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
Condition: Epilepsy
MeSH terms: Epilepsy; Seizures
Intervention: Retigabine 900mg/day; Retigabine 600mg/day; Placebo
Intervention description: Study drug will be administered three times a day in a double blind manner. The starting dose of retigabine will be 300 mg/day. This dose will be increased by 150 mg/day per week to reach the target dose of 900mg/day over a 4 week Titration Phase). The subject will then continue to receive 900mg/day for the next 12 weeks (Maintenance Phase). Eligible subjects will then be offered an opportunity to enter an open label extension (OLE) study. After a 4 week transition phase, eligible subjects will start the OLE on retigabine 900mg/day.; Study drug will be administered three times a day in a double blind manner. The starting dose of retigabine will be 300mg/day. This dose will be increased by 150 mg/day per week to reach the target dose of 600mg/day over 2 weeks. The subject will then continue to receive 600mg/day for the next 14 weeks (2 weeks of the Titration Phase and 12 weeks of the Maintenance Phase). Eligible subjects will then be offered an opportunity to enter an open label extension (OLE) study. After a 4 week Transition Phase (3 weeks on retigabine 600mg/day, 1 week on retigabine 750mg/day) eligible subjects will start the OLE on retigabine 900mg/day.; Study drug will be administered three times a day in a double blind manner. Subjects randomised to placebo will receive the same number, size and colour of tablets as the 600mg/day and 900mg/day treatment arms for the duration of the 4 week Titration Phase and the 12 week Maintenance Phase. Eligible subjects will then be offered an opportunity to enter an open label extension (OLE) study. The starting dose of retigabine will be 300 mg/day. This dose will be increased by 150 mg/day per week to reach dose of 750mg/day over the 4 weeks of the Transition Phase. On completion of the Transition Phase eligible subjects will start the OLE on retigabine 900mg/day.
Intervention MeSH terms: Ezogabine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 76.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Retigabine IR; Asian Subjects; Adjunctive Therapy; Efficacy; Drug-Resistant; Safety & tolerability; Partial-Onset Seizures; Epilepsy

Summary:

      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.
    

Eligibility criteria:

        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.