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

Partial-Onset Seizures Clinical Trial

— RESTORE2  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00235755
• Other study ID #: VRX-RET-E22-302
• Secondary ID: EUDRACT No. 2005
• Status: Completed
• Phase: Phase 3
• First received: October 6, 2005
• Last updated: April 8, 2015
• Start date: December 2005
• Est. completion date: April 2008

Study information

• Verified date: April 2015
• 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 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).

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 information / eligibility

• Status: Completed
• Enrollment: 539
• Est. completion date: April 2008
• Est. primary completion date: April 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 3, patients will enter a 12 week maintenance phase.
• 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.
• Placebo
Oral tablet.

Locations

Country	Name	City	State
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Monash Medical Centre	Clayton	Victoria
Australia	North Coast Neurology Centre	Maroochydore	Queensland
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Austin & Repatriation Medical Centre	West Heidelberg	Victoria
Belgium	A. Z. Middelheim -- Department of Neurology	Antwerp
Belgium	AZ Sint-Jan	Brugge
Belgium	Universitaire Ziekenhuizen Gasthuisberg -- Department Neurology	Leuven
Belgium	Centre Neurologique William Lennox	Ottignies
France	Hopital Neurologique Pierre Wertheimer	Lyon
France	CHU Pontchaillou	Rennes Cedex
France	Hopital Civil de Strasbourg	Strasbourg
France	Centre Medical de La Teppe	Tain L'Hermitage
Germany	University of Bonn -- Department for Epileptplogy	Bonn
Germany	Zentrum Epilepsie Erlangen (ZEE) der Universitaet Erlangen	Erlangen
Germany	Georg-August-Universitaet Goettingen	Goettingen
Germany	Universitaetsklinik Mainz Neurologische Klinik	Mainz
Germany	Universitaet Giessen / Marburg Neurologie	Marburg
Germany	Theatinerstrasse 44	Munich
Germany	Universitaetsklinikum Ulm	Ulm
Hungary	Natl. Inst. of Psychiatry and Neurology	Budapest
Hungary	Orszagos Idegsebeszeti Tudomanyos Intezet	Budapest
Israel	Barzilai Medical Center	Ashkelon
Israel	Assaf Harofeh Medical Center	Beer Yaakov
Israel	Rambam Medical Center	Haifa
Israel	Wolfson Medical Center	Holon
Israel	Western Galilee Hospital	Nahariya
Israel	Chaim Sheba Medical Center	Ramat Gan
Israel	Kaplan Medical Center	Rechovot
Israel	Tel-Aviv Sourasky Medical Center	Tel Aviv
Poland	NZOZ Przychodnia Internistyczno - Stomatologiczna "Kendron"	Bialystok
Poland	Wojewodzki Szpital Specjalistyczny im.Mikolaja Kopernika	Gdansk
Poland	Katedra i Klinika Neurologii Slaskiej Akademii Medycznej	Katowice
Poland	WSS im.Kardynala S. Wyszynskiego	Lublin
Poland	Specjalistyczna Przychodnia Lekarska Medikard	Padlewskiego 4	Plock
Poland	Instytut Psychiatrii i Neurologii II Oddzial Neurologii	Warsaw
Poland	Prywatna Wielospecjalistyczna Lecznica Medyczna "Zycie"	Warsaw
Russian Federation	Interregional Clinical Diagnostic Centre	Kazan
Russian Federation	City Hospital # 1	Moscow
Russian Federation	Clinic of Nervous Diseases of Sechenov's Moscow Med. Academy	Moscow
Russian Federation	District Antiepileptic Centre City Clinical Hospital # 71	Moscow
Russian Federation	Military Medical Academy n.a. S.M.Kirov	St. Petersburg
Russian Federation	St.Petersburg State Medical University n.a. I.P.Pavlov	St. Petersburg
South Africa	Carl Bremer Hospital	Belville	West Cape
South Africa	University of the Free State	Bloemfontein	Gauteng
South Africa	Groote Schuur Hospital	Cape Town	Western Cape
South Africa	Panorama Medi-Clinic	Cape Town
South Africa	Inkosi Albert Luthuli Central Hospital	Durban	KwaZulu-Natal
South Africa	Johannesburg Hospital	Johannesburg	Gauten
South Africa	Triple M Research	Port Elizabeth	East Cape
South Africa	Wilgers MR & Medical Centre	Pretoria	Gauteng
South Africa	Sunninghill & Kopano Clinical Trials	Sunninghill	Gauteng
Spain	Hospital de La Santa Creu i Sant Pau	Barcelona
Spain	Hospital de Cruces	Bilbao
Spain	Hosp. Virgen de las Nieves	Granada
Spain	Hospital Ruber Internacional de Madrid	Madrid
Spain	Hosp de Donostia	San Sebastian
Spain	Hosp. Clinico Univ. Lozano Blesa	Zaragoza
Ukraine	Psychosomatic Center of Dnepropetr. Regional Clinic	Dnepropetrovsk
Ukraine	Kharkiv State Medical University	Kharkiv
Ukraine	Institute of Neurology, Psychiatry and Narcology of AMS, Ukr	Kharkov
Ukraine	Epilepsy Center of Municipal Clinical Psychoneurological Hospital	Kiev
Ukraine	Odessa Regional Clinical Hospital	Odessa
United Kingdom	Fylde Coast Hospital	Blackpool
United Kingdom	Western Infirmary (Epilepsy)	Glasgow
United Kingdom	Walton Centre for Neurology & Neurosurgery	Liverpool
United Kingdom	Royal London Hospital	London
United Kingdom	The James Cook University Hospital	Middlesbrough	Mersyd
United States	Mid-Atlantic Epilepsy and Sleep Center	Bethesda	Maryland
United States	Neurological Clinic-Texas	Dallas	Texas

Sponsors (2)

Lead Sponsor	Collaborator
GlaxoSmithKline	Valeant Pharmaceuticals International, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  France,  Germany,  Hungary,  Israel,  Poland,  Russian Federation,  South Africa,  Spain,  Ukraine,  United Kingdom, 

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 valu es indicate a reduction in seizure frequency.	Baseline (Week -7 through Week 0), DB Phase (Week 1 through Week 16)	No
Primary	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	No
Secondary	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	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 5 through Week 16	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 are included in the "No reduction" category.	Baseline (Week -7 through Week 0), Week 1 through Week 16	No
Secondary	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	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 5 through Week 16	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 5 through Week 16	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 16	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 16	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 5 through Week 16	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 16	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 Maintenance Phase divided by the number of days in the Maintenance Phase x 100%.	Week 5 through Week 16	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 16/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 16/end of treatment phase	No
Secondary	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	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 16	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 16	No
Secondary	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	No
Secondary	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	No