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 is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00789828
First received: November 12, 2008
Last updated: April 24, 2014
Last verified: April 2014
Results First Received: March 1, 2012  
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
Conditions: Tuberous Sclerosis
Subependymal Giant Cell Astrocytoma
Interventions: Drug: Everolimus
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients in the study were randomized in a 2:1 ratio (Everolimus: Placebo).

Reporting Groups
  Description
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.
Placebo Matching Placebo was administered orally.

Participant Flow:   Overall Study
    Everolimus     Placebo  
STARTED     78     39  
COMPLETED     2 [1]   8  
NOT COMPLETED     76     31  
Ongoing in Double Blind                 76                 31  
[1] Completed means discontinued the double-blind treatment period.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
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.
Placebo Matching Placebo was administered orally.
Total Total of all reporting groups

Baseline Measures
    Everolimus     Placebo     Total  
Number of Participants  
[units: participants]
  78     39     117  
Age  
[units: years]
Mean ± Standard Deviation
  10.1  ± 5.9     10.3  ± 7.3     10.2  ± 6.4  
Age, Customized  
[units: Participants]
     
<3 years     13     7     20  
3-18 years     55     26     81  
≥18 years     10     6     16  
Gender  
[units: participants]
     
Female     29     21     50  
Male     49     18     67  



  Outcome Measures
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1.  Primary:   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) ]
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Measure Type Primary
Measure Title Subependymal Giant Cell Astrocytomas (SEGA) Response Rate
Measure Description 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.
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)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set (FAS) consisted of all randomized patients.

Reporting Groups
  Description
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.
Placebo Matching Placebo was administered orally.

Measured Values
    Everolimus     Placebo  
Number of Participants Analyzed  
[units: participants]
  78     39  
Subependymal Giant Cell Astrocytomas (SEGA) Response Rate  
[units: percentage¬†of¬†participants]
Number ( 95% Confidence Interval )
  34.6  
  ( 24.2 to 46.2 )  
  0.0  
  ( 0.0 to 9.0 )  

No statistical analysis provided for Subependymal Giant Cell Astrocytomas (SEGA) Response Rate



2.  Secondary:   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 ]

3.  Secondary:   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) ]

4.  Secondary:   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) ]

5.  Secondary:   Change From Baseline in Angiogenesis Biomarkers   [ Time Frame: Baseline, Week 4, Week 12, Week 24, Week 36 and Week 48 ]
Results not yet posted.   Anticipated Posting Date:   09/2014   Safety Issue:   No

6.  Secondary:   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 ]
Results not yet posted.   Anticipated Posting Date:   09/2014   Safety Issue:   Yes


  Serious Adverse Events
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Time Frame No text entered.
Additional Description No text entered.

Reporting Groups
  Description
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.
Placebo Matching placebo was administered orally.

Serious Adverse Events
    Everolimus     Placebo  
Total, serious adverse events      
# participants affected / at risk     15/78 (19.23%)     3/39 (7.69%)  
Gastrointestinal disorders      
Abdominal pain † 1    
# participants affected / at risk     1/78 (1.28%)     0/39 (0.00%)  
General disorders      
Pyrexia † 1    
# participants affected / at risk     3/78 (3.85%)     0/39 (0.00%)  
Immune system disorders      
Hypersensitivity † 1    
# participants affected / at risk     1/78 (1.28%)     0/39 (0.00%)  
Infections and infestations      
Adenovirus infection † 1    
# participants affected / at risk     1/78 (1.28%)     0/39 (0.00%)  
Bronchitis † 1    
# participants affected / at risk     2/78 (2.56%)     1/39 (2.56%)  
Bronchopneumonia † 1    
# participants affected / at risk     1/78 (1.28%)     0/39 (0.00%)  
Febrile infection † 1    
# participants affected / at risk     1/78 (1.28%)     0/39 (0.00%)  
Gastroenteritis † 1    
# participants affected / at risk     2/78 (2.56%)     0/39 (0.00%)  
Gastroenteritis viral † 1    
# participants affected / at risk     2/78 (2.56%)     0/39 (0.00%)  
Gastrointestinal infection † 1    
# participants affected / at risk     1/78 (1.28%)     0/39 (0.00%)  
Otitis media † 1    
# participants affected / at risk     1/78 (1.28%)     0/39 (0.00%)  
Pneumonia † 1    
# participants affected / at risk     2/78 (2.56%)     0/39 (0.00%)  
Respiratory tract infection viral † 1    
# participants affected / at risk     1/78 (1.28%)     0/39 (0.00%)  
Upper respiratory tract infection † 1    
# participants affected / at risk     2/78 (2.56%)     0/39 (0.00%)  
Urinary tract infection † 1    
# participants affected / at risk     1/78 (1.28%)     0/39 (0.00%)  
Metabolism and nutrition disorders      
Dehydration † 1    
# participants affected / at risk     1/78 (1.28%)     0/39 (0.00%)  
Nervous system disorders      
Convulsion † 1    
# participants affected / at risk     3/78 (3.85%)     2/39 (5.13%)  
Grand mal convulsion † 1    
# participants affected / at risk     1/78 (1.28%)     0/39 (0.00%)  
Status epilepticus † 1    
# participants affected / at risk     2/78 (2.56%)     0/39 (0.00%)  
Psychiatric disorders      
Agitation † 1    
# participants affected / at risk     1/78 (1.28%)     0/39 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 13.1




  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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