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Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM) (EXIST-2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00790400
First received: November 10, 2008
Last updated: January 3, 2017
Last verified: January 2017
Results First Received: May 23, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions: Tuberous Sclerosis Complex (TSC)
Lymphangioleiomyomatosis (LAM)
Interventions: Drug: Everolimus (RAD001)
Drug: Everolimus Placebo

  Participant Flow


  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 Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Placebo Placebo was given by continuous oral daily dosing of two 5 mg tablets.
Total Total of all reporting groups

Baseline Measures
   Everolimus   Placebo   Total 
Overall Participants Analyzed 
[Units: Participants]
 79   39   118 
Age 
[Units: Years]
Mean (Standard Deviation)
 32.5  (10.37)   31.0  (9.64)   32.0  (10.12) 
Age, Customized 
[Units: Participants]
     
<30 years   35   20   55 
≥ 30 years   44   19   63 
Gender 
[Units: Participants]
Count of Participants
     
Female      52  65.8%      26  66.7%      78  66.1% 
Male      27  34.2%      13  33.3%      40  33.9% 


  Outcome Measures
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1.  Primary:   Angiomyolipoma Response Rate as Per Central Radiology Review   [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 years ]
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Measure Type Primary
Measure Title Angiomyolipoma Response Rate as Per Central Radiology Review
Measure Description

Angiomyolipoma response defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; there were no kidney increases in volume > 20% from nadir. The patient did not have any angiomyolipoma-related bleeding of ≥ grade 2.

For the everolimus (core/extension periods) treatment group, the baseline means the latest value on or before starting everolimus.

Time Frame From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 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 Full Analysis Set (FAS) is defined according to the Intention-to-Treat principle and consists of all randomized patients.

Reporting Groups
  Description
Everolimus Randomized (Core Period) Study drug was given by continuous oral daily dosing of two 5 mg tablets.
Placebo Randomized (Core Period) Placebo was given by continuous oral daily dosing of two 5 mg tablets.
Everolimus (Core and/or Extension Period) Patients initially randomized in everolimus and patients initially randomized in placebo but who crossed-over to everolimus during extension.

Measured Values
   Everolimus Randomized (Core Period)   Placebo Randomized (Core Period)   Everolimus (Core and/or Extension Period) 
Participants Analyzed 
[Units: Participants]
 79   39   112 
Angiomyolipoma Response Rate as Per Central Radiology Review 
[Units: Percentage of Participants]
Number (95% Confidence Interval)
 41.8 
 (30.8 to 53.4) 
 0 
 (0.0 to 9.0) 
 58.0 
 (48.3 to 67.3) 


Statistical Analysis 1 for Angiomyolipoma Response Rate as Per Central Radiology Review
Groups [1] Everolimus Randomized (Core Period) vs. Placebo Randomized (Core Period)
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Clopper-Pearson
P Value [4] <0.0001
[1] Additional details about the analysis, such as null hypothesis and power calculation:
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[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
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[3] Other relevant method information, such as adjustments or degrees of freedom:
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[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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2.  Secondary:   Time to Angiomyolipoma Progression as Per Central Radiology Review   [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years ]

3.  Secondary:   Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)   [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 years ]

4.  Secondary:   Percentage of Participants With Renal Impairment   [ Time Frame: Day 1 up to 28 days after end of treatment ]

5.  Secondary:   Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker   [ Time Frame: 4 weeks, 12 weeks, 24 weeks, 36 weeks 48 weeks, 60 weeks, 72 weeks ]

6.  Secondary:   Everolimus Trough Concentrations (Cmin)   [ Time Frame: Prior to dosing at weeks 2, 4, 12, 24, 48 ]

7.  Secondary:   Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose   [ Time Frame: 2 hours post-dose administration at Weeks 2, 4, 12, 24, 48 ]

8.  Secondary:   Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response   [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 years ]

9.  Secondary:   Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response   [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years ]

10.  Secondary:   Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR)   [ Time Frame: From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years ]


  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
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