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A Placebo-controlled Study of Efficacy & Safety of 2 Trough-ranges of Everolimus as Adjunctive Therapy in Patients With Tuberous Sclerosis Complex (TSC) & Refractory Partial-onset Seizures (EXIST-3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01713946
Recruitment Status : Completed
First Posted : October 25, 2012
Results First Posted : November 7, 2018
Last Update Posted : November 7, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Tuberous Sclerosis Complex-associated Refractory Seizures
Interventions Drug: RAD001
Drug: Placebo
Drug: Antiepileptic drug (1 to 3 only)
Drug: open label RAD001 (only used for post-extension phase)
Enrollment 366
Recruitment Details 355 patients were planned to be enrolled and a total of 366 patients were randomized: 117 to the everolimus targeted low-trough arm (LT), 130 to the everolimus targeted high-trough (HT) arm, and 119 to treatment with placebo.
Pre-assignment Details  
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL Participants who received placebo dispersible tablets for oral suspension at study start and switched to everolimus in Extension.
Period Title: Overall Study
Started 117 130 119 [1]
Completed Core Phase 110 122 114
Continued in Ext. Phase 110 119 114
Completed Ext. Phase 79 92 81
Continued in Post-Ext. Phase 78 90 81
Completed Post-Ext Phase 74 85 75
Did Not Continue in Ext Phase 0 3 0
Did Not Cont. in Post-Ext Phase 1 2 0
Completed 74 85 75
Not Completed 43 45 44
Reason Not Completed
Death             0             2             2
Adverse Event             19             14             13
Withdrawal by Subject             12             12             8
Lack of Efficacy             8             8             14
Protocol Violation             2             4             1
Lost to Follow-up             0             0             1
Administrative problems             1             0             0
Did not continue in Ext             0             3             0
Did not continue in Post-Ext. Phase             1             2             0
Patients never switched to everolimus             0             0             5
[1]
Of the 119 patients initially randomized to the Placebo arm, 5 patients never switched to everolimus
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo Total
Hide Arm/Group Description Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL Participants were randomized to receive placebo dispersible tablets for oral suspension. Total of all reporting groups
Overall Number of Baseline Participants 117 130 119 366
Hide Baseline Analysis Population Description
Full Analysis Set: The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization.
Age, Continuous   [1] 
Median (Full Range)
Unit of measure:  Years
Number Analyzed 117 participants 130 participants 119 participants 366 participants
9.72
(2.2 to 56.3)
10.08
(2.3 to 50.5)
10.34
(2.2 to 52.0)
10.06
(2.2 to 56.3)
[1]
Measure Analysis Population Description: The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization.
Age, Customized   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 117 participants 130 participants 119 participants 366 participants
< 6 years
33
  28.2%
37
  28.5%
34
  28.6%
104
  28.4%
6 to <12 years
37
  31.6%
39
  30.0%
37
  31.1%
113
  30.9%
12 to <18 years
26
  22.2%
31
  23.8%
25
  21.0%
82
  22.4%
18 to <65 years
21
  17.9%
23
  17.7%
23
  19.3%
67
  18.3%
[1]
Measure Analysis Population Description: The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization.
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 117 participants 130 participants 119 participants 366 participants
Female
53
  45.3%
65
  50.0%
58
  48.7%
176
  48.1%
Male
64
  54.7%
65
  50.0%
61
  51.3%
190
  51.9%
[1]
Measure Analysis Population Description: The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization.
Race/Ethnicity, Customized   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 117 participants 130 participants 119 participants 366 participants
Caucasian
76
  65.0%
84
  64.6%
77
  64.7%
237
  64.8%
Asian
29
  24.8%
31
  23.8%
27
  22.7%
87
  23.8%
Black
2
   1.7%
1
   0.8%
1
   0.8%
4
   1.1%
Native American
0
   0.0%
1
   0.8%
0
   0.0%
1
   0.3%
Pacific Islander
1
   0.9%
0
   0.0%
0
   0.0%
1
   0.3%
Other
9
   7.7%
13
  10.0%
14
  11.8%
36
   9.8%
[1]
Measure Analysis Population Description: The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization.
Weight   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 117 participants 130 participants 119 participants 366 participants
38.69  (22.802) 40.75  (27.267) 40.50  (24.923) 40.01  (25.093)
[1]
Measure Analysis Population Description: The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization.
Height   [1] 
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 117 participants 130 participants 119 participants 366 participants
135.65  (26.171) 136.25  (28.234) 135.67  (27.097) 135.87  (27.145)
[1]
Measure Analysis Population Description: The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization.
Body surface area   [1] 
Mean (Standard Deviation)
Unit of measure:  M^2
Number Analyzed 117 participants 130 participants 119 participants 366 participants
1.18  (0.437) 1.20  (0.501) 1.20  (0.476) 1.20  (0.472)
[1]
Measure Analysis Population Description: The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization.
Body mass index   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 117 participants 130 participants 119 participants 366 participants
19.29  (5.283) 19.56  (6.233) 19.78  (5.484) 19.55  (5.689)
[1]
Measure Analysis Population Description: The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization.
1.Primary Outcome
Title Core Phase: European Medicine Agency (EMA): Seizure Frequency Response Rate
Hide Description Comparison of response rates in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm. Response means at least a 50% reduction from baseline in partial-onset seizure frequency during the maintenance period of the core phase.
Time Frame Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Overall Number of Participants Analyzed 117 130 119
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of responders
28.2
(20.3 to 37.3)
40.0
(31.5 to 49.0)
15.1
(9.2 to 22.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Everolimus LT Target of 3 to 7 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.008
Comments [Not Specified]
Method Bonferroni-Holm
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.21
Confidence Interval (2-Sided) 95%
1.16 to 4.20
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Everolimus HT Target of 9 to 15 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Bonferroni-Holm
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.93
Confidence Interval (2-Sided) 95%
2.10 to 7.32
Estimation Comments [Not Specified]
2.Primary Outcome
Title Core Phase: Food & Drug Administration (FDA): Percentage Change From Baseline in Partial Onset-seizure Frequency
Hide Description

Comparison of median percent change from baseline in weekly seizure frequency in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm during maintenance period of the core phase. Percentage change from baseline in average weekly seizure frequency during the maintenance period of the Core phase (SFcfb) = 100 × (SFB - SFM) ÷ SFB where:

SFB is the average weekly seizure frequency in the Baseline phase SFM is the average weekly seizure frequency in the maintenance period of the Core phase A positive percentage change from baseline (SFcfb) means a reduction in seizure frequency whereas a negative percentage change from baseline (SFcfb) means an increase in seizure frequency.

Time Frame Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Overall Number of Participants Analyzed 117 130 119
Median (95% Confidence Interval)
Unit of Measure: Percentage change from baseline
29.29
(18.82 to 41.88)
39.55
(35.03 to 48.74)
14.86
(0.11 to 21.71)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Everolimus LT Target of 3 to 7 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method Bonferroni-Holm
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value 15.96
Confidence Interval (2-Sided) 95%
1.98 to 31.68
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Everolimus HT Target of 9 to 15 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Bonferroni-Holm
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 27.46
Confidence Interval (2-Sided) 95%
16.36 to 43.36
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Seizure-free Patients During the Maintenance Period of the Core Phase
Hide Description Comparison of seizure freedom (100% reduction in seizure frequency) in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm during maintenance period of the core phase. Seizure free means a 100% reduction from baseline in partial-onset seizure frequency during maintenance period of the core phase.
Time Frame Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Overall Number of Participants Analyzed 117 130 119
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of seizure-free participants
5.1
(1.9 to 10.8)
3.8
(1.3 to 8.7)
0.8
(0.0 to 4.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Everolimus LT Target of 3 to 7 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 6.55
Confidence Interval (2-Sided) 95%
0.77 to 55.73
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Everolimus HT Target of 9 to 15 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.99
Confidence Interval (2-Sided) 95%
0.57 to 44.03
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Core Phase: Percentage of Patients With at Least a 25% Reduction in Seizure Frequency
Hide Description Comparison of percentage of patients with at least ≥ 25% reduction in seizure frequency in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm during maintenance period of the core phase. At least 25% reduction from baseline in partial-onset seizure frequency during maintenance period of the core phase.
Time Frame Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Overall Number of Participants Analyzed 117 130 119
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
52.1
(42.7 to 61.5)
70.0
(61.3 to 77.7)
37.8
(29.1 to 47.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Everolimus LT Target of 3 to 7 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.77
Confidence Interval (2-Sided) 95%
1.05 to 2.97
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Everolimus HT Target of 9 to 15 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.82
Confidence Interval (2-Sided) 95%
2.25 to 6.48
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Core Phase: Distribution of Reduction From Baseline in Seizure Frequency
Hide Description Comparison of percentage of patients in six categories of seizure reduction from baseline (≤ -25% (exacerbation); > -25% to < 25% (no change); ≥ 25% to < 50%; ≥ 50% to < 75%; ≥ 75% to < 100%; 100% (seizure-freedom)) in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm during maintenance period of the core phase
Time Frame Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Overall Number of Participants Analyzed 117 130 119
Measure Type: Number
Unit of Measure: Percentage of participants
100% (seizure free) 5.1 3.8 0.8
≥ 75 to <100 (75% responder) 6.0 15.4 5.0
≥ 50 to <75 (50% responder) 17.1 20.8 9.2
≥ 25 to <50 (25% responder) 23.9 30.0 22.7
>-25 to <25 (No change) 35.0 18.5 41.2
≤ -25 (Exacerbation) 12.8 11.5 20.2
Missing (missing) 0.0 0.0 0.8
6.Secondary Outcome
Title Core Phase: Changes From Baseline in Number of Seizure-free Days
Hide Description Comparison of seizure-free days relative to baseline in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm during maintenance period of the core phase
Time Frame Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Overall Number of Participants Analyzed 117 130 119
Median (Full Range)
Unit of Measure: Number of seizure-free days -per 28 days
2.00
(-23.1 to 27.7)
4.01
(-10.0 to 27.5)
0.47
(-13.4 to 21.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Everolimus LT Target of 3 to 7 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.4
Confidence Interval (2-Sided) 95%
-0.4 to 3.1
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Everolimus HT Target of 9 to 15 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 4.2
Confidence Interval (2-Sided) 95%
2.5 to 5.9
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Core Phase: Probability That a Patient Remains On-treatment up to a Specified Time Point
Hide Description

Comparison of time to treatment discontinuation in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm during the core phase. Treatment duration is defined as the time from randomization until the date of permanent study treatment discontinuation (for any reason) at any time during the Core phase.

The percentage event-free probability estimate is the estimated probability that a patient will remain on-treatment up to a specified time point (Week 6, 12, 18)

Time Frame Week 6, Week 12, Week 18
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Overall Number of Participants Analyzed 117 130 119
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage event-free prob. estimates
Week 6
97.4
(92.3 to 99.2)
96.2
(91.0 to 98.4)
99.2
(94.2 to 99.9)
Week 12
95.7
(90.0 to 98.2)
95.4
(90.0 to 97.9)
97.5
(92.4 to 99.2)
Week 18
70.1
(60.9 to 77.5)
71.5
(62.9 to 78.5)
75.6
(66.9 to 82.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Everolimus LT Target of 3 to 7 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.27
Confidence Interval (2-Sided) 95%
0.77 to 2.07
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Everolimus HT Target of 9 to 15 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.20
Confidence Interval (2-Sided) 95%
0.74 to 1.96
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Core Phase: Change From Baseline in the QOLCE Overall Quality-of-life Score for Patients <11 Years
Hide Description Comparison of quality of life in the everolimus (from 3 age specific questionnaires) low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm at the end of the core phase. The Quality of Life Childhood Epilepsy (QOLCE) questionnaire, used for patients < 11 years at baseline, was completed by the patient’s parent or caregiver. It consists of 16 subscales (13 multi-item scales and 3 single item scales) and one overall quality-of-life score. Scores range from 0-100, with higher scores corresponding to improved QoL. The Overall Quality of Life Score is computed by adding each subscale score for each individual and then dividing by 16.
Time Frame Baseline, Week 18
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Overall Number of Participants Analyzed 65 69 63
Median (Full Range)
Unit of Measure: scores on a scale
Baseline Number Analyzed 63 participants 68 participants 55 participants
52.3
(26 to 75)
56.5
(26 to 76)
55.3
(33 to 74)
End of Core Phase Number Analyzed 56 participants 56 participants 50 participants
53.6
(24 to 79)
59.5
(36 to 78)
57.2
(20 to 77)
Change from Baseline Number Analyzed 55 participants 56 participants 47 participants
0.2
(-25 to 24)
0.0
(-19 to 18)
1.0
(-18 to 28)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Everolimus LT Target of 3 to 7 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least square means
Estimated Value -1.1
Confidence Interval (2-Sided) 95%
-4.4 to 2.1
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Everolimus HT Target of 9 to 15 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least square means
Estimated Value 1.0
Confidence Interval (2-Sided) 95%
-2.2 to 4.3
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Core Phase: Change From Baseline in the QOLIE-AD-48 Overall Quality-of-life Score for Patients >=11 to 18 Years
Hide Description Comparison of quality of life (from 3 age specific questionnaires) in the everolimus low-trough treatment arm (3-7 ng/mL), hightrough treatment arm (9-15 ng/mL) and placebo arm at the end of the core phase. The Quality of Life in Epilepsy Inventory for Adolescents-48 (QOLIE-AD-48) is a survey of health-related quality of life for adolescents 11 to 18 years of age with epilepsy. The QOLIE-AD-48 is completed by the patient. It contains 48 items which assess 8 subscales. Scores range from 0-100, with higher scores corresponding to improved QoL. The overall quality of life score is obtained by summing a linear combination of the 8 subscale scores, where each subscale is multiplied by a relative weight that is provided in the original publication.
Time Frame Baseline, Week 18
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Overall Number of Participants Analyzed 31 38 33
Median (Full Range)
Unit of Measure: scores on a scale
Baseline Number Analyzed 13 participants 15 participants 14 participants
56.1
(43 to 86)
58.8
(35 to 81)
59.6
(13 to 88)
End of Core Phase Number Analyzed 13 participants 13 participants 12 participants
58.5
(47 to 89)
60.7
(46 to 74)
65.4
(29 to 87)
Change from Baseline Number Analyzed 12 participants 13 participants 12 participants
4.7
(-11 to 11)
5.8
(-13 to 38)
7.2
(-18 to 25)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Everolimus LT Target of 3 to 7 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least square means
Estimated Value -2.1
Confidence Interval (2-Sided) 95%
-10.5 to 6.2
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Everolimus HT Target of 9 to 15 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least square means
Estimated Value 0.4
Confidence Interval (2-Sided) 95%
-7.8 to 8.6
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Core Phase: Change From Baseline in the QOLIE-31-P Overall Quality-of-life Score for Patients Aged >=18 Years
Hide Description Comparison of quality of life (from 3 age specific questionnaires) in the everolimus low-trough treatment arm (3-7 ng/mL), hightrough treatment arm (9-15 ng/mL) and placebo arm at the end of the core phase. The Quality of Life in Epilepsy Inventory-31-Problems (QOLIE-31-P) is a survey of health-related quality of life for adults with epilepsy. The QOLIE-31-P is completed by the patient. It contains 39 items, of which a total of 30 are used to make up 7 different subscales. Scores range from 0-100, with higher scores indicating a greater level of functioning and QoL. The overall quality of life score is obtained by summing a linear combination of the 7 subscale scores, where each subscale is multiplied by a relative weight that is obtained from the patient's answer to 7 items of this questionnaire.
Time Frame Baseline, Week 18
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Overall Number of Participants Analyzed 21 23 23
Median (Full Range)
Unit of Measure: scores on a scale
Baseline Number Analyzed 11 participants 11 participants 15 participants
39.5
(13 to 64)
43.2
(5 to 89)
43.6
(11 to 83)
End of Core Phase Number Analyzed 10 participants 11 participants 12 participants
48.6
(11 to 54)
37.1
(6 to 97)
54.8
(26 to 90)
Change from Baseline Number Analyzed 10 participants 11 participants 12 participants
-0.5
(-17 to 34)
0.4
(-47 to 20)
5.3
(-16 to 36)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Everolimus LT Target of 3 to 7 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least square means
Estimated Value -2.8
Confidence Interval (2-Sided) 95%
-17.9 to 12.3
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Everolimus HT Target of 9 to 15 ng/mL, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in least square means
Estimated Value -7.7
Confidence Interval (2-Sided) 95%
-22.0 to 6.6
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Core Phase: Change From Baseline in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score
Hide Description Comparison of adaptive functioning using the VABS-II composite score in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm. The Vineland II assesses an individual's development of personal independence & social responsibility. The questionnaire contains 433 items which assess 15 subdomains organized into the five domains of Communication, Daily Living Skills, Socialization, Motor Skills and Maladaptive Behavior. The overall Adaptive Behavior Composite (ABC) score is obtained by summing the standard scores of the first four domain scores for patients aged less than 7 years, or the first 3 domain scores for patients aged 7 or older (the Maladaptive Behavior domain is optional). The ABC standard score ranges from 20 to 160 with a mean of 100 and a standard deviation of 15. Higher scores correspond to improved adaptive level. Note that 2 questionnaires with ABC scores<20 (data issues) were included in this analysis.
Time Frame Baseline, 18 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The safety Set comprised all patients who received at least one dose of study treatment and had at least one post-baseline safety assessment in the Core phase (where the statement that a patient had no AE constitutes a safety assessment).
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Overall Number of Participants Analyzed 75 93 76
Median (Full Range)
Unit of Measure: scores on a scale
Baseline Number Analyzed 34 participants 34 participants 32 participants
58.00
(20.0 to 112.0)
56.50
(20.0 to 102.0)
55.00
(20.0 to 103.0)
End of Core Phase Number Analyzed 28 participants 39 participants 31 participants
54.00
(6.0 to 121.0)
55.00
(20.0 to 111.0)
55.00
(20.0 to 105.0)
Change from Baseline Number Analyzed 18 participants 23 participants 23 participants
-1.00
(-21.0 to 15.0)
0.00
(-13.0 to 15.0)
0.00
(-12.0 to 10.0)
12.Secondary Outcome
Title Long Term Evaluation: Effect of Everolimus Over Time in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score
Hide Description Comparison of adaptive functioning using the VABS-II composite score in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm. The Vineland II assesses an individual's development of personal independence & social responsibility. The questionnaire contains 433 items which assess 15 subdomains organized into the five domains of Communication, Daily Living Skills, Socialization, Motor Skills and Maladaptive Behavior. The overall Adaptive Behavior Composite (ABC) score is obtained by summing the standard scores of the first four domain scores for patients aged less than 7 years, or the first 3 domain scores for patients aged 7 or older (the Maladaptive Behavior domain is optional). The ABC standard score ranges from 20 to 160 with a mean of 100 and a standard deviation of 15. Higher scores correspond to improved adaptive level. Note that 2 questionnaires with ABC scores<20 (data issues) were included in this analysis.
Time Frame Baseline, Weeks 18, 42, 66 and 90
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Long Term Evaluation (LTE) efficacy set consists of all patients who received at least one dose of everolimus and had at least one efficacy assessment while on everolimus.
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo Everolimus Long Term Evaluation (LTE)
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Participants who were treated with everolimus either in the Core or Extension phases of the study and were evaluated for longer term safety and efficacy.
Overall Number of Participants Analyzed 0 0 0 239
Median (Full Range)
Unit of Measure: scores on a scale
Baseline Number Analyzed 0 participants 0 participants 0 participants 88 participants
56.00
(20.0 to 112.0)
Week 18 Number Analyzed 0 participants 0 participants 0 participants 94 participants
53.50
(4.0 to 121.0)
Week 42 Number Analyzed 0 participants 0 participants 0 participants 94 participants
55.50
(20.0 to 111.0)
Week 66 Number Analyzed 0 participants 0 participants 0 participants 88 participants
57.00
(20.0 to 112.0)
Week 90 Number Analyzed 0 participants 0 participants 0 participants 66 participants
49.50
(20.0 to 150.0)
13.Secondary Outcome
Title Core Phase: Change From Baseline in Wechsler Nonverbal Composite Score
Hide Description The brief version of the WNV consists of a 2-subtest battery: only Matrices and Recognition subtests for patients under 8, and Matrices and Spatial Span subtests for patients aged 8 to 21. Based on the raw scores obtained from the subtests, standardized z-scores were calculated for each subtest using the following formula: Zscore = (X - b)/Sb where X is the raw score of the subtest, b and Sb represent the mean and standard deviation respectively of the subtest score recorded at baseline for the study population. The composite WNV score was computed by summing up the Z-scores of the 3 subtests of the WNV (i.e. matrices, recognition, and coding for patients aged <8 years and matrices, spatial span, and coding for patients aged 8 to 21 years). The composite WNV score has no range.
Time Frame Baseline, Week 18
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The safety Set comprised all patients who received at least one dose of study treatment and had at least one post-baseline safety assessment in the Core phase (where the statement that a patient had no AE constitutes a safety assessment.
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo Everolimus Long Term Evaluation (LTE)
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Participants who were treated with everolimus either in the Core or Extension phases of the study and were evaluated for longer term safety and efficacy.
Overall Number of Participants Analyzed 89 94 85 0
Median (Full Range)
Unit of Measure: scores on a scale
Baseline Number Analyzed 63 participants 63 participants 52 participants 0 participants
-0.48
(-2.3 to 8.1)
-0.69
(-2.3 to 9.6)
-1.11
(-2.3 to 8.3)
End of Core Phase Number Analyzed 60 participants 63 participants 48 participants 0 participants
-0.04
(-2.3 to 8.1)
-0.89
(-2.3 to 7.5)
-0.51
(-2.3 to 10.1)
Change from Baseline Number Analyzed 58 participants 59 participants 46 participants 0 participants
0.00
(-2.5 to 1.6)
0.00
(-10.0 to 2.1)
0.00
(-3.3 to 1.7)
14.Secondary Outcome
Title Long Term Evaluation: Effect of Everolimus Over Time in the Overall Wechsler Nonverbal Composite Score
Hide Description The brief version of the WNV consists of a 2-subtest battery: only Matrices and Recognition subtests for patients under 8, and Matrices and Spatial Span subtests for patients aged 8 to 21. Based on the raw scores obtained from the subtests, standardized z-scores were calculated for each subtest using the following formula: Zscore = (X - b)/Sb where X is the raw score of the subtest, b and Sb represent the mean and standard deviation respectively of the subtest score recorded at baseline for the study population. The composite WNV score was computed by summing up the Z-scores of the 3 subtests of the WNV (i.e. matrices, recognition, and coding for patients aged <8 years and matrices, spatial span, and coding for patients aged 8 to 21 years). The composite WNV score has no range
Time Frame Baseline, Weeks 18, 42, 66 and 90
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Long Term Evaluation (LTE) efficacy set consists of all patients who received at least one dose of everolimus and had at least one efficacy assessment while on everolimus.
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo Everolimus Long Term Evaluation (LTE)
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Participants who were treated with everolimus either in the Core or Extension phases of the study and were evaluated for longer term safety and efficacy.
Overall Number of Participants Analyzed 0 0 0 265
Median (Full Range)
Unit of Measure: scores on a scale
Baseline Number Analyzed 0 participants 0 participants 0 participants 151 participants
-0.53
(-2.3 to 10.1)
Week 18 Number Analyzed 0 participants 0 participants 0 participants 160 participants
-0.44
(-2.3 to 9.5)
Week 42 Number Analyzed 0 participants 0 participants 0 participants 139 participants
-0.36
(-2.3 to 10.8)
Week 66 Number Analyzed 0 participants 0 participants 0 participants 104 participants
0.13
(-2.3 to 9.1)
Week 90 Number Analyzed 0 participants 0 participants 0 participants 82 participants
-0.06
(-2.3 to 9.0)
15.Secondary Outcome
Title Core Phase: Response Rate in Seizure Frequency by Time Normalized Minimum Concentration
Hide Description Comparison of response rate in seizure frequency for 5 categories of time-normalized minimum concentration (Cmin, TN) (< 3 ng/mL; 3-7 ng/mL; >7-<9 ng/mL; 9-15 ng/mL; >15 ng/mL). Response rate is the percentage of patients with ≥ 50% reduction from baseline in average weekly partial-onset seizure frequency during the maintenance period of the Core phase.
Time Frame Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Confirmed PK Sample Set from all everolimus-treated patients in the Safety Set was defined as: Cmin collected prior to dose administration on the same treatment day and 20-28 hours after the previous dose, at steady state, and with no evidence of vomiting within 4 hours of the previous dose.
Arm/Group Title <3 ng/mL 3-7 ng/mL >7-<9 ng/mL 9-15 ng/mL >15 ng/mL
Hide Arm/Group Description:
Observed TN-Cmin concentration during the maintenance of the core phase: <3 ng/mL
Observed TN-Cmin concentration during the maintenance of the core phase:3 - 7 ng/mL
Observed TN-Cmin concentration during the maintenance of the core phase: >7 - <9 ng/mL
Observed TN-Cmin concentration during the maintenance of the core phase: 9 - 15 ng/mL
Observed TN-Cmin concentration during the maintenance of the core phase: >15 ng/mL
Overall Number of Participants Analyzed 14 147 52 30 2
Median (95% Confidence Interval)
Unit of Measure: Percentage of responders
14.3
(1.8 to 42.8)
29.9
(22.7 to 38.0)
44.2
(30.5 to 58.7)
50.0
(31.3 to 68.7)
50.0
(1.3 to 98.7)
16.Secondary Outcome
Title Core Phase: Median Percentage Change From Baseline in Seizure Frequency by Time Normalized Minimum Concentration
Hide Description Percentage change from baseline in average weekly seizure frequency during the maintenance period of the Core phase is calculated as follow: (SFcfb) = 100 × (SFB - SFM) ÷ SFB where SFB is the average weekly seizure frequency in the Baseline phase and SFM is the average weekly seizure frequency in the maintenance period of the Core phase. A positive percentage change from baseline (SFcfb) means a reduction in seizure frequency whereas a negative percentage change from baseline (SFcfb) means an increase in seizure frequency.
Time Frame Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Confirmed PK Sample Set from all everolimus-treated patients in the Safety Set was defined as: Cmin collected prior to dose administration on the same treatment day and 20-28 hours after the previous dose, at steady state, and with no evidence of vomiting within 4 hours of the previous dose.
Arm/Group Title <3 ng/mL 3-7 ng/mL >7-<9 ng/mL 9-15 ng/mL >15 ng/mL
Hide Arm/Group Description:
Observed TN-Cmin concentration during the maintenance of the core phase: <3 ng/mL
Observed TN-Cmin concentration during the maintenance of the core phase:3 - 7 ng/mL
Observed TN-Cmin concentration during the maintenance of the core phase: >7 - <9 ng/mL
Observed TN-Cmin concentration during the maintenance of the core phase: 9 - 15 ng/mL
Observed TN-Cmin concentration during the maintenance of the core phase: >15 ng/mL
Overall Number of Participants Analyzed 14 147 52 30 2
Median (95% Confidence Interval)
Unit of Measure: Percentage change
20.55
(-8.45 to 35.39)
35.56
(24.43 to 41.88)
39.72
(28.02 to 62.79)
47.69
(36.46 to 66.32)
61.56
(42.73 to 80.38)
17.Secondary Outcome
Title Long Term Evaluation: Relationship Between Seizure Frequency and Time-normalized Everolimus Concentration at Trough (Cmin,TN) - Repeated Measures Analysis
Hide Description A repeated measures analysis considering fixed 2-week intervals and including the level of exposure (time-normalized Cmin values), the time on-treatment and the seizure frequency at baseline quantified the estimated percentage change over 2 weeks in seizure frequency associated with a double exposure to everolimus, 15 days more on treatment and half the seizure frequency at baseline. A positive percentage change means a reduction in seizure frequency whereas a negative percentage change means an increase in seizure frequency.
Time Frame During everolimus treatment from start of everolimus up to the end of the extension phase, an average of 1.7 year
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Confirmed PK Sample Set from all everolimus-treated patients in the Longer-term Evaluation (LTE) Safety Set, was defined as follows: Cmin collected prior to dose administration on the same treatment day and 20-28 hours after the previous dose, at steady state, and with no evidence of vomiting within 4 hours of the previous dose
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo Everolimus Long Term Evaluation (LTE)
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Participants who were treated with everolimus either in the Core or Extension phases of the study and were evaluated for longer term safety and efficacy.
Overall Number of Participants Analyzed 0 0 0 358
Mean (95% Confidence Interval)
Unit of Measure: % change over 2-wk in seizures freq.
By doubling the time-normalized Cmin (log scale)
8.93
(6.87 to 10.95)
By reporting half the seizure freq. at baseline
48.82
(46.37 to 51.15)
By adding 12 weeks on treatmen
6.42
(4.53 to 8.27)
18.Secondary Outcome
Title Core Phase: Impact of Everolimus on Anti-epileptic Drugs (AEDs) Concentrations
Hide Description Impact of everolimus on AED concentrations at trough. Pre-dose plasma samples to measure AED concentrations were measured at at Visits 1 (Screening), 2 (Baseline), 3, and 5. Effects of everolimus on the exposure of antiepileptic drugs was assessed by comparing the anti-epileptic drug concentrations at Visits 1 and 2 (AEDs alone) and at Visits 3 and 5 (AEDs plus everolimus).
Time Frame Baseline, Weeks 1 & 3
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Confirmed PK Sample Set from all everolimus-treated patients in the Safety Set and Long-term Evaluation (LTE) Safety Set was defined as: Cmin collected prior to dose administration on the same treatment day and 20-28 hours after the previous dose, at steady state, and with no evidence of vomiting within 4 hours of the previous dose.
Arm/Group Title Valporic Acid Carbamazepine Clobazam N-desmethylclobazam Topiramate TRI477 TRI476 Clonazepam Zonisamide Phenobarbital Phenytoin
Hide Arm/Group Description:
Antiepileptic drug
antiepileptic drug
antiepileptic drug
antiepileptic drug
antiepileptic drug
antiepileptic drug
antiepileptic drug
antiepileptic drug
antiepileptic drug
antiepileptic drug
antiepileptic drug
Overall Number of Participants Analyzed 86 34 37 37 34 31 31 17 12 11 7
Geometric Mean (90% Confidence Interval)
Unit of Measure: ng/mL
0.962
(0.913 to 1.014)
1.108
(1.016 to 1.208)
1.093
(1.037 to 1.153)
1.071
(1.017 to 1.127)
0.983
(0.872 to 1.108)
1.086
(0.913 to 1.291)
1.194
(0.936 to 1.523)
1.065
(0.974 to 1.163)
1.028
(0.971 to 1.089)
0.957
(0.886 to 1.034)
1.020
(0.874 to 1.190)
19.Secondary Outcome
Title Long Term Evaluation: Percentage Change From Start of Everolimus in Seizure Frequency by Time Window
Hide Description

Percentage change from start of everolimus in average weekly seizure frequency (SFcfe) = 100 × (SFe - SFtw) ÷ SFe where:

SFe is the average weekly seizure frequency in the 8-week period before start of everolimus SFtw is the average weekly seizure frequency in a 12-week time window A positive percentage change from start of everolimus (SFcfe) means a reduction in seizure frequency whereas a negative percentage change from start of everolimus (SFcfe) means an increase in seizure frequency.

Time Frame Baseline (8-week period before start of everolimus), Week 7 to 18, Week 19 to 30, and 12 weeks thereafter up to Week 102
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The LTE Efficacy Set included 361 patients who received at least one dose of everolimus in Core and Extension phase and had at least one valid postbaseline efficacy evaluation.
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo Everolimus Long Term Evaluation (LTE)
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Participants who were treated with everolimus either in the Core or Extension phases of the study and were evaluated for longer term safety and efficacy.
Overall Number of Participants Analyzed 0 0 0 361
Median (95% Confidence Interval)
Unit of Measure: Percent change
Week 18 Number Analyzed 0 participants 0 participants 0 participants 352 participants
31.65
(28.51 to 36.09)
Week 30 Number Analyzed 0 participants 0 participants 0 participants 335 participants
35.74
(29.37 to 39.06)
Week 42 Number Analyzed 0 participants 0 participants 0 participants 320 participants
42.86
(34.44 to 48.15)
Week 54 Number Analyzed 0 participants 0 participants 0 participants 299 participants
46.05
(39.93 to 53.61)
Week 66 Number Analyzed 0 participants 0 participants 0 participants 282 participants
49.07
(38.26 to 55.56)
Week 78 Number Analyzed 0 participants 0 participants 0 participants 252 participants
51.69
(43.88 to 61.58)
Week 90 Number Analyzed 0 participants 0 participants 0 participants 222 participants
57.33
(47.37 to 67.01)
Week 102 Number Analyzed 0 participants 0 participants 0 participants 191 participants
59.69
(52.13 to 70.94)
20.Secondary Outcome
Title Seizure Free Rates by Time Window
Hide Description Percentage of seizure-free participants for each 12-week time window.
Time Frame Weeks 18, 30, 42, 54, 66, 78, 90 & 102
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The LTE Efficacy Set included 361 patients who received at least one dose of everolimus in Core and Extension phase and had at least one valid post baseline efficacy evaluation.
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo Everolimus Long Term Evaluation (LTE)
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Participants who were treated with everolimus either in the Core or Extension phases of the study and were evaluated for longer term safety and efficacy.
Overall Number of Participants Analyzed 0 0 0 361
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of seizure-free participants
Week 18 Number Analyzed 0 participants 0 participants 0 participants 352 participants
3.98
(2.2 to 6.6)
Week 30 Number Analyzed 0 participants 0 participants 0 participants 335 participants
6.87
(4.4 to 10.1)
Week 42 Number Analyzed 0 participants 0 participants 0 participants 320 participants
8.44
(5.6 to 12.0)
Week 54 Number Analyzed 0 participants 0 participants 0 participants 299 participants
8.70
(5.8 to 12.5)
Week 66 Number Analyzed 0 participants 0 participants 0 participants 282 participants
10.99
(7.6 to 15.2)
Week 78 Number Analyzed 0 participants 0 participants 0 participants 252 participants
13.49
(9.5 to 18.3)
Week 90 Number Analyzed 0 participants 0 participants 0 participants 222 participants
14.86
(10.5 to 20.2)
Week 102 Number Analyzed 0 participants 0 participants 0 participants 191 participants
15.18
(10.4 to 21.1)
21.Secondary Outcome
Title Core Phase: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes
Hide Description Comparison of suicidality using the C-SSRS in the everolimus low-trough treatment arm (3-7 ng/mL), high-trough treatment arm (9-15 ng/mL) and placebo arm. The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used for suicide assessment developed by multiple institutions, including Columbia University, with NIMH support. The scale is evidence-supported and is part of a national and international public health initiative involving the assessment of suicidality. There are different scoring systems depending on the population. The important elements to note are that the higher the scores on the individual items and the more “yes” items, the higher the suicide risk.
Time Frame Baseline, Week 18
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Safety Set comprised all patients who received at least one dose of study treatment and had at least one post-Baseline safety assessment in the Core phase (where the statement that a patient had no AE constitutes a safety assessment).
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Overall Number of Participants Analyzed 117 130 119
Measure Type: Number
Unit of Measure: Participants
Completed suicide 0 0 0
Suicide attempt 1 0 0
Prep actions toward imminent suicidal behavior 2 0 0
Suicidal ideation 3 1 0
Self-injurious behavior without suicide intent 0 0 0
22.Secondary Outcome
Title Long Term Evaluation: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes
Hide Description The C-SSRS was completed at each visit. The table below presents the number of patients who reported at least one completed suicide, one suicide attempt, one preparatory action toward imminent suicidal behavior, one suicidal ideation and one self-injurious behavior without suicidal intent at any time point after starting everolimus.
Time Frame During everolimus treatment from start of everolimus up to permanent discontinuation of everolimus, an average of 2.3 years
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The LTE Efficacy Set included 361 patients who received at least one dose of everolimus in Core and Extension phase and had at least one valid post-baseline efficacy evaluation.
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Placebo Everolimus Long Term Evaluation (LTE)
Hide Arm/Group Description:
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL
Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL
Participants were randomized to receive placebo dispersible tablets for oral suspension.
Participants who were treated with everolimus either in the Core or Extension phases of the study and were evaluated for longer term safety and efficacy.
Overall Number of Participants Analyzed 0 0 0 361
Measure Type: Number
Unit of Measure: Participants
Completed suicide 0
Suicidal attempt 1
Prep. actions toward imminent suicidal behavior 2
Suicidal ideation 7
Self-injurious behavior without suicide intent 1
Time Frame Adverse Events were collected during everolimus treatment from start of everolimus up to permanent discontinuation of everolimus, an average of 2.3 years
Adverse Event Reporting Description The summary tables below include all adverse events starting or worsening on or after the first dose of everolimus, and starting no later than 30 days after the date of last dose of everolimus. Adverse events starting during the placebo period were not counted.
 
Arm/Group Title Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Everolimus Start Ext Everolimus All
Hide Arm/Group Description Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL Participants were randomized to receive everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL Participants who received placebo dispersible tablets for oral suspension at study start and switched to everolimus in Extension. Participants who were treated with everolimus either in the Core or Extension phases of the study and were evaluated for longer term safety and efficacy.
All-Cause Mortality
Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Everolimus Start Ext Everolimus All
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/117 (0.85%)   2/130 (1.54%)   1/114 (0.88%)   4/361 (1.11%) 
Show Serious Adverse Events Hide Serious Adverse Events
Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Everolimus Start Ext Everolimus All
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   50/117 (42.74%)   49/130 (37.69%)   38/114 (33.33%)   137/361 (37.95%) 
Blood and lymphatic system disorders         
Anaemia  1  2/117 (1.71%)  0/130 (0.00%)  1/114 (0.88%)  3/361 (0.83%) 
Febrile neutropenia  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Leukocytosis  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Leukopenia  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Pancytopenia  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Thrombocytopenia  1  1/117 (0.85%)  0/130 (0.00%)  1/114 (0.88%)  2/361 (0.55%) 
Cardiac disorders         
Cardiac arrest  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Ear and labyrinth disorders         
Ear pain  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Eye disorders         
Blepharitis  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Meibomianitis  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Retinal detachment  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Retinopathy proliferative  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Gastrointestinal disorders         
Abdominal distension  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Abdominal pain  1  0/117 (0.00%)  1/130 (0.77%)  1/114 (0.88%)  2/361 (0.55%) 
Constipation  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Diarrhoea  1  3/117 (2.56%)  2/130 (1.54%)  0/114 (0.00%)  5/361 (1.39%) 
Food poisoning  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Gastric ileus  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Gastrooesophageal reflux disease  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Intestinal ischaemia  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Mouth ulceration  1  3/117 (2.56%)  0/130 (0.00%)  1/114 (0.88%)  4/361 (1.11%) 
Nausea  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Stomatitis  1  2/117 (1.71%)  1/130 (0.77%)  1/114 (0.88%)  4/361 (1.11%) 
Swollen tongue  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Vomiting  1  1/117 (0.85%)  1/130 (0.77%)  2/114 (1.75%)  4/361 (1.11%) 
General disorders         
Asthenia  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Fatigue  1  0/117 (0.00%)  2/130 (1.54%)  0/114 (0.00%)  2/361 (0.55%) 
Pyrexia  1  5/117 (4.27%)  4/130 (3.08%)  2/114 (1.75%)  11/361 (3.05%) 
Sudden unexplained death in epilepsy  1  0/117 (0.00%)  2/130 (1.54%)  0/114 (0.00%)  2/361 (0.55%) 
Hepatobiliary disorders         
Hepatitis  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Immune system disorders         
Anaphylactic reaction  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Infections and infestations         
Abscess  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Abscess limb  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Appendicitis  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Bacteraemia  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Bronchitis  1  1/117 (0.85%)  3/130 (2.31%)  2/114 (1.75%)  6/361 (1.66%) 
Campylobacter colitis  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Cellulitis  1  1/117 (0.85%)  0/130 (0.00%)  2/114 (1.75%)  3/361 (0.83%) 
Corona virus infection  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Croup infectious  1  1/117 (0.85%)  2/130 (1.54%)  0/114 (0.00%)  3/361 (0.83%) 
Dacryocanaliculitis  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Ear infection  1  1/117 (0.85%)  0/130 (0.00%)  1/114 (0.88%)  2/361 (0.55%) 
Febrile infection  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Gastroenteritis  1  5/117 (4.27%)  5/130 (3.85%)  4/114 (3.51%)  14/361 (3.88%) 
Gastroenteritis viral  1  0/117 (0.00%)  1/130 (0.77%)  1/114 (0.88%)  2/361 (0.55%) 
Gastrointestinal infection  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
H1N1 influenza  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Herpangina  1  1/117 (0.85%)  1/130 (0.77%)  0/114 (0.00%)  2/361 (0.55%) 
Influenza  1  3/117 (2.56%)  1/130 (0.77%)  2/114 (1.75%)  6/361 (1.66%) 
Lower respiratory tract infection  1  1/117 (0.85%)  0/130 (0.00%)  1/114 (0.88%)  2/361 (0.55%) 
Lung infection  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Mastoiditis  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Meningitis  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Oral herpes  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Osteomyelitis  1  0/117 (0.00%)  2/130 (1.54%)  0/114 (0.00%)  2/361 (0.55%) 
Otitis media  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Periorbital cellulitis  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Perirectal abscess  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Pharyngitis  1  2/117 (1.71%)  1/130 (0.77%)  1/114 (0.88%)  4/361 (1.11%) 
Pharyngitis streptococcal  1  0/117 (0.00%)  2/130 (1.54%)  0/114 (0.00%)  2/361 (0.55%) 
Pneumonia  1  16/117 (13.68%)  13/130 (10.00%)  9/114 (7.89%)  38/361 (10.53%) 
Pneumonia bacterial  1  0/117 (0.00%)  1/130 (0.77%)  1/114 (0.88%)  2/361 (0.55%) 
Pneumonia influenzal  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Pneumonia mycoplasmal  1  2/117 (1.71%)  0/130 (0.00%)  1/114 (0.88%)  3/361 (0.83%) 
Pneumonia viral  1  0/117 (0.00%)  1/130 (0.77%)  2/114 (1.75%)  3/361 (0.83%) 
Pseudocroup  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Pyelonephritis  1  2/117 (1.71%)  2/130 (1.54%)  0/114 (0.00%)  4/361 (1.11%) 
Pyelonephritis acute  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Respiratory tract infection  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Rotavirus infection  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Sepsis  1  1/117 (0.85%)  1/130 (0.77%)  0/114 (0.00%)  2/361 (0.55%) 
Septic shock  1  0/117 (0.00%)  1/130 (0.77%)  1/114 (0.88%)  2/361 (0.55%) 
Sinusitis  1  1/117 (0.85%)  1/130 (0.77%)  1/114 (0.88%)  3/361 (0.83%) 
Skin infection  1  0/117 (0.00%)  1/130 (0.77%)  1/114 (0.88%)  2/361 (0.55%) 
Tonsillitis  1  0/117 (0.00%)  2/130 (1.54%)  3/114 (2.63%)  5/361 (1.39%) 
Tooth abscess  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Tooth infection  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Upper respiratory tract infection  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Urinary tract infection  1  3/117 (2.56%)  0/130 (0.00%)  0/114 (0.00%)  3/361 (0.83%) 
Urosepsis  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Varicella  1  1/117 (0.85%)  0/130 (0.00%)  1/114 (0.88%)  2/361 (0.55%) 
Viraemia  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Viral infection  1  0/117 (0.00%)  0/130 (0.00%)  3/114 (2.63%)  3/361 (0.83%) 
Injury, poisoning and procedural complications         
Craniocerebral injury  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Fall  1  2/117 (1.71%)  1/130 (0.77%)  0/114 (0.00%)  3/361 (0.83%) 
Femur fracture  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Head injury  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Humerus fracture  1  0/117 (0.00%)  2/130 (1.54%)  0/114 (0.00%)  2/361 (0.55%) 
Tibia fracture  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Tongue injury  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Toxicity to various agents  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Investigations         
Hepatic enzyme increased  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Oxygen saturation decreased  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Urine output decreased  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Metabolism and nutrition disorders         
Decreased appetite  1  2/117 (1.71%)  0/130 (0.00%)  0/114 (0.00%)  2/361 (0.55%) 
Dehydration  1  1/117 (0.85%)  0/130 (0.00%)  1/114 (0.88%)  2/361 (0.55%) 
Feeding intolerance  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Hypocalcaemia  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Hypokalaemia  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Hyponatraemia  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Hypophagia  1  1/117 (0.85%)  1/130 (0.77%)  0/114 (0.00%)  2/361 (0.55%) 
Hypophosphataemia  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Musculoskeletal and connective tissue disorders         
Arthralgia  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Nervous system disorders         
Ataxia  1  1/117 (0.85%)  0/130 (0.00%)  2/114 (1.75%)  3/361 (0.83%) 
Dizziness  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Dyskinesia  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Encephalopathy  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Epilepsy  1  2/117 (1.71%)  0/130 (0.00%)  0/114 (0.00%)  2/361 (0.55%) 
Febrile convulsion  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Generalised tonic-clonic seizure  1  0/117 (0.00%)  1/130 (0.77%)  1/114 (0.88%)  2/361 (0.55%) 
Headache  1  0/117 (0.00%)  2/130 (1.54%)  0/114 (0.00%)  2/361 (0.55%) 
Ischaemic stroke  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Lethargy  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Loss of consciousness  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Moyamoya disease  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Seizure  1  7/117 (5.98%)  7/130 (5.38%)  4/114 (3.51%)  18/361 (4.99%) 
Seizure cluster  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Status epilepticus  1  7/117 (5.98%)  6/130 (4.62%)  2/114 (1.75%)  15/361 (4.16%) 
Stupor  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Tremor  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Psychiatric disorders         
Affect lability  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Aggression  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Confusional state  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Insomnia  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Mental status changes  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Mood altered  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Psychotic disorder  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Renal and urinary disorders         
Acute kidney injury  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Post streptococcal glomerulonephritis  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Reproductive system and breast disorders         
Menorrhagia  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Respiratory, thoracic and mediastinal disorders         
Aspiration  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Cough  1  1/117 (0.85%)  0/130 (0.00%)  1/114 (0.88%)  2/361 (0.55%) 
Interstitial lung disease  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Lung disorder  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Pneumonia aspiration  1  1/117 (0.85%)  1/130 (0.77%)  0/114 (0.00%)  2/361 (0.55%) 
Pneumonitis  1  0/117 (0.00%)  1/130 (0.77%)  1/114 (0.88%)  2/361 (0.55%) 
Pulmonary haemorrhage  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Respiratory failure  1  1/117 (0.85%)  1/130 (0.77%)  0/114 (0.00%)  2/361 (0.55%) 
Skin and subcutaneous tissue disorders         
Erythema nodosum  1  0/117 (0.00%)  1/130 (0.77%)  1/114 (0.88%)  2/361 (0.55%) 
Rash  1  0/117 (0.00%)  1/130 (0.77%)  0/114 (0.00%)  1/361 (0.28%) 
Rash generalised  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Skin lesion  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
Social circumstances         
Sexual abuse  1  0/117 (0.00%)  0/130 (0.00%)  1/114 (0.88%)  1/361 (0.28%) 
Vascular disorders         
Hypertension  1  1/117 (0.85%)  0/130 (0.00%)  0/114 (0.00%)  1/361 (0.28%) 
1
Term from vocabulary, MedDRA (20.1)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Everolimus LT Target of 3 to 7 ng/mL Everolimus HT Target of 9 to 15 ng/mL Everolimus Start Ext Everolimus All
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   110/117 (94.02%)   126/130 (96.92%)   109/114 (95.61%)   345/361 (95.57%) 
Blood and lymphatic system disorders         
Anaemia  1  10/117 (8.55%)  7/130 (5.38%)  4/114 (3.51%)  21/361 (5.82%) 
Neutropenia  1  4/117 (3.42%)  9/130 (6.92%)  1/114 (0.88%)  14/361 (3.88%) 
Gastrointestinal disorders         
Abdominal pain  1  10/117 (8.55%)  4/130 (3.08%)  5/114 (4.39%)  19/361 (5.26%) 
Abdominal pain upper  1  7/117 (5.98%)  10/130 (7.69%)  5/114 (4.39%)  22/361 (6.09%) 
Aphthous ulcer  1  11/117 (9.40%)  23/130 (17.69%)  10/114 (8.77%)  44/361 (12.19%) 
Constipation  1  9/117 (7.69%)  12/130 (9.23%)  7/114 (6.14%)  28/361 (7.76%) 
Dental caries  1  6/117 (5.13%)  2/130 (1.54%)  3/114 (2.63%)  11/361 (3.05%) 
Diarrhoea  1  45/117 (38.46%)  42/130 (32.31%)  30/114 (26.32%)  117/361 (32.41%) 
Mouth ulceration  1  36/117 (30.77%)  44/130 (33.85%)  22/114 (19.30%)  102/361 (28.25%) 
Nausea  1  6/117 (5.13%)  7/130 (5.38%)  3/114 (2.63%)  16/361 (4.43%) 
Stomatitis  1  41/117 (35.04%)  48/130 (36.92%)  41/114 (35.96%)  130/361 (36.01%) 
Vomiting  1  28/117 (23.93%)  35/130 (26.92%)  16/114 (14.04%)  79/361 (21.88%) 
General disorders         
Fatigue  1  8/117 (6.84%)  11/130 (8.46%)  5/114 (4.39%)  24/361 (6.65%) 
Pyrexia  1  47/117 (40.17%)  56/130 (43.08%)  31/114 (27.19%)  134/361 (37.12%) 
Infections and infestations         
Bronchitis  1  11/117 (9.40%)  17/130 (13.08%)  8/114 (7.02%)  36/361 (9.97%) 
Conjunctivitis  1  11/117 (9.40%)  8/130 (6.15%)  6/114 (5.26%)  25/361 (6.93%) 
Ear infection  1  11/117 (9.40%)  19/130 (14.62%)  3/114 (2.63%)  33/361 (9.14%) 
Gastroenteritis  1  13/117 (11.11%)  15/130 (11.54%)  7/114 (6.14%)  35/361 (9.70%) 
Gingivitis  1  9/117 (7.69%)  4/130 (3.08%)  0/114 (0.00%)  13/361 (3.60%) 
Hordeolum  1  6/117 (5.13%)  5/130 (3.85%)  4/114 (3.51%)  15/361 (4.16%) 
Influenza  1  16/117 (13.68%)  18/130 (13.85%)  9/114 (7.89%)  43/361 (11.91%) 
Lower respiratory tract infection  1  7/117 (5.98%)  1/130 (0.77%)  2/114 (1.75%)  10/361 (2.77%) 
Nasopharyngitis  1  33/117 (28.21%)  35/130 (26.92%)  26/114 (22.81%)  94/361 (26.04%) 
Pharyngitis  1  11/117 (9.40%)  18/130 (13.85%)  8/114 (7.02%)  37/361 (10.25%) 
Respiratory tract infection  1  3/117 (2.56%)  0/130 (0.00%)  6/114 (5.26%)  9/361 (2.49%) 
Rhinitis  1  9/117 (7.69%)  9/130 (6.92%)  5/114 (4.39%)  23/361 (6.37%) 
Sinusitis  1  3/117 (2.56%)  15/130 (11.54%)  8/114 (7.02%)  26/361 (7.20%) 
Tonsillitis  1  11/117 (9.40%)  9/130 (6.92%)  4/114 (3.51%)  24/361 (6.65%) 
Upper respiratory tract infection  1  32/117 (27.35%)  42/130 (32.31%)  22/114 (19.30%)  96/361 (26.59%) 
Urinary tract infection  1  12/117 (10.26%)  10/130 (7.69%)  6/114 (5.26%)  28/361 (7.76%) 
Viral infection  1  9/117 (7.69%)  7/130 (5.38%)  2/114 (1.75%)  18/361 (4.99%) 
Injury, poisoning and procedural complications         
Arthropod bite  1  2/117 (1.71%)  7/130 (5.38%)  1/114 (0.88%)  10/361 (2.77%) 
Contusion  1  5/117 (4.27%)  8/130 (6.15%)  3/114 (2.63%)  16/361 (4.43%) 
Fall  1  15/117 (12.82%)  10/130 (7.69%)  8/114 (7.02%)  33/361 (9.14%) 
Laceration  1  3/117 (2.56%)  4/130 (3.08%)  6/114 (5.26%)  13/361 (3.60%) 
Skin abrasion  1  6/117 (5.13%)  5/130 (3.85%)  2/114 (1.75%)  13/361 (3.60%) 
Investigations         
Blood cholesterol increased  1  14/117 (11.97%)  20/130 (15.38%)  17/114 (14.91%)  51/361 (14.13%) 
Blood triglycerides increased  1  5/117 (4.27%)  10/130 (7.69%)  6/114 (5.26%)  21/361 (5.82%) 
Low density lipoprotein increased  1  6/117 (5.13%)  8/130 (6.15%)  3/114 (2.63%)  17/361 (4.71%) 
Weight decreased  1  10/117 (8.55%)  7/130 (5.38%)  8/114 (7.02%)  25/361 (6.93%) 
Metabolism and nutrition disorders         
Decreased appetite  1  13/117 (11.11%)  20/130 (15.38%)  6/114 (5.26%)  39/361 (10.80%) 
Hyperlipidaemia  1  4/117 (3.42%)  9/130 (6.92%)  2/114 (1.75%)  15/361 (4.16%) 
Hypertriglyceridaemia  1  9/117 (7.69%)  12/130 (9.23%)  6/114 (5.26%)  27/361 (7.48%) 
Nervous system disorders         
Headache  1  19/117 (16.24%)  19/130 (14.62%)  10/114 (8.77%)  48/361 (13.30%) 
Somnolence  1  8/117 (6.84%)  9/130 (6.92%)  4/114 (3.51%)  21/361 (5.82%) 
Psychiatric disorders         
Aggression  1  5/117 (4.27%)  8/130 (6.15%)  1/114 (0.88%)  14/361 (3.88%) 
Agitation  1  7/117 (5.98%)  1/130 (0.77%)  2/114 (1.75%)  10/361 (2.77%) 
Insomnia  1  8/117 (6.84%)  8/130 (6.15%)  2/114 (1.75%)  18/361 (4.99%) 
Irritability  1  5/117 (4.27%)  4/130 (3.08%)  7/114 (6.14%)  16/361 (4.43%) 
Reproductive system and breast disorders         
Menstruation irregular  1  1/117 (0.85%)  7/130 (5.38%)  3/114 (2.63%)  11/361 (3.05%) 
Respiratory, thoracic and mediastinal disorders         
Cough  1  29/117 (24.79%)  33/130 (25.38%)  15/114 (13.16%)  77/361 (21.33%) 
Epistaxis  1  4/117 (3.42%)  12/130 (9.23%)  3/114 (2.63%)  19/361 (5.26%) 
Nasal congestion  1  4/117 (3.42%)  7/130 (5.38%)  1/114 (0.88%)  12/361 (3.32%) 
Oropharyngeal pain  1  5/117 (4.27%)  10/130 (7.69%)  5/114 (4.39%)  20/361 (5.54%) 
Rhinorrhoea  1  10/117 (8.55%)  9/130 (6.92%)  3/114 (2.63%)  22/361 (6.09%) 
Skin and subcutaneous tissue disorders         
Acne  1  6/117 (5.13%)  14/130 (10.77%)  6/114 (5.26%)  26/361 (7.20%) 
Alopecia  1  4/117 (3.42%)  8/130 (6.15%)  2/114 (1.75%)  14/361 (3.88%) 
Dermatitis  1  7/117 (5.98%)  2/130 (1.54%)  2/114 (1.75%)  11/361 (3.05%) 
Dry skin  1  6/117 (5.13%)  3/130 (2.31%)  2/114 (1.75%)  11/361 (3.05%) 
Rash  1  14/117 (11.97%)  21/130 (16.15%)  13/114 (11.40%)  48/361 (13.30%) 
Vascular disorders         
Hypertension  1  6/117 (5.13%)  7/130 (5.38%)  6/114 (5.26%)  19/361 (5.26%) 
1
Term from vocabulary, MedDRA (20.1)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Results Point of Contact
Name/Title: Clinical Disclosure Office
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01713946     History of Changes
Other Study ID Numbers: CRAD001M2304
2011-000860-90 ( EudraCT Number )
First Submitted: October 9, 2012
First Posted: October 25, 2012
Results First Submitted: April 25, 2018
Results First Posted: November 7, 2018
Last Update Posted: November 7, 2018