A three-arm, randomized, double-blind, placebo-controlled study of the efficacy and safety of two trough-ranges of everolimus as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures

1. Male or female between the ages of 2 and 65 years (except in Europe where the minimum age will be 1 at the request of the EMA).;2. 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. ;4. Uncontrolled partial-onset seizures; must meet the following: ;a. 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. ;b. 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.;c. 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. ;d. Prior epilepsy surgery is allowed if performed at least 12 months before study entry. ;5. 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). ;6. 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:

a. AST and ALT levels < 2.5 x ULN ;b. serum bilirubin <1.5 × ULN (this limit does not apply to patients with an elevated indirect bilirubin, if they have Gilbert*s Syndrome);c. serum creatinine < 1.5 x ULN ;d. hemoglobin * 9 g/dL ;e. platelets * 80,000/mm3 ;f. absolute neutrophil count * 1,000/mm3 ;9. Written informed consent. Subjects or their legal guardians must have the ability to comprehend the informed consent form and be willing to provide informed consent. ;10. Patient or caregiver must be able to reliably record seizures and keep a daily diary and recall adverse events.

1. Patients with seizures secondary to metabolic, toxic, infectious or psychogenic disorder or drug abuse or current seizures related to an acute medical illness ;2. Presence of only non-motor partial seizures (Criteria Not Applicable per Amendment 2);3. Patients with TSC who have SEGA in need of immediate surgical intervention;4. Patients under two years of age with untreated infantile spasms;5. Within 52 weeks prior to study entry, an episode of status epilepticus as defined in the protocol;6. Patients with history of seizure clusters (where individual seizures cannot be accurately counted;according to the judgment of the investigator) occurring within 26 weeks prior to study entry;7. Patients who require rescue medication during the Baseline phase for more than 6 days;8. Patients with non-TSC related progressive encephalopathy;9. Patients who weigh less than 12 kg;10. Patients with coexisting malignancies within the 3 years prior to randomization, except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin. ;11. Patients with any severe and/or uncontrolled medical conditions at randomization such as: ;a. Symptomatic congestive heart failure of New York Heart Association Class III or IV, history of left ventricular ejection fraction (LVEF) <50%, QTc interval >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;b. Significant symptomatic deterioration of lung function ;c. 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);d. liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis ;e. Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN;f. Active skin, mucosa, ocular or GI disorders of Grade > 1. ;g. Active (acute or chronic) or uncontrolled severe infections;h. 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;14. Patients who have had a major surgery or significant traumatic injury within 4 weeks of study entry. ;15. 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;17. Patients being treated with felbamate, unless treatment has been continuous for * 1 years ;18. 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.) ;19. Prior treatment with any investigational drug within the preceding 4 weeks prior to study entry.;20. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent at study entry. Topical or inhaled corticosteroids are allowed. ;21. 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 treatment with a topical mTOR inhibitor (sirolimus, temsirolimus, everolimus) within 4 weeks of study entry. ;22. Patients with a known hypersensitivity to everolimus or other rapamycinanalogues (sirolimus, temsirolimus) or to its excipients. ;23. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study ;24. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. ;25. Patient with a score of 4 or 5 on the Suicidal Ideation item within 2 years of Screening, or any *yes* on the Suicidal Behavior item of the Columbia-Suicide Severity Rating Scale at Screening or baseline,- who upon follow up with a healthcare professional are found to be severely depressed or suicidal.;26. Maintenance of a diet consisting of <40 g of carbohydrate per day within 3 months of
screening.