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 is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00790400
First received: November 10, 2008
Last updated: January 14, 2014
Last verified: January 2014
Results First Received: May 23, 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 Complex (TSC)
Lymphangioleiomyomatosis (LAM)
Interventions: Drug: Everolimus (RAD001)
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
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Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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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.

Participant Flow:   Overall Study
    Everolimus     Placebo  
STARTED     79     39  
COMPLETED     7 [1]   13  
NOT COMPLETED     72     26  
Ongoing in Double-blind                 72                 26  
[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 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  
Number of Participants  
[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]
     
Female     52     26     78  
Male     27     13     40  



  Outcome Measures
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1.  Primary:   Angiomyolipoma Response Rate as Per Central Radiology Review (Double-blind Period)   [ 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 analysis cut-off date (30-June-2011). ]

Measure Type Primary
Measure Title Angiomyolipoma Response Rate as Per Central Radiology Review (Double-blind Period)
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

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 analysis cut-off date (30-June-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) is defined according to the Intention-to-Treat principle and consists of all randomized patients. Patients were to be analyzed according to the treatment that they were assigned to at randomization.

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.

Measured Values
    Everolimus     Placebo  
Number of Participants Analyzed  
[units: participants]
  79     39  
Angiomyolipoma Response Rate as Per Central Radiology Review (Double-blind Period)  
[units: Percentage of Participants]
Number ( 95% Confidence Interval )
  41.8  
  ( 30.8 to 53.4 )  
  0  
  ( 0.0 to 9.0 )  

No statistical analysis provided for Angiomyolipoma Response Rate as Per Central Radiology Review (Double-blind Period)



2.  Secondary:   Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period)   [ 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 analysis cut-off date (30-June-2011). ]

Measure Type Secondary
Measure Title Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period)
Measure Description Time to angiomyolipoma progression (TTAP) is defined as time from date of randomization to date of first documented angiomyolipoma progression. Angiomyolipoma progression was defined as one or more of the following: • Increase from nadir of ≥ 25% in angiomyolipoma volume to value greater than baseline • The appearance of a new angiomyolipoma ≥ 1.0 cm in longest diameter •An increase from nadir of 20% or more in the volume of either kidney to a value greater than baseline •Angiomyolipoma-related bleeding grade ≥ 2
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 analysis cut-off date (30-June-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) is defined according to the Intention-to-Treat principle and consists of all randomized patients. Patients were to be analyzed according to the treatment that they were assigned at randomization.

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.

Measured Values
    Everolimus     Placebo  
Number of Participants Analyzed  
[units: participants]
  79     39  
Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period)  
[units: months]
Median ( 95% Confidence Interval )
  NA  
  ( NA to NA ) [1]
  11.37  
  ( 11.07 to NA ) [2]
[1] The median time to Angiomyolipoma Progression could not be estimated because <50% of patients had an Angiomyolipoma Progression during the time period.
[2] The upper limit was not estimable in the study as it is longer than the estimated time period till data cut-off date (30-June-2011)

No statistical analysis provided for Time to Angiomyolipoma Progression as Per Central Radiology Review (Double-blind Period)



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 analysis cut-off date (30-June-2011). ]

Measure Type Secondary
Measure Title Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)
Measure Description Skin lesion response rate in the double-blind period was determined only among patients with at least one skin lesion at baseline, and is the percentage of this group of patients with a best overall skin lesion response on the Physician’s Global Assessment of Clinical Condition (PGA) of either 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 analysis cut-off date (30-June-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) is defined according to the Intention-to-Treat principle and consists of all randomized patients. Patients were to be analyzed according to the treatment that they were assigned at randomization.

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.

Measured Values
    Everolimus     Placebo  
Number of Participants Analyzed  
[units: participants]
  77     37  
Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)  
[units: Percentage of participants]
Number ( 95% Confidence Interval )
  26  
  ( 16.6 to 37.2 )  
  0  
  ( 0.0 to 9.5 )  

No statistical analysis provided for Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)



4.  Secondary:   Percentage of Participants With Renal Impairment   [ 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 analysis cut-off date (30-June-2011). ]

Measure Type Secondary
Measure Title Percentage of Participants With Renal Impairment
Measure Description Renal Impairment was measured by glomerular filtration rate which was calculated using the Modification of Diet in Renal Disease formula. Percentage of participants with renal impairment was reported.
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 analysis cut-off date (30-June-2011).  
Safety Issue Yes  

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 safety set consists of all patients who received at least one dose of the double-blind study drug with a valid post-baseline assessment.

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.

Measured Values
    Everolimus     Placebo  
Number of Participants Analyzed  
[units: participants]
  79     39  
Percentage of Participants With Renal Impairment  
[units: Percentage of Participants]
   
Glomerular filtration rate <30 ml/min/1.73m^2     2.5     7.7  
Glomerular filtration rate≥ 30 ml/min/1.73m^2     97.5     92.3  

No statistical analysis provided for Percentage of Participants With Renal Impairment



5.  Secondary:   Change From Baseline in Plasma Angiogenic Molecules   [ Time Frame: Baseline, 12 Months ]
Results not yet reported.   Anticipated Reporting Date:   12/2014   Safety Issue:   No


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

Reporting Groups
  Description
Everolimus Everolimus
Placebo Placebo

Serious Adverse Events
    Everolimus     Placebo  
Total, serious adverse events      
# participants affected / at risk     15/79 (18.99%)     7/39 (17.95%)  
Blood and lymphatic system disorders      
Bone marrow oedema † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Cardiac disorders      
Cardiovascular insufficiency † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Gastrointestinal disorders      
Caecitis † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Constipation † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Volvulus † 1    
# participants affected / at risk     0/79 (0.00%)     1/39 (2.56%)  
General disorders      
Fatigue † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Hepatobiliary disorders      
Bile duct stenosis † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Immune system disorders      
Hypersensitivity † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Infections and infestations      
Appendicitis † 1    
# participants affected / at risk     2/79 (2.53%)     0/39 (0.00%)  
Bronchitis † 1    
# participants affected / at risk     0/79 (0.00%)     1/39 (2.56%)  
Gastrointestinal infection † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Pneumonia † 1    
# participants affected / at risk     1/79 (1.27%)     1/39 (2.56%)  
Pyelonephritis † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Tonsillitis † 1    
# participants affected / at risk     0/79 (0.00%)     1/39 (2.56%)  
Wound infection † 1    
# participants affected / at risk     0/79 (0.00%)     1/39 (2.56%)  
Injury, poisoning and procedural complications      
Fall † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Metabolism and nutrition disorders      
Decreased appetite † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Gout † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Musculoskeletal and connective tissue disorders      
Back pain † 1    
# participants affected / at risk     0/79 (0.00%)     1/39 (2.56%)  
Joint effusion † 1    
# participants affected / at risk     2/79 (2.53%)     0/39 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Angiomyolipoma † 1    
# participants affected / at risk     0/79 (0.00%)     1/39 (2.56%)  
Nervous system disorders      
Complex regional pain syndrome † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Convulsion † 1    
# participants affected / at risk     2/79 (2.53%)     0/39 (0.00%)  
Grand mal convulsion † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Psychiatric disorders      
Affective disorder † 1    
# participants affected / at risk     0/79 (0.00%)     1/39 (2.56%)  
Hallucination † 1    
# participants affected / at risk     0/79 (0.00%)     1/39 (2.56%)  
Renal and urinary disorders      
Renal failure acute † 1    
# participants affected / at risk     2/79 (2.53%)     0/39 (0.00%)  
Respiratory, thoracic and mediastinal disorders      
Bronchospasm † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Pleuritic pain † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Skin and subcutaneous tissue disorders      
Angioedema † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Vascular disorders      
Hypertensive crisis † 1    
# participants affected / at risk     1/79 (1.27%)     0/39 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, 14.0




  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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