Study PTG116878, a Dose-Optimization Study of Ezogabine/Retigabine Immediate Release Tablets Versus Placebo in the Adjunctive Treatment of Subjects With Partial-Onset Seizures
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Percent Change in the 28-day Total Partial Seizure Frequency (POS) Within Each Stratum From Week 0 (End of Baseline Phase) Through Week 18 (End of Maintenance Phase)
研究概览
简要总结
This is a Phase IV adjunctive treatment dose-optimization study evaluating the efficacy, safety, and health outcomes of ezogabine/retigabine immediate release (IR) (GW582892) compared with placebo in adult subjects with partial-onset seizures (POS). This randomized, double-blind, placebo-controlled, parallel-group, multicenter study will compare ezogabine/retigabine IR (investigator-selected daily doses of 600 milligram (mg)/day, 750 mg/day, 900 mg/day, 1050 mg/day or 1200 mg/day) with placebo. Study drug will be taken three times a day (TID) in equally or unequally divided doses.
The study design includes up to a 10-week (wk) Screening (≤2 wks)/Baseline (8 wks) Phase, a Titration Phase (2 wks), Dose-Optimization Phase (8 wks), Maintenance Phase (8 wks), and Taper/Follow-Up Phase (3 wks). The total duration of the study for each subject will be approximately 31 wks, and at minimum approximately 27 wks if subjects provide reliable 28-day retrospective seizure data.
Approximately 280 subjects will be screened with approximately 208 subjects randomly assigned to 1 of 2 treatment groups in a 2:1 ratio (ezogabine/retigabine IR, or placebo).
Subjects will be instructed to start investigational product (IP) the day after the baseline visit. During the first week of the Titration Phase, subjects will be taking 300 mg/day (100 mg TID). During the second week, subjects will be taking 450 mg/day (150 mg/day TID).
At the beginning of the Dose-Optimization Phase (3rd week of study drug) subjects will take 600 mg/day (200 mg TID) for one week. Thereafter during the Dose-Optimization Phase, subjects will continue to increase their daily dose by 150 mg per week until they have achieved their optimal tolerated dose. During this phase, the investigator may choose to have the subject stay on his/her designated dose for another week before attempting a dose increase until reaching a dose of 1200 mg/day. In addition, in the context of tolerability issues, the subject may be reduced to the preceding dose level for one week before attempting to increase the dose again at the next scheduled time point until the subject reaches optimal dose. Subjects unable to tolerate a minimum of 600 mg/day will be discontinued from the study.
The Maintenance Phase will begin at Week 10 (Visit 8) and will last 8 weeks. During the Maintenance Phase, subjects will remain on the daily TID dose achieved at the end of the Dose-Optimization Phase.
Seizure type and frequency will be monitored throughout the study via a Seizure Calendar and will be evaluated at each study visit. Subjects will be instructed to complete the daily Seizure Calendar during each phase of the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •A male or female of 18 years of age or above capable of giving written informed consent
- •Have a confident diagnosis of epilepsy for >=6 months with partial-onset seizures (POS), i.e., simple or complex POS with or without secondary generalization (classified according to the International League Against Epilepsy (ILAE) Guidelines, prior to the Screening Visit
- •Currently receiving monotherapy treatment with an antiepileptic drug (AED) at a stable dose for at least 28 days prior to the screening visit (Visit 1). If the subject is taking a barbiturate (e.g., phenobarbital), the dose must be stable for ≥3 months prior to the Screening Visit. Note: Subjects who have received previous adjunctive treatment but are currently taking one AED are eligible for enrolment.
- •Investigator-confirmed partial seizure frequency rate of ≥3 partial seizures per 28 days over the 8 weeks preceding the screening visit and must not have been seizure-free for ≥ 21 consecutive days.
- •Female of non-child bearing potential, or female of child-bearing potential willing to use protocol-specified methods of contraception to prevent pregnancy during the study.
- •Capable to comply with dosing of study drug, background AED, all study procedures and to maintain an accurate and complete daily written Seizure Calendar and Functional Status Diary
排除标准
- •Have generalized epilepsy (e.g. Lennox-Gastaut, Juvenile Myoclonic epilepsy, Absence, etc.) or non-epileptic seizures.
- •Have had innumerable seizures within the 12-month period prior to the Screening Visit where the individual seizures cannot be counted.
- •Have had status epilepticus within 12 months prior to screening
- •Have a history of pseudo seizures, non-epileptic events or any other type of psychogenic seizures that could be confused with seizures.
- •Have been treated with felbamate or vigabatrin within the 6 months prior to Screening. If a subject has been previously treated with vigabatrin >6 months prior to Screening, a visual perimetry test performed within 6 months prior to Screening must show normal visual fields or no worsening of recognized visual field abnormalities as compared with prior to vigabatrin treatment
- •Benzodiazepines used in any manner other than acute usage as defined in this protocol will be considered concurrent AED usage and will not be permitted
- •Are using Central Nervous System (CNS)-active medication (other than concomitant AED therapy), unless the subject has been stabilized on such medication for at least 1 month prior to the Screening Visit.
- •Are using herbal treatments with CNS activity within at least 1 month prior to the Screening Visit
- •Have received ezogabine/retigabine in a previous study or have taken POTIGA or TROBALT.
- •Are currently following or planning to follow the ketogenic diet
- •Have an active Vagus Nerve Stimulator (VNS) to control seizures
- •Are planning surgery to control seizures during the study
- •Have impaired renal function as judged by a creatinine clearance of <50 mL/min
- •Have a history of urinary retention or risk factors for urinary retention that in the investigator's judgment could potentially affect subject safety.
- •Have an average corrected QT interval (QTc), using Bazett's QT correction (QTcB), ≥450msec or ≥480msec for subjects with bundle branch block at the time of the Screening Visit
- •Liver function tests: alanine aminotransferase (ALT) is ≥2 times the upper limit of normal (ULN); alkaline phosphatase and bilirubin are >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%).
- •Are suffering from acute or progressive neurological disease, severe psychiatric disease, or severe mental abnormalities that are likely to interfere with the objectives of the study
- •Have a history of malignancy within the past 2 years; with the exception of basal cell carcinoma
- •Have unstable liver disease [chronic stable hepatitis B and C are acceptable if subject otherwise meets entry criteria; chronic stable Hepatitis B to be excluded if significant immunosuppressive agents administered due to risk of hepatitis B reactivation]
- •Have any medical condition that, in the investigator's judgment, is considered to be clinically significant and could potentially affect subject safety or study outcome, including but not limited to: clinically significant cardiac, renal, hepatic condition, or a condition that affects the absorption, distribution, metabolism or excretion of drugs
- •Have an active suicidal plan/intent or have had active suicidal thoughts in the past 6 months. Have history of suicide attempt in the last 2 years or more than 1 lifetime suicide attempt.
- •Have a history of substance abuse (alcohol or drugs) or substance dependence within 12 months prior to screening
- •Have a known hypersensitivity to any components of the study medication
- •Have taken an investigational drug, or used an investigational device, within the previous 30 days prior to screening or plans to take an investigational drug anytime during the study.
研究组 & 干预措施
Titration Phase: Ezogabine/Retigabine 300 mg
Subjects receive Ezogabine/Retigabine 300 mg equally divided TID over Wk 1
干预措施: Ezogabine/Retigabine IR (Drug)
Titration Phase: Placebo 300 mg
Subjects receive matching Placebo
干预措施: Placebo (Drug)
Titration Phase: Ezogabine/Retigabine 450 mg
Subjects receive Ezogabine/Retigabine 450 mg equally divided TID over Wk 2
干预措施: Ezogabine/Retigabine IR (Drug)
Titration Phase: Placebo 450 mg
Subjects receive matching Placebo
干预措施: Placebo (Drug)
Dose-Optimization Phase: Ezogabine/Retigabine 600 mg
Subjects receive Ezogabine/Retigabine 600 mg equally divided (200 mg TID) over Wk 3 or until they achieve their optimal tolerated dose as assessed by the Investigator
干预措施: Ezogabine/Retigabine IR (Drug)
Dose-Optimization Phase: Placebo 600 mg
Subjects receive matching Placebo
干预措施: Placebo (Drug)
Dose-Optimization Phase: Ezogabine/Retigabine 750 mg
Subjects receive Ezogabine/Retigabine 750 mg equally or unequally divided TID over Wk 4 or until they achieve their optimal tolerated dose as assessed by the Investigator
干预措施: Ezogabine/Retigabine IR (Drug)
Dose-Optimization Phase: Placebo 750 mg
Subjects receive matching Placebo
干预措施: Placebo (Drug)
Dose-Optimization Phase: Ezogabine/Retigabine 900 mg
Subjects receive Ezogabine/Retigabine 900 mg equally or unequally divided TID over Wk 5 or until they achieve their optimal tolerated dose as assessed by the Investigator
干预措施: Ezogabine/Retigabine IR (Drug)
Dose-Optimization Phase: Placebo 900 mg
Subjects receive matching Placebo
干预措施: Placebo (Drug)
Dose-Optimization Phase: Ezogabine/Retigabine 1050 mg
Subjects receive Ezogabine/Retigabine 1050 mg equally or unequally divided TID over Wk 6 or until they achieve their optimal tolerated dose as assessed by the Investigator
干预措施: Ezogabine/Retigabine IR (Drug)
Dose-Optimization Phase: Placebo 1050 mg
Subjects receive matching Placebo
干预措施: Placebo (Drug)
Dose-Optimization Phase: Ezogabine/Retigabine 1200 mg
Subjects receive Ezogabine/Retigabine 1200 mg equally divided (400 mg TID) over Wk 7 or until they achieve their optimal tolerated dose as assessed by the Investigator
干预措施: Ezogabine/Retigabine IR (Drug)
Dose-Optimization Phase: Placebo 1200 mg
Subjects receive matching Placebo
干预措施: Placebo (Drug)
Maintenance Phase:Ezogabine/Retigabine
Subjects receive Ezogabine/Retigabine at the daily dose achieved (equally or unequally divided TID) at the end of the Dose-Optimization Phase for 8 Weeks (600 mg, 750 mg, 900 mg, 1050 mg, or 1200 mg)
干预措施: Ezogabine/Retigabine IR (Drug)
Maintenance Phase: Placebo
Subjects receive matching Placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Percent Change in the 28-day Total Partial Seizure Frequency (POS) Within Each Stratum From Week 0 (End of Baseline Phase) Through Week 18 (End of Maintenance Phase)
时间窗: Week 0 (end of Baseline Phase) through Week 18 (end of Maintenance Phase)
The percent change in 28-day total POS frequency within each stratum (sodium channel blocker or non-sodium channel blocker) background antiepileptic drug (AED) was to be summarized as the supportive analysis. The total 28-day POS value is defined as the total number of POS reported during the evaluation period divided by the total number of applicable days during the evaluation period with this quotient multiplied by 28 days. The applicable days are the days in which the participant had non-missing seizure data (i.e., either 0 or \> 0 seizures recorded). Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.
Percent Change in the 28-day Total Partial Seizure Frequency (POS) From Week 0 (End of Baseline Phase) Through Week 18 (End of Maintenance Phase)
时间窗: Week 0 (end of Baseline Phase) through Week 18 (end of Maintenance Phase)
The efficacy of ezogabine/retigabine IR as an adjunctive treatment was to be evaluated by the percent change in the total partial seizure frequency, which was recorded by participants in the daily seizure calendar. The total 28-day POS rate is defined as the total number of POS reported during the evaluation period divided by the total number of applicable days during the evaluation period with this quotient multiplied by 28 days. The applicable days are the days in which the participant had non-missing seizure data (i.e., either 0 or \> 0 seizures recorded). Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.
次要结局
- Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in Hematocrit(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in Red Blood Cell (RBC) Count(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in Mean Corpuscle Hemoglobin(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in Albumin and Total Protein(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase, Lactate Dehydrogenase and Gamma Glutamyltransferase (GGT)(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Uric Acid and Creatinine(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Percent Change in 28-day Total Partial Seizure Frequency (POS) for the Indicated Intervals: Maintenance Phase and the Dose-Optimization Phase + Maintenance Phase(Week 3 (start of Dose -Optimization Phase) to Week 18 (end of Maintenance Phase))
- Incidence of New Seizure Types in Participants Without a History of These Seizure Types(Week 0 (end of Baseline Phase) to Week 21 (end of Taper Phase))
- Number of Participants at Each Dose During the Maintenance Phase and Average Maintenance Dose Over All Participants(Week 11 (start of Maintenance Phase) to Week 18 (end of Maintenance Phase))
- Number of Participants With Early Study Discontinuation(Week 0 (end of Baseline Phase) to Week 21 (end of Taper Phase))
- Number of Par. Experiencing >=50% Reduction in 28-day Total Partial Seizure Frequency (POS) for the Intervals: Double-blind Period (Titration Phase + Dose-Optimization Phase + Maintenance Phase), Maintenance Phase and Dose-Optimization + Maintenance Phase(Week 0 (end of Baseline Phase) through Week 18 (end of Maintenance Phase))
- Change From Baseline in the Number of Seizure Free Days for the Indicated Intervals: Double-blind Period (Titration Phase + Dose-Optimization Phase + Maintenance Phase), Maintenance Phase and the Dose-Optimization + Maintenance Phase(Week 0 (end of Baseline Phase) to Week 18 (end of Maintenance Phase))
- Percent Change From Baseline in Functional Status (Epilepsy-related Worry and Activity Limitation) and Productivity (Missed Work or School) to the End of the Dose-Optimization Phase and the End of the Maintenance Phase(Week 3 (start of Dose -Optimization Phase) to Week 18 (end of Maintenance Phase))
- Change From Baseline in Body Weight(Screening, Week 0 (end of Baseline Phase), Week 2 (end of Titration Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Number of Seizure Free Participants for the Indicated Intervals: Maintenance Phase and the Dose-Optimization Phase + Maintenance Phase(Week 3 (start of Dose-Optimization Phase) to Week 18 (end of Maintenance Phase))
- Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)(Screening, Week 0 (end of Baseline Phase), Week 2 (end of Titration Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in Heart Rate(Screening, Week 0 (end of Baseline Phase), Week 2 (end of Titration Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in the QT Interval Using Bazett's Correction (QTcB) and QT Interval Using Fridericia's Correction (QTcF)(Screening, Week 0 (end of Baseline Phase), Week 2 (end of Titration Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in the Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Segmented Neutrophils and Red Blood Cell (RBC) Distribution Width(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in the Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Segmented Neutrophils, White Blood Cell (WBC) Count and Platelet Count(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in Post-void Residual (PVR) Urinary Bladder Ultrasound Volume(Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase) and Week 18 (end of Maintenance Phase))
- Number of Participants With the Indicated Assessment Events of Suicidal Behavior, Suicidal Ideation or Non-suicidal Self Injurious Behavior Via the Columbia Suicide Severity Rating Scale (C-SSRS)(Week 0 (end of Baseline Phase), Week 2 (end of Titration Phase), Week 4, Week 6 and Week 8)
- Change From Baseline in Calcium, Chloride, Potassium, Sodium, Glucose, Magnesium, Phosphorus Inorganic, Bicarbonate and Urea/Blood Urea Nitrogen (BUN)(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in BUN/Creatinine Ratio(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in Creatinine Clearance(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in Urine Specific Gravity (USG)(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))
- Change From Baseline in Urine Potential of Hydrogen (pH)(Screening, Week 0 (end of Baseline Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase))