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

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ClinicalTrials.gov Identifier: NCT03198949
Recruitment Status : Recruiting
First Posted : June 26, 2017
Last Update Posted : April 10, 2019
Sponsor:
Information provided by (Responsible Party):
Yonsei University

Brief 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.


Condition or disease Intervention/treatment Phase
Epilepsy and Focal Cortical Dysplasia II Drug: Afinitor (everolimus) Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
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)
Masking Description: During baseline phase and core phase, double-blind is maintained. Only one independent investigator who check trough drug level of everolimus and and one pharmacist who dispenes IND will be exposed. All the rest of the researchers will be masked.
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : May 24, 2018
Estimated Primary Completion Date : April 30, 2020
Estimated Study Completion Date : April 30, 2020


Arm Intervention/treatment
Experimental: everolimus first arm
All subjects will receive everolimus during Core phase I and placebo during Core phase II.
Drug: Afinitor (everolimus)

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.)


Placebo Comparator: placebo first arm
All subjects will receive placebo during Core phase I and everolimus during Core phase II.
Drug: Afinitor (everolimus)

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.)





Primary Outcome Measures :
  1. The number of patients who experience seizure reduction of 50% or more [ Time Frame: Seizure frequency during the last 4 weeks of core phase ]
    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


Secondary Outcome Measures :
  1. seizure-free days [ Time Frame: during last 4 weeks of core phase ]
    To evaluate seizure-free days during double-blind treatment with adjunctive everolimus compared with placebo

  2. reduction in seizure frequency [ Time Frame: during last 4 weeks of core phase ]
    To compare the reduction in seizure frequency on trough range (5-15 ng/mL) of everolimus versus placebo in patients with FCD II

  3. generalized tonic-clonic seizure-free days [ Time Frame: during last 4 weeks of core phase ]
    To evaluate generalized tonic-clonic seizure-free days during double-blind treatment with adjunctive everolimus compared with placebo

  4. reduction in generalized tonic-clonic seizure frequency [ Time Frame: during last 4 weeks of core phase ]
    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

  5. number of patients who experience generalized tonic-clonic seizure reduction of 50% or more [ Time Frame: during last 4 weeks of core phase ]
    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

  6. level of everolimus in cerebrospinal fluid (CSF) (ng/mL) [ Time Frame: One time measurement of everolimus level in CSF (ng/mL) will be performed after 52 weeks ]
    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.

  7. level of everolimus in blood (ng/mL) [ Time Frame: 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 ]
    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.

  8. adverse events related to everolimus use [ Time Frame: 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 ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03198949


Contacts
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Contact: Heung Dong Kim, MD, PhD +82 2 2228 2061 HDKIMMD@yuhs.ac

Locations
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Korea, Republic of
Yonsei University Healthcare System, Severance Hospital Recruiting
Seoul, Korea, Republic of
Contact: Heung Dong Kim, MD    +82 2 2228 2061    HDKIMMD@yuhs.ac   
Sponsors and Collaborators
Yonsei University

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Responsible Party: Yonsei University
ClinicalTrials.gov Identifier: NCT03198949    
Other Study ID Numbers: 4-2017-0299
First Posted: June 26, 2017    Key Record Dates
Last Update Posted: April 10, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Seizures
Malformations of Cortical Development
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Nervous System Malformations
Congenital Abnormalities
Sirolimus
Everolimus
Anticonvulsants
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents