A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD
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|ClinicalTrials.gov Identifier: NCT02451696|
Recruitment Status : Recruiting
First Posted : May 22, 2015
Last Update Posted : July 12, 2018
The purpose of this study is to measure if the drug called Everolimus effects mTOR signaling (an electrical activity signal in the brain) in patients with Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD) with treatment resistant epilepsy (TRE) who will be undergoing brain surgery. One group of patients will be treated with Everolimus, and another will not. Researchers will determine if there is a difference in mTOR signaling between the patients who were treated with Everolimus and those who were not. Previous studies have suggested that Everolimus may reduce seizure activity in TSC patients by decreasing mTOR signaling. Since patients with FCD may also have excess mTOR signaling brain activity, Everolimus may also reduce seizure activity in these patients.
The drug Everolimus is approved by the Food and Drug Administration to treat specific types of breast, pancreatic, and kidney cancer, a kidney tumor called an angiomyolipoma (common in patients with TSC), and TSC patients who have a brain tumor called a subependymal giant cell astrocytoma (SEGA). However, in this research it is considered to be an investigational since it is not approved for reduction in mTOR signaling and a decrease in seizure frequency. Researchers believe that Everolimus may be useful in reducing something called cortical hyperexcitability, which is the excess brain activity that can contribute to seizures.
|Condition or disease||Intervention/treatment||Phase|
|Epilepsy Tuberous Sclerosis Complex Focal Cortical Dysplasia||Drug: Everolimus||Phase 2|
This is a single center open-label pilot clinical trial of patients with TRE, ages 1 to 40 years old, with TSC or FCD who are scheduled for epilepsy surgery. Patients will be treated with everolimus for 7 to 28 days prior to epilepsy surgery with extension of time from 7 to 28 days in successive cohorts of patients. The initial cohort of at least three patients will be treated for 7 days and after the safety of therapy is assured for this group, there will be an extension of the treatment to 14 days for at least three patients. This will be extended at one week intervals/three patient groups to a maximum treatment duration of 28 days. Resected brain tissue will be analyzed for activation of mTORC1 and mTORC2 signaling pathways, glutamatergic and GABA-ergic neurotransmission using histochemistry, genetic analysis, as well as extracellular field recordings in acute ex-vivo brain slices from surgery. A blood sample, collected at the time of surgery, will be analyzed for everolimus levels and VEGF-D. All patients will undergo standardized intra-operative ECoG recordings over the primary epileptogenic region and reviewed blindly.
Subjects will be in the study for 7-28 days. The investigators will study variables listed in specific aims 1 and 2 in TSC and FCD patients treated with 7 to 28 days of everolimus and compare these to untreated control patients with TRE and TSC or FCD. A concurrent comparison group of 12 subjects will also be enrolled. They will all be undergoing routine surgery for the diagnosis of TRE with TSC or FCD.
All study procedures will be performed at the Comprehensive Epilepsy Center (CEC) with the exception of the surgery, which will be performed at Tisch Hospital.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD|
|Study Start Date :||January 2014|
|Estimated Primary Completion Date :||June 2020|
|Estimated Study Completion Date :||June 2020|
Experimental: Treated Subjects
This group will be treated with everolimus 7-28 days prior to surgery
This study will measure if the drug called Everolimus effects mTOR signaling (an electrical activity signal in the brain) in patients with Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD) with treatment resistant epilepsy (TRE) who will be undergoing brain surgery. One group of patients will be treated with Everolimus, for 7-28 days prior to epilepsy surgery and another will not. We will determine if there is a difference in mTOR signaling between the patients who were treated with Everolimus and those who were not
Other Name: Trade Name: Afinitor®
No Intervention: Reference Subjects
This group will be enrolled as reference subjects, and will be undergoing routine surgery as part of standard of care treatment. No intervention will be provided to these subjects as part of the study.
- Number of patients with adverse events [ Time Frame: 6 weeks ].Adverse event monitoring should be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose of study treatment
- Number of participants with reduced mTOR signaling [ Time Frame: 28 days ]MTor signaling is measured by peripheral VEGF-D levels, Blood and brain levels of cytokines (and TNF-α) and inflammatory proteins (HMGB1)at the time of surgery, Brain glutamate and GABA receptor expression at the time of surgery, and Blood levels of everolimus at the time of surgery
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): NCT02451696
|Contact: Maria Hopkinsemail@example.com|
|Contact: Sherry Ann Santarina||646-558-0843||SherryAnn.Santarina@nyumc.org|
|United States, New York|
|New York University Langone Medical Center||Recruiting|
|New York, New York, United States, 10016|
|Contact: Maria Hopkins 646-558-0842 Maria.Hopkins@nyumc.org|
|Contact: Anjanette Burns 347-578-4066 firstname.lastname@example.org|
|Sub-Investigator: Howard Weiner, MD|
|Sub-Investigator: Maria Hopkins, RN|
|Sub-Investigator: Erin Conway, RN|
|Sub-Investigator: Spiros Manolatos|
|Principal Investigator:||Orrin Devinsky, MD||New York University School of Medicine|