A Study Investigating the Anti-epileptic Efficacy of Afinitor (Everolimus) in Patients With Refractory Seizures Who Have Focal Cortical Dysplasia Type II (FCD II)
Condition: Epilepsy and Focal Cortical Dysplasia II
MeSH terms: Seizures; Malformations of Cortical Development; Focal Cortical Dysplasia
Study type: Interventional
Phase: Phase 2

Summary: 
      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: 
      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.

        1. 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.

        2. 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)].

        3. 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.

        4. 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.
    

Intervention name(s): Afinitor (everolimus)
Intervention type(s): Drug
Intervention description(s): 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.)
Intervention MeSH terms: Everolimus
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment