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Open-label Extension Study of the Phase 3 VRX-RET-E22-301 Double-Blind Trial

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00310375
First received: March 30, 2006
Last updated: October 4, 2016
Last verified: July 2016
  Purpose
The purpose of this study is to evaluate the safety and tolerability of long-term therapy with retigabine administered as adjunctive therapy in adult epilepsy patients with partial-onset seizures, who completed the VRX-RET-E22-301 double-blind study. The efficacy of long-term treatment with retigabine and patient quality of life will also be assessed.

Condition Intervention Phase
Epilepsy
Drug: Ezogabine: USAN Retigabine (International Nonproprietary Name)
Phase 3

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multicenter, Open-label, Long-term, Safety, Tolerability and Efficacy Study of Retigabine in Adult Epilepsy Patients With Partial-onset Seizures (Extension of Study VRX-RET-E22-301)

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Participants With Treatment-emergent Serious Adverse Event (SAE) and Adverse Event (AE) [ Time Frame: Assessed up to a maximum of 9 years ]
    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization (unplanned hospital stay) or prolongation of existing hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect. Treatment-emergent AE was defined as an AE with an onset on or after the day of first dose of the study medication and on or before 30 days after the last dose date. AEs reported during parent study and worsened after first dose of RTG in this OLE study were also reported.

  • Number of Participants With Treatment-emergent Adverse Events Leading to Withdrawal From Study Drug [ Time Frame: Assessed up to a maximum of 9 years ]
    Treatment-emergent AE was defined as an AE with an onset on or after the day of first dose of the study medication and on or before 30 days after the last dose date. AEs reported during parent study and worsened after first dose of RTG in this OLE study were also reported.

  • Kaplan-Meier Estimate of the Probability of Discontinuation (d/c) From Study Drug [ Time Frame: Assessed up to a maximum of 9 years ]
    The time frame of premature study discontinuation was defined as the time from the day of first the study medication to the time of withdrawal from study drug. For those who have a taper dose start date, the time of withdrawal was the day before the start of taper dose. For those without a taper dose start date, the time of withdrawal was the last dose date. Participants who switched to the commercial product were censored at the last dose of study drug in the Kaplan-Meier analysis. All participants who withdrew from study drug prematurely but didn't switch to commercial product were counted as "events". Kaplan-Meier estimate of the probability of discontinuation at the specified time or earlier. Number of Participants continuing on RTG at each time of withdrawal were analyzed (represented as n=X in category title).

  • Change From Baseline in Blood Pressure [ Time Frame: Baseline and Up to Month 108 ]
    Systolic blood pressure (SBP) and diastolic blood pressure (DBP) was obtained in supine (Su) position and again in standing (St) position after the participant was standing for approximately 2 minutes at each study visit (Month 1, Month 3, Month 6, Month 9, Month 12 and every 4 months after Month 12). Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Not Applicable (NA) indicates that data were not available.

  • Change From Baseline in Heart Rate [ Time Frame: Baseline and Up to Month 108 ]
    Heart rate (HR) was measured in supine (Su) position and again in standing (St) position after the participant was standing for approximately 2 minutes at each study visit (Month 1, Month 3, Month 6, Month 9, Month 12 and every 4 months after Month 12). Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available.

  • Change From Baseline in Body Temperature [ Time Frame: Baseline and Up to Month 108 ]
    Body temperature was measured in degree Celsius at each study visit (Month 1, Month 3, Month 6, Month 9, Month 12 and every 4 months after Month 12). Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available

  • Change From Baseline in Weight [ Time Frame: Baseline and Up to Month 108 ]
    Weight was measured in ordinary indoor clothing (without shoes) and was recorded at each study visit (On Month 1, Month 3, Month 6, Month 9, Month 12 and every 4 months after Month 12). Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available.

  • Change From Baseline in the 12-lead Electrocardiogram (ECG) Parameters-PR Interval, QRS Duration, Uncorrected QT (uQT) Interval, Corrected QT (Bazett's Correction) Interval (QTcB), Corrected QT (Friedericia's Correction) Interval (QTcF) [ Time Frame: Baseline and Up to Month 108 ]
    A 12-lead ECG was performed at each study visit during the first year of the study (Month 1, Month 3, Month 6, Month 9, Month 12) and annually after one year. The following electrocardiogram parameters are presented PR Interval, QRS Duration, Uncorrected QT interval (uQT), Corrected QT (Bazett's correction) interval (QTcB), Corrected QT (Friedericia's correction) interval (QTcF). Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available.

  • Change From Baseline in the 12-lead Electrocardiogram (ECG) Parameter-RR Interval [ Time Frame: Baseline and Up to Month 108 ]
    A 12-lead ECG was performed at each study visit during the first year of the study (Month 1, Month 3, Month 6, Month 9, Month 12) and annually after one year. The following electrocardiogram parameters are presented: RR Interval. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

  • Change From Baseline in Electrocardiogram (ECG) Parameter-QRS Axis [ Time Frame: Baseline and Up to Month 108 ]
    A 12-lead ECG was performed at each study visit during the first year of the study (Month 1, Month 3, Month 6, Month 9, Month 12) and annually after one year. ECG parameter QRS Axis is presented here. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

  • Change From Baseline in Hematology Parameters- Bands, Basophils, Eosinophils, Lymphocytes, Metamyelocyte, Monocytes, Neutrophils, Platelets, White Blood Cells Count (WBC) [ Time Frame: Baseline and Up to Month 108 ]
    Following hematology parameters were assessed, Bands (Band neutrophils), Basophils, Eosinophils, Lymphocytes, Metamyelocyte, Monocytes, Neutrophils, Platelets and WBC. Hematology parameters were assessed at Month 1, Month 2, Month 3, Month 6, Month 8, Month 9, Month 10, Month 12 and every 4 months after Month 12. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available.

  • Change From Baseline in Hematology Parameter-Red Blood Cell Count [ Time Frame: Baseline and Up to Month 108 ]
    Red Blood Cell count (RBC) was assessed at Month 1, Month 2, Month 3, Month 6, Month 8, Month 9, Month 10, Month 12 and every 4 months after Month 12. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available..

  • Change From Baseline in Haematocrit [ Time Frame: Baseline and Up to Month 108 ]
    Haematocrit was assessed at Month 1, Month 2, Month 3, Month 6, Month 8, Month 9, Month 10, Month 12 and every 4 months after Month 12. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

  • Change From Baseline in Haemoglobin [ Time Frame: Baseline and Up to Month 108 ]
    Haemoglobin was assessed at Month 1, Month 2, Month 3, , Month 6, Month 8, Month 9, Month 10, Month 12 and every 4 months after Month 12. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available..

  • Change From Baseline in Chemistry Parameters-Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) [ Time Frame: Baseline and Up to Month 108 ]
    Alkaline phosphatase (AP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) were assessed at Month 1, Month 3, , Month 6, Month 9, Month 12 and every 4 months after Month 12. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available.

  • Change From Baseline in Chemistry Parameters-Bicarbonate, Blood Urea Nitrogen (BUN), Calcium, Chloride, Cholesterol, Non-fasting Glucose, Phosphorus, Potassium, Sodium, Urea [ Time Frame: Baseline and Up to Month 108 ]
    Bicarbonate (Bic.), BUN, Calcium (Ca), Chloride (Cl), Cholesterol (Cho.), Non-fasting glucose (NFG), Phosphorus (P), Potassium (Ka), Sodium (Na), Urea were assessed at Month 1, Month 3, , Month 6, Month 9, Month 12 and every 4 months after Month 12. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available.

  • Change From Baseline in Chemistry Parameters -Creatinine, Total Bilirubin (TB), Uric Acid (UA) [ Time Frame: Baseline and Up to Month 108 ]
    Creatinine, Total bilirubin (TB), Uric acid (UA) were assessed at Month 1, Month 3, , Month 6, Month 9, Month 12 and every 4 months after Month 12. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available.

  • Change From Baseline in Chemistry Parameter-Total Protein [ Time Frame: Baseline and Up to Month 108 ]
    Total Protein (TP) was assessed at Month 1, Month 3, , Month 6, Month 9, Month 12 and every 4 months after Month 12. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles)

  • Change From Baseline in Urine Specific Gravity [ Time Frame: Baseline and Up to Month 108 ]
    Urine Specific gravity (USG) was assessed at Month 1, Month 3, , Month 6, Month 9, Month 12 and every 4 months after Month 12. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available.

  • Change From Baseline in Urine Power of Hydrogen (pH) [ Time Frame: Baseline and Up to Month 108 ]
    Urine pH was assessed at Month 1, Month 3, , Month 6, Month 9, Month 12 and every 4 months after Month 12. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available.

  • Change From Baseline in Post-void Residual Bladder Ultrasound Volume [ Time Frame: Baseline and Up to Month 108 ]
    Post-void residual (PVR) bladder was assessed using ultrasound scan to assess urinary retention at Month 1, Month 3, Month 12 and annually after Month 12. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles)

  • Change From Baseline in Overall American Urological Association (AUA) Symptom Index Score [ Time Frame: Baseline and Up to Month 108 ]
    An AUA Symptom Index is a 7-item Likert-scored scale describing urinary bladder function and was completed by the Investigator to assess the participant's urinary voiding function at Month 1, Month 3, Month 12 and annually after Month 12. The index scale ranges from 0-35, where higher scores are indicative of a worse issue. Scores are categorized as 0-7 mild, 8-19 moderate and >19 severe. Baseline assessment in this study is defined as the last assessment for the endpoint in parent study taken prior to the first active treatment with Retigabine. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles)

  • Number of Participants With Abnormal Results in Physical Examination [ Time Frame: Up to Month 108 ]
    A complete physical examination was performed at the end of each 12 month study cycle. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). If a participant had an abnormal result for at least one body system of exam, that participant was included in the 'Abnormal' category

  • Number of Participants With Abnormal Results of Neurological Examination [ Time Frame: Up to Month 108 ]
    Participants were assessed at Month 1, Month 3, Month 6, Month 9, Month 12 and every 4 months after Month 12. Participants in the worst category among the results of all neurological examination parameters are presented. Abnormal results were categorised as Abnormal not Clinically Significant (AbNCS)and Abnormal and Clinically Significant (AbCS). Only those participants available at the specified time points were analyzed (represented by n=X in the category titles)

  • Number of Participants With Pigmentation of Non-retinal Ocular Tissue [ Time Frame: Assessed up to a maximum of 9 years ]
    The ophthalmologist/retina specialist determined the presence or absence of abnormal discoloration of all non-retinal ocular tissues. Only those participants available at the specified time points were analyzed.

  • Number of Participants With Pigmentation of Retinal Ocular Tissue [ Time Frame: Assessed up to a maximum of 9 years ]
    The ophthalmologist/retina specialist determined the presence or absence of abnormal discoloration of retinal ocular tissues. It included Pigmentary abnormalities in the macula, of peripheral retina as well as in both of them.. Only those participants available at the specified time points were analyzed.

  • Number of Participants With Abnormal Pigmentation of Skin, Including the Skin Around the Eyes and the Eyelids, Lips, Nails, or Mucosa [ Time Frame: Assessed up to a maximum of 9 years ]
    An assessment of the participant's nails, lips, skin and mucosa was completed by the investigator at the 4 monthly study visits. The assessment of the participant's skin included assessment of the skin around the eyes and the eyelids,lips, nails, and mucosa

  • Number of Participants With a Clinically Significant Decrease in Visual Acuity From Initial Examination [ Time Frame: Assessed up to a maximum of 9 years ]
    A comprehensive eye examination was conducted by retina specialist or general ophthalmologist to assess best corrected visual acuity. An initial comprehensive eye examination was completed by an ophthalmologist for all participants. This exam was not associated with a specific visit. Thereafter, eye examinations was performed approximately every 6 months. Eye examination was introduced following protocol amendment and was conducted in all participants. Participants discontinued before implementation of this amendment and who have not had a comprehensive eye examination and skin examination (and follow-up by a dermatologist, if clinically indicated) were asked to return to the clinic for an evaluation of their skin (and follow-up dermatology examination, if clinically indicated) and for a comprehensive eye examination. Number of Par. with both initial and at least one follow-up exam while on RTG treatment were analyzed.

  • Number of Participants With a Decrease in Confrontational Visual Field From Initial Examination [ Time Frame: Assessed up to a maximum of 9 years ]
    Decrease in confrontation visual field is defined as a participant having a normal initial exam and an abnormal exam thereafter or, a response of clinically significant worsening in either eye since the last assessment.


Secondary Outcome Measures:
  • Percentage Change From Baseline in the 28-day Partial Seizure [ Time Frame: Assessed up to a maximum of 9 years ]
    Twenty-eight-day total partial seizure frequency during the study is defined as the sum of total partial seizures from First date (Baseline visit date +1 if no seizures on Baseline or Baseline visit date if seizures reported on the Baseline) to Last date (last visit date for seizure record with non-missing response), divided by applicable days, standardized by 28 days. The applicable days are the days in which the subject had non-missing seizure data. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed.

  • Number of Responders [ Time Frame: Assessed up to a maximum of 9 years ]
    A participant was classified as a responder if there is an at least 50% reduction from Baseline in the 28-day total Partial Seizure frequency. Baseline was defined as the parent study Baseline. Only those participants available at the specified time points were analyzed.

  • Number of Participants Who Were Seizure Free for Any 6 Continuous Months [ Time Frame: Assessed up to a maximum of 9 years ]
    Number of seizure free days is defined as the number of applicable days without any seizures (partial, generalized or unclassified). Only the days in which a subject had non-missing seizure data were considered as applicable days. Duration of exposure is defined using a window range allowed for each scheduled visit. At least 6 months of exposure is defined as >= 173 days of exposure since the window range for Month 6 visit is +/- 7 days. Only those participants available at the specified time points were analyzed.

  • Number of Participants Who Were Seizure Free for Any 12 Continuous Months [ Time Frame: Assessed up to a maximum of 9 years ]
    Duration of exposure is defined using a window range allowed for each scheduled visit. At least 12 months of exposure is defined as >= 353 days of exposure since the window range for Month 12 visit is +/- 7 days. Only those participants available at the specified time points were analyzed.

  • Percentage of Seizure-free Days [ Time Frame: Assessed up to a maximum of 9 years ]
    Number of seizure free days is defined as the number of applicable days without any seizures (partial, generalized or unclassified). Only the days in which a participant had non-missing seizure data was considered as applicable days

  • Change From Baseline in Quality of Life in Epilepsy (QOLIE)-31-P Questionnaire [ Time Frame: Assessed up to a maximum of 9 years ]
    The QOLIE-31-P (Version 2.0) was utilized to assess quality of life. The QOLIE-31-P assessment was completed by the participants at Baseline, Month 3, Month 6, Month 9, Month 12 and annually after Month 12. The QOLIE has 7 sub scales as energy fatigue, emotional well being, social functioning, cognitive, medication effects, seizure worry and overall QOL. The assessment range for the overall score and the sub-scales is 0-100, where higher scores indicate greater well being. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles)


Enrollment: 181
Study Start Date: May 2006
Study Completion Date: November 2015
Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ezogabine: USAN Retigabine (International Nonproprietary Name)
Film-coated tablets - 50mg, 100mg or 300mg
Drug: Ezogabine: USAN Retigabine (International Nonproprietary Name)
Film-coated tablets containing 50 mg, 100 mg, or 300 mg of retigabine per tablet. Dosage and frequency will be specific to each patient so long as the patient receives between 600 and 1200 mg of retigabine per day. The duration will be until the trial concludes or the patient leaves the trial.
Other Names:
  • GKE-841
  • D-23129
  • GW582892X

Detailed Description:
This Phase 3 trial is an open-label extension study of the placebo-controlled, double-blind VRX-RET-E22-301 trial. Patients who have completed the VRX-RET-E22-301 trial and who meet inclusion and exclusion criteria will be treated with 600-1200 mg/day of retigabine as an adjunct therapy to their current antiepileptic drugs (AEDs) or vagal nerve stimulation. Treatment will be continued until retigabine is commercially available, or until the program is discontinued. Patients will be recruited from 45-50 sites in the United States, Canada, Mexico, Brazil, and Argentina. The safety and tolerability of long-term therapy with retigabine administered as adjunctive therapy in adult epilepsy patients with partial-onset seizures will be evaluated. In addition, the efficacy of long-term treatment with retigabine and patient quality of life will be assessed.
  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient has successfully completed the Maintenance and Transition phases of Study VRX-RET-E22-301 for the treatment of partial-onset seizures
  • Patient is expected to benefit from participation in the study in the opinion of the Investigator.

Exclusion Criteria:

  • Patient meets any of the withdrawal criteria in the previous VRX-RET-E22-301 study or is experiencing an ongoing serious adverse event.
  • Patient is receiving any investigational drug or using any experimental device in addition to Retigabine for treatment of epilepsy or any other medical condition.
  • Patient has any other condition that would prevent compliance with the study procedures or proper reporting of adverse events.
  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: NCT00310375

  Show 51 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00310375     History of Changes
Other Study ID Numbers: VRX-RET-E22-303  RTG115098 
Study First Received: March 30, 2006
Results First Received: July 27, 2016
Last Updated: October 4, 2016

Keywords provided by GlaxoSmithKline:
Epilepsy
Partial Seizures
Potassium Channels
Anticonvulsant
Complex Partial Seizures
Epilepsies, Partial
RTG115098

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

ClinicalTrials.gov processed this record on February 24, 2017