A Placebo-controlled Study of Efficacy & Safety of 2 Trough-ranges of Everolimus as Adjunctive Therapy in Patients With Tuberous Sclerosis Complex (TSC) & Refractory Partial-onset Seizures

Inclusion Criteria

• 1. Male or female between the ages of 2 and 65 years (except in Europe where minimum age will be 1).
• Clinically definite diagnosis of TSC per modified Gomez criteria 3. Diagnosis of partial-onset epilepsy according to the classification of the International League Against Epilepsy (1989) and revised in 2009.
• Uncontrolled partial-onset seizures; must meet the following:
• At least 16 reported quantifiable partial-onset seizures over the Baseline period with no continuous 21-day seizure-free period between Visit 1 (Screening Visit) and Visit 2 (Randomization visit), as per data captured in daily seizure diaries.
• Prior history of failure to control partial-onset seizures despite having been treated with two or more sequential regimens of single or combined antiepileptic drugs.
• Prior or concurrent use of vagal nerve stimulator (VNS) is allowed. If the patient is using VNS, device stimulator parameters must remain constant throughout the study.
• Prior epilepsy surgery is allowed if performed at least 12 months before study entry.
• Must be receiving one, two, or three AEDs at a stable dose for at least 4 weeks at the start of the 8-week prospective Baseline phase, remain on the same regimen throughout the Baseline phase, and intend to continue the same regimen throughout the 18-week double blind Core phase (rescue medications are permitted).
• If female of child bearing potential, documentation of negative pregnancy test at time of informed consent and must use highly effective contraception during the study and for 8 weeks after stopping treatment 7. Sexually active males must use a condom during intercourse while taking study drug, and for 8 weeks after stopping study treatment 8. Hepatic, renal and blood laboratory values within the following range at screening :
• AST and ALT levels 460ms, congenital QT syndrome, unstable angina pectoris, myocardial infarction within 6 months of study entry, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease.
• Significant symptomatic deterioration of lung function
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, malabsorption syndrome or small bowel resection).
• liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis
• Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN.
• Active skin, mucosa, ocular or GI disorders of Grade > 1.
• Active (acute or chronic) or uncontrolled severe infections.
• A known history of HIV seropositivity or other active viral infections. 12. Patients with an active, bleeding diathesis. 13. Patient with uncontrolled hyperlipidemia: fasting serum cholesterol > 300 mg/dL OR >7.75 mmol/L AND fasting triglycerides > 2.5 x ULN.
• Patients who have had a major surgery or significant traumatic injury within 4 weeks of study entry.
• Patients with a prior history of organ transplant. 16. Patients receiving more than 3 antiepileptic drugs at any time in the baseline phase or at randomization or who change the dose of the AEDs during 4 weeks before screening or during the baseline period.
• Patients being treated with felbamate, unless treatment has been continuous for ≥ 1 year.
• Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of study entry (including chemotherapy, radiation therapy, antibody based therapy, etc.).
• Prior treatment with any investigational drug within the preceding 4 weeks prior to study entry.
• Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent at study entry. Topical or inhaled corticosteroids are allowed.
• Patients who have received prior treatment with a systemic mTOR inhibitor (sirolimus, temsirolimus, everolimus) within 24 months of study entry. Patients who have received prior