Study in Pediatric Subjects With Epilepsy

Study Overview
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Brief Summary
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This is an open-label study to evaluate the pharmacokinetics, safety and tolerability of ezogabine/retigabine in subjects aged 12 years to less than 18 years with uncontrolled partial onset seizures or Lennos-Gastaut syndrome.

Official Title
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Open-label, Multiple Dose Study to Evaluate the Parmacokinetics, Safety and Tolerability of Ezogabine/Retigabine as Adjunctive Treatment in Subjects Aged From 12 Years to Less Than 18 Years With Partial Onset Seizures or Lennox-Gastaut Syndrome

Conditions
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Epilepsy

Intervention / Treatment
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* Drug: ezogabine/retigabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between 12 and 18 years of age. Diagnosis of uncontrolled partial onset seizures (with or without secondarily generalized seizures) or Lennox-Gastaut syndrome. Taking between one and three antiepileptic drugs. Able to swallow tablets. Females must be of : (1) Non-childbearing potential or (2) Child-bearing potential and agrees to use acceptable contraception. Exclusion Criteria: Epilepsy secondary to progressive cerebral disease, tumor or any progressive neurodegenerative disease. History of status epilepticus in the last six months. Currently treated with felbamate or has been treated with vigabatrin within the past 6 months. Following the ketogenic diet. Suicidal intent or history of suicide attempt in the last 2 years. Elevated liver enzymes or abnormal kidney function. Current disturbance of micturition or known urinary obstructions. History of vesicoureteric reflux. Abnormal post-void residual bladder ultrasound. Urinary retention and/or required urinary catheterization in the preceding 6 months. Abnormal urine sample at screening/.baseline. Abnormal blood sample at screening. Clinically significant arrhythmias. Abnormal ECG at screening. BMI lower than the 10th percentile for age and gender or subject weighs less than 30kg.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ezogabine/retigabine<br>ezogabine dose escalation | Drug: ezogabine/retigabine<br>* ezogabine dose escalation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) Following Oral Administration of Ezogabine/Retigabine | The steady state pharmacokinetic profile following oral administration of ezogabine/retigabine included determining the area under the curve over the dosing interval (AUC[0-tau]). The area under the plasma concentration-time curve over the dosing interval (AUC[0-tau]) was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 to estimate AUC(0-tau). | Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 | 
| Apparent Clearance (CL/F) Following Oral Administration of Ezogabine/Retigabine | Clearance (CL/F) is defined as dose/AUC(0-tau). Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 to estimate CL/F. | Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 | 
| Maximum Observed Concentration (Cmax) and Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) Following Oral Administration of Ezogabine/Retigabine | Cmax is defined as the first occurrence of the maximum observed plasma concentration. Ctau refers to the pre-dose (trough) concentration after the dosing interval which is equal to the minimum observed concentration (Cmin) at Steady State. Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 to estimate Cmax and Ctau. | Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 | 
| Apparent Volume of Distribution (Vd/F) Following Oral Administration of Ezogabine/Retigabine | The volume of distribution (Vd/F) is defined as MRT*CL/F, where MRT is the mean residence time (calculated as AUMC[0-tau]/AUC[0-tau], where AUMC[0-tau] is the area under the first moment curve determined as the area under the concentration*time versus time curve). Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 to estimate the apparent volume of distribution. | Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Event (AE) | An AE is defined as 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 AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. | From the start of the first titration until follow-up (assessed up to 46 days) | 
| Change From Baseline in Albumin and Total Protein at Day 7 Post Each Up-titration | Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit. | Baseline (Screening), Day 7, Day 21, and Day 35 | 
| Change From Baseline in Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, and Gamma Glutamyl Transferase at Day 7 Post Each Up-titration | Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit. | Baseline (Screening), Day 7, Day 21, and Day 35 | 
| Change From Baseline in Direct Bilirubin, Total Bilirubin, Creatinine, and Uric Acid at Day 7 Post Each Up-titration | Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit. | Baseline (Screening), Day 7, Day 21, and Day 35 | 
| Change From Baseline in Calcium, Chloride, Carbon Dioxide Content/Bicarbonate, Glucose, Potassium, Sodium, Inorganic Phosphorus, and Urea/Blood Urea Nitrogen (BUN) at Day 7 Post Each Up-titration | Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit. | Baseline (Screening), Day 7, Day 21, and Day 35 | 
| Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Total ANC [Total Absolute Neutrophil Count]), Platelet Count, and White Blood Cell Count at Day 7 Post Each Up-titration | Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit. | Baseline (Screening), Day 7, Day 21, and Day 35 | 
| Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Day 7 Post Each Up-titration | Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit. | Baseline (Screening), Day 7, Day 21, and Day 35 | 
| Change From Baseline in Hematocrit at Day 7 Post Each Up-titration | Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit. The International System of Units (SI) Fraction of one unit (1) is reported here. | Baseline (Screening), Day 7, Day 21, and Day 35 | 
| Change From Baseline in Mean Corpuscle Hemoglobin at Day 7 Post Each Up-titration | Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit. | Baseline (Screening), Day 7, Day 21, and Day 35 | 
| Change From Baseline in Mean Corpuscle Volume at Day 7 Post Each Up-titration | Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit. | Baseline (Screening), Day 7, Day 21, and Day 35 | 
| Change From Baseline in Red Blood Cell Count at Day 7 Post Each Up-titration | Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit. | Baseline (Screening), Day 7, Day 21, and Day 35 | 
| Number of Participants With the Indicated Urinalysis Parameter Dipstick Test Results From Screening to Follow-up | Urinalysis parameters analyzed included: urine occult blood (UOB), urine glucose (UG), urine ketones (UK), and urine protein (UP). The dipstick was a strip used to detect the presence or absence of these parameters in the urine sample. The dipstick test provides results in a semi-quantitative manner, and results can be read as negative (Neg), Trace, and 80, indicating proportional concentrations in the urine sample. Urinalysis parameters were assessed at Titration 1 (T1; 300 mg/day), Titration 2 (T2; 450 mg/day), Titration 3 (T3; 600 mg/day), Titration 4 (T4; 750 mg/day), and Titration 5 (T5; 900 mg/day). | Screening, Day 1 (D1), Day 7 (D7), Day 14 (D14), Day 21 (D21), Day 28 (D28), Day 35 (D35), and at the Follow-up Visit (up to Day 46) | 
| Percent Change From Baseline in 28-day Seizure Frequency Rate | Participants or their caregivers recorded the number of seizures experienced by the participant, by seizure type (e.g., simple partial seizure [seizure that affects only a small region of the brain; consciousness is unaffected], complex partial seizure [seizure associated with unilateral cerebral hemisphere involvement and causing impairment of awareness or responsiveness], etc.), as well as by duration of episodes of innumerable seizure activity, in their daily diaries during all phases of this study. Percent change from baseline is defined as 100 * (rate in a given period minus the baseline rate) / (baseline rate). baseline seizures are defined as those seizures that occurred after Screening and before the start of the treatment. Post-baseline seizures are defined as those seizures that occurred from the start of the treatment until the start of Follow-up. Seizure frequency rate was computed as: 28 * (number of seizures during given period / number of days in given period). | Baseline (Screening) and until Follow-up or early discontinuation (assessed up to 46 days) | 
| Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the Last Time of Quantifiable Concentration (AUC [0-t]) for the N-acetyl Metabolite of Ezogabine/Retigabine | The area under the curve was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 to assess the plasma n-acetyl metabolite (NAMR) of ezogabine/retigabine following oral administration of ezogabine/retigabine. | Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 | 
| Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) for the N-acetyl Metabolite of Ezogabine/Retigabine | Ctau refers to the pre-dose (trough) concentration at the end of the dosing interval which is equivalent to the minimum observed concetration (Cmin) at Steady State. Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 to assess the Ctau for n-acetyl metabolite (NAMR) of ezogabine/retigabine following oral administration of ezogabine/retigabine. | Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 | 
| Time to Maximum Concentration (Tmax) Following Oral Administration of Ezogabine/Retigabine | Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 to assess plasma Tmax. | Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 | 
| Plasma Half Life at Steady State (t1/2) Following Oral Administration of Ezogabine/Retigabine | Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 to assess plasma t1/2. Steady-state t1/2 is derived as (Vd/F) / (CL/F), where Vd/F is defined as the apparent volume of distribution after extravascular (e.g., oral) administration, and CL/F is defined as the apparent clearance following oral dosing. | Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | An ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT interval corrected for heart rate (QTc intervals) was used. Measurements were taken 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 14 for up-titration to 450 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 28 for up-titration to 750 mg/day dose; Day 35 for up-titration to 900 mg/day dose). ECG parameters were assessed at Titration 1 (T1; 300 mg/day): Day 1 pre-dose, Day 1 at 3 hours (h), pre-dose, and 3 h post-dose. Titration 2 (T2; 450 mg/day): Day 7. Titration 3 (T3; 600 mg/day): pre-dose and 3 h post-dose. Titration 3 Dose Held (T3DH): pre-dose. Titration 4 (T4; 750 mg/day): Day 7. Titration 5 (T5; 900 mg/day): pre-dose and 3 h post-dose. The number of participants with abnormal (Abn) clinically significant (CS) and not clinically significant (NCS) ECG findings was recorded. The investigator determined if an ECG finding was CS or NCS. | Baseline (Screening) and Day 7 post up-titration, up to Day 35 | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points | Vital sign assessment included the measurement of systolic and diastolic blood pressure at Titration 1 (T1; 300 mg/day): Day 1 pre-dose, Day 1 at 3 hours (h), Day 7 pre-dose, and 3 h post dose. Titration 2 (T2; 450 mg/day): Day 7. Titration 3 (T3; 600 mg/day): Day 21 pre-dose and 3 h post-dose. Titration 3 Dose Held (T3DH): pre-dose. Titration 4 (T4; 750 mg/day): Day 7. Titration 5 (T5; 900 mg/day): Day 35 pre-dose and 3 h post-dose. Measurements were taken 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 14 for up-titration to 450 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 28 for up-titration to 750 mg/day dose; Day 35 for up-titration to 900 mg/day dose). Change from baseline was calculated by subtracting the baseline value from the individual post-dose values. Baseline is defined as as the Day 1 pre-dose value. | Baseline (Screening) and Day 7 post up-titration, up to Day 35 | 
| Change From Baseline in Heart Rate (HR) | Vital sign assessment included heart rate measurement and was assessed at Titration 1 (T1; 300 mg/day): Day 1 pre-dose, Day 1 at 3 hours (h), pre-dose and 3 h post-dose. Titration 2 (T2; 450 mg/day): Day 7. Titration 3 (T3; 600 mg/day): pre-dose and 3 h post-dose. Titration 3 Dose Held (T3DH): pre-dose. Titration 4 (T4; 750 mg/day): Day 7. Titration 5 (T5; 900 mg/day): pre-dose and 3 h post-dose. Measurements were taken 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 14 for up-titration to 450 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 28 for up-titration to 750 mg/day dose; Day 35 for up-titration to 900 mg/day dose). Change from baseline was calculated by subtracting the baseline value from the individual post-dose values. Baseline is defined as as the Day 1 pre-dose value. | Baseline (Screening) and Day 7 post up-titration, up to Day 35 | 
| Change From Baseline in Post Void Residual Ultrasound at Day 21 | A post void residual (PVR) bladder ultrasound was carried out as a measure of bladder function. PVR was clinically indicated following the occurrence of adverse events relating to the lower urinary tract (e.g., micturition difficulties, including urinary hesitancy or urinary retention). These assessments were also repeated following drug withdrawal following such events. A prompt follow-up PVR was recommended if a high score was obtained from a participant on the Pediatric Lower Urinary Tract Symptom scale (the PLUTS scale is a clinician-rated scale used to assess lower urinary tract symptoms, including urinary retention) and if the clinician felt that the participant was at risk or had symptoms of urinary retention. PVR was measured at Day 7 of Titration 3 (600 mg/day). Baseline is defined as the Screening visit. | Screening and Day 7 of Titration 3 (Day 21) | 
| Number of Participants With the Indicated Neurological Abnormality | Abnormal Central Nervous System (CNS) symptoms were assessed by a full and brief neurological examination. A full neurological examination included assessment of mental status, cranial nerves, gait, coordination, sensation, speech/language, muscle strength, muscle tone, and reflexes. A brief neurological examination included assessment of mental status, cranial nerves, gait, coordination, reflexes, and speech/language. Neurological parameters assessed were memory impairment, impaired intellect, decreased attention, psychomotor slowing, decreased muscle strength, hpertonia, somnolence, right and left bicpes, right and left brachioradialis, right and left knee, right and left ankle, and right and left planter response. Neurological examination was performed at Day 7 of Titration 3 (600 mg/day). | Screening and Day 7 of Titration 3 (Day 21) |