Medical University n.a. I.P.Pavlov
• South Africa
  • Cape Town, South Africa, 7550
    • Panorama Medi-Clinic
  • East Cape
    • Port Elizabeth, East Cape, South Africa, 6001
      • Triple M Research
  • Gauten
    • Johannesburg, Gauten, South Africa, 2193
      • Johannesburg Hospital
  • Gauteng
    • Bloemfontein, Gauteng, South Africa, 9300
      • University of the Free State
    • Pretoria, Gauteng, South Africa, 0041
      • Wilgers MR & Medical Centre
    • Sunninghill, Gauteng, South Africa, 2157
      • Sunninghill & Kopano Clinical Trials
  • KwaZulu-Natal
    • Durban, KwaZulu-Natal, South Africa, 4091
      • Inkosi Albert Luthuli Central Hospital
  • West Cape
    • Belville, West Cape, South Africa, 7531
      • Carl Bremer Hospital
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7925
      • Groote Schuur Hospital
• Spain
  • Barcelona, Spain, 08025
    • Hospital de la Santa Creu i Sant Pau
  • Bilbao, Spain, 48903
    • Hospital de Cruces
  • Granada, Spain, 18013
    • Hosp. Virgen de las Nieves
  • Madrid, Spain, 28034
    • Hospital Ruber Internacional de Madrid
  • San Sebastian, Spain, 20014
    • Hosp de Donostia
  • Zaragoza, Spain, 50009
    • Hosp. Clinico Univ. Lozano Blesa
• Ukraine
  • Dnepropetrovsk, Ukraine, 49616
    • Psychosomatic Center of Dnepropetr. Regional Clinic
  • Kharkiv, Ukraine, 61022
    • Kharkiv State Medical University
  • Kharkov, Ukraine, 61068
    • Institute of Neurology, Psychiatry and Narcology of AMS, Ukr
  • Kiev, Ukraine, 04080
    • Epilepsy Center of Municipal Clinical Psychoneurological Hospital
  • Odessa, Ukraine, 65025
    • Odessa regional clinical Hospital
• United Kingdom
  • Blackpool, United Kingdom, LANARK FY3 8BP
    • Fylde Coast Hospital
  • Glasgow, United Kingdom, G11 6NT
    • Western Infirmary (Epilepsy)
  • Liverpool, United Kingdom, L9 7LJ
    • Walton Centre for Neurology & Neurosurgery
  • London, United Kingdom, GT LON E1 1BB
    • Royal London Hospital
  • Mersyd
    • Middlesbrough, Mersyd, United Kingdom, T&W TS4 3BW
      • The James Cook University Hospital
• United States
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Mid-Atlantic Epilepsy and Sleep Center
  • Texas
    • Dallas, Texas, United States, 75230
      • Neurological Clinic-Texas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Oral tablet.
Experimental: Retigabine 600 mg	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 3, patients will enter a 12 week maintenance phase.; Other Names: GKE-841; D-23129; 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 5, patients will enter a 12 week maintenance phase.; Other Names: GKE-841; D-23129
Experimental: Retigabine 900 mg	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 3, patients will enter a 12 week maintenance phase.; Other Names: GKE-841; D-23129; 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 5, patients will enter a 12 week maintenance phase.; Other Names: GKE-841; D-23129

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in the 28-day Total Partial Seizure (PS) Frequency From Baseline (BL) to the End of the Double-blind (DB) Phase (Titration and Maintenance Phases)	28-day total PS (PSs [also called focal seizures] are seizures limited to a specific area of the brain) frequency in the BL period = (Number [No.] of total PSs reported in the BL period divided by the No. of days of available total PS data in the BL period) x 28 days. 28-day total PS frequency in the DB period = (No. of total PSs reported in the DB period divided by the No. of days of available total PS data in the DB period) x 28 days. Percent change = ([value in the DB period minus value at BL] divided by the BL value) x 100%. Negative valu es indicate a reduction in seizure frequency.	Baseline (Week -7 through Week 0), DB Phase (Week 1 through Week 16)
Number of Participants Classified as Responders and Non-responders During the Maintenance Phase	Responders were participants with at least a 50% reduction in the 28-day total partial seizure frequency in the Maintenance Phase as compared to the Baseline period.	Week 5 through Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Were Responders and Non-responders During the DB Phase	Responders were participants with at least a 50% reduction in the 28-day total partial seizure frequency in the DB Phase as compared to the Baseline period. Participants without any post-baseline data were considered non-responders.	Week 1 through Week 16
Percent Change From Baseline (BL) in the 28-day Total Partial Seizure Frequency During the Maintenance Phase	28-day total partial seizure frequency in the BL period = (No. of total partial seizures reported in the BL period divided by the No. of days of available total partial seizure data in the BL period) x 28 days. 28-day total partial seizure frequency in the Maintenance Phase = (No. of total partial seizures reported in the Maintenance Phase divided by the No. of days of available total partial seizure data in the same phase) x 28 days. Percent change = (value in the Maintenance Phase minus value at BL divided by the BL value) x 100%. Negative values indicate a reduction in seizure frequency.	Baseline (Week -7 through Week 0), Week 5 through Week 16
Number of Participants With a Reduction in the 28-day Total Partial Seizure Frequency From Baseline to the End of DB Phase (Titration and Maintenance Phases) by Indicated Quartile Reduction Categories	Participants who experienced a reduction from Baseline in the 28-day total partial seizure frequency were categorized as having a reduction of 75-100%, 50-<75%, 25-<50%, or <25%, in addition to having no reduction. This quartile cutting was specified in the study protocol. Participants without any post-baseline data are included in the "No reduction" category.	Baseline (Week -7 through Week 0), Week 1 through Week 16
Number of Participants With a Reduction in the 28-day Total Partial Seizure Frequency From Baseline to the DB Phase (Titration and Maintenance Phases) by Indicated Decile Reduction and Increase Categories	Participants who experienced a reduction from Baseline in the 28-day total partial seizure frequency were categorized in decile cutting, i.e., reduction categories of 90-100%, 80-<90%, 70-<80%, 60-<70%, 50-<60%, 40-<50%, 30-<40%, 20-<30%, 10-<20%, >0-<10%, and increase categories of 0-10%, >10-20%, >20-30%, >30% (FDA endpoint). Participants without any post-baseline data were included in the category 0-10% increase category.	Baseline (Week -7 through Week 0), Week 1 through Week 16
Number of Participants With the Indicated Reduction From Baseline in the 28-day Total Partial Seizure Frequency During the Maintenance Phase	Participants who experienced a reduction from Baseline in the 28-day total partial seizure frequency were categorized as having a >75%, a 50-75%, or a <50% reduction, in addition to having no reduction (EMEA endpoint).	Baseline (Week -7 through Week 0), Week 5 through Week 16
Number of Participants Who Experienced the Indicated Level of Exacerbation and Reduction in the 28-day Total Partial Seizure Frequency From Baseline During the Maintenance Phase	Participants who experienced an exacerbation from Baseline in the 28-day total partial seizure frequency were categorized as having a 0-25% or a >25% increase (EMEA endpoint). The number of participants experiencing a >0% reduction from Baseline in the 28-day total partial seizure frequency are also presented.	Baseline (Week -7 through Week 0), Week 5 through Week 16
Number of Participants Reporting New Seizure Types in the Indicated Categories During the DB Phase (Titration and Maintenance Phases) That Were Not Reported at Baseline	New seizure types included those seizures which were not reported by any participant at Baseline.	Baseline (Week -7 through Week 0), Week 1 through Week 16
Number of Participants Who Were Seizure-free During the DB Phase (Titration and Maintenance Phases)	Participants were considered to be seizure-free if they had not reported any seizures during the DB treatment period (Weeks 1-18). For a participant to be seizure free during the DB Phase, the participant had to be seizure free both Week 7 to Week 18 and Week 1 to Week 6. A participant could be seizure free Week 7 to Week 18 (during the Maintenance Phase), but not seizure free Week 1 to Week 6. Hence, there are fewer participants being reported as seizure free from Week 1 to Week 18 than from Week 7 to Week 18.	Week 1 through Week 16
Number of Participants Who Were Seizure-free During the Maintenance Phase	Participants were considered to be seizure-free if they had not reported any seizures during the Maintenance Phase.	Week 5 through Week 16
Percentage of Seizure-free Days During the DB Phase (Titration and Maintenance Phases)	A seizure-free day was a day without any seizures. For a participant to be seizure free during the DB Phase, the participant had to be seizure free both Week 7 to Week 18 and Week 1 to Week 6. A participant could be seizure free Week 7 to Week 18 (during the Maintenance Phase), but not seizure free Week 1 to Week 6. Hence, there are fewer participants being reported as seizure free from Week 1 to Week 18 than from Week 7 to Week 18. The percentage of seizure-free days was calculated as the total number of days without seizures in the DB period divided by the number of days in DB period x 100%.	Week 1 through Week 16
Percentage of Seizure-free Days During the Maintenance Phase	A seizure-free day was a day without any seizures. The percentage of seizure-free days was calculated as the total number of days without seizures in the Maintenance Phase divided by the number of days in the Maintenance Phase x 100%.	Week 5 through Week 16
Clinical Global Impression-Improvement (CGI-I) Score at the End of the Maintenance Phase	Clinical Global Impression of Improvement (CGI-I) is a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the treatment. Scores on the scale are rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.	Week 16/end of treatment phase
Patient Global Impression (PGI) Score at the End of the Maintenance Phase	PGI is a participant-rated scale of improvement that was administered at the end of the Maintenance Phase in order to assess the participant's impression of his or her own improvement. PGI assessments were scored using a 7-point scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.	Week 16/end of treatment phase
Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) at BL (Week 0) and Weeks 4, 8, and 16	The QOLIE-31-P is a 31-item questionnaire evaluating a participant's QOL perception in 7 domains: seizure worry, emotional well being, energy/fatigue, cognitive functioning, medication effects, social functioning, overall QOL. Precoded numeric values for some domains are such that a higher number reflects a more favorable health state; others are such that a higher number reflects a less favorable state. Precoded values are first converted to 0-100 point scores; higher converted scores always reflect better QOL. The overall score is derived by weighting and then summing the 7 domain scores.	End of Baseline (Week 0), Weeks 4, 8, and 16
Number of Participants Whose Clinical Laboratory Values Were Deemed an Adverse Event by the Investigator (>=2% in Any Treatment Arm)	Clinically important changes in laboratory values were to be reported as an adverse event if they met one of the following criteria: (1) intervention required; (2) change in dose of study drug required; (3) other treatment/therapy required; (4) association with other diagnoses.	Week 1 through Week 16
Number of Participants Who Reported the Indicated Renal and Urinary Disorder Adverse Events at a Frequency Threshold of 2% (in Any Treatment Arm)	A summary of the adverse events classified as renal or urinary disorders and in which at least 2% (rounded to an integer) of participants in any treatment arm reported during the study is presented.	Week 1 through Week 16
Change From Baseline in Post-void Residual Urine Volume at Weeks 8 and 16 of the Maintenance Phase	Post-void residual (PVR) urine refers to the amount of urine remaining in the bladder after normal urination. To investigate the possible effects of retigabine on bladder function, all participants underwent post-void residual bladder ultrasound at Baseline and during the Maintenance Phase. The PVR bladder ultrasound was performed by a urologist, a qualified ultrasound technician, or a qualified study nurse who was certified to do PVR bladder ultrasound. Change from Baseline in PVR residual volume was calculated as the values at Week 10 and Week 16 minus the value at Baseline.	Baseline (Week -7 through 0), Weeks 8 and 16
Number of Participants With a >=7% Increase in Body Weight During Weeks 2 and 4 of theTitration Phase and Weeks 6, 8, 12, and 16 of the Maintenance Phase	The number of participants with recorded weight gain of >=7% over their baseline weight was measured.	Weeks 2 and 4 of Titration Phase and Weeks 6, 8, 12, and 16 of Maintenance Phase

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Collaborators: Bausch Health Americas, Inc.

Publications and helpful links

General Publications

• Brodie MJ, Lerche H, Gil-Nagel A, Elger C, Hall S, Shin P, Nohria V, Mansbach H; RESTORE 2 Study Group. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology. 2010 Nov 16;75(20):1817-24. doi: 10.1212/WNL.0b013e3181fd6170. Epub 2010 Oct 13.
• Tompson DJ, Crean CS. Clinical pharmacokinetics of retigabine/ezogabine. Curr Clin Pharmacol. 2013 Nov;8(4):319-31. doi: 10.2174/15748847113089990053.
• Brickel N, Gandhi P, VanLandingham K, Hammond J, DeRossett S. The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels. Epilepsia. 2012 Apr;53(4):606-12. doi: 10.1111/j.1528-1167.2012.03441.x. Epub 2012 Mar 16.
• Porter RJ, Burdette DE, Gil-Nagel A, Hall ST, White R, Shaikh S, DeRossett SE. Retigabine as adjunctive therapy in adults with partial-onset seizures: integrated analysis of three pivotal controlled trials. Epilepsy Res. 2012 Aug;101(1-2):103-12. doi: 10.1016/j.eplepsyres.2012.03.010. Epub 2012 Apr 16.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (Actual): April 1, 2008
• Study Completion (Actual): April 1, 2008

Study Registration Dates

• First Submitted: October 6, 2005
• First Submitted That Met QC Criteria: October 6, 2005
• First Posted (Estimate): October 10, 2005

Study Record Updates

• Last Update Posted (Actual): April 21, 2017
• Last Update Submitted That Met QC Criteria: March 23, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Epilepsy; Anticonvulsant; Partial Seizures; Potassium Channels; Complex Partial Seizures
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Epilepsy; Seizures; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Anticonvulsants; Ezogabine
• Other Study ID Numbers: VRX-RET-E22-302

Plan for Individual participant data (IPD)

Study Data/Documents

1. Study Protocol
   Information identifier: VRX-RET-E22-302
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Individual Participant Data Set
   Information identifier: VRX-RET-E22-302
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Annotated Case Report Form
   Information identifier: VRX-RET-E22-302
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Clinical Study Report
   Information identifier: VRX-RET-E22-302
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Statistical Analysis Plan
   Information identifier: VRX-RET-E22-302
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Dataset Specification
   Information identifier: VRX-RET-E22-302
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Informed Consent Form
   Information identifier: VRX-RET-E22-302
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register