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

NCT01648101 | Terminated Phase 3 Results

• 1 other identifier: 114855
• Study Type: interventional
• Target: 76
• Locations: 7 countries
• Sites: 41

Brief 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.

Conditions

Epilepsy

Keywords

Retigabine IR; Asian Subjects; Adjunctive Therapy; Efficacy; Drug-Resistant; Safety & tolerability; Partial-Onset Seizures; Epilepsy

Outcome Measures

Primary Outcomes (1)

• Number of Placebo and Retigabine 900 mg Responders During the Maintenance Phase (MP)

  A responder is defined as a par. with \>=50% reduction in the 28 day total partial on-set seizure (POS) frequency from the Baseline Phase (BP) to the MP, randomly assigned to retigabine 900 mg/day compared with placebo. The total 28-day POS rate was defined as: (total number of POS over the evaluable period (MP) / number of days of seizure (sz) data in the evaluable period) \*28 days. In the event of one or more innumerable seizures (IS) occurring on a day, these were to be counted as an additional 10 seizures for that day, regardless of the number of occurrences of IS on that day. The number of applicable days in a phase for seizure data is calculated as: the end date of MP minus start date of the MP minus days on which seizures were recorded as "Not done" + 1). Each occurrence of status epilepticus (SE) was counted as 1 seizure (whether partial or not).

  Baseline (BL); Week 4 up to Week 16

Secondary Outcomes (13)

• Number of Placebo and Retigabine 600 mg Responders During the MP

  Baseline; Week 4 up to Week 16

• Number of Responders From the BP to the Treatment Phase (TrP)

  From Baseline up to Week 16

• Percent Change From Baseline in the 28-day Total POS Frequency During the MP

  Baseline; Week 4 up to Week 16

• Percent Change From Baseline in the 28-day Total POS Frequency During the TrP

  From Baseline up to Week 16

• Percent Change From Baseline in the 28-day Total POS Frequency During the MP Categorized as: no Change/Increase, >0% to <50% Decrease, 50% to 75% Decrease, and >75% to 100% Decrease

  Baseline; Week 4 up to Week 16

Study Arms (3)

Retigabine 900mg

EXPERIMENTAL

900mg total daily dose

Drug: Retigabine 900mg/day

Retigabine 600mg

EXPERIMENTAL

600mg total daily dose

Drug: Retigabine 600mg/day

Placebo

PLACEBO COMPARATOR

Placebo

Other: Placebo

Interventions

Retigabine 900mg/day DRUG

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.

Retigabine 900mg

Retigabine 600mg/day DRUG

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.

Retigabine 600mg

Placebo OTHER

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.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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%).

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (41)

GSK Investigational Site

Hang Hau, Hong Kong

Location

GSK Investigational Site

Hong Kong, Hong Kong

Location

GSK Investigational Site

Kowloon, Hong Kong

Location

GSK Investigational Site

Shatin, Hong Kong

Location

GSK Investigational Site

Kuala Lumpur, 59100, Malaysia

Location

GSK Investigational Site

Seberang Jaya, 13700, Malaysia

Location

GSK Investigational Site

Cebu City, 6000, Philippines

Location

GSK Investigational Site

Davao City, 8000, Philippines

Location

GSK Investigational Site

Manila, 1003, Philippines

Location

GSK Investigational Site

Singapore, 119074, Singapore

Location

GSK Investigational Site

Busan, 602-715, South Korea

Location

GSK Investigational Site

Busan, 612-865, South Korea

Location

GSK Investigational Site

Daegu, 700-712, South Korea

Location

GSK Investigational Site

Daegu, 705-718, South Korea

Location

GSK Investigational Site

Daejeon, 301-721, South Korea

Location

GSK Investigational Site

Gyeonggi-do, 442-723, South Korea

Location

GSK Investigational Site

Gyeonggi-do, 463-707, South Korea

Location

GSK Investigational Site

Incheon, 405-760, South Korea

Location

GSK Investigational Site

Seoul, 110-744, South Korea

Location

GSK Investigational Site

Seoul, 120-752, South Korea

Location

GSK Investigational Site

Seoul, 135-710, South Korea

Location

GSK Investigational Site

Seoul, 135-720, South Korea

Location

GSK Investigational Site

Seoul, 136-705, South Korea

Location

GSK Investigational Site

Seoul, 137-701, South Korea

Location

GSK Investigational Site

Seoul, 138-736, South Korea

Location

GSK Investigational Site

Seoul, 143-729, South Korea

Location

GSK Investigational Site

Seoul, 150-713, South Korea

Location

GSK Investigational Site

Changhua, 50006, Taiwan

Location

GSK Investigational Site

Kaohsiumg, 386, Taiwan

Location

GSK Investigational Site

Kaohsiung City, 83301, Taiwan

Location

GSK Investigational Site

New Taipei City, 10016, Taiwan

Location

GSK Investigational Site

Taichung, 40705, Taiwan

Location

GSK Investigational Site

Tainan, 70403, Taiwan

Location

GSK Investigational Site

Tainan, 71004, Taiwan

Location

GSK Investigational Site

Taipei, 11031, Taiwan

Location

GSK Investigational Site

Taipei, 110, Taiwan

Location

GSK Investigational Site

Tau-Yuan, 333, Taiwan

Location

GSK Investigational Site

Bangkok, 10330, Thailand

Location

GSK Investigational Site

Bangkok, 10400, Thailand

Location

GSK Investigational Site

Chiang Mai, 50200, Thailand

Location

GSK Investigational Site

Khon Kaen, 40002, Thailand

Location

Related Publications (1)

• Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1981 Aug;22(4):489-501. doi: 10.1111/j.1528-1157.1981.tb06159.x. No abstract available.

  PMID: 6790275 BACKGROUND

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Epilepsy

Interventions

ezogabine

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Limitations and Caveats

RTG114855 was designed for registration of retigabine as add-on treatment of drug-resistant POS in South Korea/Taiwan/ Vietnam. GSK decided not to pursue registration in these countries and terminated the study early based on new safety information.

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 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2012
• First Posted: July 24, 2012
• Study Start: August 29, 2012
• Primary Completion: December 1, 2013
• Study Completion: December 23, 2013
• Last Updated: August 13, 2018
• Results First Posted: September 8, 2014

Record last verified: 2018-06

Data Sharing

• IPD Sharing: Will share

Locations

TH (4); HK (4); MY (2); SG (1); PH (3); KR (17); TW (10)