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

Study PTG116878, a Dose-Optimization Study of Ezogabine/Retigabine Immediate Release Tablets Versus Placebo in the Adjunctive Treatment of Subjects With Partial-Onset Seizures

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.

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

• Liver function tests: alanine aminotransferase (ALT) is ≥2 times the upper limit of normal (ULN); alkaline phosphatase and bilirubin are >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%).

• Are suffering from acute or progressive neurological disease, severe psychiatric disease, or severe mental abnormalities that are likely to interfere with the objectives of the study

• Have a history of malignancy within the past 2 years; with the exception of basal cell carcinoma

• Have unstable liver disease [chronic stable hepatitis B and C are acceptable if subject otherwise meets entry criteria; chronic stable Hepatitis B to be excluded if significant immunosuppressive agents administered due to risk of hepatitis B reactivation]

• Have any medical condition that, in the investigator's judgment, is considered to be clinically significant and could potentially affect subject safety or study outcome, including but not limited to: clinically significant cardiac, renal, hepatic condition, or a condition that affects the absorption, distribution, metabolism or excretion of drugs

• Have an active suicidal plan/intent or have had active suicidal thoughts in the past 6 months. Have history of suicide attempt in the last 2 years or more than 1 lifetime suicide attempt.

• Have a history of substance abuse (alcohol or drugs) or substance dependence within 12 months prior to screening

• Have a known hypersensitivity to any components of the study medication

• Have taken an investigational drug, or used an investigational device, within the previous 30 days prior to screening or plans to take an investigational drug anytime during the study.