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Everolimus (RAD001) Therapy for Epilepsy in Patients With Tuberous Sclerosis Complex

Phase 1/Phase 2
2 Years
Open (Enrolling)
Epilepsy, Tuberous Sclerosis Complex

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Trial Information

Everolimus (RAD001) Therapy for Epilepsy in Patients With Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a genetic disorder with an incidence at birth of 1 in
6000. This disorder is characterized by the development of benign tumors in multiple organ
systems, including the brain. The primary neurological manifestations of TSC are epilepsy,
mental retardation and autism. Epilepsy is most common, occurring in 80-90% of patients,
and often the seizures are severe, unremitting, and uncontrolled by current anticonvulsant
medications. It is generally accepted that the seizures arise from cortical and subcortical
tubers and surrounding tissue in the brain. These tubers are caused by mutations in the
tumor suppressor genes TSC1 or TSC2. The protein products of these genes, hamartin and
tuberin, act as negative regulators of the PI3K/PKB(Akt)/mTOR signaling pathway that
regulates cell growth and proliferation Everolimus is an immunosuppressant drug that also
inhibits mTOR signaling and is capable of reversing aberrant mTOR-dependent effects that
occur when hamartin or tuberin are absent or defective. Thus, we hypothesize that drugs
like everolimus may be therapeutically useful for the treatment of refractory epilepsy in
patients with TSC.

Inclusion Criteria:

- Male or female individuals aged two years and older.

- History of epilepsy and at least eight reported seizures in previous 30 days prior to
informed consent

- Failure of two or more approved antiepileptic drug therapies

- Clinically definite diagnosis of tuberous sclerosis (modified Gomez criteria or
positive genetic test)

- Parents/Caregivers are English-speaking (primary or secondary language acceptable)

- If female and of child bearing potential, documentation of negative pregnancy test at
time of informed consent. Sexually active pre-menopausal female or male patients
must use adequate contraceptive measures, excluding use of estrogen-containing birth
control contraceptive regimen while on study medication. Prior hysterectomy, tubal
ligation, complete abstinence, barrier methods which include both a cervical
diaphragm and spermicidal jelly, intrauterine devices (IUD), progesterone based
contraceptives, or vasectomy in partner are all acceptable forms of contraception

- Adequate bone marrow function as shown by ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L,
and Hb >9 g/dL

- Adequate liver function as shown by serum bilirubin ≤ 1.5 x upper limit of normal
(ULN), ALT and AST ≤ 2.5x ULN, INR and PTT ≤1.5. (Anticoagulation is allowed if
target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for
>2 weeks at time of randomization.)

- Adequate renal function as shown by a serum creatinine ≤ 1.5 x ULN

- Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5
x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can
only be included after initiation of appropriate lipid lowering medication

Exclusion Criteria:

- Significant hematological or hepatic abnormality (i.e., transaminase levels > 2.5 x
ULN or serum bilirubin >1.5 x ULN, Hemoglobin < 9 g/dL, platelets < 80,000/ mm3,
absolute neutrophil count < 1,000/mm3)

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks of the start of study drug (including chemotherapy,
radiation therapy, antibody based therapy, etc.)

- Patients, who have had a major surgery or significant traumatic injury within 4 weeks
of start of study drug, patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia) or patients that may require
major surgery during the course of the study

- Prior treatment with any investigational drug within the preceding 4 weeks prior to
informed consent

- Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent. Topical or inhaled corticosteroids are allowed

- Patients should not receive immunization with attenuated live vaccines within one
week of informed consent or during study period

- Patients with coexisting malignancies within past 3 years, except for adequately
treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- Symptomatic congestive heart failure of New York heart Association Class III or
IV, unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within 6 months of start of study drug, serious uncontrolled cardiac
arrhythmia or any other clinically significant cardiac disease

- Severely impaired lung function defined as spirometry and DLCO that is 50% of
the normal predicted value and/or 02 saturation that is 88% or less at rest on
room air and/or requirement for continuous supplemental O2

- Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN

- Active (acute or chronic) or uncontrolled severe infections

- Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent

- A known history of HIV seropositivity

- Impairment of gastrointestinal function or gastrointestinal disease that
may significantly alter the absorption of everolimus (e.g., ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or
small bowel resection)

- Patients with an active, bleeding diathesis

- Female patients who are pregnant or breast feeding, or adults of
reproductive potential who are not using effective birth control methods.

- Patients who have received prior treatment with an mTOR inhibitor
(sirolimus, temsirolimus, everolimus).

- Patients with a known hypersensitivity to RAD001 (everolimus) or other
rapamycin(sirolimus, temsirolimus) or to its excipients

- History of noncompliance to medical regimens

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The percentage of subjects with reduction is seizure frequency

Outcome Time Frame:

Week 16

Safety Issue:


Principal Investigator

Darcy Krueger, M.D. Ph.D

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Hospital Medical Center, Cincinnati


United States: Food and Drug Administration

Study ID:




Start Date:

May 2010

Completion Date:

March 2015

Related Keywords:

  • Epilepsy
  • Tuberous Sclerosis Complex
  • Epilepsy
  • Tuberous Sclerosis Complex
  • Everolimus
  • RAD001
  • Mammalian Target of Rapamycin (MTOR)
  • Epilepsy
  • Sclerosis
  • Tuberous Sclerosis



Baylor College of MedicineHouston, Texas  77030
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039