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

This study has been completed.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
First received: November 12, 2008
Last updated: May 18, 2015
Last verified: May 2015
This study evaluated the efficacy and safety of Everolimus in treating patients with Subependymal Giant Cell Astrocytomas associated with Tuberous Sclerosis Complex.

Condition Intervention Phase
Tuberous Sclerosis
Subependymal Giant Cell Astrocytoma
Drug: Everolimus
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Placebo-controlled Study of Everolimus in the Treatment of Patients With Subependymal Giant Cell Astrocytomas (SEGA) Associated With Tuberous Sclerosis Complex (TSC)

Resource links provided by NLM:

Further study details as provided by Novartis:

Primary Outcome Measures:
  • Subependymal Giant Cell Astrocytomas (SEGA) Response Rate [ 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 ]
    Sega response Rate is defined as the percentage of patients whose best overall status is response as determined by Independent Central Radiology Review. SEGA response was defined as: (1) a ≥ 50% reduction in SEGA volume relative to baseline (where SEGA volume was the sum of all target SEGA lesion volumes identified at baseline); and (2) no unequivocal worsening of non-target SEGA lesions, no new SEGA lesions (≥ 1 cm in longest diameter), and no new or worsening hydrocephalus.

Secondary Outcome Measures:
  • 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 ]

Enrollment: 118
Study Start Date: August 2009
Study Completion Date: October 2014
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
Placebo Comparator: Placebo
Matching Placebo administered orally.
Drug: Placebo
Placebo was provided as a matching tablet and was blisterpacked under aluminum foil in units of 10.


Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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

  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00789828

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Sponsors and Collaborators
Novartis Pharmaceuticals
Study Director: Novartis Pharmaceuticlas Novartis Pharmaceuticals
  More Information

Additional Information:
No publications provided by Novartis

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

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00789828     History of Changes
Other Study ID Numbers: CRAD001M2301, 2007-006997-27
Study First Received: November 12, 2008
Results First Received: March 1, 2012
Last Updated: May 18, 2015
Health Authority: United States: Food and Drug Administration
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Germany: Federal Institute for Drugs and Medical Devices
Italy: Ministry of Health
Netherlands: Medicines Evaluation Board (MEB)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by Novartis:
Tuberous Sclerosis
Subependymal Giant Cell Astrocytoma
Mamalian Target Rapamycin

Additional relevant MeSH terms:
Tuberous Sclerosis
Congenital Abnormalities
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Malformations of Cortical Development
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Multiple Primary
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neoplastic Syndromes, Hereditary
Nervous System Diseases
Nervous System Malformations
Neurocutaneous Syndromes
Neurodegenerative Diseases
Neuroectodermal Tumors
Pathologic Processes
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents

ClinicalTrials.gov processed this record on November 24, 2015