Epilepsy and Focal Cortical Dysplasia IIPhase 2NCT03198949

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

A Phase 2 study testing Afinitor (everolimus) in people with Epilepsy and Focal Cortical Dysplasia II, run by Yonsei University at 1 site in South Korea.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 4 to 40 years
Conditions the study is for: Epilepsy and Focal Cortical Dysplasia II
What is being tested?: Afinitor (everolimus)
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 23 participants
Where: 1 siteSouth Korea
Study dates: 24 May 2018to 11 Sep 2020
Phase: Phase 2
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 4 to 40 years
All sexes
No healthy volunteers
Child, Adult

Who may be able to join

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.

Who cannot join

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

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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.

Trial locations and contacts

1 site in 1 country.

South Korea1 site

Yonsei University Healthcare System, Severance Hospital
Seoul

Other trials in South Korea

About this study

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)

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.

Read the 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.

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.

Conditions: Epilepsy and Focal Cortical Dysplasia II
Being tested: Afinitor (everolimus)
Medical subject headings: Epilepsy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Afinitor (everolimus)Drug
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.)

Study groups in NCT03198949
Study group	Role	What they receive
everolimus first arm	Experimental	All subjects will receive everolimus during Core phase I and placebo during Core phase II. Receives: Drug: Afinitor (everolimus)
placebo first arm	Placebo comparator	All subjects will receive placebo during Core phase I and everolimus during Core phase II. Receives: Drug: Afinitor (everolimus)

What is being measured

The primary outcome is the main question the study is designed to answer.

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
Measured: Seizure frequency during the last 4 weeks of core phase

Secondary outcomes (8)

seizure-free days
To evaluate seizure-free days during double-blind treatment with adjunctive everolimus compared with placebo
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

24 May 201811 Sep 2020

First posted26 Jun 2017
Study start24 May 2018
Primary completion11 Sep 2020
Study completion11 Sep 2020

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Epilepsy and Focal Cortical Dysplasia IIStudies of the same condition, open and under way.
More trials run by Yonsei UniversityThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
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 blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 23 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03198949
Sponsor's protocol ID: 4-2017-0299
Status last verified: Apr 2021
First submitted: 13 Jun 2017
Last updated: 20 Apr 2021
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No

Publications

Kim SH, Kang HC, Roh YH, Hahn J, Min KL, Lee SJ, Yang D, Choi HS, Park S, Lee JH, Lee SG, Kim SH, Chang MJ, Kim HD. Efficacy and safety of everolimus for patients with focal cortical dysplasia type 2. Epilepsia Open. 2025 Feb;10(1):243-257. doi: 10.1002/epi4.13104. Epub 2024 Nov 28.
PubMed 39607729

Study at a glance

From the registry record, last updated by the sponsor on 20 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

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)
ClinicalTrials.gov ID: NCT03198949
Acronym / sponsor ID: 4-2017-0299
Conditions: Epilepsy and Focal Cortical Dysplasia II
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 23 participants (actual)
Lead sponsor: Yonsei UniversityUniversity, hospital or other
Study start: 24 May 2018 (actual)
Primary completion: 11 Sep 2020 (actual)
Study completion: 11 Sep 2020 (actual)
First posted: 26 Jun 2017 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

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.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2
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.

Arm	Type	Receives
everolimus first arm	Experimental	Drug: Afinitor (everolimus)All subjects will receive everolimus during Core phase I and placebo during Core phase II.
placebo first arm	Placebo comparator	Drug: Afinitor (everolimus)All subjects will receive placebo during Core phase I and everolimus during Core phase II.

Who may qualify

Ages: 4 to 40 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Child, Adult

Key inclusion criteria (8 listed)

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.

Key exclusion criteria (12 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
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.)	Drug	everolimus first arm, placebo first arm

Primary outcome

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

8 secondary outcomes

seizure-free days
Time frame: during last 4 weeks of core phase
reduction in seizure frequency
Time frame: during last 4 weeks of core phase
generalized tonic-clonic seizure-free days
Time frame: during last 4 weeks of core phase
reduction in generalized tonic-clonic seizure frequency
Time frame: during last 4 weeks of core phase
number of patients who experience generalized tonic-clonic seizure reduction of 50% or more
Time frame: during last 4 weeks of core phase
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
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
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

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 20 Apr 2021.
Derived from this study: PubMed 39607729Kim SH, Kang HC, Roh YH, Hahn J, Min KL, Lee SJ, Yang D, Choi HS, Park S, Lee JH, Lee SG, Kim SH, Chang MJ, Kim HD. Efficacy and safety of everolimus for patients with focal cortical dysplasia type 2. Epilepsia Open. 2025 Feb;10(1):243-257. doi: 10.1002/epi4.13104. Epub 2024 Nov 28.
Individual participant dataSharing planned: No

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Afinitor (everolimus) in people with Epilepsy and Focal Cortical Dysplasia II, run by Yonsei University at 1 site in South Korea.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 20 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The number of patients who experience seizure reduction of 50% or more (time frame: Seizure frequency during the last 4 weeks of core phase). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03198949, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Apr 2021.