A Long-term, Safety, Tolerability, and Efficacy Study of Retigabine Immediate-release (IR) in Asian Adults With Partial Onset Seizures

Epilepsy Clinical Trial

Official title:

A Multicentre, Open-label, Long-term, Safety, Tolerability, and Efficacy Study of Retigabine Immediate-release (IR) in Asian Adults With Partial Onset Seizures (Extension of Study RTG114855)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01777139
• Other study ID #: 114873
• Status: Completed
• Phase: Phase 3
• Start date: April 11, 2013
• Est. completion date: September 13, 2017

Study information

• Verified date: March 2020
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicentre, long-term, open-label extension (OLE) study to assess the long-term safety, tolerability and efficacy of retigabine immediate-release (IR) as adjunctive therapy in adult Asian subjects with drug-resistant partial-onset seizures (POS).

Description:

Subjects who successfully complete the Maintenance Phase of Study RTG114855 (parent study) and are expected to benefit from therapy with retigabine IR will be eligible for this OLE study. The study will consist of Screening (1 day), Open-Label Treatment and Follow-up (3 weeks) phase. Subjects will initially receive a starting dose of retigabine IR at 900 milligram (mg)/day and the same concurrent antiepileptic drug (AED) regimen that they were receiving at the final visit of the Transition Phase of the parent study. After the first week of the OLE study, the dose of retigabine IR may be adjusted to between 600 and 1200 mg/day, with dose adjustments in increments or decrements of 150 mg/week, based on efficacy and tolerability. In addition, the dose and number of concurrent AEDs may also be adjusted to meet each individual subject's needs. The efficacy and safety issues will be assessed throughout the study; subjects will be instructed to call the investigator if they experience any efficacy or tolerability issues between the study visits. As the duration of the study will be determined based on the following four conditions: 1) regulatory approval and commercialisation of retigabine IR; 2) retigabine IR is not approved by the regulatory authorities; 3) the study is terminated by the Sponsor for reasons including, but not limited to, safety issues; or 4) the subject is withdrawn or withdraws consent, 4 years will be considered as a guide to the duration of the study. The safety and tolerability endpoints are incidence and severity of adverse events (AEs); proportion of subjects with AEs leading to discontinuation; change from Baseline in vital sign measurements and weight; change from Baseline in electrocardiogram parameters; change from Baseline in haematology, chemistry, and urinalysis parameters; changes from Baseline in American Urological Association Symptom Index and post-void residual bladder ultrasound volumes; and summary of the Columbia-Suicide Severity Rating Scale. Efficacy will be assessed by calculating the percent change from Baseline (parent study) in 28-day total POS frequency for the entire open-label Treatment Phase of this OLE study. This will also be calculated based on duration of exposure. Responder rate (defined as a >/=50% reduction from Baseline in 28-day total POS frequency) will also be summarised for the entire open-label Treatment Phase and by duration of exposure.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: September 13, 2017
• Est. primary completion date: December 14, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• The subject has successfully completed the Maintenance Phase and Transition Phase of Study RTG114855.

• The subject is expected, in the opinion of the investigator, to benefit from participation in this OLE study.

• The subject or the caregiver is able and willing to maintain an accurate and complete written daily seizure calendar for the entire duration of the study.

• The subject has given written informed consent, or has a legally authorized representative who has given written informed consent, prior to the performance of any study assessments.

• A female subject is eligible to enrol and participate in the study if she is of:

nonchildbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is premenarchal or 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, and postmenopausal females defined as being amenorrhoeic for >1 year with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms). However, if indicated, this should be confirmed by oestradiol 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.

• Childbearing potential, has a negative urine or serum pregnancy test at Screening.

• Is not pregnant or lactating or planning to become pregnant during the study.

Exclusion Criteria:

• Has met any of the withdrawal criteria in the parent study (RTG114855) or has, in the opinion of the investigator, clinically significant abnormal laboratory or ECG findings that preclude entry into RTG114873.

• Is planning to begin treatment with an investigational drug (other than retigabine) and/or an experimental device for the treatment of epilepsy or any other medical condition.

• Has any medical condition that, in the investigator's judgement, 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 condition; or a condition that affects the absorption, distribution, metabolism, or excretion of drugs.

• Is unwilling or unable to follow the study procedures or reporting of AEs.

• Has active suicidal plan/intent or has had active suicidal thoughts in the past 6 months or has history of suicide attempt in the last 2 years or >1 lifetime suicide attempt.

Related Conditions & MeSH terms

• Epilepsy
• Seizures

Intervention

Drug:
• Retigabine IR
Retigabine IR tablets will be available in 5 strengths: 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg.

Locations

Country	Name	City	State
Korea, Republic of	GSK Investigational Site	Busan
Korea, Republic of	GSK Investigational Site	Busan
Korea, Republic of	GSK Investigational Site	Daegu
Korea, Republic of	GSK Investigational Site	Daejeon
Korea, Republic of	GSK Investigational Site	Gyeonggi-do
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Malaysia	GSK Investigational Site	Kuala Lumpur
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Khon Kaen

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

Korea, Republic of,  Malaysia,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Treatment Emergent (TE) Serious Adverse Events (SAEs) and Non-SAEs	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. Any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function is SAE. TEAE refers to an AE for which the onset was on or after the date of the first RTG dose in this study and on or before 30 days after the last RTG dose date. AEs that started in the parent study that worsened in this study were also considered as TEAEs. Safety population comprised of participants who take at least 1 dose of study medication after they have enrolled into this OLE study. Number of participants with TE-SAEs and non-SAEs (with incidence >= 5%) have been presented.	Up to 4 years
Primary	Percentage of Participants With TEAEs Leading to Study Discontinuation	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. TEAE refers to an AE for which the onset was on or after the date of the first RTG dose in this study and on or before 30 days after the last RTG dose date. Percentage of participants with TEAEs leading to study discontinuation were presented.	Up to 4 years
Primary	Number of Participants With Potential Clinical Concern (PCC) Values of Change From Baseline for Vital Signs	The vital signs were evaluated as per PCC Criteria. The vital signs included systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). The vital signs were measured in a seated position after 5 minutes of rest. PCC range for DBP was increase or decrease of >=20, for SBP was increase or decrease of >=15 and for heart rate was increase or decrease of >=15. A Baseline assessment in this OLE study was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Number of participants with vital sign values of PCC at any Post-Baseline visit were presented.	Baseline and up to 4 years
Primary	Number of Participants With PCC Values of Change From Baseline for Body Weight	Body weight of participants were measured as a measure of safety. PCC range for body weight was increase or decrease of >=7 percent. A Baseline assessment in this OLE study was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Number of participants with PCC values of body weight at any Post-Baseline visit were presented.	Baseline and up to 4 years
Primary	Number of Participants With PCC Values of Change From Baseline for Electrocardiogram (ECG) Parameters	Single measurements of 12-lead ECGs were obtained in a supine position after at least 10 minutes of rest using an ECG machine that automatically calculates the heart rate (HR) as beats per minute (bpm) and measures PR, QRS, Bazett's correction QT interval (QTcB) and Friedericia's correction QT interval (QTcF) in milliseconds (msec). A Baseline assessment in this OLE study was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Number of participants with PCC values of ECG parameters at any Post-Baseline visit were presented. For the 'Any Post Baseline' value, only the worst case finding was counted for each participant.	Baseline and up to 4 years
Primary	Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Total Neutrophils, and White Blood Cell Count (WBC)	Blood samples were collected from participants for evaluation of change from Baseline in hematology parameters including basophils, eosinophils, lymphocytes,monocytes, platelet count, total neutrophils, and WBC. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and standard deviation (SD) were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in Hematocrit	Blood samples were collected from participants for evaluation of hematocrit. Hematocrit is a ratio of red blood cells to the total volume of blood. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC)	Blood samples were collected from participants to evaluate change from Baseline in hemoglobin and MCHC levels. Baseline assessment in this OLE study was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in Mean Corpuscle Hemoglobin (MCH) Level	Blood samples were collected from participants to evaluate change from Baseline in MCH levels. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in Mean Corpuscle Volume (MCV) and Mean Platelet Volume (MPV)	Blood samples were collected from participants to evaluate change from Baseline in MCV and MPV levels. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in Red Blood Cell (RBC) Count	Blood samples were collected from participants to evaluate change from Baseline in RBC count. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in Red Cell Distribution Width (RDW)	Blood samples were collected from participants to evaluate change from Baseline in RDW. RDW is a parameter that measures variation in red blood cell size or red blood cell volume. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in Alanine Amino Transferase (ALT), Alkaline Phosphatase (Alk. Phosph.), Aspartate Aminotransferase (AST), Creatine Kinase (CK), Gamma Glutamyl Transferase (GGT) and Lactate Dehydrogenase (LD)	Blood samples collected from participants to evaluate change from Baseline in clinical chemistry parameters included ALT, Alk. phosph., AST,CK, GGT and LD. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in Albumin and Total Protein	Blood samples were collected from participants to evaluate change from Baseline in albumin and total protein. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in Blood Urea Nitrogen (BUN)/Creatinine Ratio	Blood samples were collected from participants to evaluate change from Baseline in BUN/creatinine. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in Calcium, Carbon Dioxide (CO2) Content/Bicarbonate (Bicarb), Chloride, Glucose, Magnesium, Potassium, Sodium, Urea/BUN	Blood samples were collected from participants to evaluate change from Baseline in calcium, CO2 content/Bicarb, chloride, glucose, magnesium, potassium, sodium, and urea/BUN. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in Creatinine, Direct Bilirubin, Total Bilirubin, and Uric Acid	Blood samples were collected from participants to evaluate change from Baseline in creatinine, direct bilirubin, total bilirubin, and uric acid. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in Urine Albumin/Creatinine Ratio	Urine samples were collected from participants to evaluate change from Baseline in urine albumin/creatinine ratio. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated. NA indicates data was not available as standard deviation could not be calculated for single participant.	Baseline and up to 4 years
Primary	Number of Participants With Abnormal Urinalysis Values (Categorical Data)	Urine samples were collected from participants to analyze presence of abnormal urinalysis parameters including glucose, ketones, RBC, WBC, occult blood and protein. Abnormal urinalysis values have been presented for all parameters. Only those participants with data available at specific time points were analyzed (represented by n= X in the category titles).	Up to 4 years
Primary	Specific Gravity of Urine at Indicated Time Points	Urine samples were collected to analyze specific gravity of urine. Specific gravity, is a measure of urine concentration and is measured using a chemical test. Specific gravity measurements provide a comparison of the amount of substances dissolved in urine as compared to pure water. If there were no solutes present, the specific gravity of urine would be 1.000 the same as pure water. Specific gravity between 1.002 and 1.035 could be considered as normal. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).	Up to 4 years
Primary	Potential of Hydrogen (pH) of Urine at Indicated Time Points	Urine Samples were collected to analyze pH. pH is a measure of hydrogen ion concentration and used to determine the acidity or alkalinity of urine. pH scale ranges from 0 to 14. A neutral pH is 7.0. The higher number indicates the more basic (alkaline) nature of urine and lower the number indicates the more acidic urine. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).	Up to 4 years
Primary	Change From Baseline in Urine Creatinine Concentration	Urine samples were collected from participants to evaluate change from Baseline in Urine creatinine concentration. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Change From Baseline in American Urological Association (AUA) Symptom Scale Scores	The effect of RTG on bladder function was assessed using AUA symptom index. It is a 7-item Likert-scored scale with seven questions, each with six potential responses. Responses to each of 7 questions were scored from 0 (no symptom at all) to 5 (almost always symptoms present) which were summmed to get total possible score ranging from 0 to 35 with higher scores indicating worse symptom severity. The total score for all questions was classified as mild (0-7), moderate (8-19) or severe (>19). Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).	Baseline and up to 4 years
Primary	Change From Baseline in Post-void Residual (PVR) Bladder Ultrasound Volumes	The PVR bladder ultrasound was used to assess the effects of RTG on bladder function. Baseline was defined as the last assessment of that endpoint in parent study RTG114855 taken prior to the first active treatment with RTG IR. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles). Mean and SD were calculated.	Baseline and up to 4 years
Primary	Number of Participants With Suicidal Ideation or Behavior During Treatment Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)	Number of participants with suicidal ideation or behavior during treatment were assessed using the C-SSRS score scale. It is a brief questionnaire designed to assess severity and change in suicidality by integrating both behavior and ideation using a semi-structured interview to probe participant responses. It consists of an assessment of suicidal ideation (ranging from "desire to be dead" to "active suicidal ideation with specific plan and intent") and an assessment of suicidal behavior (ranging from "preparatory acts or behavior" to "completed suicide").	Up to 4 years
Primary	Number of Participants Who Discontinued From RTG	The number of participants who discontinued from RTG treatment has been presented.	Up to 4 years
Primary	Percentage of Participants With Retinal Pigmentary Abnormalities	Percentage of participants with abnormal findings after eye examination were evaluated. Abnormalities detected on-treatment in study RTG114873 were presented. Retinal pigmentary abnormalities included abnormalities in the macula, peripheral retina and unspecified location.	Up to 4 years
Primary	Percentage of Participants With Pigmentation of Non-retinal Ocular Tissues	Percentage of participants with abnormal findings after eye examination were evaluated. Abnormalities detected on-treatment in study RTG114873 were presented. Pigmentation of non-retinal ocular tissues included pigmentation of the sclera and/or conjunctiva, cornea, iris and lens.	Up to 4 years
Primary	Percentage of Participants With Dermatologist-confirmed Abnormal Discoloration	Percentage of participants with abnormal findings after skin examination (including the skin around the eyes and the eyelids, lips, nails, or mucosa) were evaluated.	Up to 4 years
Primary	Percentage of Participants With a Clinically Significant Decrease in Visual Acuity From Initial Examination	Percentage of participants with a clinically significant decrease in visual acuity from initial examination were evaluated. Only abnormalities occurring on-treatment in study RTG114873 were presented.	Up to 4 years
Primary	Percentage of Participants With Decrease in Confrontational Visual Field From Initial Examination	Percentage of participants with decrease in confrontational visual field from initial examination were evaluated. Only abnormalities occurring on-treatment in study RTG114873 were presented.	Up to 4 years
Primary	Percentage of Responders to POS Frequency	A responder was defined as a participant experiencing a >=50 percent reduction in 28 day total POS frequency from Baseline. A responder rate was calculated overall and based on duration of exposure. As this was an OLE study, Baseline was defined by the parent study Baseline period. Percentage of responders were evaluated from study RTG114873 Day 1 through the last dosing day, excluding the Taper Phase.	Up to 4 years
Primary	Percent Change From Baseline in 28-day Total POS Frequency	The 28-day total POS frequency was calculated as the number of total POS reported during the treatment phase, divided by the number of applicable days in the treatment phase, then multiplying this ratio by 28. In this formula, innumerable seizures were counted as 10 seizures and status epilepticus was counted as 1 seizure. As this was an OLE study, Baseline was defined by the parent study Baseline period. The percent change from Baseline was calculated as the 28-day total POS on-treatment frequency (during dosing in this study, not including the taper phase) minus the Baseline 28-day total POS frequency, with this difference being divided by the Baseline 28-day partial seizure rate, and the resulting quantity multiplied by 100. It was calculated as overall and by duration of exposure. Mean and SD were presented.	Baseline and up to 4 years
Primary	Number of Participants With Resolution of Abnormal Eye Pigmentation After Discontinuation of RTG	The ophthalmologist/retina specialist determined the presence or absence of retinal and non-retinal ocular abnormalities. Retinal abnormalities included abnormalities in the macula and/or the peripheral retina. This analysis was performed on the All SFUCP Subjects population which comprised of all participants who enter the SFUCP.	Up to 1.4 years
Primary	Number of Participants With Resolution of Dermatologist-confirmed Abnormal Discoloration After Discontinuation of RTG	The skin examination included assessment of the skin around the eyes and the eye lids, lips, nails, and mucosa. Participants who enter the SFUCP who had on-treatment finding(s) of abnormal discoloration of skin, lips, nails or mucosa confirmed by a dermatologist, underwent assessments performed by a dermatologist at 6-monthly intervals.	Up to 1.4 years