Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

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:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00789828
First received: November 12, 2008
Last updated: January 4, 2016
Last verified: January 2016
Results First Received: March 1, 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
Subependymal Giant Cell Astrocytoma
Interventions: Drug: Everolimus
Drug: Placebo

  Participant Flow
  Hide 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
  Hide 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  
Number of Participants  
[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
  Hide 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) ]

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)  
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 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)  
Number of Participants Analyzed  
[units: participants]
  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) ]

Measure Type Secondary
Measure Title Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period
Measure Description Seizure frequency per 24 hours was defined as the number of seizures in the electroencephalography (EEG) divided by the number of hours in the EEG, multiplied by 24. Seizure frequency was evaluated using a 24-hour video-EEG. Seizure frequency was listed as missing if the actual EEG recording duration was < 18 hours.
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)  
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 analysis was performed in the FAS population. Missing values were imputed using last observation carried forward approach for core period while raw count for extension period.

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)  
Number of Participants Analyzed  
[units: participants]
  78     39     34  
Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period  
[units: Seizure frequency]
Mean (Standard Deviation)
  -1.24  (6.12)     -0.24  (5.7)     -6.07  (9.719)  

No statistical analysis provided for Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period



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) ]

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)  
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 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)  
Number of 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) ]

Measure Type Secondary
Measure Title Time to SEGA Response
Measure Description Participants were assessed for time to 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 utilised 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 Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)  
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 analysis was performed in the FAS population.

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.
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)     Everolimus (Extension Period)  
Number of Participants Analyzed  
[units: participants]
  27     64  
Time to SEGA Response  
[units: months]
Median (95% Confidence Interval)
  2.99  
  (2.79 to 5.36)  
  5.32  
  (3.02 to 5.59)  

No statistical analysis provided for Time to SEGA Response



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) ]

Measure Type Secondary
Measure Title Duration of SEGA Response
Measure Description Duration of SEGA response was defined as time from the date of the first documented SEGA response until the date of the first documented SEGA progression. Duration of SEGA response was evaluated only for participants who achieved a SEGA response. The time to SEGA progression was censored if SEGA progression was not observed before the first to occur out of (i) analysis cut-off date (ii) the date when systemic anti-SEGA medication is started, (iii) the date of a SEGA-related surgery or (iv) the date of death. Since, no case of SEGA progression was observed in core study which resulted in censored duration of SEGA response. Only 5 SEGA responders experienced a SEGA progression in extension period.
Time Frame Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)  
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 analysis was performed in the FAS population. Here, "Number of participants analysed" signifies the participants assessed for 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.
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)     Everolimus (Extension Period)  
Number of Participants Analyzed  
[units: participants]
  27     64  
Duration of SEGA Response  
[units: months]
Median (95% Confidence Interval)
  NA  
  [1]
  NA  
  [2]
[1] Median was not achieved as no case of SEGA progression was observed.
[2] Median was not achieved as only 5 events of SEGA progression were observed.

No statistical analysis provided for Duration of SEGA Response



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) ]

Measure Type Secondary
Measure Title Time to SEGA Worsening
Measure Description Time to SEGA worsening was defined as the time from the start of everolimus to date of the first SEGA worsening. SEGA worsening was defined as either; increase from nadir of ≥ 25% in SEGA volume or unequivocal worsening of non-target SEGA lesions, or appearance of new SEGA lesion ≥ 1.0 cm in longest diameter, or new or worsening hydrocephalus. The median value was not reached in either treatment arm of core period as SEGA worsening was observed in less participants (everolimus - 7 and placebo - 8).
Time Frame Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)  
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 analysis was performed in the FAS population. Here, "Number of participants analysed" signifies the participants assessed for time to SEGA worsening 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)  
Number of Participants Analyzed  
[units: participants]
  78     39     111  
Time to SEGA Worsening  
[units: months]
Median (95% Confidence Interval)
  NA  
  [1]
  NA  
  [2]
  55.72  
  (55.72 to N/A) [3]
[1] Median was not achieved as only 7 events of SEGA progression were observed.
[2] Median was not achieved as only 8 events of SEGA progression were observed.
[3] Median upper value was not available as only single of SEGA progression were observed.

No statistical analysis provided for Time to SEGA Worsening



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) ]

Measure Type Secondary
Measure Title Percentage of Participants With Skin Lesions Assessed Using Physician's Global Assessement Overall Score
Measure Description Skin lesions included hypomelanotic macules, the shagreen patch, periungual or subungual fibromas, facial angiofibromas and/or forehead plaques. Response was evaluated using the Physician’s Global Assessment of Clinical Condition (PGA) on a 7-point scale: Grade 0 = complete clinical response, indicated absence of disease, Grade 1, 2, and 3 = partial response, indicated improvements of ≥ 50% but < 100%, Grade 4, 5 = stable disease, indicated some or no improvements of 25% - < 50% and 6 = progressive disease, indicated worse than at baseline evaluation by > 25%. Response rate was determined for participants with ≥ 1 skin lesion at baseline, defined as the percentage of participants with overall status as complete clinical response or partial response.
Time Frame End of core period (Week 48), and end of extension period (up to 4 years)  
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 analysis was performed in the FAS population. Here, "Number of participants analysed" signifies the participants assessed for skin lesion response 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)  
Number of Participants Analyzed  
[units: participants]
  72     38     105  
Percentage of Participants With Skin Lesions Assessed Using Physician's Global Assessement Overall Score  
[units: Percentage of participants]
Number (95% Confidence Interval)
  41.7  
  (30.2 to 53.9)  
  10.5  
  (2.9 to 24.8)  
  58.1  
  (48.1 to 67.7)  

No statistical analysis provided for Percentage of Participants With Skin Lesions Assessed Using Physician's Global Assessement Overall Score



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) ]

Measure Type Secondary
Measure Title Duration of Skin Lesion Response in Everolimus Treated Participants
Measure Description Duration of skin lesion response was defined as the time from the first skin lesion response until the first skin lesion progression, defined as worsening of lesion by > 25% or more from baseline.
Time Frame Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)  
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 analysis was performed in the FAS population. Here, “Number of participants analysed” signifies everolimus treated responders with best overall skin lesion response during the core and extension period, 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.
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)     Everolimus (Extension Period)  
Number of Participants Analyzed  
[units: participants]
  30     61  
Duration of Skin Lesion Response in Everolimus Treated Participants  
[units: months]
Median (95% Confidence Interval)
  NA  
  [1]
  NA  
  [1]
[1] Median was not achieved as no case of skin lesion was observed.

No statistical analysis provided for Duration of Skin Lesion Response in Everolimus Treated Participants



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 ]

Measure Type Secondary
Measure Title Everolimus Blood Concentration (C2h) at 2 Hours Post Dose
Measure Description The participants were assessed for everolimus blood concentration at 2 hours time point after dose administration on the same day, if the participant did not vomit between previous dose and blood sample collection. Tandem liquid chromatography-mass spectrometry method was used for evaluation. C2h values were categorized as < 20 ng/mL, 20-50 ng/mL, and > 50 ng/mL, concentrations below the lower limit of quantification were entered as 0 ng/mL.
Time Frame 2 hours post dose on Week 6, Week 24, Week 48, Week 96, Week 144, and Week 240  
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 analysis was performed in the Safety Set population (Only evaluable PK Samples), defined as participants who received at least one dose of the double-blind study drug, with a valid post baseline assessment. The 'n' signifies those participants evaluable for this measure at specified time points for each group, 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.
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)     Everolimus (Extension Period)  
Number of Participants Analyzed  
[units: participants]
  78     111  
Everolimus Blood Concentration (C2h) at 2 Hours Post Dose  
[units: ng/mL]
Mean (Standard Deviation)
   
Week 6 (n= 37, 47)     27.52  (15.24)     27.74  (16.202)  
Week 24 (n= 11, 13)     38.7  (15.76)     39.25  (14.662)  
Week 48 (n= 1, 3)     23.2 [1]   49.73  (28.884)  
Week 96 (n= 0, 6)     NA [2]   31.63  (21.902)  
Week 144 (n= 0, 6)     NA [2]   26.33  (11.908)  
Week 240 (n= 0, 0)     NA [2]   NA [2]
[1] Only one participant was evaluable, so value was not available.
[2] No participant was evaluable, so value was not available.

No statistical analysis provided for Everolimus Blood Concentration (C2h) at 2 Hours Post Dose



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 ]

Measure Type Secondary
Measure Title Everolimus Trough Concentrations (Cmin) at 24 Hours After Last Dose
Measure Description The participants were assessed for everolimus trough concentration (Cmin) at 24 hours time point after previous dose administration, at a steady state following 5 days of consistent dosing, if the participant did not vomit within 4 hours of previous dose. Tandem liquid chromatography-mass spectrometry method was used for evaluation. Cmin values were categorized as <5 ng/mL, 5-10 ng/mL, and >10 ng/mL, concentrations below the lower limit of quantification were entered as 0 ng/mL.
Time Frame 24 hours post dose on Week 6, Week 24, Week 48, Week 72, Week 96, Week 144, and Week 240  
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 analysis was performed in the Safety Set population. The 'n' signifies those participants evaluable for this measure at specified time points for each group, 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.
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)     Everolimus (Extension Period)  
Number of Participants Analyzed  
[units: participants]
  78     111  
Everolimus Trough Concentrations (Cmin) at 24 Hours After Last Dose  
[units: ng/mL]
Mean (Standard Deviation)
   
Week 6 (n= 64, 94)     5.8  (3.68)     6.09  (3.708)  
Week 24 (n= 64, 89)     6.59  (3.43)     6.86  (3.504)  
Week 48 (n= 23, 86)     7.28  (3.11)     7.07  (3.214)  
Week 72 (n= 4, 92)     6.08  (2.19)     7.25  (3.66)  
Week 96 (n= 0, 83)     NA [1]   7.09  (3.697)  
Week 144 (n= 0, 69)     NA [1]   7.28  (3.35)  
Week 240 (n= 0, 13)     NA [1]   5.85  (2.507)  
[1] No participant was evaluable, so value was not available.

No statistical analysis provided for Everolimus Trough Concentrations (Cmin) at 24 Hours After Last Dose



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) ]

Measure Type Secondary
Measure Title Percentage of Participants With Renal Impairment During Core Period
Measure Description Renal function was assessed using glomerular filtration rate (GFR) based on age measure; Modification of Diet in Renal Disease (MDRD) formula for participants aged 18 years or older, defined as GFR equal to 32788*(serum creatinine (micromol/L)^-1.154)*(age^-0.203 )*(0.742, if female)*(1.210, if black), and Schwartz formula for participants less than 18 years defined as GFR equal to 0.41*height (cm)/ Serum creatinine (mg/dL). Participants with severe renal impairment defined as GFR < 30 mL/min/1.73 m^2 and participants with National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 3/4 serum creatinine were reported.
Time Frame Day 1 up to 28 days after end of treatment (Core period)  
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 analysis was performed in the SAF population. Here, "Number of participants analysed" signifies the participants assessed for renal function 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.

Measured Values
    Everolimus (Core Period)     Placebo (Core Period)  
Number of Participants Analyzed  
[units: participants]
  78     39  
Percentage of Participants With Renal Impairment During Core Period  
[units: Percentage of participants]
   
Grade 3 or 4     0     0  
Grade 1 or 2     3.8     0  
Grade 0     96.2     100  

No statistical analysis provided for Percentage of Participants With Renal Impairment During Core Period




  Serious Adverse Events


  Other Adverse Events
  Hide Other Adverse Events

Time Frame Serious Adverse Events were monitored from date of First Participant First Visit (FPFV) until Last Participant Last Visit (LPLV), 48 weeks and all other adverse events are monitored from First Participant First Treatment (FPFT) until LPLV, up to 4 years.
Additional Description For safety, the reporting arms have been created on the basis of actual exposure to study treatment

Frequency Threshold
Threshold above which other adverse events are reported   5  

Reporting Groups
  Description
Everolimus Treated (Core and Extension Period) Participants who received everolimus treatment in core period and continued to receive evrolimus treatment in extension period.
Placebo (Core) Then Everolimus Treated (Extension Period) Participants who received placebo in core period and then received evrolimus treatment in extension period.
Placebo Treated (Core Period) Participants who received placebo in core period.

Other Adverse Events
    Everolimus Treated (Core and Extension Period)     Placebo (Core) Then Everolimus Treated (Extension Period)     Placebo Treated (Core Period)  
Total, other (not including serious) adverse events        
# participants affected / at risk     77/78 (98.72%)     33/33 (100.00%)     6/6 (100.00%)  
Blood and lymphatic system disorders        
Anaemia † 1      
# participants affected / at risk     6/78 (7.69%)     1/33 (3.03%)     0/6 (0.00%)  
Neutropenia † 1      
# participants affected / at risk     8/78 (10.26%)     3/33 (9.09%)     0/6 (0.00%)  
Ear and labyrinth disorders        
Ear pain † 1      
# participants affected / at risk     2/78 (2.56%)     2/33 (6.06%)     0/6 (0.00%)  
Vertigo † 1      
# participants affected / at risk     0/78 (0.00%)     0/33 (0.00%)     1/6 (16.67%)  
Endocrine disorders        
Hypothyroidism † 1      
# participants affected / at risk     0/78 (0.00%)     0/33 (0.00%)     1/6 (16.67%)  
Gastrointestinal disorders        
Abdominal pain † 1      
# participants affected / at risk     5/78 (6.41%)     0/33 (0.00%)     1/6 (16.67%)  
Abdominal pain upper † 1      
# participants affected / at risk     5/78 (6.41%)     3/33 (9.09%)     0/6 (0.00%)  
Constipation † 1      
# participants affected / at risk     11/78 (14.10%)     2/33 (6.06%)     0/6 (0.00%)  
Dental caries † 1      
# participants affected / at risk     5/78 (6.41%)     2/33 (6.06%)     0/6 (0.00%)  
Diarrhoea † 1      
# participants affected / at risk     21/78 (26.92%)     7/33 (21.21%)     0/6 (0.00%)  
Enteritis † 1      
# participants affected / at risk     2/78 (2.56%)     0/33 (0.00%)     1/6 (16.67%)  
Mouth ulceration † 1      
# participants affected / at risk     33/78 (42.31%)     6/33 (18.18%)     0/6 (0.00%)  
Nausea † 1      
# participants affected / at risk     7/78 (8.97%)     1/33 (3.03%)     0/6 (0.00%)  
Oral pain † 1      
# participants affected / at risk     4/78 (5.13%)     1/33 (3.03%)     0/6 (0.00%)  
Stomatitis † 1      
# participants affected / at risk     29/78 (37.18%)     21/33 (63.64%)     1/6 (16.67%)  
Toothache † 1      
# participants affected / at risk     1/78 (1.28%)     2/33 (6.06%)     0/6 (0.00%)  
Vomiting † 1      
# participants affected / at risk     24/78 (30.77%)     6/33 (18.18%)     1/6 (16.67%)  
General disorders        
Asthenia † 1      
# participants affected / at risk     0/78 (0.00%)     2/33 (6.06%)     0/6 (0.00%)  
Fatigue † 1      
# participants affected / at risk     16/78 (20.51%)     2/33 (6.06%)     0/6 (0.00%)  
Pyrexia † 1      
# participants affected / at risk     25/78 (32.05%)     7/33 (21.21%)     2/6 (33.33%)  
Immune system disorders        
Seasonal allergy † 1      
# participants affected / at risk     5/78 (6.41%)     5/33 (15.15%)     0/6 (0.00%)  
Infections and infestations        
Abscess † 1      
# participants affected / at risk     0/78 (0.00%)     0/33 (0.00%)     1/6 (16.67%)  
Body tinea † 1      
# participants affected / at risk     0/78 (0.00%)     2/33 (6.06%)     0/6 (0.00%)  
Bronchitis † 1      
# participants affected / at risk     14/78 (17.95%)     5/33 (15.15%)     1/6 (16.67%)  
Cellulitis † 1      
# participants affected / at risk     4/78 (5.13%)     0/33 (0.00%)     0/6 (0.00%)  
Conjunctivitis † 1      
# participants affected / at risk     7/78 (8.97%)     5/33 (15.15%)     0/6 (0.00%)  
Croup infectious † 1      
# participants affected / at risk     4/78 (5.13%)     0/33 (0.00%)     0/6 (0.00%)  
Ear infection † 1      
# participants affected / at risk     14/78 (17.95%)     4/33 (12.12%)     0/6 (0.00%)  
Fungal infection † 1      
# participants affected / at risk     0/78 (0.00%)     3/33 (9.09%)     0/6 (0.00%)  
Gastroenteritis † 1      
# participants affected / at risk     4/78 (5.13%)     2/33 (6.06%)     0/6 (0.00%)  
Gastroenteritis viral † 1      
# participants affected / at risk     9/78 (11.54%)     4/33 (12.12%)     0/6 (0.00%)  
Gastrointestinal infection † 1      
# participants affected / at risk     1/78 (1.28%)     2/33 (6.06%)     0/6 (0.00%)  
Gastrointestinal viral infection † 1      
# participants affected / at risk     4/78 (5.13%)     1/33 (3.03%)     0/6 (0.00%)  
Influenza † 1      
# participants affected / at risk     6/78 (7.69%)     2/33 (6.06%)     0/6 (0.00%)  
Laryngitis † 1      
# participants affected / at risk     4/78 (5.13%)     0/33 (0.00%)     0/6 (0.00%)  
Nasopharyngitis † 1      
# participants affected / at risk     30/78 (38.46%)     15/33 (45.45%)     1/6 (16.67%)  
Oral candidiasis † 1      
# participants affected / at risk     2/78 (2.56%)     0/33 (0.00%)     1/6 (16.67%)  
Otitis media † 1      
# participants affected / at risk     16/78 (20.51%)     5/33 (15.15%)     0/6 (0.00%)  
Pharyngitis † 1      
# participants affected / at risk     12/78 (15.38%)     7/33 (21.21%)     0/6 (0.00%)  
Pharyngitis streptococcal † 1      
# participants affected / at risk     15/78 (19.23%)     2/33 (6.06%)     1/6 (16.67%)  
Pneumonia † 1      
# participants affected / at risk     12/78 (15.38%)     3/33 (9.09%)     1/6 (16.67%)  
Respiratory tract infection † 1      
# participants affected / at risk     6/78 (7.69%)     1/33 (3.03%)     0/6 (0.00%)  
Respiratory tract infection viral † 1      
# participants affected / at risk     7/78 (8.97%)     3/33 (9.09%)     0/6 (0.00%)  
Rhinitis † 1      
# participants affected / at risk     8/78 (10.26%)     2/33 (6.06%)     0/6 (0.00%)  
Sinusitis † 1      
# participants affected / at risk     17/78 (21.79%)     4/33 (12.12%)     1/6 (16.67%)  
Tracheitis † 1      
# participants affected / at risk     0/78 (0.00%)     0/33 (0.00%)     1/6 (16.67%)  
Upper respiratory tract infection † 1      
# participants affected / at risk     23/78 (29.49%)     7/33 (21.21%)     3/6 (50.00%)  
Urinary tract infection † 1      
# participants affected / at risk     7/78 (8.97%)     1/33 (3.03%)     0/6 (0.00%)  
Varicella † 1      
# participants affected / at risk     4/78 (5.13%)     0/33 (0.00%)     0/6 (0.00%)  
Viral infection † 1      
# participants affected / at risk     6/78 (7.69%)     3/33 (9.09%)     0/6 (0.00%)  
Vulvovaginal mycotic infection † 1      
# participants affected / at risk     1/78 (1.28%)     1/33 (3.03%)     1/6 (16.67%)  
Injury, poisoning and procedural complications        
Arthropod bite † 1      
# participants affected / at risk     3/78 (3.85%)     4/33 (12.12%)     0/6 (0.00%)  
Excoriation † 1      
# participants affected / at risk     4/78 (5.13%)     0/33 (0.00%)     0/6 (0.00%)  
Fall † 1      
# participants affected / at risk     2/78 (2.56%)     0/33 (0.00%)     2/6 (33.33%)  
Hand fracture † 1      
# participants affected / at risk     0/78 (0.00%)     0/33 (0.00%)     1/6 (16.67%)  
Laceration † 1      
# participants affected / at risk     2/78 (2.56%)     2/33 (6.06%)     0/6 (0.00%)  
Limb injury † 1      
# participants affected / at risk     2/78 (2.56%)     1/33 (3.03%)     1/6 (16.67%)  
Lip injury † 1      
# participants affected / at risk     0/78 (0.00%)     1/33 (3.03%)     1/6 (16.67%)  
Investigations        
Activated partial thromboplastin time prolonged † 1      
# participants affected / at risk     4/78 (5.13%)     1/33 (3.03%)     0/6 (0.00%)  
Blood cholesterol increased † 1      
# participants affected / at risk     11/78 (14.10%)     3/33 (9.09%)     1/6 (16.67%)  
Blood fibrinogen decreased † 1      
# participants affected / at risk     5/78 (6.41%)     6/33 (18.18%)     0/6 (0.00%)  
Blood glucose increased † 1      
# participants affected / at risk     0/78 (0.00%)     0/33 (0.00%)     1/6 (16.67%)  
Blood lactate dehydrogenase increased † 1      
# participants affected / at risk     6/78 (7.69%)     0/33 (0.00%)     0/6 (0.00%)  
Blood triglycerides increased † 1      
# participants affected / at risk     7/78 (8.97%)     0/33 (0.00%)     0/6 (0.00%)  
Carbon dioxide decreased † 1      
# participants affected / at risk     4/78 (5.13%)     0/33 (0.00%)     0/6 (0.00%)  
Cardiac murmur † 1      
# participants affected / at risk     0/78 (0.00%)     0/33 (0.00%)     1/6 (16.67%)  
International normalised ratio increased † 1      
# participants affected / at risk     4/78 (5.13%)     1/33 (3.03%)     0/6 (0.00%)  
Low density lipoprotein increased † 1      
# participants affected / at risk     6/78 (7.69%)     2/33 (6.06%)     1/6 (16.67%)  
Neutrophil count decreased † 1      
# participants affected / at risk     6/78 (7.69%)     1/33 (3.03%)     0/6 (0.00%)  
Weight decreased † 1      
# participants affected / at risk     5/78 (6.41%)     1/33 (3.03%)     0/6 (0.00%)  
Metabolism and nutrition disorders        
Decreased appetite † 1      
# participants affected / at risk     12/78 (15.38%)     6/33 (18.18%)     0/6 (0.00%)  
Dehydration † 1      
# participants affected / at risk     2/78 (2.56%)     1/33 (3.03%)     2/6 (33.33%)  
Hypercholesterolaemia † 1      
# participants affected / at risk     11/78 (14.10%)     3/33 (9.09%)     0/6 (0.00%)  
Hyperlipidaemia † 1      
# participants affected / at risk     6/78 (7.69%)     0/33 (0.00%)     0/6 (0.00%)  
Hypertriglyceridaemia † 1      
# participants affected / at risk     4/78 (5.13%)     2/33 (6.06%)     0/6 (0.00%)  
Musculoskeletal and connective tissue disorders        
Pain in extremity † 1      
# participants affected / at risk     6/78 (7.69%)     0/33 (0.00%)     0/6 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)        
Skin papilloma † 1      
# participants affected / at risk     3/78 (3.85%)     0/33 (0.00%)     1/6 (16.67%)  
Nervous system disorders        
Convulsion † 1      
# participants affected / at risk     31/78 (39.74%)     13/33 (39.39%)     4/6 (66.67%)  
Dizziness † 1      
# participants affected / at risk     6/78 (7.69%)     3/33 (9.09%)     0/6 (0.00%)  
Epilepsy † 1      
# participants affected / at risk     3/78 (3.85%)     2/33 (6.06%)     1/6 (16.67%)  
Headache † 1      
# participants affected / at risk     13/78 (16.67%)     6/33 (18.18%)     1/6 (16.67%)  
Migraine with aura † 1      
# participants affected / at risk     0/78 (0.00%)     0/33 (0.00%)     1/6 (16.67%)  
Psychiatric disorders        
Abnormal behaviour † 1      
# participants affected / at risk     6/78 (7.69%)     0/33 (0.00%)     0/6 (0.00%)  
Aggression † 1      
# participants affected / at risk     10/78 (12.82%)     3/33 (9.09%)     0/6 (0.00%)  
Agitation † 1      
# participants affected / at risk     6/78 (7.69%)     1/33 (3.03%)     0/6 (0.00%)  
Anxiety † 1      
# participants affected / at risk     10/78 (12.82%)     3/33 (9.09%)     0/6 (0.00%)  
Insomnia † 1      
# participants affected / at risk     11/78 (14.10%)     4/33 (12.12%)     0/6 (0.00%)  
Irritability † 1      
# participants affected / at risk     5/78 (6.41%)     1/33 (3.03%)     0/6 (0.00%)  
Obsessive-compulsive disorder † 1      
# participants affected / at risk     5/78 (6.41%)     0/33 (0.00%)     0/6 (0.00%)  
Sleep disorder † 1      
# participants affected / at risk     1/78 (1.28%)     3/33 (9.09%)     0/6 (0.00%)  
Reproductive system and breast disorders        
Amenorrhoea † 1      
# participants affected / at risk     5/78 (6.41%)     0/33 (0.00%)     0/6 (0.00%)  
Respiratory, thoracic and mediastinal disorders        
Cough † 1      
# participants affected / at risk     23/78 (29.49%)     10/33 (30.30%)     1/6 (16.67%)  
Epistaxis † 1      
# participants affected / at risk     4/78 (5.13%)     3/33 (9.09%)     0/6 (0.00%)  
Nasal congestion † 1      
# participants affected / at risk     2/78 (2.56%)     2/33 (6.06%)     0/6 (0.00%)  
Oropharyngeal pain † 1      
# participants affected / at risk     6/78 (7.69%)     1/33 (3.03%)     0/6 (0.00%)  
Rhinorrhoea † 1      
# participants affected / at risk     4/78 (5.13%)     2/33 (6.06%)     0/6 (0.00%)  
Skin and subcutaneous tissue disorders        
Acne † 1      
# participants affected / at risk     18/78 (23.08%)     4/33 (12.12%)     0/6 (0.00%)  
Dermatitis † 1      
# participants affected / at risk     1/78 (1.28%)     2/33 (6.06%)     0/6 (0.00%)  
Dry skin † 1      
# participants affected / at risk     4/78 (5.13%)     1/33 (3.03%)     0/6 (0.00%)  
Eczema † 1      
# participants affected / at risk     5/78 (6.41%)     0/33 (0.00%)     0/6 (0.00%)  
Rash † 1      
# participants affected / at risk     12/78 (15.38%)     2/33 (6.06%)     0/6 (0.00%)  
Vascular disorders        
Hypertension † 1      
# participants affected / at risk     11/78 (14.10%)     1/33 (3.03%)     0/6 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA V17.0



  Limitations and Caveats
  Hide 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