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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) Following Oral Administration of Ezogabine/Retigabine
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
ezogabine/retigabine
ezogabine dose escalation
干预措施: ezogabine/retigabine (Drug)
结局指标
主要结局
The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) Following Oral Administration of Ezogabine/Retigabine
时间窗: Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35
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).
Maximum Observed Concentration (Cmax) and Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) Following Oral Administration of Ezogabine/Retigabine
时间窗: Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35
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.
Apparent Volume of Distribution (Vd/F) Following Oral Administration of Ezogabine/Retigabine
时间窗: Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35
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.
Apparent Clearance (CL/F) Following Oral Administration of Ezogabine/Retigabine
时间窗: Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35
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.
次要结局
- Change From Baseline in Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, and Gamma Glutamyl Transferase at Day 7 Post Each Up-titration(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(Baseline (Screening), Day 7, Day 21, and Day 35)
- Change From Baseline in Mean Corpuscle Hemoglobin at Day 7 Post Each Up-titration(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(Baseline (Screening), Day 7, Day 21, and Day 35)
- Change From Baseline in Albumin and Total Protein at Day 7 Post Each Up-titration(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(Baseline (Screening), Day 7, Day 21, and Day 35)
- Change From Baseline in Mean Corpuscle Volume at Day 7 Post Each Up-titration(Baseline (Screening), Day 7, Day 21, and Day 35)
- Change From Baseline in Red Blood Cell Count at Day 7 Post Each Up-titration(Baseline (Screening), Day 7, Day 21, and Day 35)
- Number of Participants With Any Adverse Event (AE)(From the start of the first titration until follow-up (assessed up to 46 days))
- Change From Baseline in Direct Bilirubin, Total Bilirubin, Creatinine, and Uric Acid at Day 7 Post Each Up-titration(Baseline (Screening), Day 7, Day 21, and Day 35)
- Percent Change From Baseline in 28-day Seizure Frequency Rate(Baseline (Screening) and until Follow-up or early discontinuation (assessed up to 46 days))
- Change From Baseline in Hematocrit at Day 7 Post Each Up-titration(Baseline (Screening), Day 7, Day 21, and Day 35)
- 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(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(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(Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35)
- Change From Baseline in Heart Rate (HR)(Baseline (Screening) and Day 7 post up-titration, up to Day 35)
- Change From Baseline in Post Void Residual Ultrasound at Day 21(Screening and Day 7 of Titration 3 (Day 21))
- Time to Maximum Concentration (Tmax) 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)
- Number of Participants With Abnormal Electrocardiogram (ECG) Findings(Baseline (Screening) and Day 7 post up-titration, up to Day 35)
- Number of Participants With the Indicated Urinalysis Parameter Dipstick Test Results From Screening to Follow-up(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))
- Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points(Baseline (Screening) and Day 7 post up-titration, up to Day 35)
- Number of Participants With the Indicated Neurological Abnormality(Screening and Day 7 of Titration 3 (Day 21))