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) ]

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 ]

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) ]

Measure Type Secondary
Measure Title Time to SEGA Progression Based on Independent Central Radiology Review
Measure Description 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
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  
Time to SEGA Progression Based on Independent Central Radiology Review  
[units: Months]
Median ( 95% Confidence Interval )
  NA  
  ( NA to NA ) [1]
  NA  
  ( NA to NA ) [2]
[1] NA = Median duration was not reached in either arm. Number of patients who had SEGA Progression was n=0 for Everolimus.
[2] NA = Median duration was not reached in either arm. Number of patients who had SEGA Progression was n=6 for Placebo.

No statistical analysis provided for Time to SEGA Progression Based on Independent Central Radiology Review



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) ]

Measure Type Secondary
Measure Title Skin Lesion Response Rate as Per Investigator Assessment Using the Physician's Global Assessment of Clinical Condition (PGA)
Measure Description 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%
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)  
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, restricted to patients having at least one skin lesion at baseline.

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 concentrations.
Placebo Matching Placebo was administered orally.

Measured Values
    Everolimus     Placebo  
Number of Participants Analyzed  
[units: participants]
  72     38  
Skin Lesion Response Rate as Per Investigator Assessment Using the Physician's Global Assessment of Clinical Condition (PGA)  
[units: percentage of participants]
Number ( 95% Confidence Interval )
  41.7  
  ( 30.2 to 53.9 )  
  10.5  
  ( 2.9 to 24.8 )  

No statistical analysis provided for Skin Lesion Response Rate as Per Investigator Assessment Using the Physician's Global Assessment of Clinical Condition (PGA)



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 reported.   Anticipated Reporting 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 reported.   Anticipated Reporting Date:   09/2014   Safety Issue:   Yes


  Serious Adverse Events


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

Frequency Threshold
Threshold above which other adverse events are reported   5%  

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.

Other Adverse Events
    Everolimus     Placebo  
Total, other (not including serious) adverse events      
# participants affected / at risk     75/78     33/39  
Blood and lymphatic system disorders      
Neutropenia † 1    
# participants affected / at risk     4/78 (5.13%)     1/39 (2.56%)  
Gastrointestinal disorders      
Constipation † 1    
# participants affected / at risk     6/78 (7.69%)     0/39 (0.00%)  
Diarrhoea † 1    
# participants affected / at risk     10/78 (12.82%)     2/39 (5.13%)  
Mouth ulceration † 1    
# participants affected / at risk     25/78 (32.05%)     2/39 (5.13%)  
Nausea † 1    
# participants affected / at risk     6/78 (7.69%)     0/39 (0.00%)  
Oral pain † 1    
# participants affected / at risk     4/78 (5.13%)     0/39 (0.00%)  
Stomatitis † 1    
# participants affected / at risk     24/78 (30.77%)     8/39 (20.51%)  
Toothache † 1    
# participants affected / at risk     1/78 (1.28%)     2/39 (5.13%)  
Vomiting † 1    
# participants affected / at risk     13/78 (16.67%)     5/39 (12.82%)  
General disorders      
Asthenia † 1    
# participants affected / at risk     0/78 (0.00%)     2/39 (5.13%)  
Fatigue † 1    
# participants affected / at risk     11/78 (14.10%)     1/39 (2.56%)  
Irritability † 1    
# participants affected / at risk     4/78 (5.13%)     1/39 (2.56%)  
Pyrexia † 1    
# participants affected / at risk     15/78 (19.23%)     6/39 (15.38%)  
Infections and infestations      
Bronchitis † 1    
# participants affected / at risk     6/78 (7.69%)     3/39 (7.69%)  
Ear infection † 1    
# participants affected / at risk     7/78 (8.97%)     1/39 (2.56%)  
Fungal infection † 1    
# participants affected / at risk     0/78 (0.00%)     2/39 (5.13%)  
Nasopharyngitis † 1    
# participants affected / at risk     14/78 (17.95%)     9/39 (23.08%)  
Otitis media † 1    
# participants affected / at risk     7/78 (8.97%)     2/39 (5.13%)  
Pharyngitis † 1    
# participants affected / at risk     8/78 (10.26%)     1/39 (2.56%)  
Pharyngitis streptococcal † 1    
# participants affected / at risk     7/78 (8.97%)     1/39 (2.56%)  
Pneumonia † 1    
# participants affected / at risk     5/78 (6.41%)     0/39 (0.00%)  
Respiratory tract infection † 1    
# participants affected / at risk     5/78 (6.41%)     1/39 (2.56%)  
Respiratory tract infection viral † 1    
# participants affected / at risk     5/78 (6.41%)     0/39 (0.00%)  
Rhinitis † 1    
# participants affected / at risk     6/78 (7.69%)     2/39 (5.13%)  
Sinusitis † 1    
# participants affected / at risk     3/78 (3.85%)     2/39 (5.13%)  
Upper respiratory tract infection † 1    
# participants affected / at risk     11/78 (14.10%)     7/39 (17.95%)  
Viral infection † 1    
# participants affected / at risk     2/78 (2.56%)     2/39 (5.13%)  
Investigations      
Blood cholesterol increased † 1    
# participants affected / at risk     5/78 (6.41%)     1/39 (2.56%)  
Blood lactate dehydrogenase increased † 1    
# participants affected / at risk     5/78 (6.41%)     0/39 (0.00%)  
Low density lipoprotein increased † 1    
# participants affected / at risk     4/78 (5.13%)     1/39 (2.56%)  
Neutrophil count decreased † 1    
# participants affected / at risk     6/78 (7.69%)     0/39 (0.00%)  
Metabolism and nutrition disorders      
Decreased appetite † 1    
# participants affected / at risk     6/78 (7.69%)     2/39 (5.13%)  
Hypercholesterolaemia † 1    
# participants affected / at risk     5/78 (6.41%)     1/39 (2.56%)  
Musculoskeletal and connective tissue disorders      
Pain in extremity † 1    
# participants affected / at risk     6/78 (7.69%)     0/39 (0.00%)  
Nervous system disorders      
Convulsion † 1    
# participants affected / at risk     17/78 (21.79%)     10/39 (25.64%)  
Dizziness † 1    
# participants affected / at risk     4/78 (5.13%)     2/39 (5.13%)  
Headache † 1    
# participants affected / at risk     6/78 (7.69%)     3/39 (7.69%)  
Psychiatric disorders      
Aggression † 1    
# participants affected / at risk     6/78 (7.69%)     1/39 (2.56%)  
Insomnia † 1    
# participants affected / at risk     4/78 (5.13%)     0/39 (0.00%)  
Sleep disorder † 1    
# participants affected / at risk     0/78 (0.00%)     2/39 (5.13%)  
Respiratory, thoracic and mediastinal disorders      
Cough † 1    
# participants affected / at risk     10/78 (12.82%)     4/39 (10.26%)  
Epistaxis † 1    
# participants affected / at risk     4/78 (5.13%)     1/39 (2.56%)  
Skin and subcutaneous tissue disorders      
Acne † 1    
# participants affected / at risk     7/78 (8.97%)     2/39 (5.13%)  
Rash † 1    
# participants affected / at risk     9/78 (11.54%)     2/39 (5.13%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 13.1



  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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