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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) (EXIST-1)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00789828
First Posted: November 13, 2008
Last Update Posted: February 3, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
Results First Submitted: March 1, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, 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
The study was conducted at 24 centers in 10 countries.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A total of 117 participants were enrolled and randomized into the core period. Only 111 participants completing the core period, continued in the open-label extension period of the study.

Reporting Groups
  Description
Everolimus Participants received oral dose of everolimus 4.5 milligram/square meter (mg/m^2) daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 nanogram/millilitre (ng/mL). Dose adjustments were permitted based on safety and whole blood trough concentrations.
Placebo Participants received oral dose of placebo matching to everolimus daily.

Participant Flow for 2 periods

Period 1:   Core Period (48 Weeks)
    Everolimus   Placebo
STARTED   78   39 
COMPLETED   78   33 
NOT COMPLETED   0   6 
Administrative problems                0                1 
Withdrawal by Subject                0                4 
Lost to Follow-up                0                1 

Period 2:   Open-label Extension Period (4 Years)
    Everolimus   Placebo
STARTED   111 [1]   0 [2] 
COMPLETED   82   0 
NOT COMPLETED   29   0 
Adverse Event                10                0 
Withdrawal by Subject                6                0 
Lost to Follow-up                3                0 
Administrative problems                7                0 
Death                1                0 
Disease progression                1                0 
New treatment for indication under study                1                0 
[1] Of 117 participants only 111 completed the core period and continued in the extension period
[2] No participant received placebo.



  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 (Core Period) Participants received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 ng/mL. Dose adjustments were permitted based on safety and whole blood trough concentrations.
Placebo (Core Period) Participants received oral dose of placebo matching to everolimus daily.
Total Total of all reporting groups

Baseline Measures
   Everolimus (Core Period)   Placebo (Core Period)   Total 
Overall Participants Analyzed 
[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
  Show All Outcome Measures

1.  Primary:   Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response   [ Time Frame: End of core period (Week 48), and end of extension period (up to 4 years) ]

2.  Secondary:   Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period   [ Time Frame: Baseline (Core period) to Week 24 (Core period), Baseline (Extension period, Week 24 post-core baseline) to Week 24 (Extension period, Week 48 post-core baseline) ]

3.  Secondary:   Time to SEGA Progression   [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]
  Hide Outcome Measure 3

Measure Type Secondary
Measure Title Time to SEGA Progression
Measure Description Time to SEGA progression was defined as time between randomisation to time to first SEGA progression. SEGA progression was defined as either one or more of the following criteria: 1. 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 nadir is the lowest SEGA volume obtained for the participant previously in the trial), 2. unequivocal worsening of non-target SEGA lesions, 3. appearance of new SEGA lesion ≥ 1.0 cm in longest diameter, 4. new or worsening hydrocephalus. The median TTSP based on central radiology review was not reached in any treatment arms; Only 6 events of SEGA progressions were observed in the placebo group of core period.
Time Frame Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)  

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 analysis was performed in the FAS population. Here "Number of participants analysed" signifies the participants assessed for time to SEGA progression during the study for each arm, respectively.

Reporting Groups
  Description
Everolimus (Core Period) Participants received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 ng/mL. Dose adjustments were permitted based on safety and whole blood trough concentrations.
Placebo (Core Period) Participants received oral dose of placebo matching to everolimus daily.
Everolimus (Extension Period) Participants received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain blood trough concentrations in range of 5-15 ng/mL.

Measured Values
   Everolimus (Core Period)   Placebo (Core Period)   Everolimus (Extension Period) 
Participants Analyzed 
[Units: Participants]
 78   39   111 
Time to SEGA Progression 
[Units: Months]
Median (95% Confidence Interval)
 NA [1]   NA [2]   NA [3] 
[1] Median was not reached as no participant experienced disease progression during core period.
[2] Median was not reached as only 6 participants experienced disease progression during core period.
[3] Median was not reached as no participant experienced disease progression during extension period.

No statistical analysis provided for Time to SEGA Progression



4.  Secondary:   Time to SEGA Response   [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

5.  Secondary:   Duration of SEGA Response   [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

6.  Secondary:   Time to SEGA Worsening   [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

7.  Secondary:   Percentage of Participants With Skin Lesions Assessed Using Physician's Global Assessement Overall Score   [ Time Frame: End of core period (Week 48), and end of extension period (up to 4 years) ]

8.  Secondary:   Duration of Skin Lesion Response in Everolimus Treated Participants   [ Time Frame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years) ]

9.  Secondary:   Everolimus Blood Concentration (C2h) at 2 Hours Post Dose   [ Time Frame: 2 hours post dose on Week 6, Week 24, Week 48, Week 96, Week 144, and Week 240 ]

10.  Secondary:   Everolimus Trough Concentrations (Cmin) at 24 Hours After Last Dose   [ Time Frame: 24 hours post dose on Week 6, Week 24, Week 48, Week 72, Week 96, Week 144, and Week 240 ]

11.  Secondary:   Percentage of Participants With Renal Impairment During Core Period   [ Time Frame: Day 1 up to 28 days after end of treatment (Core period) ]


  Serious Adverse Events


  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
No text entered.


  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.


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


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 ( EudraCT Number )
First Submitted: November 12, 2008
First Posted: November 13, 2008
Results First Submitted: March 1, 2012
Results First Posted: May 1, 2012
Last Update Posted: February 3, 2016