Efficacy and Safety of Everolimus (RAD001) in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (TSC)(EXIST-1)

• Change From Baseline to Week 24 in Total Seizure Frequency Per 24 Hours From Video EEG as Per Central Reader. [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
  The video EEG recordings were sent to a Central Reader for interpretation and recording of seizure frequency/type. Seizure frequency per 24 hours is defined as the number of seizures in the EEG divided by the number of hours in the EEG, multiplied by 24. Seizure frequency was listed as missing if the actual EEG recording duration was <18 hours.
• Time to SEGA Progression Based on Independent Central Radiology Review [ Time Frame: From date of randomization until the earliest date of first documented SEGA progression, date of further anti-SEGA medication (including open-label Everolimus)/surgery or analysis cut-off date (02-Mar-2011) ] [ Designated as safety issue: No ]
  Time to SEGA progression was defined as time from date of randomization to date of first documented SEGA progression. SEGA progression was defined as one or more of: Increase from nadir of ≥ 25% in SEGA volume to a value greater than baseline SEGA volume (where SEGA volume is the sum of the volumes of all target SEGA lesions identified at baseline, and where nadir is the lowest SEGA volume obtained for the patient previously in the trial) or unequivocal worsening of non-target SEGA lesions, or appearance of new SEGA lesion ≥ 1.0 cm in longest diameter, or new or worsening hydrocephalus
• Skin Lesion Response Rate as Per Investigator Assessment Using the Physician's Global Assessment of Clinical Condition (PGA) [ Time Frame: From date of randomization until the earliest date of first skin lesion progression, date of start of further therapy against skin lesions (including open-label Everolimus) or analysis cut-off date (02-Mar-2011) ] [ Designated as safety issue: No ]
  Response rate determined among patients with ≥ 1 skin lesion at baseline (BL) and defined as the percentage of patients whose best overall status is complete clinical response or partial response. Response was evaluated using the PGA which is a 7-point scale that allows the investigator to evaluate improvement or worsening of the patient's skin disease compared to BL. Assessment was designed to consider skin lesions as a whole. Complete clinical response required a grading of 0 indicating the absence of disease. Grade 1, 2, and 3 = partial response, indicating improvements of ≥ 50% but < 100%
• Change From Baseline in Angiogenesis Biomarkers [ Time Frame: Baseline, Week 4, Week 12, Week 24, Week 36 and Week 48 ] [ Designated as safety issue: No ]
• Changes in Renal Function Assessed Using Creatinine Clearance/Globerular Filtration Rate. [ Time Frame: From start of treatment and assessed on a continuous basis through the duration of the study ] [ Designated as safety issue: Yes ]

• • Time to Subependymal Giant Cell Astrocytoma progression through MRIs at screening, 12, 24 and 48 weeks and annually thereafter [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (4-5 years). ] [ Designated as safety issue: Yes ]
• • Skin lesion response rate tracked by digital photographs [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (4-5 years). ] [ Designated as safety issue: Yes ]
• • Change from baseline in biomarkers collected during the first years of study [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (4-5 years). ] [ Designated as safety issue: Yes ]
• • Changes in renal function by assessing creatinine clearance levels throughout the study [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (4-5 years). ] [ Designated as safety issue: Yes ]
• • Safety assessed on a continuous basis throughout study [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (4-5 years). ] [ Designated as safety issue: Yes ]
• • Change from baseline in frequency of epileptiform events monitored by 24 hour EEG at baseline and 6 months [ Time Frame: Biomarkers assessed throughout the first year of the study only. All other outcomes are assessed through the duration of the study (4-5 years). ] [ Designated as safety issue: Yes ]

This study evaluated the efficacy and safety of Everolimus in treating patients with Subependymal Giant Cell Astrocytomas associated with Tuberous Sclerosis Complex.

• Tuberous Sclerosis
• Subependymal Giant Cell Astrocytoma

• Drug: Everolimus
  Everolimus was formulated as tablets of 1.0-mg strength and was blisterpacked under aluminum foil in units of 10 tablets.
  Other Name: RAD001
• Drug: Placebo
  Placebo was provided as a matching tablet and was blisterpacked under aluminum foil in units of 10.

• Experimental: Everolimus
  Everolimus was administered orally at a starting dose of 4.5mg/m^2 daily and subsequently titrated to attain whole blood trough concentration of 5 to 15 ng/mL. Dose adjustments were permitted based on safety and whole blood trough concentrations.
  Intervention: Drug: Everolimus
• Placebo Comparator: Placebo
  Matching Placebo administered orally.
  Intervention: Drug: Placebo

Inclusion Criteria:

• All Ages
• Definite diagnosis of Tuberous Sclerosis according to the modified Gomez criteria
• At least one Subependymal Giant Cell Astrocytoma of at least 1 cm in diameter
• Evidence of SEGA worsening as compared to prior MRI scans
• Females of child bearing potential must use birth control
• Written informed consent

Exclusion Criteria:

• SEGA related surgery is likely to be required in the opinion of the investigator
• Recent heart attack, cardiac related chest pain or stroke
• Severely impaired lung function
• Severe liver dysfunction
• Severe kidney dysfunction
• Pregnancy or breast feeding
• Current infection
• History of organ transplant
• Surgery within two months prior to study enrollment
• Prior therapy with a medication in the same class as Everolimus
• Uncontrolled high cholesterol
• Uncontrolled diabetes
• HIV
• Patients with metal implants thus prohibiting MRI evaluations

Other protocol-defined inclusion/exclusion criteria may apply