Effect of Haemodialysis on the Pharmacokinetics of Ezogabine/Retigabine and Its N-acetyl Metabolite

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01480609
First received: October 27, 2011
Last updated: September 20, 2012
Last verified: September 2012
  Purpose

This in an open-label, single dose, fixed sequence, two treatment period study enrolling 8 patients (to obtain 6 evaluable) with end stage renal disease (ESRD) receiving haemodialysis. Patients will remain in the unit during each treatment period from admission to the collection of the final PK sample. The doses of ezogabine/retigabine in the two treatment periods will be separated by at least 7 days.


Condition Intervention Phase
Epilepsy
Drug: Retigabine / Ezogabine
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open Label, Single-dose, Fixed Sequence, Two Treatment Period Study to Assess the Effect of Haemodialysis on the Pharmacokinetics of Ezogabine/Retigabine and the N-acetyl Metabolite of Ezogabine/Retigabine (NAMR).

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Clearance (Cl/F), clearance during dialysis (CLD) and fraction of total clearance attributed to dialysis (FD) of ezogabine/retigabine and NAMR [ Time Frame: During Dialysis (0-1, 1-2, 2-3, and 3-4 hour) ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters

  • AUC(0-t), AUC (0-∞), T½, Cmax, Tmax of ezogabine/retigabine and NAMR in plasma. Amount of ezogabine/retigabine and NAMR cleared by dialysis (AD) [ Time Frame: 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, 48, 60 and 68 hours ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters


Secondary Outcome Measures:
  • Nmber of Safety and tolerability parameters, including adverse event, clinical laboratory, and vital signs assessments [ Time Frame: Participants will be assessed for the duration of the study - an expected average of 3 weeks ] [ Designated as safety issue: No ]
    Safety Parameters


Enrollment: 8
Study Start Date: November 2011
Study Completion Date: April 2012
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Dose-Dialysis
Subjects will be dosed with study drug followed by a scheduled dialysis session
Drug: Retigabine / Ezogabine
Active Comparator: Dialysis-Dose
Subjects will be dosed following the completion of their scheduled dialysis session
Drug: Retigabine / Ezogabine

Detailed Description:

Treatment Period 1: Subjects will be admitted on Day -1 when baseline assessments will be performed. On Day 1 subjects will receive a single dose of 100mg ezogabine/retigabine immediate release (IR) and dialysis will start 4 hours post-dose. Pharmacokinetic (PK) samples will be collected up to approximately 68 hours post-dose.

Samples of dialysate will be collected in 0-1, 1-2, 2-3, and 3-4 hour (if available) aliquots, timed from the start of dialysis. The volume of dialysate collected in each aliquot will be recorded.

Four samples of predialyzer ("arterial" line) blood and four samples of postdialyzer ("venous" line) blood will be obtained during the haemodialysis procedure at approximately one hour intervals starting immediately prior to the start of the procedure and finishing at the end of the procedure.

Subjects will be discharged from the unit following the collection of the last PK sample.

Treatment Period 2: Subjects will be admitted on Day -1 when baseline assessments will be performed. On Day 1 following the completion of their scheduled dialysis session subjects will receive a single dose of 100mg ezogabine/retigabine IR. PK samples will be collected up to approximately 68 hours post-dose.

Subjects will be discharged from the unit following the collection of the last PK sample.

In both treatment periods, PK blood samples will be obtained pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, 48, 60 and 68 hours (or just prior next dialysis session - whichever is sooner) post-dose. Subjects will be discharged after the final post-dose draw.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female 18 years or older, at the time of signing the informed consent.
  • ESRD patients with minimal or no residual renal function and receiving stabilised haemodialysis regimen.
  • Body mass index with the range of 18-42 kg/m2 at screening.
  • A female subject is eligible to participate if she is of:

    • Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods listed.
    • Child-bearing potential and agrees to use one of the contraception methods listed. Female subjects must agree to use contraception until at least 1 week post-last dose.
  • Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed. This criterion must be followed from the time of the first dose of study medication until at least 1 week post-last dose.
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

  • Subjects with fluctuating or rapidly deteriorating condition that is not adequately controlled by medications
  • Subjects with signs of a clinically significant infection.
  • Has active suicidal plan/intent or has had active suicidal thoughts in the past 6 months. Has history of suicide attempt in the last 2 years or more than 1 lifetime suicide attempt.
  • Subjects with any other medical condition which, in the judgement of the investigator and medical monitor, could jeopardize the integrity of the data derived from that subject or the safety of the subject
  • Clinically relevant laboratory or physical examination abnormalities (except for renal function tests or deviation of clinical laboratory values that are related to renal impairment).
  • Subjects with blood pressure, after resting for ≥ 3 minutes, higher than 160/95 mmHg or lower than 100/50 mmHg. The patients receiving anthihypertensive treatment need to be on a stabilised treatment for three months.
  • The screening ECGs measurements must be within the limit indicated in the protocol.
  • Any significant arrhythmia which, in the opinion of the principal investigator and GSK medical monitor, will interfere with the safety for the individual subject.
  • History of hemoglobinopathy.
  • A radiological test involving contrast dye within 4 weeks prior to screening.
  • Poor peripheral venous access.
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • A positive pre-study drug/alcohol screen.
  • A positive test for HIV antibody.
  • History of regular alcohol consumption within 6 months of the study.
  • 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.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
  • Pregnant females
  • Lactating females.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Subject is mentally or legally incapacitated.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01480609

Locations
United States, Minnesota
GSK Investigational Site
Minneapolis, Minnesota, United States, 55404
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01480609     History of Changes
Other Study ID Numbers: 115214
Study First Received: October 27, 2011
Last Updated: September 20, 2012
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Ezogabine
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 27, 2014