An Open Label, Randomised, Repeat Dose Study to Assess the Pharmacokinetic Performance of Five Ezogabine/Retigabine Modified Release (MR) Formulations at Steady State Compared to the Immediate Release (IR) Formulation.

NCT01332513 | Completed Phase 1

• 1 other identifier: 114552
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, single centre, repeat dose, up- titration study in healthy male and female subjects to assess the pharmacokinetic (PK) performance of five prototypes of ezogabine modified release tablet formulations. The study will consist of a screening period, a treatment phase (consisting of a titration phase, bioavailability phase and food effect phase) and a post-treatment follow-up visit. The study duration from screening to follow up will be approximately 7 weeks. No study procedures will start before informed consent is obtained. Subjects will remain in the clinical unit for the duration of the treatment period (35 days). Subjects will receive repeat doses of ezogabine for up to 34 days starting at a dose of 100 mg IR TID (300mg TDD) with a standard meal (to be consumed 30 min prior to dosing) for Days 1-3, on days 4-6 subjects will receive 150mg IR TID (450mg TDD). On Day 7 through to the end of the study subjects will receive ezogabine (Mr or IR) at a dose of 600mgTDD. On Day 7 subjects will enter into a 6-way cross over period to investigate the 5 MR formulations being tested (each at 300mg BID) and the single IR formulation (at 200mg TID). Subjects will receive each formulaition for 4 days and blood samples for pharmacokinetic analysis will be collected up to 24 hours post dose on each 4th day (PK days). On Day 31 subjects will enter into a food effect phase to investigate the 5 MR formulations being tested (each at 600mg QD). Subjects in this period will have a PK day on Day 33 (following a standard breakfast), and on Day 34 (following a high fat breakfast) to investigate a food effect on the PK profile of ezogabine.

Conditions

Epilepsy

Keywords

Healthy Volunteers

Outcome Measures

Primary Outcomes (1)

• Area under the curve from zero to 24 hours at steady-state of ezogabine

  Days 10, 14, 18, 22, 26 and 30

Secondary Outcomes (6)

• Area under the curve of ezogabine from zero to 24 hours at steady-state

  Days 33 and 34

• Cmax of ezogabine at steady state

  Days 10, 14, 18, 22, 26, 30, 33 and 34

• Tmax of ezogabine at steady-state

  Days 10, 14, 18, 22, 26, 30, 33 and 34

• Cmin of ezogabine at steady state

  Days 10, 14, 18, 22, 26, 30, 33 and 34

• Cmax:Cmin Ratio of ezogabine

  Days 10, 14, 18, 22, 26, 30, 33 and 34

Study Arms (6)

ABFCED sequence

EXPERIMENTAL

Each subject will participate in six study periods in the bioavailability phase, wherein the subjects will receive a 300 milligram (mg) twice daily (BID) dosing of ezogabine modified release (MR) tablet in periods A, B, C, D and E and will receive 200 mg three times daily (TID) dosing of ezogabine immediate release (IR) tablet in period F. Following the completion of the crossover phase, subjects will be re-randomized to one of five cohorts receiving 600 mg doses of either G, H, I, J or K for the food effect phase.

Drug: Investigational Medicinal Product (MR1); Drug: Investigational Medicinal Product (MR2); Drug: Investigational Medicinal Product (MR3); Drug: Investigational Medicinal Product (MR4); Drug: Investigational Medicinal Product (MR5); Drug: Investigational Medicinal Product (IR)

BCADFE sequence

EXPERIMENTAL

Each subject will participate in six study periods in the bioavailability phase, wherein the subjects will receive a 300 mg BID dosing of ezogabine MR in periods A, B, C, D and E and will receive 200 mg TID dosing of ezogabine IR in period F. Following the completion of the crossover phase, subjects will be re-randomized to one of five cohorts receiving 600 mg doses of either G, H, I, J or K for the food effect phase.

Drug: Investigational Medicinal Product (MR1); Drug: Investigational Medicinal Product (MR2); Drug: Investigational Medicinal Product (MR3); Drug: Investigational Medicinal Product (MR4); Drug: Investigational Medicinal Product (MR5); Drug: Investigational Medicinal Product (IR)

CDBEAF sequence

EXPERIMENTAL

Each subject will participate in six study periods in the bioavailability phase, wherein the subjects will receive a 300 mg BID dosing of ezogabine MR in periods A, B, C, D and E and will receive 200 mg TID dosing of ezogabine IR in period F. Following the completion of the crossover phase, subjects will be re-randomized to one of five cohorts receiving 600 mg doses of either G, H, I, J or K for the food effect phase.

Drug: Investigational Medicinal Product (MR1); Drug: Investigational Medicinal Product (MR2); Drug: Investigational Medicinal Product (MR3); Drug: Investigational Medicinal Product (MR4); Drug: Investigational Medicinal Product (MR5); Drug: Investigational Medicinal Product (IR)

DECFBA sequence

EXPERIMENTAL

Each subject will participate in six study periods in the bioavailability phase, wherein the subjects will receive a 300 mg BID dosing of ezogabine MR in periods A, B, C, D and E and will receive 200 mg TID dosing of ezogabine IR in period F. Following the completion of the crossover phase, subjects will be re-randomized to one of five cohorts receiving 600 mg doses of either G, H, I, J or K for the food effect phase.

Drug: Investigational Medicinal Product (MR1); Drug: Investigational Medicinal Product (MR2); Drug: Investigational Medicinal Product (MR3); Drug: Investigational Medicinal Product (MR4); Drug: Investigational Medicinal Product (MR5); Drug: Investigational Medicinal Product (IR)

EFDACB sequence

EXPERIMENTAL

Each subject will participate in six study periods in the bioavailability phase, wherein the subjects will receive a 300 mg BID dosing of ezogabine MR in periods A, B, C, D and E and will receive 200 mg TID dosing of ezogabine IR in period F. Following the completion of the crossover phase, subjects will be re-randomized to one of five cohorts receiving 600 mg doses of either G, H, I, J or K for the food effect phase.

Drug: Investigational Medicinal Product (MR1); Drug: Investigational Medicinal Product (MR2); Drug: Investigational Medicinal Product (MR3); Drug: Investigational Medicinal Product (MR4); Drug: Investigational Medicinal Product (MR5); Drug: Investigational Medicinal Product (IR)

FAEBDC sequence

EXPERIMENTAL

Each subject will participate in six study periods in the bioavailability phase, wherein the subjects will receive a 300 mg BID dosing of ezogabine MR in periods A, B, C, D and E and will receive 200 mg TID dosing of ezogabine IR in period F. Following the completion of the crossover phase, subjects will be re-randomized to one of five cohorts receiving 600 mg doses of either G, H, I, J or K for the food effect phase.

Drug: Investigational Medicinal Product (MR1); Drug: Investigational Medicinal Product (MR2); Drug: Investigational Medicinal Product (MR3); Drug: Investigational Medicinal Product (MR4); Drug: Investigational Medicinal Product (MR5); Drug: Investigational Medicinal Product (IR)

Interventions

Investigational Medicinal Product (MR1) DRUG

Ezogabine MR1 at a dose strength of 300 mg will be orally administered with approximately 250 milliliter (mL) of water to group A subjects during the bioavailability phase. For the food effect phase subjects in group G will be orally administered MR1 tablets at a dose strength of 600 mg.

ABFCED sequence; BCADFE sequence; CDBEAF sequence; DECFBA sequence; EFDACB sequence; FAEBDC sequence

Investigational Medicinal Product (MR2) DRUG

Ezogabine MR2 at a dose strength of 300 mg will be orally administered to group B subjects with approximately 250 mL of water during the bioavailability phase. For the food effect phase subjects in group H will be orally administered MR2 tablets at a dose strength of 600 mg.

ABFCED sequence; BCADFE sequence; CDBEAF sequence; DECFBA sequence; EFDACB sequence; FAEBDC sequence

Investigational Medicinal Product (MR3) DRUG

Ezogabine MR3 will be orally administered with approximately 250 mL of water to group C subjects during the bioavailability phase. For the food effect phase subjects in group I will be orally administered MR3 tablets at a dose strength of 600 mg.

ABFCED sequence; BCADFE sequence; CDBEAF sequence; DECFBA sequence; EFDACB sequence; FAEBDC sequence

Investigational Medicinal Product (MR4) DRUG

Ezogabine MR4 will be orally administered with approximately 250 mL of water to group D subjects during the bioavailability phase. For the food effect phase subjects in group J will be orally administered MR4 tablets at a dose strength of 600 mg.

ABFCED sequence; BCADFE sequence; CDBEAF sequence; DECFBA sequence; EFDACB sequence; FAEBDC sequence

Investigational Medicinal Product (MR5) DRUG

Ezogabine MR5 will be orally administered with approximately 250 mL of water to group E subjects during the bioavailability phase. For the food effect phase subjects in group K will be orally administered MR5 tablets at a dose strength of 600 mg.

ABFCED sequence; BCADFE sequence; CDBEAF sequence; DECFBA sequence; EFDACB sequence; FAEBDC sequence

Investigational Medicinal Product (IR) DRUG

Ezogabine IR at dose strengths of 50 mg and 200 mg will be orally administered with approximately 250 mL of water.

ABFCED sequence; BCADFE sequence; CDBEAF sequence; DECFBA sequence; EFDACB sequence; FAEBDC sequence

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy as determined by a responsible and experienced physician
• Male or female between 18 and 60 years of age inclusive, at the time of signing the informed consent.
• A female subject is eligible to participate if she is of:
• Non-childbearing potential defined
• Child-bearing potential and agrees to use one of the contraception methods listed
• Male subjects must agree to use one of the contraception methods listed
• Body weight \> 50 kg and body mass index (BMI) within the range of 18 - 30kg/m2 (inclusive).
• Normal or High Normal blood pressure
• hr holter with no clinically significant findings.
• QTcB or QTcF \< 450 msec at screening and pre-dose.
• Creatinine Clearance within the normal range at screening and pre-dose.
• Liver function test within normal limits at screening and pre-dose.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

You may not qualify if:

• Subjects who are vegetarian or vegan, or for any other reason be unwilling to consume a high fat meal.
• The subject has either a previous disease or current medical condition
• Has made a suicide attempt in the past or, in the investigator's judgment, poses significant suicide risk.
• Presence of clinically significant proteinuria or hematuria or other clinically significant findings in urinalysis.
• Subjects with symptoms of urinary dysfunction.
• Subjects whose ECG shows PR interval is \>220 msec, or presence of intraventricular conduction disturbances (complete or incomplete BBB), at screening or prior to dosing.
• Presence of clinically significant arrhythmias.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• Current or chronic liver disease or biliary abnormalities. Medical history positive for biliary signs and symptoms (cholecystectomy is acceptable).
• History of regular alcohol consumption within 6 months of the study.
• A positive drug/alcohol screen at screening and / or pre-dose.
• A positive test for HIV antibody.
• The subjects smokes more than 10 cigarettes per week.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Baltimore, Maryland, 21225, United States

Location

Related Links

• Results for study 114552 can be found on the GSK Clinical Study Register.
• 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

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 7, 2011
• First Posted: April 11, 2011
• Study Start: February 10, 2011
• Primary Completion: May 23, 2011
• Study Completion: May 23, 2011
• Last Updated: June 19, 2018

Record last verified: 2018-06

Data Sharing

• IPD Sharing: Will share

Locations

US (1)