| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| KCNQ2 Developmental and Epileptic Encephalopathy |
|
| E.1.1.1 | Medical condition in easily understood language |
| KCNQ2 Developmental and Epileptic Encephalopathy |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10077380 |
| E.1.2 | Term | Epileptic encephalopathy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of XEN496 as adjunctive therapy in reducing seizure frequency compared to placebo in pediatric subjects with KCNQ2-DEE |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the proportion of pediatric subjects with KCNQ2-DEE who achieve a ≥50% reduction from baseline in seizure frequency when taking XEN496, compared with placebo.
• To evaluate Caregiver Global Impression of of Change (CaGI-C) and Caregiver Global Impression of Severity (CaGI-S) scores in pediatric subjects with KCNQ2-DEE taking XEN496, compared with placebo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Parent(s) or guardian(s) fully comprehends the nature and risks of the study and is able and willing to give informed consent in writing, prior to the subject entering the study, in accordance with local legal requirements.
2. Male or female subjects aged from 1 month (44 weeks postmenstrual age) to less than 6 years, with a body weight of ≥3.0 kg, at screening (Visit 1).
3. Documented evidence of a genetic test result from an appropriately accredited laboratory, consistent with a diagnosis of KCNQ2-DEE (pathogenic, likely pathogenic, variant of unknown significance, or inconclusive but unlikely to support an alternate diagnosis).
4. Seizure onset within 2 weeks after birth and EEG and documented clinical history consistent with KCNQ2-DEE.
5. Magnetic resonance imaging (MRI) has been performed and is without evidence of structural abnormalities, including but not limited to, hypoxia, hypoxia-ischemia, ischemia (arterial or venous), stroke, sinovenous thrombosis, intracranial hemorrhage, or focal or global brain malformation. Brain MRI changes that are described as being associated with the KCNQ2-DEE and presumed to be secondary to the disease itself, will not be exclusionary.
6. Must have had ≥4 focal tonic or other countable motor seizures in the month (28 days) prior to screening, documented by caregiver report or investigator medical notes.
7. Subjects will be taking 1 and no more than the maximum required number concomitant ASMs. All doses must be stable for the required duration prior to screening and expected to be maintained throughout the duration of the study (until the end of the treatment period).
8. VNS is allowed and will not be counted as a concomitant ASM. The VNS device must be implanted for at least 6 months before before screening, and the device settings must be stable for the required duration prior to screening and throughout the duration of the study. Use of the VNS device magnet is allowed.
9. Ketogenic diet is allowed and will not be counted as a concomitant ASM. The subject must be on a stable dietary regimen that produces ketosis for the required period of time prior to screening, and is expected to maintain the regimen throughout the study.
10. In the opinion of the investigator, the caregiver is able and willing to maintain an accurate and complete daily diary to monitor seizures, diaper count (when required) and administration of study drug and concomitant medications. |
|
| E.4 | Principal exclusion criteria |
1. Presence of a pathogenic or likely pathogenic variant in an additional gene associated with other epilepsy syndromes. (Variants in other epilepsy-associated genes that are not known to be pathogenic or are not likely to be pathogenic based upon adjudication review will not be a basis for exclusion.)
2. Presence of a known gain-of-function variant in the KCNQ2 gene, or clinical characteristics consistent with previously reported pathogenic gain-of-function variants in the KCNQ2 gene, such as subjects with infantile spasms without a history of neonatal-onset seizures.
3. Seizures secondary to infection, neoplasia, demyelinating disease, degenerative neurological disease, or CNS disease deemed progressive, metabolic illness, or progressive degenerative disease.
4. Confirmed diagnosis of infantile spasms within the past month prior to screening.
5. History or presence of any significant medical or surgical condition or uncontrolled medical illness at screening including, but not limited to, cardiovascular, gastrointestinal, hematologic, hepatic, ocular, pulmonary, renal, or urogenital systems, or other conditions that would not justify the subject’s participation in the study, as determined by the investigator’s benefit-risk assessment.
6. QT interval corrected for heart rate by Fridericia’s formula (QTcF) of >440 msec. In addition, subjects with a history of arrhythmia, prolonged QT, heart disease or subjects taking medications known to increase the QT interval.
7. History of hyperbilirubinemia, which lasts longer than 1 week will require exclusion of hepatic disease before entering the study.
8. History of bilirubin-induced neurological dysfunction.
9. Current disturbance of micturition or known urinary obstructions or history of bladder or urinary dysfunction including abnormal post-void residual bladder ultrasound, vesicoureteral reflux, urinary retention, or required urinary catheterization in the preceding 6 months.
10. Subjects who are known to have a terminal illness.
11. Any clinically significant laboratory abnormalities or clinically significant abnormalities on pre-study physical examination, vital signs, or ECG that in the judgment of the investigator indicates a medical problem that would preclude study participation.
12. Subjects who are planned to begin to follow a ketogenic or other specialized dietary therapy during the study.
13. Caregiver history of chronic noncompliance with their child’s prescribed drug regimens that has not been corrected.
14. Exposure to any other investigational drug or device within 5 half-lives or 30 days prior to screening (Visit 1), whichever is longer or plans to participate in another drug or device trial at any time during the study.
15. Concurrent enrollment in any other type of medical research judged by the investigator not to be scientifically or medically compatible with this study.
16. Subjects using felbamate who have presented with clinically significant abnormalities and/or hepatic dysfunction during felbamate treatment, and subjects who have taken felbamate for less than 6 months prior to screening
17. Subjects who are currently taking adrenocorticotropic hormone.
18. Subjects who did not tolerate ezogabine when taken previously.
19. Subjects with a known hypersensitivity to ezogabine or any of the excipients in the study drug. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change from baseline in monthly (28 day) countable motor seizure frequency during the blinded treatment period, as recorded by caregivers in a daily seizure diary. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The baseline average frequency (per 28 days) will use seizures counted during the baseline period, consist of all evaluable data up to 6 weeks prior to the date of 1st study drug date. The double-blind treatment period will start from the 1st study drug date through Visit 22 (end of treatment study visit), or double-blind treatment termination date, whichever is earlier. Also, seizure data collected after the change in background antiseizure medication (ASM) will be excluded as well. |
|
| E.5.2 | Secondary end point(s) |
• Proportion of subjects with ≥50% reduction in monthly (28 day) seizure frequency from baseline.
• Caregiver Global Impression of Changescores (CaGI-C) for the subject’s overall condition and for seizures.
• Change from baseline in Caregiver Global Impression of Severity (CaGI-S) for the subject’s overall condition and for seizures. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• The key secondary efficacy endpoint is the proportion of subjects with ≥50% reduction in seizure frequency from baseline, derived based on the primary endpoint of percent change from baseline in monthly seizure frequency. The analysis will also be performed based on data in maintenance period only.
• The CaGI-C will be summarized at each of the post-baseline visit.
• The CaGI-S for overall condition and seizure severity will be summarized by treatment group at baseline and each of the post-baseline visit, by assessing the number and percent of patients who changed from baseline to each of the post-baseline categories. |
|
| 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 | Yes |
| 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 | 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 | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Australia |
| Canada |
| United States |
| France |
| Spain |
| Italy |
| Belgium |
|
| 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
|
| The end of the study is defined as completion of the last visit for the last subject in this study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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