A Phase 2 interventional study of Everolimus in Epilepsy, Tuberous Sclerosis Complex and Focal Cortical Dysplasia, sponsored by NYU Langone Health. Completed at 1 site in United States. Open to participants aged 2 Years to 40 Years. Per ClinicalTrials.gov, last updated 2021-09-01.
Sponsored by NYU Langone Health · Phase 2, Interventional, and Treatment
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.
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.
109 studies on the registry are indexed under Tuberous Sclerosis; 27 are open to participants now.
This study's enrollment of 15 is below the median of 50 across 70 interventional studies indexed under Tuberous Sclerosis.
Browse Tuberous Sclerosis studies →NYU Langone Health is the lead sponsor of 1,391 studies on the registry; 254 are open to participants now.
Of its 227 completed or terminated interventional studies of FDA-regulated products, 191 (84%) have results posted.
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Exclusion Criteria
This group will be treated with everolimus 7-28 days prior to surgery
Drug: Everolimus
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.
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
Also known as: Trade Name: Afinitor®
Number of Patients With Adverse Events
.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
Time frame: 6 weeks
Blood Everolimus Levels
mTOR signaling in blood
Time frame: 28 days
Blood Total VEGF Levels (Not Only VEGF-D)
Time frame: 28 days
mTOR Brain Tissue-S6 Phosphate by Western Blot
Time frame: 28 days
HMGB1 Expression in Brain Tissue
HMGB1 expression is measured through label-free quantification (LFQ). LFQ is a method in mass spectroscopy that determines the relative amount of proteins in biological samples. The unit of measure is LFQ intensity; a higher LFQ intensity indicates greater HMGB1 expression.
Time frame: 28 days
| Milestone | Treated Subjects | Reference Subjects |
|---|---|---|
| Started | 5 | 10 |
| Completed | 4 | 10 |
| Not completed | 1 | 0 |
| Withdrew: Surgery postponed | 1 | 0 |
.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
| Participants | Treated Subjects | Reference Subjects |
|---|---|---|
| Number of Patients With Adverse Events | 0 | 0 |
mTOR signaling in blood
| ng/ml | Treated Subjects | Reference Subjects |
|---|---|---|
| Blood Everolimus Levels | 12.35 ± 5.36 | 2 ± 0 |
| pg/ml | Treated Subjects | Reference Subjects |
|---|---|---|
| Blood Total VEGF Levels (Not Only VEGF-D) | 56.5 ± 46.9 | 50.85 ± 54.1 |
| normalized val-protein relative to actin | Treated Subjects | Reference Subjects |
|---|---|---|
| mTOR Brain Tissue-S6 Phosphate by Western Blot | 0.49 ± 0.54 | 0.81 ± 0.22 |
HMGB1 expression is measured through label-free quantification (LFQ). LFQ is a method in mass spectroscopy that determines the relative amount of proteins in biological samples. The unit of measure is LFQ intensity; a higher LFQ intensity indicates greater HMGB1 expression.
| LFQ intensity | Treated Subjects | Reference Subjects |
|---|---|---|
| HMGB1 Expression in Brain Tissue | 14.85 ± 0.6 | 15.06 ± 0.35 |
Collected over 30 days. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Treated Subject | 0/4 (0%) | 0/4 (0%) | 0/4 (0%) |
| Reference Subject | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) |
| Age, Continuous(years) | Treated Subjects | Reference Subjects | Total |
|---|---|---|---|
| Mean | 18.25 ± 10.1 | 13.1 ± 12.3 | 14.6 ± 11.6 |
| Sex: Female, Male(Participants) | Treated Subjects | Reference Subjects | Total |
|---|---|---|---|
| Female | 3 | 6 | 9 |
| Male | 1 | 4 | 5 |
| Race (NIH/OMB)(Participants) | Treated Subjects | Reference Subjects | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 0 | 0 | 0 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 4 | 10 | 14 |
| Region of Enrollment(participants) | Treated Subjects | Reference Subjects | Total |
|---|---|---|---|
| United States | 4 | 10 | 14 |
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