E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Uncontrolled partial onset seizures or Lennox Gastaut Syndrome |
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E.1.1.1 | Medical condition in easily understood language |
Epilepsy that affects one part of the brain (partial onset seizures) which may or may not be followed by a seizure affecting all of the brain. Seizures that occur with Lennox-Gastaut syndrome. |
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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 | 10061334 |
E.1.2 | Term | Partial seizures |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 | 10048816 |
E.1.2 | Term | Lennox-Gastaut syndrome |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 long-term safety and tolerability of retigabine/ezogabine as adjunctive treatment in subjects with either partial onset seizures (12 to <18 years old) or Lennox-Gastaut Syndrome (12 to <30 years old) who have participated in a previous (“parent”) study. |
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E.2.2 | Secondary objectives of the trial |
To explore the long-term efficacy of retigabine/ezogabine as adjunctive treatment in subjects with either partial onset seizures (12 to <18 years old) or Lennox-Gastaut Syndrome (12 to <30 years old) who have participated in a previous (“parent”) study.
To evaluate the population pharmacokinetics of retigabine/ezogabine as adjunctive treatment in subjects with either partial onset seizures (12 to <18 years old) or Lennox-Gastaut Syndrome (12 to <30 years old) who have participated in a previous (“parent”) study. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. The subject has participated in either a Phase II or Phase III retigabine/ezogabine clinical trial evaluating partial onset seizures or seizures comprising Lennox-Gastaut syndrome and met the requirements defined in the parent study to transition into the
open-label extension study.
2. The investigator and caregiver consider it beneficial for the subject to receive retigabine/ezogabine.
3. Female subjects of child-bearing potential (after menarche) must either not be sexually active or must be practicing an acceptable method of contraception (documented in the medical chart) from two weeks prior to administration of study medication and for 28 days after completion or premature discontinuation from the study (see Appendix 2).
4. Subject is living with his/her custodial parent(s) or legal guardian(s) and has contact with them on a daily basis.
5. Written informed consent is obtained from the subjects parent/guardian and accompanying assent from subject. The subject, and/or his/her custodial parents(s) or legal guardian(s) have the ability to comprehend the key components of the informed
consent form. |
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E.4 | Principal exclusion criteria |
1. Has insufficient ability to articulate the presence or absence of urinary tract symptoms.
2. Has experienced an adverse event, clinically significant laboratory abnormality or was discontinued from the parent study due to a reason that in the investigator’s judgment would preclude enrollment to the study.
3. Has a urine sample with any of the following at the Eligibility Assessment Visit, confirmed by repeat sample:
- Urine specific gravity >1.035
- Urine pH <4.6 or >8.0
- ≥2+ proteinuria
- Casts or crystals (any type)
- >5 RBC/HPF, unrelated to menses (i.e. this criterion will not apply if sample taken within 5 days of menses, in female subjects that have experienced menarche). Note: The above criterion applies to urine samples analyzed by the central laboratory and not to urine dipstick testing.
4. Has a blood sample with any of the following at the Eligibility Assessment Visit, confirmed by repeat sample:
– BUN >21 mg/dl for 12 year old, or >25 mg/dl for >12 year old.
– Creatinine >1.03 mg/dl (F), or >1.3 mg/dl (M)
– Uric acid >7.5 mg/dl (F), or >8.5 mg/dl (M)
– Chloride >108 mEq/L
– Parameters for calcium, inorganic phosphorous or CO2 that are clinically significant as judged by the investigator.
5. Has presence of clinically significant hepatic laboratory values: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >2x upper limit of normal (ULN); alkaline phosphatase and bilirubin ≥1.5xULN (isolated bilirubin >1.5ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
6. Has presence of clinically significant cardiac arrhythmias.
7. Has any abnormality on 12-lead ECG at the Eligibility Assessment Visit which is clinically significant in the opinion of the investigator, or has a corrected QT interval (using either Bazett’s or Fridericia’s) >500msec ( >530 msec for subjects with Bundle Branch Block), uncorrected QT interval >600msec, or change from baseline
QTc >60msec. Note: If the ECG indicates a prolonged QTc interval outside these limits, two further ECGs should be performed and the average QTc value of these triplicate ECGs will be calculated. If the average value exceeds the stated limits, the subject is not eligible.
8. Has a history of one or more renal calculi.
9. Has disturbances of micturition or known urinary obstructions, including renal calculi, (incontinence concomitant with seizures is not considered a disturbance of micturition).
10. Has a documented anatomical stricture or other anatomical abnormality of the urinary tract system that has the potential to interfere with urinary flow.
11. Has experienced clinically significant urinary retention and/or required urinary catheterization in the preceding 6 months.
12. Has experienced 2 or more objectively documented urinary tract infections in the preceding 12 months.
13. Has a history of inadequate fluid intake and clinically significant dehydration in the preceding 6 months.
14. Within the preceding month, has taken anti-cholinergic medication on an ongoing basis.
15. 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 one lifetime suicide attempt.
16. Is planning surgery or implantation of a vagus nerve stimulator to control seizures during the study.
17. Is currently or has been abusing substance(s) or any medications in the 12 months prior to the Eligibility Assessment Visit.
18. Has taken an investigational drug (exception retigabine/ezogabine), or used an investigational device, within the previous 30 days prior to the Eligibility Assessment Visit or plans to take an investigational drug anytime during the study.
19. Females who are lactating or are pregnant (positive urine human chorionic gonadotropin (hCG) test at the Eligibility Assessment Visit).
20. Unwillingness or inability to follow the procedures outlined in the protocol.
21. The subject is felt, by the investigator, to be unsuitable (on the basis of health e.g. progressive neurological disease, severe psychiatric illness; compliance, caregiver availability, or for any other reason) for inclusion in the study.
22. Children in care |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Incidence of adverse events (AEs) and serious adverse events (SAEs).
• Incidence of AEs leading to withdrawal.
• Incidence of vital signs outside normal ranges and pre-determined clinically important ranges.
• Summary and change from baseline in vital signs (including blood pressure, heart rate) and height, weight, and body mass index.
• Summary and change from baseline of electrocardiogram (ECG) parameters.
• Summary of ECG assessment and interpretation of clinical significance based on investigator judgment.
• Change from baseline in hematology, chemistry and urinalysis parameters.
• Incidence of hematology, chemistry and urinalysis parameters outside normal ranges and pre-determined clinically important ranges.
• Change from baseline in bladder volume as assessed by the post-void residual (PVR) ultrasound.
• Changes from baseline in cognition, behavior and learning, as measured by the Leiter-R, Child Behavior Checklist, and Wide Range Assessment of Memory and Learning 2nd Edition, respectively. Note: Lennox-Gastaut Syndrome subjects will
be assessed for behavior and where mental disability is not prohibitive, for cognition and learning.
• Summary of sexual maturity over time based on the Tanner Stages of Puberty in subjects <18 years old.
• Time to withdrawal.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Overall and at selected time periods. |
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E.5.2 | Secondary end point(s) |
• Percent change from baseline in seizure frequency and percentage of responders (defined as >50% reduction from baseline in seizure frequency).
• Clinical Global Impression-Improvement (CGI-I) and Severity (CGIS).
• Summary of and change from baseline in child health status as measured by the Child Health Questionnaire in subjects <18 years old.
• During the first year of the study, pharmacokinetics (PK) blood samples will be collected at 1, 3, 6 and 12 months and from Year 2, every 4 months.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall and at selected time periods.
During the first year of the study, pharmacokinetics (PK) blood samples will be collected at 1, 3, 6 and 12 months and from Year 2, every 4 months.
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 |
Tolerability
Health Outcomes |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | No |
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 | No |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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The study will continue until i) retigabine/ezogabine is approved for the indications under study; ii) retigabine/ezogabine is not approved by regulatory authorities for the indications under study; or iii) termination of the study by the sponsor for reasons including, but not limited to safety issues. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 9 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |