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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)

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ClinicalTrials.gov Identifier: NCT00789828
Recruitment Status : Completed
First Posted : November 13, 2008
Results First Posted : May 1, 2012
Last Update Posted : February 3, 2016
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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

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

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

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) ]
  Hide Outcome Measure 1

Measure Type Primary
Measure Title Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response
Measure Description Participants were assessed for SEGA response, defined as 50% reduction from baseline in SEGA volume (where SEGA volume was the sum of the volumes of all target SEGA lesions identified at baseline, and confirmed with a second scan performed approximately 12 weeks later), no unequivocal worsening of non-target SEGA lesions, no new SEGA lesions (≥ 1 cm in longest diameter), and no new or worsening hydrocephalus. Multi-phase brain MRI was utilized to identify SEGA lesions. SEGA response rate was defined as the percentage of participants whose best overall status was SEGA response as determined by Independent Central Radiology Review. The Kaplan-Meier estimate was used for determining time to SEGA response.
Time Frame End of core period (Week 48), 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 primary analysis was performed in Full Analysis Set (FAS) population, defined as all randomized participants involved in the study.

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   78   39   111 
Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response 
[Units: Percentage of participants]
Number (95% Confidence Interval) 		 34.6 
 (24.2 to 46.2)  		 0.0 
 (0.0 to 9.0)  		 57.7 
 (47.9 to 67) 

No statistical analysis provided for Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response



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) ]
  Show Outcome Measure 2

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   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) ]
  Show Outcome Measure 4

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) ]
  Show Outcome Measure 5

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) ]
  Show Outcome Measure 6

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) ]
  Show Outcome Measure 7

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) ]
  Show Outcome Measure 8

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 ]
  Show Outcome Measure 9

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 ]
  Show Outcome Measure 10

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) ]
  Show Outcome Measure 11


  Serious Adverse Events


  Other Adverse Events


  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.


  More Information