Assessment of the Efficacy and Safety of 2 Doses of Retigabine Immediate Release (900 mg/Day and 600 mg/Day) Used as Adjunctive Therapy in Adult Asian Subjects With Drug-resistant Partial-onset Seizures

A Randomised, Double-blind, Placebo-controlled, Parallel-group, Multicentre Study to Determine the Efficacy and Safety of 2 Doses of Retigabine Immediate Release (900 mg/Day and 600 mg/Day) Used as Adjunctive Therapy in Adult Asian Subjects With Drug-resistant Partial-onset Seizures.

The immediate release (IR) formulation of retigabine has been shown to be superior to placebo as adjunctive therapy in 3 adequate and well-controlled studies in subjects with drug-resistant partial-onset seizures (POS) who had previously failed to respond to two or more antiepileptic drugs (AEDs) and were still having seizures despite current treatment with 1, 2, or 3 AEDs. However, of 1244 subjects randomly assigned to treatment in these 3 clinical studies, only 10 were Asian subjects and only 5 of these Asian subjects were randomly assigned to treatment with retigabine. Therefore, this Phase III study is being conducted to evaluate the efficacy, safety and tolerability, and health outcomes of retigabine, at doses of 900 mg/day and 600 mg/day, compared with placebo in adult Asian subjects with drug-resistant POS.

This is a Phase III study evaluating the efficacy, safety and tolerability, and health outcomes of 2 doses of retigabine immediate release (IR) (GW582892) compared with placebo in adult Asian subjects with drug-resistant partial-onset seizures (POS) who are already taking 1, 2, or 3 antiepileptic drugs (AEDs). This randomised, double-blind, placebo-controlled, parallel-group study will compare retigabine IR at doses of 900 mg/day and 600 mg/day taken in equally divided doses three times a day with placebo.

The study design includes an 8-week Screening/Baseline Phase, a 16-week Treatment Phase (4-week Titration Phase and 12-week Maintenance Phase), and a 4-week Transition or Taper/Follow-up Phase. Approximately 500 subjects will be screened and enrolled with approximately 354 subjects randomly assigned to 1 of 3 treatment groups in a ratio of 1:1:1 (retigabine 900 mg/day, retigabine 600 mg/day, or placebo). The total duration of the study for each subject will be approximately 28 weeks. At the end of the Maintenance Phase, eligible subjects will be given the opportunity to enrol in an open-label extension study.

The primary efficacy endpoint is the proportion of responders, defined as subjects with >/=50% reduction in 28 day total POS frequency, from the Baseline Phase to the Maintenance Phase, in subjects randomly assigned to retigabine 900 mg/day compared with placebo. The key secondary efficacy endpoint is the proportion of responders, defined as subjects with >/=50% reduction in 28 day total POS frequency, from the Baseline Phase to the Maintenance Phase, in subjects randomly assigned to retigabine 600 mg/day compared with placebo.

The safety and tolerability endpoints are incidence and severity of adverse events (AEs); proportion of subjects with AEs leading to discontinuation; change from Baseline in vital sign measurements and weight; change from Baseline in electrocardiogram parameters; change from Baseline in haematology, chemistry, and urinalysis parameters; changes from Baseline in American Urological Association Symptom Index and post-void residual bladder ultrasound volumes; and summary of the Columbia-Suicide Severity Rating Scale.

Inclusion Criteria:

Subjects eligible for enrolment in the study must meet all of the following criteria:

• Asian men or women ≥18 years of age at the time of consent.
• Have a confident diagnosis of epilepsy with POS with or without secondary generalisation (classified according to International League Against Epilepsy, 1981) for ≥2 years and is having POS despite having been treated in the past with ≥2 approved AEDs either alone or together at adequate doses for a sufficient length of time in the opinion of the investigator.
• Have had, within the last 10 years, 1 electroencephalogram or video electroencephalogram and 1 brain magnetic resonance imaging or computerised tomography scan with results consistent with a diagnosis of POS. If diagnostic studies are negative and if history during clinical assessment suggests a diagnosis of POS, and other diseases have been excluded, the subject can be enrolled.
• Have a documented 28-day partial seizure frequency rate of ≥4 partial seizures over the 8 weeks preceding the screening visit. subjects should not be seizure free for ≥21 consecutive days. In subjects with simple partial seizures, only seizures with motor signs will be counted towards meeting the inclusion criteria.
• Currently being treated with a stable regimen of 1, 2, or 3 AEDs for ≥1 month prior to the screening visit. If the subject is taking barbiturates (e.g., phenobarbital), the dose of the barbiturate must have been stable for ≥3 months prior to the screening visit Note: Vagus Nerve Stimulator: VNS will not be counted as a concurrent AED. Subjects with surgically implanted VNS will be allowed to enter the study provided that all of the following conditions are met: a. The VNS has been in place for ≥6 months prior to the screening visit; b. The settings must have remained constant for ≥1 month prior to the screening visit and remain constant throughout the study; c. The battery is expected to last for the duration of the study; d. Subjects who are considering implantation of a VNS are excluded from participation in the study. Note: Benzodiazepines: The chronic use of a benzodiazepine as a concurrent AED is permitted as long as the dose is kept constant for ≥1 month prior to the screening visit and remains constant throughout the study.
• Able and willing to maintain an accurate and complete daily written seizure calendar or has a caregiver who is able and willing to maintain an accurate and complete daily written seizure calendar.
• Able to understand and willing to provide written informed consent, or has a legally authorised representative able to so, before any protocol-specific procedures are performed.
• A female subject is eligible to enter and participate in the study if she is: a. Of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is postmenopausal); Premenopausal females with a documented (medical report verification) hysterectomy with or without oophorectomy or bilateral oophorectomy when reproductive status has been confirmed by hormone level assessment; Postmenopausal females defined as being amenorrheic for greater than 1 year with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms). However, if indicated, this should be confirmed by estradiol and follicle-stimulating hormone levels consistent with menopause (according to local laboratory ranges). Women who have not been confirmed as postmenopausal should be advised to use contraception as listed in the protocol: b. Of childbearing potential, has a negative serum pregnancy test at Screening and a negative urine and serum pregnancy test at randomisation, and agrees to satisfy one of the requirements listed in the protocol: c. Not pregnant or lactating (breastfeeding) or planning to become pregnant during the study.
• Liver function tests: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2 times the upper limit of normal (ULN); alkaline phosphatase (ALP) and bilirubin </=1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%).

Exclusion Criteria:

Subjects meeting any of the following criteria must not be enrolled in the study:

• Have generalised epilepsy (such as Lennox-Gastaut syndrome, juvenile myoclonic epilepsy, absence epilepsy, etc.), innumerable seizures within the 12-month period prior to study entry where the individual seizures cannot be counted, or nonepileptic seizures.
• Have had status epilepticus (other than simple partial status epilepticus) within the 12 months prior to Screening.
• Have had previous exposure to retigabine.
• Have impaired renal function as judged by a creatinine clearance of <50 mL/min.
• Have a history of substance abuse (alcohol or drugs) or substance dependence within 12 months prior to Screening.
• Have taken an investigational drug, or used an investigational device, within the 30 days prior to Screening or plans to take another investigational drug at any time during the study.
• Are currently following or planning to follow a ketogenic diet.
• 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 recognised visual field abnormalities as compared with prior to vigabatrin treatment.
• Are using central nervous system (CNS)-active medication (other than concomitant AED therapy), unless the subject has been stabilised on such medication for more than 1 month prior to Screening; or currently taking medications known to lower seizure threshold (e.g., antipsychotics) and monoamine oxidase (MAO) inhibitors.
• Are using herbal treatments with CNS activity within 1 month prior to Screening.
• Are planning surgery during the study to control seizures.
• 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 urinary retention or risk factors for urinary retention that in the investigator's judgment could potentially affect subject safety.
• 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, or hepatic conditions; or a condition that affects the absorption, distribution, metabolism or excretion of drugs.
• Have an average corrected QT interval (QTc; either QTcB Bazett's correction or QTcF Fridericia's correction) ≥450 msec or ≥480 msec for subjects with bundle branch block at the time of Screening.
• Have active suicidal plan/intent or have had active suicidal thoughts in the past 6 months. Have a history of suicide attempt in the last 2 years or more than 1 lifetime suicide attempt.
• Have a history of malignancy within the past 2 years, with the exception of basal cell carcinoma.
• Have a known hypersensitivity to any components of the study medication.

Randomisation Criteria:

Subjects must also meet the following criteria at the end of the Baseline Phase (Visit 3) and before randomisation and administration of the first dose of study medication:

• Have a documented 28-day total POS frequency rate of ≥4 POS over an 8 week Baseline Phase. Note: In subjects with simple partial seizures, although all seizures occurring during the Baseline Phase will be collected, only seizures with motor signs will be counted toward qualification for meeting the randomisation criteria.
• Have not had a seizure-free period of ≥21 consecutive days during the Baseline Phase.
• Have not had innumerable seizures (defined as an episode of seizure activity lasting <30 minutes during which several seizures occur with such frequency that the initiation and termination of each individual seizure cannot be distinguished) during the 8 week Baseline Phase.
• Have not had an episode of status epilepticus (other than simple partial status epilepticus) during the 8 week Baseline Phase
• Have not required dose adjustments of concurrent AEDs, addition of new AEDs, discontinuation of existing AEDs, changes to VNS settings, or acute use of benzodiazepines for the treatment of seizures during the Baseline Phase.