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

Partial-Onset Seizures Clinical Trial

— RESTORE1  

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Parallel-Group Phase 3 Study to Determine the Efficacy and Safety of Retigabine (1200 mg/Day) Used as Adjunctive Therapy in Refractory Epilepsy Patients With Partial-Onset Seizures

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00232596
• Other study ID #: VRX-RET-E22-301
• Status: Completed
• Phase: Phase 3
• First received: September 30, 2005
• Last updated: March 15, 2012
• Start date: September 2005
• Est. completion date: January 2008

Study information

• Verified date: September 2011
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 306
• Est. completion date: January 2008
• Est. primary completion date: January 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Partial-Onset Seizures
• Seizures

Intervention

Drug:
• Retigabine
Oral tablet. The starting daily dose will be 300 mg/day administered orally in three equally divided doses. This dosage will be increased by 150 mg/day (50 mg/dose) at 1-week intervals (titration phase). At the beginning of Week 7, patients will enter a 12 week maintenance phase
• Placebo
Oral tablet.

Locations

Country	Name	City	State
Argentina	Hospital General de Agudos "Dr. J.M. Ramos Mejia"	Capital Federal	CBA
Argentina	Hospital General de Agudos "Dr. Teodoro Alvarez"	Capital Federal	CBA
Argentina	Hospital Italiano de Buenos Aires	Capital Federal	CBA
Argentina	Fundacion Lennox	Cordoba	CRD
Argentina	Hospital Privado Centro Medico de Cordoba	Cordoba	CRD
Argentina	Sanatorio del Salvador II	Cordoba	CRD
Brazil	Hospital das Clinicas de Ribeirao Preto -- Universidade de Sa Neurologia	Ribeirao Preto	SP
Brazil	Hospital Universitario Prof Edgard Santos -- UFBA	Salvador	BA
Brazil	Hospital das Clinicas da Fac de Medicina de Sao Paulo	Sao Paulo	SP
Brazil	Hospital Sao Paulo -- Escola Paulista de Medicina -- UNIFESP	Sao Paulo	SP
Canada	Foothills Medical Center	Calgary	Alberta
Canada	Glenrose Rehabilitation Center	Edmonton	Alberta
Canada	CHUM -- Hôpital Notre-Dame	Montréal	Quebec
Canada	Health Sciences Centre	St. John's	Newfoundland and Labrador
Mexico	Antiguo Hospital Civil de Guadalajara	Guadalajara	Jalisco
Mexico	Instituto Nacional de Neurologia y Neurocirugia	La Fama	DF
Mexico	Centro Medico	Mexico	DF
Mexico	Hospital de Psiquiatria San Fernando, IMSS	Mexico	DF
Mexico	instituto Nacional de Neurologia y Neurocirugia	Mexico, DF
Mexico	Hospital y Clinica OCA S.A. de C.V.	Monterrey	Nuevo Leon
Mexico	Hospital Central Dr. Ignacio Morones Prieto	San Luis Potosi	SLP
Mexico	CIF BIOTEC, Medica Sur	Tlalpan	DF
United States	McFarland Clinic	Ames	Iowa
United States	Asheville Neurology Specialists	Asheville	North Carolina
United States	Mid-Atlantic Epilepsy and Sleep Center	Bethesda	Maryland
United States	University of Alabama -- Department of Neurology/Epilepsy Center	Birmingham	Alabama
United States	University of Virginia Comprehensive Epilepsy Program	Charlottesville	Virginia
United States	The Comprehensive Epilepsy Care Center for Children and Adults	Chesterfield	Missouri
United States	Delta Waves	Colorado Springs	Colorado
United States	Medical City Dallas Hospital	Dallas	Texas
United States	Neurological Clinic of Texas	Dallas	Texas
United States	University of Colorado Health Science Center	Denver	Colorado
United States	Henry Ford Hospital	Detroit	Michigan
United States	Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Memorial Hermann Hospital	Houston	Texas
United States	North Alabama Neuroscience Research Associates	Huntsville	Alabama
United States	University of Florida -- Shands Jacksonville	Jacksonville	Florida
United States	UCSD Thornton Hospital	La Jolla	California
United States	University of Kentucky	Lexington	Kentucky
United States	Clinical Trials Inc.	Little rock	Arkansas
United States	University of Southern California	Los Angeles	California
United States	West Los Angeles VA Healthcare Center	Los Angeles	California
United States	University of Miami	Miami	Florida
United States	Meharry Medical College	Nashville	Tennessee
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Beth Israel Medical Center	New York	New York
United States	Neurology Clinic	Northport	Alabama
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	Virginia Commonwealth University Medical Center	Richmond	Virginia
United States	Lovelace Scientific Resources	Sarasota	Florida
United States	Minnesota Epilepsy Group, P.A.	St. Paul	Minnesota
United States	Medical University of Ohio at Toledo	Toledo	Ohio
United States	Oregon Neurology PC	Tualatin	Oregon

Sponsors (2)

Lead Sponsor	Collaborator
GlaxoSmithKline	Valeant Pharmaceuticals International, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  Mexico, 

References & Publications (1)

JA French, MD; BW Abou-Khalil MD; RF Leroy, MD; EMT Yacubian, MD; P Shin MS,5 S Hall PhD, H Mansbach MD, and V Nohria MD7 on behalf of the RESTORE 1/Study 301 Investigators. Retigabine Efficacy and Safety Trial for Partial Onset Epilepsy (RESTORE 1): Double-blind, randomized, placebo-controlled trial of retigabine 1200 mg/day as adjunctive therapy in adults with partial-onset seizures. [Neurology].

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline (Week -7 through Week 0), Week 1 through Week 18	No
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.	Week 7 through Week 18	No
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.	Week 1 through Week 18	No
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.	Baseline (Week -7 through Week 0), Week 7 through Week 18	No
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.	Baseline (Week -7 through Week 0), Week 1 through Week 18	No
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.	Baseline (Week -7 through Week 0), Week 1 through Week 18	No
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).	Baseline (Week -7 through Week 0), Week 7 through Week 18	No
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.	Baseline (Week -7 through Week 0), Week 7 through Week 18	No
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.	Baseline (Week -7 through Week 0), Week 1 through Week 18	No
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.	Week 1 through Week 18	No
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.	Week 7 through Week 18	No
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%.	Week 1 through Week 18	No
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%.	Week 7 through Week 18	No
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.	Week 18/end of treatment phase	No
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.	Week 18/end of treatment phase	No
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.	End of Baseline (Week 0), Weeks 6, 10, and 18	No
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.	Week 1 through Week 24	No
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.	Week 1 through Week 24	No
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.	Baseline (Week -7 through Week 0), Weeks 10 and 18	No
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.	Weeks 2, 4, 6 of Titration Phase and Weeks 7, 8, 10, 14, and 18 of Maintenance Phase	No