A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD

• ClinicalTrials.gov Identifier: NCT02451696
• Recruitment Status: Completed
• First Posted: May 22, 2015
• Results First Posted: September 1, 2021
• Last Update Posted: September 1, 2021
• Sponsor: NYU Langone Health
• Information provided by (Responsible Party): NYU Langone Health

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Epilepsy; Tuberous Sclerosis Complex; Focal Cortical Dysplasia
• Intervention: Drug: Everolimus
• Enrollment: 15

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Treated Subjects	Reference Subjects
Arm/Group Description	This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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	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
Period Title: Overall Study
Started	5	10
Completed	4	10
Not Completed	1	0
Reason Not Completed
Surgery postponed	1	0

Baseline Characteristics

Arm/Group Title		Treated Subjects	Reference Subjects	Total
Arm/Group Description		This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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	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.	Total of all reporting groups
Overall Number of Baseline Participants		4	10	14
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	4 participants	10 participants	14 participants
		18.25 (10.1)	13.1 (12.3)	14.6 (11.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	4 participants	10 participants	14 participants
	Female	3 75.0%	6 60.0%	9 64.3%
	Male	1 25.0%	4 40.0%	5 35.7%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	4 participants	10 participants	14 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	0 0.0%	0 0.0%	0 0.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	4 100.0%	10 100.0%	14 100.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	4 participants	10 participants	14 participants
		4	10	14

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Adverse Events
Description	.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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treated Subjects	Reference Subjects
Arm/Group Description:	This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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	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.
Overall Number of Participants Analyzed	4	10
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%

2. Secondary Outcome

Title	Blood Everolimus Levels
Description	mTOR signaling in blood
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treated Subjects	Reference Subjects
Arm/Group Description:	This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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	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.
Overall Number of Participants Analyzed	4	10
Mean (Standard Deviation); Unit of Measure: ng/ml
	12.35 (5.36)	2 (0)

3. Secondary Outcome

Title	Blood Total VEGF Levels (Not Only VEGF-D)
Description	[Not Specified]
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treated Subjects	Reference Subjects
Arm/Group Description:	This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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	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
Overall Number of Participants Analyzed	4	10
Mean (Standard Deviation); Unit of Measure: pg/ml
	56.5 (46.9)	50.85 (54.1)

4. Secondary Outcome

Title	mTOR Brain Tissue-S6 Phosphate by Western Blot
Description	[Not Specified]
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treated Subjects	Reference Subjects
Arm/Group Description:	This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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	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
Overall Number of Participants Analyzed	4	10
Mean (Standard Deviation); Unit of Measure: normalized val-protein relative to actin
	0.49 (0.54)	0.81 (0.22)

5. Secondary Outcome

Title	HMGB1 Expression in Brain Tissue
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treated Subjects	Reference Subjects
Arm/Group Description:	This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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	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
Overall Number of Participants Analyzed	4	10
Mean (Standard Deviation); Unit of Measure: LFQ intensity
	14.85 (0.6)	15.06 (0.35)

Adverse Events

Time Frame	30 days
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Treated Subject	Reference Subject
Arm/Group Description	This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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	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.
All-Cause Mortality
	Treated Subject	Reference Subject
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/4 (0.00%)	0/10 (0.00%)
Serious Adverse Events
	Treated Subject	Reference Subject
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/4 (0.00%)	0/10 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Treated Subject	Reference Subject
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/4 (0.00%)	0/10 (0.00%)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr. Orrin Devinsky
• Organization: NYU Langone
• Phone: 646-558-0800
• EMail: od4@nyu.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Leitner DF, Kanshin E, Askenazi M, Siu Y, Friedman D, Devore S, Jones D, Ueberheide B, Wisniewski T, Devinsky O. Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia. PLoS One. 2022 May 19;17(5):e0268597. doi: 10.1371/journal.pone.0268597. eCollection 2022.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT02451696
• Other Study ID Numbers: 14-00245
• First Submitted: October 8, 2014
• First Posted: May 22, 2015
• Results First Submitted: November 17, 2020
• Results First Posted: September 1, 2021
• Last Update Posted: September 1, 2021