A Study Investigating the Anti-epileptic Efficacy of Afinitor (Everolimus) in Patients With Refractory Seizures Who Have Focal Cortical Dysplasia Type II (FCD II)

Study Overview
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Brief Summary
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This is a prospective, randomized, double-blind, placebo-controlled cross over study designed to evaluate the efficacy and safety of everolimus (trough 5-15 ng/mL) given as adjunctive therapy in patients with focal cortical dysplasia type II who already failed more than two antiepileptic drugs and surgery. This study will assess the impact of everolimus to placebo on seizure frequency in focal cortical dysplasia type II. The number of patients who experience seizure reduction of 50% or more will be counted during last 4 weeks of each core phase.

Detailed Description
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This is a prospective, randomized, double-blind, placebo-controlled cross over study to evaluate the efficacy and safety of everolimus (trough 5-15 ng/mL) given as adjunctive therapy in patients with FCDII who already failed more than 2 antiepileptic drugs and surgery. Baseline phase (4 weeks, week -4 -1): From Screening Visit (Week -4, V1) to starting titration visit at Week -1 (V2). For baseline seizure frequency calculations, the 4-week prospective period seizure counts will be totaled. Antiepileptic drug use will be assessed, and patients are required to be on a stable dose of AEDs. All patients who meet eligibility criteria will be randomized in a 1:1 ratio to treatment first arm and placebo first arm. Core phase I (12 weeks, week 0 11) 2.1.Titration I period (4 weeks, week 0 3): Everolimus doses will be 4.5mg/m2 po daily given at first time and then during the 4-week titration period everolimus dose may get adjusted to reach trough concentration of 5 - 15 ng/mL. At week 2 (V3), 3 (V4) pre-dose PK blood samples will be taken for potential dose adjustments. 2.2. Maintenance I period (8 weeks, week 4 11): After the completion of the titration period, the vast majority of patients are expected to continue at their current dose level during the entire 8 week maintenance period. However, the possibility of further titration does still exist, based on the planned pre-dose PK blood samples that will be collected every 4 weeks [week 4(V5) and 8(V6)]. Core phase II (12 weeks, week 12 23): After the completion of the core phase I, the everolimus first group will be changed to the placebo and the placebo first group will take everolimus. Dose titration method is same with core phase I. Unblinded extension phase (29 weeks, week 24-52): After approval, all enrolled patients will be offered the opportunity to enter the unblinded extension phase of the study at the end of week 23 and continue everolimus. Everolimus will be provided to every study patient during the extension phase of 29 weeks. During the extension phase Everolimus doses will be titrated based on pre-dose PK blood samples at week 24 (V12), 28 (V13), 40 (V14), seizure frequency and everolimus tolerability. At week 52 (V15), the final analysis which include serum and CSF PK studies will be performed.

Official Title
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A Prospective, Randomized, Double-blind, Placebo-controlled Cross Over Study Investigating the Anti-epileptic Efficacy of Afinitor (Everolimus) in Patients With Refractory Seizures Who Have Focal Cortical Dysplasia Type II (FCD II)

Conditions
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Epilepsy and Focal Cortical Dysplasia II

Intervention / Treatment
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* Drug: Afinitor (everolimus)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between the ages of 4 and 40 Pathologically confirmed Focal Cortical Dysplasia type II (FCDII) Refractory seizure in spite of at least 2 antiepileptic drugs (AEDs) and surgery Subjects must have experienced at least 3 seizure events per month for two months retrospectively among 3 months prior to the baseline period in spite of using 1 AED or more. Must be at least one antiepileptic drug at a stable dose for at least 4 weeks at the start of the 4-week prospective baseline phase, remain on the same regimen throughout the baseline phase. VNS and ketogenic diet are allowed. If the patient is using VNS, device stimulator parameters must remain constant throughout the baseline phase. If the patient is on ketogenic diet, the ratio of the diet must remain constant throughout the baseline phase. At least 3 seizures throughout the baseline phase. Subjects and their legal guardians must have the ability to comprehend the informed consent form and be willing to provide informed consent. For subjects who are too young or unable to comprehend the written consent, a legal guardian who is able to describe and provide an understanding of the informed consent to the subject must sign the consent form on behalf of the subject. Exclusion Criteria: Patients who need hospitalization due to causes not related to FCDII or epilepsy Patients who are pregnant or planning on becoming pregnant Patients with seizures secondary to causes other than focal cortical dysplasia Immunocompromised patients Patients who have received prior treatment with a systemic mTOR inhibitor Patients who do not follow up last one year Patients who do not show EEG abnormalities Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable Patients with positive HBV Ag Patients who receive live vaccination during baseline study Patients with a known hypersensitivity to everolimus or other rapamycin-analogues(sirolimus, temsirolimus) or to its excipients Patients who have galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, or other genetic problems related to lactose digestion.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a prospective, randomized, double-blind, placebo-controlled cross over study to evaluate the efficacy and safety of everolimus (trough 5-15 ng/mL) given as adjunctive therapy in patients with FCDII who already failed more than 2 antiepileptic drugs and surgery.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: everolimus first arm<br>All subjects will receive everolimus during Core phase I and placebo during Core phase II. | Drug: Afinitor (everolimus)<br>* Everolimus doses will be 4.5mg/m2 po daily given at first time and then during the 4-week titration period everolimus dose may get adjusted to reach trough concentration of 5 - 15 ng/mL. (In order to keep the blind, placebo doses will be also adjusted during core phase based on a random scheme of dose changes.)<br>|
| Placebo Comparator: placebo first arm<br>All subjects will receive placebo during Core phase I and everolimus during Core phase II. | Drug: Afinitor (everolimus)<br>* Everolimus doses will be 4.5mg/m2 po daily given at first time and then during the 4-week titration period everolimus dose may get adjusted to reach trough concentration of 5 - 15 ng/mL. (In order to keep the blind, placebo doses will be also adjusted during core phase based on a random scheme of dose changes.)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of patients who experience seizure reduction of 50% or more | During last 4 weeks of core phase, to compare the number of patients who experience seizure reduction of 50% or more on trough range (5-15 ng/mL) of everolimus versus placebo in FCD II with drug-resistant epilepsy | Seizure frequency during the last 4 weeks of core phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| seizure-free days | To evaluate seizure-free days during double-blind treatment with adjunctive everolimus compared with placebo | during last 4 weeks of core phase | 
| reduction in seizure frequency | To compare the reduction in seizure frequency on trough range (5-15 ng/mL) of everolimus versus placebo in patients with FCD II | during last 4 weeks of core phase | 
| generalized tonic-clonic seizure-free days | To evaluate generalized tonic-clonic seizure-free days during double-blind treatment with adjunctive everolimus compared with placebo | during last 4 weeks of core phase | 
| reduction in generalized tonic-clonic seizure frequency | To compare the reduction in generalized tonic-clonic seizure frequency on trough range (5-15 ng/mL) of everolimus versus placebo in patients with FCD II | during last 4 weeks of core phase | 
| number of patients who experience generalized tonic-clonic seizure reduction of 50% or more | To compare the number of patients who experience generalized tonic-clonic seizure reduction of 50% or more on trough range (5-15 ng/mL) of everolimus versus placebo in FCD II | during last 4 weeks of core phase | 
| level of everolimus in cerebrospinal fluid (CSF) (ng/mL) | Measure level of everolimus in cerebrospinal fluid (CSF) (ng/mL) and compare the value with level of everolimus in blood (ng/mL) in relation to the percentage of seizure reduction in patients who agree to perform CSF analysis additionally. We hypothesize that some patients with target blood everolimus level would not respond to everolimus because CSF everolimus level does not proportionally increase. We aim to find differences in CSF everolimus levels between patients who respond well and patients who respond poorly. | One time measurement of everolimus level in CSF (ng/mL) will be performed after 52 weeks | 
| level of everolimus in blood (ng/mL) | To measure the level of everolimus in blood (ng/mL) in relation to the percentage of seizure reduction. We hypothesize that some patients would not respond to everolimus because everolimus level does not proportionally increase with increased intake of everolimus. | measurement of everolimus level in blood (ng/mL) will be performed at week 0, 2, 3, 4, 8, 12, 14, 15, 16, 20, 24, 28, 40, and 52 | 
| adverse events related to everolimus use | Every adverse event which occurs during the study will be collected. CTCAE 4.03 guideline will be used. Number of patients who discontinue using everolimus will be collected and the number will be compared to the number of patients who discontinue placebo during the same period. Reasons of early withdrawal will be collected. | Every week during core phase through regular study visits or call visits from week 0 to week 24. At 28, 40, and 52 during extension phase |