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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
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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
A multicenter trial conducted at 24 sites in 11 countries. As the primary analysis of the core phase of the study favored everolimus over placebo, an open-label extension phase started: patients randomized in placebo were offered to switch on everolimus and those still receiving everolimus at the end of the core phase could continue the treatment.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The trial had a 2:1 randomization in favor of the everolimus arm. 118 patients were randomized to the core phase of the study. 112 patients received everolimus during core and/or extension phase.

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 for 2 periods

Period 1:   Double-blind Period (Core Phase)
    Everolimus   Placebo
STARTED   79   39 
COMPLETED   72 [1]   26 [2] 
NOT COMPLETED   7   13 
Protocol Violation                1                0 
Progressive disease                0                9 
Adverse Event                2                4 
Abnormal lab value (s)                1                0 
Withdrawal by Subject                1                0 
Administrative problems                1                0 
Death                1                0 
[1] Completed = Completed the Core phase & moved to Extension phase
[2] Completed = 1st received Placebo in the Core phase, switched to Everolimus in Extension phase

Period 2:   Everolimus Period (Core or Extension)
    Everolimus   Placebo
STARTED   112 [1]   0 [2] 
COMPLETED   83 [3]   0 
NOT COMPLETED   29   0 
Adverse Event                9                0 
Abnormal lab value (s)                1                0 
Withdrawal by Subject                7                0 
Lost to Follow-up                1                0 
Administrative problems                2                0 
Death                1                0 
Disease progression                5                0 
Protocol Violation                1                0 
New treatment                2                0 
[1] 112 pts had Everolimus during core and/or extension (6 from placebo did not switch to Eve. in ext.)
[2] Placebo randomized patients who switched to Everolimus are reported in "Everolimus" arm.
[3] Treatment duration completed as per protocol



  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 ]

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:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



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 ]

Measure Type Secondary
Measure Title Time to Angiomyolipoma Progression as Per Central Radiology Review
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.

For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma progression is defined starting from the start of everolimus. 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 about 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 
Time to Angiomyolipoma Progression as Per Central Radiology Review 
[Units: Months]
Median (95% Confidence Interval)
 NA [1]   11.37 [2] 
 (11.07 to N/A) 
 NA [3] 
[1] Median not reached since too few number of patients with progressions (n=3).
[2] Upper limit not estimable due to few number of patients at this time point.
[3] Median not reached since too few number of patients with progressions (n=16)

No statistical analysis provided for Time to Angiomyolipoma Progression as Per Central Radiology Review



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 ]

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). A complete clinical response (CCR) requires a grading of 0 indicating the absence of disease (histological confirmation is not required). Grades 1, 2, and 3 constitute partial response, indicating improvement of at least 50 percent, but less than 100 percent improvement. 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. Only patients with at least one skin lesion at baseline are included in the analysis.

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]
 77   37   112 
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) 
 68.2 
 (58.5 to 76.9) 

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: Day 1 up to 28 days after end of treatment ]

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. Severe renal impairment was defined as a GFR of <30ml/min/1.73m2.
Time Frame Day 1 up to 28 days after end of treatment  

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.
Safety set consists of all patients who received at least 1 dose of the double-blind study drug with a valid post-baseline assessment. For the everolimus (core/extension) treatment arm, patients received at least 1 dose of everolimus with a valid post-baseline assessment, where baseline was defined as the assessment just before start of everolimus.

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 
Percentage of Participants With Renal Impairment 
[Units: Percentage of Participants]
     
Glomerular filtration rate <30 ml/min/1.73m^2   2.5   7.7   7.1 
Glomerular filtration rate≥ 30 ml/min/1.73m^2   97.5   92.3   92.9 

No statistical analysis provided for Percentage of Participants With Renal Impairment



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 ]

Measure Type Secondary
Measure Title Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker
Measure Description Blood samples for biomarker assessment were collected immediately prior to study administration. On-treatment samples was compared to baseline samples with the change from baseline.
Time Frame 4 weeks, 12 weeks, 24 weeks, 36 weeks 48 weeks, 60 weeks, 72 weeks  

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. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.

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.

Measured Values
   Everolimus Randomized (Core Period)   Placebo Randomized (Core Period) 
Participants Analyzed 
[Units: Participants]
 79   39 
Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker 
[Units: pg/mL]
Mean (Standard Deviation)
   
Week 4 (n:56, 28)   38.7  (141.89)   17.6  (57.51) 
Week 12 (n:56, 29)   43.4  (60.62)   -6.1  (46.28) 
Week 24 (n:53, 29)   31.1  (75.83)   -4.3  (44.76) 
Week 36 (n:26, 18)   18.0  (45.07)   5.4  (24.01) 
Week 48 (n:16, 8)   55.3  (80.31)   3.1  (34.55) 
Week 60 (n:0, 1)   NA [1]   -4.12 [2] 
Week 72 (n:0, 1)   NA [3]   -6.1 [2] 
[1] N/A = No patient was included at this time point, so no mean, no standard deviation (SD) could be calculated.
[2] N/A = only 1 patient was included, so no SD could be calculated
[3] N/A = No patient was included at this time point, so no mean, no SD could be calculated.

No statistical analysis provided for Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker



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

Measure Type Secondary
Measure Title Everolimus Trough Concentrations (Cmin)
Measure Description Cmin values collected prior to dose administration on the same study day and at 20-28 hours after previous dose, at steady state, and patient did not vomit within 4 hours of previous dose. Samples collected during the first 4 days of dosing were excluded from all analyses.
Time Frame Prior to dosing at weeks 2, 4, 12, 24, 48  

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 Safety Set population for patients treated only with Everolimus and with a confirmed PK sample.

Reporting Groups
  Description
Everolimus Randomized (Core Period) Study drug was given by continuous oral daily dosing of two 5 mg tablets.

Measured Values
   Everolimus Randomized (Core Period) 
Participants Analyzed 
[Units: Participants]
 79 
Everolimus Trough Concentrations (Cmin) 
[Units: ng/mL]
Mean (Standard Deviation)
 
Prior to dosing at Week 2 (n:43)   7.63  (4.32) 
Prior to dosing Week 4 (n:44)   7.72  (4.35) 
Prior to dosing Week 12 (n:49)   8.79  (6.75) 
Prior to dosing Week 24 (n:46)   9.37  (8.83) 
Prior to dosing Week 48 (n:15)   11.49  (12.01) 

No statistical analysis provided for Everolimus Trough Concentrations (Cmin)



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 ]

Measure Type Secondary
Measure Title Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose
Measure Description C2h values collected 1-3 hours after dose administration on the same study day, at steady state, and patient did not vomit between taking previous dose and blood collection. Samples collected during the first 4 days of dosing will be excluded from all analyses.
Time Frame 2 hours post-dose administration at Weeks 2, 4, 12, 24, 48  

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 Safety Set population for patients treated only with Everolimus and with a confirmed PK sample.

Reporting Groups
  Description
Everolimus Randomized (Core Period) Study drug was given by continuous oral daily dosing of two 5 mg tablets.

Measured Values
   Everolimus Randomized (Core Period) 
Participants Analyzed 
[Units: Participants]
 79 
Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose 
[Units: ng/mL]
Mean (Standard Deviation)
 
2 hours post dose administration at Week 2 (n:55)   33.38  (15.66) 
2 hours post dose administration at Week 4 (n:49)   30.89  (14.96) 
2 hours post dose administration at Week 12 (n:56)   34.48  (15.10) 
2 hours post dose administration at Week 24 (n:50)   39.27  (22.25) 
2 hours post dose administration at Week 48 (n:14)   33.20  (18.45) 

No statistical analysis provided for Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose



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 ]

Measure Type Secondary
Measure Title Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response
Measure Description

Time to angiomyolipoma response was defined as the time from the date of randomization until the date of the first documented angiomyolipoma response. 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; no kidney increases in volume > 20% from nadir; no angiomyolipoma-related bleeding of ≥ grade 2.

For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma response is from the start of everolimus. The baseline in the response definition 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 analysis was performed on the Full analysis Set for patients in Everolimus arm and who experienced an angiomyolipoma response.

Reporting Groups
  Description
Everolimus Randomized (Core Period) Study drug 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)   Everolimus (Core and/or Extension Period) 
Participants Analyzed 
[Units: Participants]
 33   65 
Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response 
[Units: Months]
Median (95% Confidence Interval)
 2.86 
 (2.79 to 3.02) 
 2.89 
 (2.79 to 3.19) 

No statistical analysis provided for Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response



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 ]

Measure Type Secondary
Measure Title Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response
Measure Description Duration of angiomyolipoma response was defined as the time from the date of the first documented angiomyolipoma response until the date of the first documented angiomyolipoma progression . Angiomyolipoma response was 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 up to about 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 analysis was performed on the Full analysis Set for patients in Everolimus arm and who experienced an angiomyolipoma response.

Reporting Groups
  Description
Everolimus Randomized (Core Period) Study drug 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)   Everolimus (Core and/or Extension Period) 
Participants Analyzed 
[Units: Participants]
 33   65 
Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response 
[Units: Months]
Median (95% Confidence Interval)
 NA [1]   NA [2] 
[1] N/A = Median not reached since no patients progressed
[2] N/A = Median not reached since too few no of patients with progressions (n=2)

No statistical analysis provided for Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response



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 ]

Measure Type Secondary
Measure Title Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR)
Measure Description Duration of skin lesion response is defined as the time from the date of the first skin lesion response until the date of the first skin lesion progression, according to the PGA (physician’s global assessment of clinical condition). A progression is when the disease is worse than at baseline evaluation by >=25% or more.
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  

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 on the Full analysis Set for patients in Everolimus arm and who experienced a best overall skin lesion response CCR or PR.

Reporting Groups
  Description
Everolimus Randomized (Core Period) Study drug 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)   Everolimus (Core and/or Extension Period) 
Participants Analyzed 
[Units: Participants]
 20   73 
Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR) 
[Units: Months]
Median (95% Confidence Interval)
 NA [1]   NA [1] 
[1] N/A = Median not reached since no patients progressed

No statistical analysis provided for Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR)




  Serious Adverse Events
  Hide Serious Adverse Events

Time Frame No text entered.
Additional Description No text entered.

Reporting Groups
  Description
Everolimus Randomized (Core & Ext) Patients who were randomized and treated with Everolimus during the Core and Extension phase
Placebo Randomized/Crossed Over to Everolimus Patients who were randomized to placebo in the Core phase and who crossed-over to Everolimus in the Extension phase
Placebo Randomized/Never Crossed-over Patients randomized to placebo who never crossed-over to Everolimus

Serious Adverse Events
    Everolimus Randomized (Core & Ext)   Placebo Randomized/Crossed Over to Everolimus   Placebo Randomized/Never Crossed-over
Total, Serious Adverse Events       
# participants affected / at risk   28/79 (35.44%)   17/33 (51.52%)   3/6 (50.00%) 
Blood and lymphatic system disorders       
Bone marrow oedema † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Cardiac disorders       
Cardiac failure congestive † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Cardiovascular insufficiency † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Ear and labyrinth disorders       
Vertigo positional † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Eye disorders       
Visual acuity reduced † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Gastrointestinal disorders       
Abdominal adhesions † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Abdominal compartment syndrome † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Abdominal hernia † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Colitis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Constipation † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Diarrhoea † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Diarrhoea haemorrhagic † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Gastric ulcer † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Ileal perforation † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Intestinal perforation † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Salivary gland calculus † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Volvulus † 1       
# participants affected / at risk   0/79 (0.00%)   0/33 (0.00%)   1/6 (16.67%) 
Vomiting † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
General disorders       
Adverse drug reaction † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Fatigue † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Hepatobiliary disorders       
Bile duct stenosis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Immune system disorders       
Hypersensitivity † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Infections and infestations       
Abscess † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Appendicitis † 1       
# participants affected / at risk   2/79 (2.53%)   0/33 (0.00%)   0/6 (0.00%) 
Bronchitis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Bronchopneumonia † 1       
# participants affected / at risk   1/79 (1.27%)   1/33 (3.03%)   0/6 (0.00%) 
Campylobacter gastroenteritis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Erysipelas † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Gastroenteritis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Gastrointestinal infection † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Incision site infection † 1       
# participants affected / at risk   0/79 (0.00%)   0/33 (0.00%)   1/6 (16.67%) 
Peritonitis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Pneumonia † 1       
# participants affected / at risk   1/79 (1.27%)   3/33 (9.09%)   0/6 (0.00%) 
Pyelonephritis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Sepsis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Tonsillitis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Urinary tract infection † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Viral infection † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Injury, poisoning and procedural complications       
Fall † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Toxicity to various agents † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Investigations       
Blood creatinine increased † 1       
# participants affected / at risk   2/79 (2.53%)   0/33 (0.00%)   0/6 (0.00%) 
Metabolism and nutrition disorders       
Decreased appetite † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Gout † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Musculoskeletal and connective tissue disorders       
Back pain † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Chondropathy † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Joint effusion † 1       
# participants affected / at risk   2/79 (2.53%)   0/33 (0.00%)   0/6 (0.00%) 
Rhabdomyolysis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Spinal osteoarthritis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Angiomyolipoma † 1       
# participants affected / at risk   0/79 (0.00%)   0/33 (0.00%)   1/6 (16.67%) 
Nasal sinus cancer † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Pancreatic carcinoma † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Nervous system disorders       
Complex regional pain syndrome † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Convulsion † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Diplegia † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Epilepsy † 1       
# participants affected / at risk   3/79 (3.80%)   3/33 (9.09%)   0/6 (0.00%) 
Generalised tonic-clonic seizure † 1       
# participants affected / at risk   2/79 (2.53%)   1/33 (3.03%)   0/6 (0.00%) 
Hydrocephalus † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Syncope † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Transient ischaemic attack † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Psychiatric disorders       
Affective disorder † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Aggression † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Alcohol abuse † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Anxiety † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Hallucination † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   1/6 (16.67%) 
Psychiatric decompensation † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Psychogenic seizure † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Psychotic disorder † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Renal and urinary disorders       
Renal failure acute † 1       
# participants affected / at risk   1/79 (1.27%)   1/33 (3.03%)   0/6 (0.00%) 
Renal failure chronic † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Renal haemorrhage † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Renal impairment † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Reproductive system and breast disorders       
Breast hypoplasia † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Endometrial hyperplasia † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Ovarian cyst † 1       
# participants affected / at risk   1/79 (1.27%)   1/33 (3.03%)   0/6 (0.00%) 
Ovarian cyst ruptured † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Bronchospasm † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Haemoptysis † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Pleuritic pain † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Pneumothorax † 1       
# participants affected / at risk   2/79 (2.53%)   1/33 (3.03%)   0/6 (0.00%) 
Skin and subcutaneous tissue disorders       
Angioedema † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Vascular disorders       
Aortic aneurysm † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Haemodynamic instability † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Hypertension † 1       
# participants affected / at risk   0/79 (0.00%)   1/33 (3.03%)   0/6 (0.00%) 
Hypertensive crisis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Thrombosis † 1       
# participants affected / at risk   1/79 (1.27%)   0/33 (0.00%)   0/6 (0.00%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA V18.1




  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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