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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00235755




Registration number
NCT00235755
Ethics application status
Date submitted
6/10/2005
Date registered
10/10/2005
Date last updated
21/04/2017

Titles & IDs
Public title
Retigabine Efficacy and Safety Trial for Partial Onset Refractory Seizures in Epilepsy
Scientific 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
Secondary ID [1] 0 0
VRX-RET-E22-302
Universal Trial Number (UTN)
Trial acronym
RESTORE2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Seizures 0 0
Condition category
Condition code
Neurological 0 0 0 0
Epilepsy
Neurological 0 0 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Retigabine
Treatment: Drugs - Retigabine
Treatment: Drugs - Placebo

Placebo Comparator: Placebo -

Experimental: Retigabine 600 mg -

Experimental: Retigabine 900 mg -


Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: Placebo
Oral tablet.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
Baseline (Week -7 through Week 0), DB Phase (Week 1 through Week 16)
Primary outcome [2] 0 0
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.
Timepoint [2] 0 0
Week 5 through Week 16
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
Week 1 through Week 16
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
Baseline (Week -7 through Week 0), Week 5 through Week 16
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
Baseline (Week -7 through Week 0), Week 1 through Week 16
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
Baseline (Week -7 through Week 0), Week 1 through Week 16
Secondary outcome [5] 0 0
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).
Timepoint [5] 0 0
Baseline (Week -7 through Week 0), Week 5 through Week 16
Secondary outcome [6] 0 0
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.
Timepoint [6] 0 0
Baseline (Week -7 through Week 0), Week 5 through Week 16
Secondary outcome [7] 0 0
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.
Timepoint [7] 0 0
Baseline (Week -7 through Week 0), Week 1 through Week 16
Secondary outcome [8] 0 0
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.
Timepoint [8] 0 0
Week 1 through Week 16
Secondary outcome [9] 0 0
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.
Timepoint [9] 0 0
Week 5 through Week 16
Secondary outcome [10] 0 0
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%.
Timepoint [10] 0 0
Week 1 through Week 16
Secondary outcome [11] 0 0
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%.
Timepoint [11] 0 0
Week 5 through Week 16
Secondary outcome [12] 0 0
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.
Timepoint [12] 0 0
Week 16/end of treatment phase
Secondary outcome [13] 0 0
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.
Timepoint [13] 0 0
Week 16/end of treatment phase
Secondary outcome [14] 0 0
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.
Timepoint [14] 0 0
End of Baseline (Week 0), Weeks 4, 8, and 16
Secondary outcome [15] 0 0
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.
Timepoint [15] 0 0
Week 1 through Week 16
Secondary outcome [16] 0 0
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.
Timepoint [16] 0 0
Week 1 through Week 16
Secondary outcome [17] 0 0
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.
Timepoint [17] 0 0
Baseline (Week -7 through 0), Weeks 8 and 16
Secondary outcome [18] 0 0
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.
Timepoint [18] 0 0
Weeks 2 and 4 of Titration Phase and Weeks 6, 8, 12, and 16 of Maintenance Phase

Eligibility
Key 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
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 0 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 0 0
North Coast Neurology Centre - Maroochydore
Recruitment hospital [3] 0 0
Monash Medical Centre - Clayton
Recruitment hospital [4] 0 0
Royal Melbourne Hospital - Parkville
Recruitment hospital [5] 0 0
Austin & Repatriation Medical Centre - West Heidelberg
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
4558 - Maroochydore
Recruitment postcode(s) [3] 0 0
3168 - Clayton
Recruitment postcode(s) [4] 0 0
3050 - Parkville
Recruitment postcode(s) [5] 0 0
3084 - West Heidelberg
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Maryland
Country [2] 0 0
United States of America
State/province [2] 0 0
Texas
Country [3] 0 0
Belgium
State/province [3] 0 0
Antwerp
Country [4] 0 0
Belgium
State/province [4] 0 0
Brugge
Country [5] 0 0
Belgium
State/province [5] 0 0
Leuven
Country [6] 0 0
Belgium
State/province [6] 0 0
Ottignies
Country [7] 0 0
France
State/province [7] 0 0
Lyonnais
Country [8] 0 0
France
State/province [8] 0 0
Rennes Cedex
Country [9] 0 0
France
State/province [9] 0 0
Strasbourg
Country [10] 0 0
France
State/province [10] 0 0
Tain L'Hermitage
Country [11] 0 0
Germany
State/province [11] 0 0
Bonn
Country [12] 0 0
Germany
State/province [12] 0 0
Erlangen
Country [13] 0 0
Germany
State/province [13] 0 0
Goettingen
Country [14] 0 0
Germany
State/province [14] 0 0
Mainz
Country [15] 0 0
Germany
State/province [15] 0 0
Marburg
Country [16] 0 0
Germany
State/province [16] 0 0
Munich
Country [17] 0 0
Germany
State/province [17] 0 0
Ulm
Country [18] 0 0
Hungary
State/province [18] 0 0
Budapest
Country [19] 0 0
Israel
State/province [19] 0 0
Ashkelon
Country [20] 0 0
Israel
State/province [20] 0 0
Beer Yaakov
Country [21] 0 0
Israel
State/province [21] 0 0
Haifa
Country [22] 0 0
Israel
State/province [22] 0 0
Holon
Country [23] 0 0
Israel
State/province [23] 0 0
Nahariya
Country [24] 0 0
Israel
State/province [24] 0 0
Ramat Gan
Country [25] 0 0
Israel
State/province [25] 0 0
Rechovot
Country [26] 0 0
Israel
State/province [26] 0 0
Tel Aviv
Country [27] 0 0
Poland
State/province [27] 0 0
Plock
Country [28] 0 0
Poland
State/province [28] 0 0
Bialystok
Country [29] 0 0
Poland
State/province [29] 0 0
Gdansk
Country [30] 0 0
Poland
State/province [30] 0 0
Katowice
Country [31] 0 0
Poland
State/province [31] 0 0
Lublin
Country [32] 0 0
Poland
State/province [32] 0 0
Warsaw
Country [33] 0 0
Russian Federation
State/province [33] 0 0
Kazan
Country [34] 0 0
Russian Federation
State/province [34] 0 0
Moscow
Country [35] 0 0
Russian Federation
State/province [35] 0 0
St. Petersburg
Country [36] 0 0
South Africa
State/province [36] 0 0
East Cape
Country [37] 0 0
South Africa
State/province [37] 0 0
Gauteng
Country [38] 0 0
South Africa
State/province [38] 0 0
Gauten
Country [39] 0 0
South Africa
State/province [39] 0 0
KwaZulu-Natal
Country [40] 0 0
South Africa
State/province [40] 0 0
West Cape
Country [41] 0 0
South Africa
State/province [41] 0 0
Western Cape
Country [42] 0 0
South Africa
State/province [42] 0 0
Cape Town
Country [43] 0 0
Spain
State/province [43] 0 0
Barcelona
Country [44] 0 0
Spain
State/province [44] 0 0
Bilbao
Country [45] 0 0
Spain
State/province [45] 0 0
Granada
Country [46] 0 0
Spain
State/province [46] 0 0
Madrid
Country [47] 0 0
Spain
State/province [47] 0 0
San Sebastian
Country [48] 0 0
Spain
State/province [48] 0 0
Zaragoza
Country [49] 0 0
Ukraine
State/province [49] 0 0
Dnepropetrovsk
Country [50] 0 0
Ukraine
State/province [50] 0 0
Kharkiv
Country [51] 0 0
Ukraine
State/province [51] 0 0
Kharkov
Country [52] 0 0
Ukraine
State/province [52] 0 0
Kiev
Country [53] 0 0
Ukraine
State/province [53] 0 0
Odessa
Country [54] 0 0
United Kingdom
State/province [54] 0 0
Mersyd
Country [55] 0 0
United Kingdom
State/province [55] 0 0
Blackpool
Country [56] 0 0
United Kingdom
State/province [56] 0 0
Glasgow
Country [57] 0 0
United Kingdom
State/province [57] 0 0
Liverpool
Country [58] 0 0
United Kingdom
State/province [58] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Bausch Health Americas, Inc.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/show/NCT00235755
Trial related presentations / 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.
Crean CS, Tompson DJ, Buraglio M. The effect of ezogabine on the pharmacokinetics of an oral contraceptive agent. Int J Clin Pharmacol Ther. 2013 Nov;51(11):847-53. doi: 10.5414/CP201916.
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. Review.
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications