Dose-Optimization, Adjunctive Treatment Study of Ezogabine/Retigabine Immediate Release in Partial-onset Seizures

NCT01721317 | Terminated Phase 4 Results

• 2 other identifiers: 1168782012-003105-10
• Study Type: interventional
• Target: 6
• Locations: 2 countries
• Sites: 11

Brief Summary

This is a Phase IV adjunctive treatment dose-optimization study evaluating the efficacy, safety, and health outcomes of ezogabine/retigabine immediate release (IR) (GW582892) compared with placebo in adult subjects with partial-onset seizures (POS). This randomized, double-blind, placebo-controlled, parallel-group, multicenter study will compare ezogabine/retigabine IR (investigator-selected daily doses of 600 milligram (mg)/day, 750 mg/day, 900 mg/day, 1050 mg/day or 1200 mg/day) with placebo. Study drug will be taken three times a day (TID) in equally or unequally divided doses. The study design includes up to a 10-week (wk) Screening (≤2 wks)/Baseline (8 wks) Phase, a Titration Phase (2 wks), Dose-Optimization Phase (8 wks), Maintenance Phase (8 wks), and Taper/Follow-Up Phase (3 wks). The total duration of the study for each subject will be approximately 31 wks, and at minimum approximately 27 wks if subjects provide reliable 28-day retrospective seizure data. Approximately 280 subjects will be screened with approximately 208 subjects randomly assigned to 1 of 2 treatment groups in a 2:1 ratio (ezogabine/retigabine IR, or placebo). Subjects will be instructed to start investigational product (IP) the day after the baseline visit. During the first week of the Titration Phase, subjects will be taking 300 mg/day (100 mg TID). During the second week, subjects will be taking 450 mg/day (150 mg/day TID). At the beginning of the Dose-Optimization Phase (3rd week of study drug) subjects will take 600 mg/day (200 mg TID) for one week. Thereafter during the Dose-Optimization Phase, subjects will continue to increase their daily dose by 150 mg per week until they have achieved their optimal tolerated dose. During this phase, the investigator may choose to have the subject stay on his/her designated dose for another week before attempting a dose increase until reaching a dose of 1200 mg/day. In addition, in the context of tolerability issues, the subject may be reduced to the preceding dose level for one week before attempting to increase the dose again at the next scheduled time point until the subject reaches optimal dose. Subjects unable to tolerate a minimum of 600 mg/day will be discontinued from the study. The Maintenance Phase will begin at Week 10 (Visit 8) and will last 8 weeks. During the Maintenance Phase, subjects will remain on the daily TID dose achieved at the end of the Dose-Optimization Phase. Seizure type and frequency will be monitored throughout the study via a Seizure Calendar and will be evaluated at each study visit. Subjects will be instructed to complete the daily Seizure Calendar during each phase of the study.

Conditions

Seizures

Keywords

Ezogabine/Retigabine; Adjunctive Treatment; Safety; Efficacy; Epilepsy; Tolerability; Immediate Release; GW582892; Dose-Optimization; Partial-Onset Seizures

Outcome Measures

Primary Outcomes (2)

• Percent Change in the 28-day Total Partial Seizure Frequency (POS) From Week 0 (End of Baseline Phase) Through Week 18 (End of Maintenance Phase)

  The efficacy of ezogabine/retigabine IR as an adjunctive treatment was to be evaluated by the percent change in the total partial seizure frequency, which was recorded by participants in the daily seizure calendar. The total 28-day POS rate is defined as the total number of POS reported during the evaluation period divided by the total number of applicable days during the evaluation period with this quotient multiplied by 28 days. The applicable days are the days in which the participant had non-missing seizure data (i.e., either 0 or \> 0 seizures recorded). Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

  Week 0 (end of Baseline Phase) through Week 18 (end of Maintenance Phase)

• Percent Change in the 28-day Total Partial Seizure Frequency (POS) Within Each Stratum From Week 0 (End of Baseline Phase) Through Week 18 (End of Maintenance Phase)

  The percent change in 28-day total POS frequency within each stratum (sodium channel blocker or non-sodium channel blocker) background antiepileptic drug (AED) was to be summarized as the supportive analysis. The total 28-day POS value is defined as the total number of POS reported during the evaluation period divided by the total number of applicable days during the evaluation period with this quotient multiplied by 28 days. The applicable days are the days in which the participant had non-missing seizure data (i.e., either 0 or \> 0 seizures recorded). Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

  Week 0 (end of Baseline Phase) through Week 18 (end of Maintenance Phase)

Secondary Outcomes (29)

• Percent Change in 28-day Total Partial Seizure Frequency (POS) for the Indicated Intervals: Maintenance Phase and the Dose-Optimization Phase + Maintenance Phase

  Week 3 (start of Dose -Optimization Phase) to Week 18 (end of Maintenance Phase)

• Number of Par. Experiencing >=50% Reduction in 28-day Total Partial Seizure Frequency (POS) for the Intervals: Double-blind Period (Titration Phase + Dose-Optimization Phase + Maintenance Phase), Maintenance Phase and Dose-Optimization + Maintenance Phase

  Week 0 (end of Baseline Phase) through Week 18 (end of Maintenance Phase)

• Number of Seizure Free Participants for the Indicated Intervals: Maintenance Phase and the Dose-Optimization Phase + Maintenance Phase

  Week 3 (start of Dose-Optimization Phase) to Week 18 (end of Maintenance Phase)

• Change From Baseline in the Number of Seizure Free Days for the Indicated Intervals: Double-blind Period (Titration Phase + Dose-Optimization Phase + Maintenance Phase), Maintenance Phase and the Dose-Optimization + Maintenance Phase

  Week 0 (end of Baseline Phase) to Week 18 (end of Maintenance Phase)

• Percent Change From Baseline in Functional Status (Epilepsy-related Worry and Activity Limitation) and Productivity (Missed Work or School) to the End of the Dose-Optimization Phase and the End of the Maintenance Phase

  Week 3 (start of Dose -Optimization Phase) to Week 18 (end of Maintenance Phase)

Study Arms (16)

Titration Phase: Ezogabine/Retigabine 300 mg

EXPERIMENTAL

Subjects receive Ezogabine/Retigabine 300 mg equally divided TID over Wk 1

Drug: Ezogabine/Retigabine IR

Titration Phase: Placebo 300 mg

PLACEBO COMPARATOR

Subjects receive matching Placebo

Drug: Placebo

Titration Phase: Ezogabine/Retigabine 450 mg

EXPERIMENTAL

Subjects receive Ezogabine/Retigabine 450 mg equally divided TID over Wk 2

Drug: Ezogabine/Retigabine IR

Titration Phase: Placebo 450 mg

PLACEBO COMPARATOR

Subjects receive matching Placebo

Drug: Placebo

Dose-Optimization Phase: Ezogabine/Retigabine 600 mg

EXPERIMENTAL

Subjects receive Ezogabine/Retigabine 600 mg equally divided (200 mg TID) over Wk 3 or until they achieve their optimal tolerated dose as assessed by the Investigator

Drug: Ezogabine/Retigabine IR

Dose-Optimization Phase: Placebo 600 mg

PLACEBO COMPARATOR

Subjects receive matching Placebo

Drug: Placebo

Dose-Optimization Phase: Ezogabine/Retigabine 750 mg

EXPERIMENTAL

Subjects receive Ezogabine/Retigabine 750 mg equally or unequally divided TID over Wk 4 or until they achieve their optimal tolerated dose as assessed by the Investigator

Drug: Ezogabine/Retigabine IR

Dose-Optimization Phase: Placebo 750 mg

PLACEBO COMPARATOR

Subjects receive matching Placebo

Drug: Placebo

Dose-Optimization Phase: Ezogabine/Retigabine 900 mg

EXPERIMENTAL

Subjects receive Ezogabine/Retigabine 900 mg equally or unequally divided TID over Wk 5 or until they achieve their optimal tolerated dose as assessed by the Investigator

Drug: Ezogabine/Retigabine IR

Dose-Optimization Phase: Placebo 900 mg

PLACEBO COMPARATOR

Subjects receive matching Placebo

Drug: Placebo

Dose-Optimization Phase: Ezogabine/Retigabine 1050 mg

EXPERIMENTAL

Subjects receive Ezogabine/Retigabine 1050 mg equally or unequally divided TID over Wk 6 or until they achieve their optimal tolerated dose as assessed by the Investigator

Drug: Ezogabine/Retigabine IR

Dose-Optimization Phase: Placebo 1050 mg

PLACEBO COMPARATOR

Subjects receive matching Placebo

Drug: Placebo

Dose-Optimization Phase: Ezogabine/Retigabine 1200 mg

EXPERIMENTAL

Subjects receive Ezogabine/Retigabine 1200 mg equally divided (400 mg TID) over Wk 7 or until they achieve their optimal tolerated dose as assessed by the Investigator

Drug: Ezogabine/Retigabine IR

Dose-Optimization Phase: Placebo 1200 mg

PLACEBO COMPARATOR

Subjects receive matching Placebo

Drug: Placebo

Maintenance Phase:Ezogabine/Retigabine

EXPERIMENTAL

Subjects receive Ezogabine/Retigabine at the daily dose achieved (equally or unequally divided TID) at the end of the Dose-Optimization Phase for 8 Weeks (600 mg, 750 mg, 900 mg, 1050 mg, or 1200 mg)

Drug: Ezogabine/Retigabine IR

Maintenance Phase: Placebo

PLACEBO COMPARATOR

Subjects receive matching Placebo

Drug: Placebo

Interventions

Ezogabine/Retigabine IR DRUG

Subjects received drug (dose strength 300 mg to 1200 mg) orally with or without food. The 3 daily doses are to be administered with approximately an 8-hour interval between them.

Dose-Optimization Phase: Ezogabine/Retigabine 1050 mg; Dose-Optimization Phase: Ezogabine/Retigabine 1200 mg; Dose-Optimization Phase: Ezogabine/Retigabine 600 mg; Dose-Optimization Phase: Ezogabine/Retigabine 750 mg; Dose-Optimization Phase: Ezogabine/Retigabine 900 mg; Maintenance Phase:Ezogabine/Retigabine; Titration Phase: Ezogabine/Retigabine 300 mg; Titration Phase: Ezogabine/Retigabine 450 mg

Placebo DRUG

Matching placebo will be available

Dose-Optimization Phase: Placebo 1050 mg; Dose-Optimization Phase: Placebo 1200 mg; Dose-Optimization Phase: Placebo 600 mg; Dose-Optimization Phase: Placebo 750 mg; Dose-Optimization Phase: Placebo 900 mg; Maintenance Phase: Placebo; Titration Phase: Placebo 300 mg; Titration Phase: Placebo 450 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A male or female of 18 years of age or above capable of giving written informed consent
• Have a confident diagnosis of epilepsy for \>=6 months with partial-onset seizures (POS), i.e., simple or complex POS with or without secondary generalization (classified according to the International League Against Epilepsy (ILAE) Guidelines, prior to the Screening Visit
• Currently receiving monotherapy treatment with an antiepileptic drug (AED) at a stable dose for at least 28 days prior to the screening visit (Visit 1). If the subject is taking a barbiturate (e.g., phenobarbital), the dose must be stable for ≥3 months prior to the Screening Visit. Note: Subjects who have received previous adjunctive treatment but are currently taking one AED are eligible for enrolment.
• Investigator-confirmed partial seizure frequency rate of ≥3 partial seizures per 28 days over the 8 weeks preceding the screening visit and must not have been seizure-free for ≥ 21 consecutive days.
• Female of non-child bearing potential, or female of child-bearing potential willing to use protocol-specified methods of contraception to prevent pregnancy during the study.
• Capable to comply with dosing of study drug, background AED, all study procedures and to maintain an accurate and complete daily written Seizure Calendar and Functional Status Diary

You may not qualify if:

• Have generalized epilepsy (e.g. Lennox-Gastaut, Juvenile Myoclonic epilepsy, Absence, etc.) or non-epileptic seizures.
• Have had innumerable seizures within the 12-month period prior to the Screening Visit where the individual seizures cannot be counted.
• Have had status epilepticus within 12 months prior to screening
• Have a history of pseudo seizures, non-epileptic events or any other type of psychogenic seizures that could be confused with seizures.
• Have been treated with felbamate or vigabatrin within the 6 months prior to Screening. If a subject has been previously treated with vigabatrin \>6 months prior to Screening, a visual perimetry test performed within 6 months prior to Screening must show normal visual fields or no worsening of recognized visual field abnormalities as compared with prior to vigabatrin treatment
• Benzodiazepines used in any manner other than acute usage as defined in this protocol will be considered concurrent AED usage and will not be permitted
• Are using Central Nervous System (CNS)-active medication (other than concomitant AED therapy), unless the subject has been stabilized on such medication for at least 1 month prior to the Screening Visit.
• Are using herbal treatments with CNS activity within at least 1 month prior to the Screening Visit
• Have received ezogabine/retigabine in a previous study or have taken POTIGA or TROBALT.
• Are currently following or planning to follow the ketogenic diet
• Have an active Vagus Nerve Stimulator (VNS) to control seizures
• Are planning surgery to control seizures during the study
• Have impaired renal function as judged by a creatinine clearance of \<50 mL/min
• Have a history of urinary retention or risk factors for urinary retention that in the investigator's judgment could potentially affect subject safety.
• Have an average corrected QT interval (QTc), using Bazett's QT correction (QTcB), ≥450msec or ≥480msec for subjects with bundle branch block at the time of the Screening Visit

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Bausch Health Americas, Inc.: collaborator

Study Sites (11)

GSK Investigational Site

Fresno, California, 93710, United States

Location

GSK Investigational Site

Santa Monica, California, 90404, United States

Location

GSK Investigational Site

Colorado Springs, Colorado, 80907, United States

Location

GSK Investigational Site

Port Charlotte, Florida, 33952, United States

Location

GSK Investigational Site

Bethesda, Maryland, 20817, United States

Location

GSK Investigational Site

Golden Valley, Minnesota, 55422, United States

Location

GSK Investigational Site

Medford, Oregon, 97504, United States

Location

GSK Investigational Site

Arlington, Texas, 76017, United States

Location

GSK Investigational Site

Kingwood, Texas, 77339, United States

Location

GSK Investigational Site

Athens, 10676, Greece

Location

GSK Investigational Site

Thessaloniki, 57010, Greece

Location

MeSH Terms

Conditions

Seizures; Epilepsy

Interventions

ezogabine

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Brain Diseases; Central Nervous System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2012
• First Posted: November 5, 2012
• Study Start: December 19, 2012
• Primary Completion: June 20, 2013
• Study Completion: June 20, 2013
• Last Updated: December 30, 2020
• Results First Posted: March 26, 2014

Record last verified: 2020-12

Locations

GR (2); US (9)