| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Epilepsy - partial-onset seizures with or without secondary generalisation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Epilepsy with 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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065336 |
| E.1.2 | Term | Partial 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 retigabine immediate release (IR) as adjunctive therapy to each of the following specified monotherapy AED treatments: carbamazepine/ oxcarbazepine, lamotrigine, levetiracetam or valproic acid in subjects with partial-onset seizures (POS) using a flexible dosing regimen. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the:
- Efficacy of retigabine (RTG) IR adjunctive therapy (AT) to the pooled set of specified AED treatments using a flexible dosing regimen (FDR).
- Safety & tolerability (S&T) of RTG IR AT to each of the following specified monotherapy (SM) AED treatments:carbamazepine/ oxcarbazepine, lamotrigine, levetiracetam or valproic acid using a FDR.
- S&T of RTG IR AT to the pooled set of specified AED treatments using a FDR.
- Effect (E) RTG IR AT to each of the SM AED treatments on functional status (worry,activity limitations) productivity & quality of life using a FDR.
- E RTG IR as AT to the pooled set of specified AED treatments on functional status (worry,activity limitations), productivity & quality of life using a FDR.
- E of RTG IR as AT to each of the SM AED treatments on patient impression (PI) of change in worry & activity limitations (w&a lim) using a FDR.
- E of RTG IR as AT to the pooled set of specified AED treatments on PI of change in w&a lim using a FDR. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for enrolment in the study, a subject must meet all of the following criteria:
1. Is greater than or equal to 18 years of age (men or women).
2. Has a confident diagnosis of epilepsy with partial-onset seizures i.e., simple or complex partial seizures with or without secondary generalisation (International League Against Epilepsy (ILAE) classification; 1981) for more than 24 weeks prior to the Baseline phase.
3. Has experienced at least 4 partial-onset seizures (i.e., simple or complex partial seizures with or without secondary generalization) during an 8-week (i.e., 56 days)
prospective Baseline Phase with at least one partial seizure occurring during each 4-
week (i.e., 28-day) period.
NOTE: With prior authorisation from the Sponsor, a maximum of 4 weeks (i.e., 28 days) of retrospective seizure data may replace up to the first 4 weeks (i.e., first 28 days) of the prospective Baseline Phase for subjects providing reliable documentation of the following (see Section 11, Appendix 3 or protocol):
• A complete daily seizure diary that includes the number, and type (i.e., simple or complex partial seizures with or without secondary generalisation), of seizures experienced each day for up to 28 consecutive days immediately prior to the prospective Baseline Phase.
• Stability of prescribed dosage of specified background AED
• Compliance with background AED
All subjects permitted to use retrospective seizure data must complete a minimum of 4 weeks (i.e., 28 days) of the prospective Baseline Phase. The retrospective Baseline Phase and prospective Baseline Phase must equal 56 consecutive days.
4. Is currently receiving a stable dose of one of the following AEDs:
carbamazepine/oxcarbazepine, lamotrigine, levetiracetam or valproic acid. The AED dose must be stable 4 weeks prior to start of collection of baseline seizure data (retrospective or prospective) and during the Baseline period.
NOTE: 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 (see Section 5.5.1.2 of protocol).
5. Is able and willing to maintain an accurate and complete daily written seizure calendar and functional status diary or has a caregiver who is able and willing to maintain an accurate and complete daily written calendar/diary for the entire duration of the study.
6. Is able to comply with dosing of study drug, background AED and all study procedures.
7. 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.
8. A female subject is eligible to enter and participate in the study if she is of:
a. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchal or post-menopausal)
• Pre-menopausal females with a documented (medical report verification) hysterectomy and/or bilateral oophorectomy only when reproductive status has been confirmed by hormone level assessment.
• Post-menopausal females defined as being amenorrhoeic for greater than one year with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms). However, if indicated, this should be confirmed by estradiol and 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 Section 11,Appendix 4 or protocol.
b. Child-bearing potential, has a negative pregnancy test at Screening, and agrees to satisfy one of the contraception methods as listed in Section 11, Appendix 4.
c. Is not pregnant or lactating or planning to become pregnant during the study.
9. French subjects only: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
|
|
| E.4 | Principal exclusion criteria |
A subject meeting any of the following criteria must not be enrolled in the study:
1. Has a current diagnosis of generalised epilepsy (e.g. Lennox-Gastaut, Juvenile Myoclonic etc.)
2. Has had status epilepticus (other than simple partial status epilepticus) within the 24 weeks prior to Baseline Visit.
3. Has participated in a previous retigabine study (subjects with documented evidence of having received placebo will be eligible).
4. Is currently or has been abusing substance(s) or other medications in the 12 months prior to Baseline visit.
5. Has 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.
6. Is currently following or planning to follow the ketogenic diet.
7. Has been treated with vigabatrin within the past 6 months prior to collection of baseline seizure data; if a subject has been previously treated with vigabatrin, a visual perimetry test after discontinuation of vigabatrin must show no visual field constriction that has been seen in some subjects taking vigabatrin.
8. Is planning surgery or implantation of Vagus Nerve Stimulator (VNS) to control seizures during the study. NOTE: Subjects with surgically implanted Vagus Nerve Stimulator (VNS) which is not functioning or has been switched off for at least 4 weeks prior to the start of collection of baseline seizure data (retrospective or prospective) and remains non-functioning/off for the duration of the study will be eligible for the study.
9. Is 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.
10. Has 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.
11. Has a QTc (either QTcB Bazett’s correction or QTcF Fridericia’s correction) greater than or equal to 450 millisecond (msec) or greater than or equal to 480msec for subjects with Bundle Branch Block at the time of screening as calculated below. Note: If the initial ECG at screening indicates a QTc interval outside these limits, two further ECGs should be performed and the average QTc value of these triplicate ECGs calculated. If the average value exceeds the stated limits, the subject is not eligible.
12. Has active suicidal plan/intent or has had active suicidal thoughts in the past 6 months. Has history of suicide attempt in the last 2 years or more than 1 lifetime suicide attempt.
13. French Subjects: the French subject has participated in any study using an investigational drug during the previous 30 days or 5 half-lives (whichever is longer). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects experiencing a greater than or equal to 50% reduction in 28-day partial-onset seizure frequency from Baseline during the combined Titration and Flexible Dose Evaluation Phases categorised by concurrent AED. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Start of week 1 to end of week 20 |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include:
-Proportion of subjects experiencing a ≥ 50% reduction in 28-day partial seizure frequency from Baseline during the combined Titration and Flexible Dose Evaluation Phase by all AED treatments combined.
-Proportion of subjects with ≥25%, ≥75%, or 100% reduction in 28-day partial seizure frequency during the combined Titration and Flexible Dose Evaluation Phase by concurrent AED and all AED treatments combined.
-Percent change from Baseline in 28-day partial seizure frequency during the combined Titration phase and Flexible Dose Evaluation Phase by concurrent AED and all AED treatments combined.
Safety and tolerability end points include:
-Type and incidence of adverse events.
-Time to premature study discontinuation.
-Change from Baseline in vital signs (blood pressure and heart rate), body weight and ECGs.
-Change from Baseline in haematology, biochemistry and urinalysis tests.
-Assessment of suicidality via Columbia Suicide Severity Rating Scale (C-SSRS).
-Change from baseline in American Urological Association Symptom Scale (AUA SS) and Post Void Residual (PVR) bladder ultrasound.
-Investigator’s assessment of subject’s optimal dose of RTG IR at V7.
Health Outcome enpoints include:
-Percentage change from Baseline in functional status (worry, activity
limitations) and productivity (missed work/school) during the combined
Titration and Flexible Dose Evaluation Phases by concurrent AED and all AEDtreatments combined.
-Patient Global Impression of Change (PGI-C) assessment of worry and activity limitations by concurrent AED and all AED treatments combined at visit 7.
-Percent change from Baseline to V7 visit in total and domain scores in theSF-36v2 (acute) by concurrent AED and all AED treatments combined. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Start of week 1 to end of week 20 |
|
| 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 | No |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| multi-centre, flexible dose |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| No comparator - Adjunctive therapy to specified monotherpay AED treatments using flexible dosing |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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
|
The end of trial will be at the end of the 16-week Flexible Dose Evaluation phase.
Subjects who complete the 16-week Flexible Dose Evaluation Phase will have the option to enter an OLE study. There will be a 3 week Taper/Follow-Up Phase for those subjects who decide not to enter the open-label extension study. |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 2 |
| 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 | 2 |
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