E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
We will investigate possible cognitive benifits of early antiepileptic drug withdrawal after pediatric epilepsy surgery. The concerning medical condition is refractory epilepsy |
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E.1.1.1 | Medical condition in easily understood language |
We will be investigate early medication withdrawal after epilepsy surgery. The concerning medical condition is epilepsy that does not respond to medical treatment |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
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 assess whether early AED withdrawal improves cognitive function, in terms of attention, information processing- and psychomotor speed, memory, language and IQ/DQ scores. Attention will be the main outcome measure, on which the power calculation is based. We will assess attention and executive function using the EpiTrack Junior and calculate IQ/DQ scores. The other neuropsychological domains will be assessed by subtests of the intelligence tests. We will compare neuropsychological outcome between the two withdrawal groups at t1 (preoperatively), t2 (at 12 months) and t3 (at 24 months). This design will allow us to assess whether early AED withdrawal improves neuropsychological scores in the AED-free patients, compared to the group that is still on medication at the first postoperative time point. It will also enable the study of differences at a later follow-up time point, when both groups have completely discontinued medication.
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E.2.2 | Secondary objectives of the trial |
- To confirm safety, in terms of seizure recurrences, long term seizure freedom and cure, of early AED withdrawal. (Previous findings of this specific subgroup, show that timing intervals to start of withdrawal and to complete discontinuation of AEDs did not relate to seizure recurrences, neither to eventual seizure freedom or cure). Determined at 20 months following intended start of AED reduction (being theoretically “at risk” during an identical time window in both groups). - To compare behavioural problems between the two withdrawal groups, parents of participants will, at both neuropsychological test points, complete a Child Behavior Checklist (CBCL) - To compare quality of life between the two withdrawal groups. Patients will, at both neuropsychological test points, complete a Pediatric Quality of Life InventoryTM (PedsQL™) and the The Hague Side Effects Scale (HASES) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Younger than 16 years at surgery, with focal non-idiopathic epilepsy, with written informed consent of parents and children when older than 12 years old. • Native speaker in the language the neuropsychological tests have to be taken • Be able to perform the EpiTrack Junior preoperatively • Underwent intentional curative epilepsy surgery • After surgery, the treating physician considers withdrawal of AEDs, with the intention to completely discontinue medication, at whatever point in time. • Both the treating physician, the patient, if capable, and the parents agree with randomization in either arm of the study • Postoperative seizure freedom was achieved (with the exception of so called running down seizures not outlasting longer than two weeks)
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E.4 | Principal exclusion criteria |
• A contraindication to be randomized to either of the two withdrawal arms • The treating physician does not want to discontinue all AEDs within a maximum time frame of eight months as prescribed in the study protocol. • Multifocal MRI abnormalities, incomplete resection of the anatomical or epileptogenic lesion certified before randomisation (if considered necessary by the treating physician by MRI) and, if a postoperative EEG is performed before randomisation, epileptic EEG abnormalities (these being the most important risk factors of seizure recurrence or unfavourable long-term seizure outcome). • Use of more than 3 AEDs at time of surgery. The reason to choose for a maximum of 3 AEDs is that clinicians would not want to wait 12 months (the late withdrawal arm) to withdraw the first AED in patients that use so many AEDs. Furthermore, withdrawing AEDs within 8 months seems reasonable and feasible for a maximum of 3 AEDs. • Patients who are on a ketogenic diet or have a vagal nerve stimulator implanted. • If surgery is primarily intended as tumor surgery and not as epilepsy surgery
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E.5 End points |
E.5.1 | Primary end point(s) |
Improvement in neuropsychological outcome measures, defined as Attention and Executive function as tested with the EpiTrack Junior, compared between groups at the different assessments (1 and 2 years after surgery)(35)
Intelligence, expressed as IQ scores for children who are capable to undergo intelligence testing, and developmental quotient (DQ) scores, for those who undergo developmental index tests. IQ and DQ measures will also be compared between groups at the 3 assessments.
Other neuropychological domains, frequently suppressed by AEDs; language, memory, learning, and visuomotor coordination and speed, are compared between groups at the different assessments. Neuropsychological tests used to assess these neuropsychological domains are part of the routine clinical testing battery and depend on the age and intellectual capability of the child. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Neuropsychological testing will be performed preoperatively, 12 months after surgery and 24 months after surgery |
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E.5.2 | Secondary end point(s) |
To confirm safety of earlier AED withdrawal; we will assess eventual seizure freedom and “cure” as outcome measures at 20 months after start of reduction. (Engel class IA or ILAE 1 for at least 1 year). We will compare the number of seizure recurrences, and regain of seizure freedom rates, between both treatment arms. We expect the same number of seizure recurrences in both groups, but possibly occurring at different time points, depending on the timing of AED discontinuation.
To assess whether early AED withdrawal improves quality of life after epilepsy surgery, we will ask parents and if possible patients to complete a Pediatric Quality of Life InventoryTM (PedsQL™) and the The Hague Side Effects Scale (HASES) at 1 and 2 years after surgery.
To assess whether early AED withdrawal improves behavior after epilepsy surgery, we will ask parents to fulfill a Child Behavior Checklist (CBCL) at 12 months and 24 ymonths after surgery.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Patients will be followed up according to normal clinical protocol. In the case of seizure recurrence, parents will contact the hospital and the date of seizure recurrence will be noted. The patient will be advised about which medication to restart and will be followed closely therafter. Eventual seizure freedom will be defined 20 months after start of AED reduction in both treatment groups (For the early group after 24 months, for the late group after 32 months). Quality of life and behavioral assessments will be together with neuropsychological assessment at 12 months and 24 months after surgery. |
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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 | No |
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 |
Benefits for the patient, with respect to cognition as a result of earlier medication withdrawal |
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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) | 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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
The group of AEDs is the same however the timing of withdrawal of AEDs is later(standard treatment) |
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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
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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 | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 end of the trial will be when the last included patient has started AED reduction 20 months ago |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |