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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: March 25, 2013
Last verified: March 2013
History of Changes
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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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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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 ]
  Hide Outcome Measure 2

Measure Type Secondary
Measure Title Change From Baseline to Week 24 in Total Seizure Frequency Per 24 Hours From Video EEG as Per Central Reader.
Measure Description 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 Frame Baseline, Week 24  
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. The analysis was done by using a last observation carried forward approach.

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  
Change From Baseline to Week 24 in Total Seizure Frequency Per 24 Hours From Video EEG as Per Central Reader.  
[units: seizures per 24 hours]
Median ( Full Range ) 		  0.0  
  ( -34.0 to 13.0 )   		  0.0  
  ( -15.9 to 14.4 )  

No statistical analysis provided for Change From Baseline to Week 24 in Total Seizure Frequency Per 24 Hours From Video EEG as Per Central Reader.



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) ]
  Show Outcome Measure 3

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) ]
  Show Outcome Measure 4

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
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Limitations and Caveats
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
No text entered.  


Results Point of Contact:  
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
phone: 862-778-8300


No publications provided by Novartis

Publications automatically indexed to this study:


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: March 25, 2013
Health Authority: United States: Food and Drug Administration
Belgium: Directorate general for the protection of Public health: Medicines
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