Clinical trial NCT01332513: 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.
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Epilepsy
Keywords: Healthy Volunteers
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-04-11
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. Healthy as determined by a responsible and experienced physician
2. Male or female between 18 and 60 years of age inclusive, at the time of signing the informed consent.
3. 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
4. Male subjects must agree to use one of the contraception methods listed
5. Body weight \> 50 kg and body mass index (BMI) within the range of 18 - 30kg/m2 (inclusive).
6. Normal or High Normal blood pressure
7. 24hr holter with no clinically significant findings.
8. QTcB or QTcF \< 450 msec at screening and pre-dose.
9. Creatinine Clearance within the normal range at screening and pre-dose.
10. Liver function test within normal limits at screening and pre-dose.
11. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. Subjects who are vegetarian or vegan, or for any other reason be unwilling to consume a high fat meal.
2. The subject has either a previous disease or current medical condition
3. Has made a suicide attempt in the past or, in the investigator's judgment, poses significant suicide risk.
4. Presence of clinically significant proteinuria or hematuria or other clinically significant findings in urinalysis.
5. Subjects with symptoms of urinary dysfunction.
6. 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.
7. Presence of clinically significant arrhythmias.
8. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
9. Current or chronic liver disease or biliary abnormalities. Medical history positive for biliary signs and symptoms (cholecystectomy is acceptable).
10. History of regular alcohol consumption within 6 months of the study.
11. A positive drug/alcohol screen at screening and / or pre-dose.
12. A positive test for HIV antibody.
13. The subjects smokes more than 10 cigarettes per week.
14. 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).
15. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
16. Use of prescription or non-prescription drugs.
17. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy.
18. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
19. Pregnant females as determined by positive serum hCG test at screening or prior to dosing.
20. Lactating females.
21. Unwillingness or inability to follow the procedures outlined in the protocol.
22. Subject is mentally or legally incapacitated.

Primary outcomes:
measure: Area under the curve from zero to 24 hours at steady-state of ezogabine
timeFrame: Days 10, 14, 18, 22, 26 and 30
Secondary outcomes:
measure: Area under the curve of ezogabine from zero to 24 hours at steady-state
timeFrame: Days 33 and 34
measure: Cmax of ezogabine at steady state
timeFrame: Days 10, 14, 18, 22, 26, 30, 33 and 34
measure: Tmax of ezogabine at steady-state
timeFrame: Days 10, 14, 18, 22, 26, 30, 33 and 34
measure: Cmin of ezogabine at steady state
timeFrame: Days 10, 14, 18, 22, 26, 30, 33 and 34
measure: Cmax:Cmin Ratio of ezogabine
timeFrame: Days 10, 14, 18, 22, 26, 30, 33 and 34
measure: Fluctuation Index (FI) of ezogabine
timeFrame: Days 10, 14, 18, 22, 26, 30, 33 and 34
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: