| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Epilepsy, partial-onset seizures |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015037 |
| E.1.2 | Term | Epilepsy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To evaluate the efficacy of ezogabine/retigabine IR as an adjunctive treatment for POS in adults with epilepsy who have inadequate control of their seizures with a single AED. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate individualized dose selection or adjustment on the basis of tolerability and efficacy in a manner intended to simulate clinical practice.
• To evaluate the safety and tolerability of ezogabine/retigabine IR as an adjunctive treatment for POS in adults with epilepsy.
• To evaluate efficacy and safety in population subsets categorized by the primary mechanism of action of the background AED to which ezogabine/retigabine IR is added (sodium channel blockers or non-sodium channel blockers).
• To evaluate the effect of ezogabine/retigabine IR as adjunctive treatment on functional status (worry, activity limitations) and productivity. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult subjects ≥18 years of age.
2. Have given written informed consent, or has a legally authorized representative who has given written informed consent, prior to the performance of any study assessments.
3. Have a confident diagnosis of epilepsy for ≥6 months with POS, i.e., simple or complex POS with or without secondary generalization, prior to the Screening Visit.
4. Currently receiving monotherapy treatment with an 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.
5. Have an 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.
6. Are able and willing to maintain an accurate and complete daily written Seizure Calendar and Functional Status Diary at specified time points or has a caregiver who is able and willing to maintain an accurate and complete daily written Seizure Calendar for the entire duration of the study.
7. Are able to comply with dosing of study drug, background AED and all study procedures.
8. A female subject is eligible to enter and participate in the study if she is:
a. Of non-childbearing potential
• 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.
• Postmenopausal females defined as being amenorrheic for greater than 1 year with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms). However, if indicated, this should be confirmed by estradiol and follicle-stimulating hormone (FSH) levels consistent with menopause (according to local laboratory ranges). Women who have not been confirmed as post-menopausal should be advised to use contraception as outlined in Appendix 1 of the study protocol.
b. Of child-bearing potential, has a negative pregnancy test at Screening and Randomization (Week 0), and agrees to satisfy one of the requirements as listed in Appendix 1of the study protocol.
c. Not pregnant (confirmed by pregnancy test) or lactating (breastfeeding) or planning to become pregnant during the study. |
|
| E.4 | Principal exclusion criteria |
1. Have generalized epilepsy (e.g. Lennox-Gastaut, Juvenile Myoclonic epilepsy, Absence, etc.) or non-epileptic seizures.
2. Have had innumerable seizures within the 12-month
period prior to the Screening Visit where the individual seizures cannot be counted.
3. Have had status epilepticus within 12 months prior to screening.
4. Have a history of pseudo seizures, non-epileptic events or any other type of psychogenic seizures that could be confused with seizures.
5. 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.
6. 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.
7. Are using 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.
8. Are using herbal treatments with CNS activity within at least 1 month prior to the Screening Visit.
9. Have received ezogabine/retigabine in a previous study or have taken POTIGA or TROBALT™.
10. Are currently following or planning to follow the ketogenic diet.
11. Have an active Vagus Nerve Stimulator (VNS) to control seizures.
12. Are planning surgery to control seizures during the study.
13. Have impaired renal function as judged by a creatinine clearance of <50 mL/min.
14. Have a history of urinary retention or risk factors for urinary retention that in the investigator’s judgment could potentially affect subject safety.
15. 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.
16. 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%).
17. 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.
18. Have a history of malignancy within the past 2 years; with the exception of basal cell carcinoma.
19. 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].
20. Have 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, hepatic condition, or a condition that affects the absorption, distribution, metabolism or excretion of drugs.
21. 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.
22. Have a history of substance abuse (alcohol or drugs) or substance dependence within 12 months prior to screening.
23. Have a known hypersensitivity to any components of the study medication.
24. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the percent change in 28-day total partial-onset seizure frequency from the Baseline Phase to the Double-Blind Phase (Titration Phase, Dose-Optimization Phase and Maintenance Phase) in subjects randomly assigned to ezogabine/retigabine IR compared with placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary efficacy endpoint analysis will be based on data collected from subject-completed Seizure Calendars. Subjects’ daily-completed seizure calendars will be reviewed and collected at clinic visits. Following Visit 3 (baseline) subjects will attend a clinic visit every two weeks for 10 weeks, and then every 4 weeks for 8 weeks, and then a follow-up visit after 3 weeks of drug taper. |
|
| E.5.2 | Secondary end point(s) |
• Percent change in total partial seizure frequency per 28 days, for the following intervals: Maintenance Phase, Dose-Optimization + Maintenance Phase
• Proportion of responders experiencing a ≥50% reduction from baseline to the end of the period, in total partial seizure frequency per 28 days, for the following intervals: Double-Blind period, Maintenance Phase, Dose-Optimization + Maintenance Phase
• Proportion of seizure free subjects for the following intervals: Maintenance Phase, and the Dose-Optimization + Maintenance Phase
• Change from baseline in the number of seizure free days for the following intervals: Double-Blind period, Maintenance Phase, and the Dose-Optimization + Maintenance Phase.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary efficacy endpoints analyses will be based on data collected from subject-completed Seizure Calendars. Subjects’ daily-completed seizure calendars will be reviewed and collected at clinic visits. Following Visit 3 (baseline) subjects will attend a clinic visit every two weeks for 10 weeks, and then every 4 weeks for 8 weeks, and then a follow-up visit after 3 weeks of drug taper. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| placebo-controlled and dose-optimization. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 21 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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