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| ID | Type | Description | Link |
|---|---|---|---|
| 2011-000860-90 | EudraCT Number |
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This study evaluated the efficacy and safety of two trough-ranges of everolimus given as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who had refractory partial-onset seizures.
The study consisted of 4 phases for each patient Baseline phase:[From Screening Week -8 (V1) to randomization visit at Week 0 (V2)], Core phase [from randomization at Week 0 (V2) to Week 18 (V11)], Extension phase [from Week 18 (V11) until 48 weeks after the last patient had completed the core phase] and Post Extension phase [from end of Extension phase to end of study].
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Everolimus LT target of 3 - 7 ng/mL | Experimental | Participants received everolimus dispersible tablets for oral suspension with titration to a low trough (LT) range of 3 to 7 ng/mL plus 1 to 3 antiepileptic drugs. |
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| Everolimus HT target of 9 -15 ng/mL | Experimental | Participants received everolimus dispersible tablets for oral suspension with titration to a high trough (HT) range of 9 to 15 ng/mL plus 1 to 3 antiepileptic drugs. |
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| Placebo | Placebo Comparator | Participants received placebo plus 1 to 3 antiepileptic drugs. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| RAD001 | Drug | Everolimus tablets for oral suspension (dispersible tablets) were packaged as 2 mg tablets in blister packs and placed in boxes with color-coded labels, color 1 or color 2. |
| Measure | Description | Time Frame |
|---|---|---|
| Core Phase: European Medicine Agency (EMA): Seizure Frequency Response Rate | 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. | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
| Core Phase: Food & Drug Administration (FDA): Percentage Change From Baseline in Partial Onset-seizure Frequency | 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. | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Seizure-free Patients During the Maintenance Period of the Core Phase | 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. |
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Inclusion Criteria:
1. Male or female between the ages of 2 and 65 years (except in Europe where minimum age will be 1).
2. Clinically definite diagnosis of TSC per modified Gomez criteria 3. Diagnosis of partial-onset epilepsy according to the classification of the International League Against Epilepsy (1989) and revised in 2009.
4. Uncontrolled partial-onset seizures; must meet the following:
At least 16 reported quantifiable partial-onset seizures over the Baseline period with no continuous 21-day seizure-free period between Visit 1 (Screening Visit) and Visit 2 (Randomization visit), as per data captured in daily seizure diaries.
Prior history of failure to control partial-onset seizures despite having been treated with two or more sequential regimens of single or combined antiepileptic drugs.
Prior or concurrent use of vagal nerve stimulator (VNS) is allowed. If the patient is using VNS, device stimulator parameters must remain constant throughout the study.
Prior epilepsy surgery is allowed if performed at least 12 months before study entry.
5. Must be receiving one, two, or three AEDs at a stable dose for at least 4 weeks at the start of the 8-week prospective Baseline phase, remain on the same regimen throughout the Baseline phase, and intend to continue the same regimen throughout the 18-week double blind Core phase (rescue medications are permitted).
6. If female of child bearing potential, documentation of negative pregnancy test at time of informed consent and must use highly effective contraception during the study and for 8 weeks after stopping treatment 7. Sexually active males must use a condom during intercourse while taking study drug, and for 8 weeks after stopping study treatment 8. Hepatic, renal and blood laboratory values within the following range at screening :
AST and ALT levels < 2.5 x ULN
serum bilirubin <1.5 × ULN (this limit does not apply to patients with an elevated indirect bilirubin, if they have Gilbert's Syndrome),
serum creatinine < 1.5 x ULN
hemoglobin ≥ 9 g/dL
platelets ≥ 80,000/mm3
absolute neutrophil count ≥ 1,000/mm3 9. Written informed consent. Subjects or their legal guardians must have the ability to comprehend the informed consent form and be willing to provide informed consent.
10. Patient or caregiver must be able to reliably record seizures and keep a daily diary and recall adverse events.
Exclusion Criteria:
1. Patients with seizures secondary to metabolic, toxic, infectious or psychogenic disorder or drug abuse or current seizures related to an acute medical illness.
2. Presence of only non-motor partial seizures (NOT APPLICABLE per Amendment 2) 3. Patients with TSC who have SEGA in need of immediate surgical intervention. 4. Patients under 2 years of age with untreated infantile spasms. 5. Within 52 weeks prior to study entry, an episode of status epilepticus as defined in the protocol.
6. Patients with history of seizure clusters (where individual seizures cannot be accurately counted according to the judgment of the investigator) occurring within 26 weeks prior to study entry.
7. Patients who require rescue medication during the baseline phase for more than 6 days 8. Patients with non-TSC related progressive encephalopathy. 9. Patients who weigh less than 12 kg. 10. Patients with coexisting malignancies within the 3 years prior to randomization, except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
11. Patients with any severe and/or uncontrolled medical conditions at randomization such as:
Symptomatic congestive heart failure of New York Heart Association Class III or IV, history of left ventricular ejection fraction (LVEF) < 50%, QTc interval >460ms, congenital QT syndrome, unstable angina pectoris, myocardial infarction within 6 months of study entry, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease.
Significant symptomatic deterioration of lung function
Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, malabsorption syndrome or small bowel resection).
liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis
Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN.
Active skin, mucosa, ocular or GI disorders of Grade > 1.
Active (acute or chronic) or uncontrolled severe infections.
A known history of HIV seropositivity or other active viral infections. 12. Patients with an active, bleeding diathesis. 13. Patient with uncontrolled hyperlipidemia: fasting serum cholesterol > 300 mg/dL OR >7.75 mmol/L AND fasting triglycerides > 2.5 x ULN.
14. Patients who have had a major surgery or significant traumatic injury within 4 weeks of study entry.
15. Patients with a prior history of organ transplant. 16. Patients receiving more than 3 antiepileptic drugs at any time in the baseline phase or at randomization or who change the dose of the AEDs during 4 weeks before screening or during the baseline period.
17. Patients being treated with felbamate, unless treatment has been continuous for ≥ 1 year.
18. Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of study entry (including chemotherapy, radiation therapy, antibody based therapy, etc.).
19. Prior treatment with any investigational drug within the preceding 4 weeks prior to study entry.
20. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent at study entry. Topical or inhaled corticosteroids are allowed.
21. Patients who have received prior treatment with a systemic mTOR inhibitor (sirolimus, temsirolimus, everolimus) within 24 months of study entry. Patients who have received prior treatment with a topical mTOR inhibitor (sirolimus, temsirolimus, everolimus) within 4 weeks of study entry.
22. Patients with a known hypersensitivity to everolimus or other rapamycin-analogues (sirolimus, temsirolimus) or to its excipients.
23. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study 24. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
25. Patients with a Score of 4 or 5 on the Suicidal Ideation item within 2 years of Screening, or any "yes" on the Suicidal Behavior item of the Columbia-Suicide Severity Rating Scale at Screening or Baseline , who upon follow up with a healthcare professional are found to be severely depressed or suicidal.
26. Maintenance of a diet consisting of <40 g of carbohydrate per day within 3 months of screening
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama at Birmingham SC | Birmingham | Alabama | 35294 | United States | ||
| TGen/APNNA |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30169322 | Derived | Curatolo P, Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, de Vries PJ, Dlugos DJ, Fan J, Ridolfi A, Pelov D, Voi M, French JA. Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial. Lancet Child Adolesc Health. 2018 Jul;2(7):495-504. doi: 10.1016/S2352-4642(18)30099-3. Epub 2018 May 24. | |
| 27613521 |
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Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Everolimus LT Target of 3 to 7 ng/mL | 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 |
| FG001 | Everolimus HT Target of 9 to 15 ng/mL |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 25, 2016 | Apr 25, 2018 |
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| Placebo | Drug | Placebo tablets for oral suspension (dispersible tablets) were packaged as 2 mg tablets in blister packs and placed in boxes with color-coded labels, color 1 or color 2. |
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| Antiepileptic drug (1 to 3 only) | Drug | no more than any 3 of the listed antiepileptic drugs could be taken with the study drug or placebo. List of allowed antiepileptic drugs were: valporic acid, carbamazepine, clobazam, N-desmethylclobazam, topiramate,TRI477, TRI476, clonazepam, zonisamide, phenobarbital, phenytoin |
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| open label RAD001 (only used for post-extension phase) | Drug | everolimus tablets for oral suspension (dispersible tablets) were packaged as 2 mg tablets in blister backs in boxes with open label design and were taken during the Post-Extension phase, where all the participants, including those who were previously on placebo, took the 2mg tablets. |
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| Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
| Core Phase: Percentage of Patients With at Least a 25% Reduction in Seizure Frequency | 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. | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
| Core Phase: Distribution of Reduction From Baseline in Seizure Frequency | 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 | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
| Core Phase: Changes From Baseline in Number of Seizure-free Days | 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 | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
| Core Phase: Probability That a Patient Remains On-treatment up to a Specified Time Point | 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) | Week 6, Week 12, Week 18 |
| Core Phase: Change From Baseline in the QOLCE Overall Quality-of-life Score for Patients <11 Years | 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. | Baseline, Week 18 |
| Core Phase: Change From Baseline in the QOLIE-AD-48 Overall Quality-of-life Score for Patients >=11 to 18 Years | 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. | Baseline, Week 18 |
| Core Phase: Change From Baseline in the QOLIE-31-P Overall Quality-of-life Score for Patients Aged >=18 Years | 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. | Baseline, Week 18 |
| Core Phase: Change From Baseline in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score | 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. | Baseline, 18 weeks |
| Long Term Evaluation: Effect of Everolimus Over Time in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score | 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. | Baseline, Weeks 18, 42, 66 and 90 |
| Core Phase: Change From Baseline in Wechsler Nonverbal Composite Score | 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. | Baseline, Week 18 |
| Long Term Evaluation: Effect of Everolimus Over Time in the Overall Wechsler Nonverbal Composite Score | 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 | Baseline, Weeks 18, 42, 66 and 90 |
| Core Phase: Response Rate in Seizure Frequency by Time Normalized Minimum Concentration | 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. | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
| Core Phase: Median Percentage Change From Baseline in Seizure Frequency by Time Normalized Minimum Concentration | 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. | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
| Long Term Evaluation: Relationship Between Seizure Frequency and Time-normalized Everolimus Concentration at Trough (Cmin,TN) - Repeated Measures Analysis | 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. | During everolimus treatment from start of everolimus up to the end of the extension phase, an average of 1.7 year |
| Core Phase: Impact of Everolimus on Anti-epileptic Drugs (AEDs) Concentrations | 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). | Baseline, Weeks 1 & 3 |
| Long Term Evaluation: Percentage Change From Start of Everolimus in Seizure Frequency by Time Window | 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. | Baseline (8-week period before start of everolimus), Week 7 to 18, Week 19 to 30, and 12 weeks thereafter up to Week 102 |
| Seizure Free Rates by Time Window | Percentage of seizure-free participants for each 12-week time window. | Weeks 18, 30, 42, 54, 66, 78, 90 & 102 |
| Core Phase: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes | 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. | Baseline, Week 18 |
| Long Term Evaluation: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes | 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. | During everolimus treatment from start of everolimus up to permanent discontinuation of everolimus, an average of 2.3 years |
| Phoenix |
| Arizona |
| 85012 |
| United States |
| University of California at Los Angeles SC | Los Angeles | California | 90095 | United States |
| Children's Hospital Oakland SC | Oakland | California | 94609 | United States |
| Children's Hospital of Orange County SC | Orange | California | 92868-3874 | United States |
| Rady Children's Hospital SC | San Diego | California | 92123 | United States |
| Children's Hospital Colorado | Aurora | Colorado | 80045 | United States |
| Connecticut Childrens Medical Center SC | Hartford | Connecticut | 06106 | United States |
| University of Chicago SC - 2 | Chicago | Illinois | 60637 | United States |
| Kennedy Krieger Institute SC | Baltimore | Maryland | 21205 | United States |
| Children's Hospital Boston SC | Boston | Massachusetts | 02115 | United States |
| Minnesota Epilepsy Group - PA SC | Saint Paul | Minnesota | 55102-2383 | United States |
| Washington University School of Medicine SC-2 | St Louis | Missouri | 63110 | United States |
| Morristown Memorial Hospital SC-2 | Morristown | New Jersey | 07962 | United States |
| New York University Medical Center SC-3 | New York | New York | 10016 | United States |
| Cincinnati Children's Hospital Medical Center SC | Cincinnati | Ohio | 45229-3039 | United States |
| Oregon Health and Science University SC - 3 | Portland | Oregon | 97239 | United States |
| Children's Hospital of Philadelphia SC | Philadelphia | Pennsylvania | 19104-4399 | United States |
| LeBonheur Childrens Medical Group SC | Memphis | Tennessee | 38103 | United States |
| Texas Scottish Rite Hospital for Children Texas Scottish | Dallas | Texas | 75219 | United States |
| Texas Children s Hospital SC | Houston | Texas | 77030 | United States |
| The University of Texas Medical School-Houston SC | Houston | Texas | 77030 | United States |
| Novartis Investigative Site | CABA | Buenos Aires | C1428AQK | Argentina |
| Novartis Investigative Site | Córdoba | X5000JJS | Argentina |
| Novartis Investigative Site | Randwick | New South Wales | 2031 | Australia |
| Novartis Investigative Site | Parkville | Victoria | 3052 | Australia |
| Novartis Investigative Site | Perth | Western Australia | 6840 | Australia |
| Novartis Investigative Site | Jette | Brussels Capital | 1090 | Belgium |
| Novartis Investigative Site | Brussels | 1070 | Belgium |
| Novartis Investigative Site | Brussels | 1200 | Belgium |
| Novartis Investigative Site | Ghent | 9000 | Belgium |
| Novartis Investigative Site | Leuven | 3000 | Belgium |
| Novartis Investigative Site | Vancouver | British Columbia | V6H 3V4 | Canada |
| Novartis Investigative Site | Montreal | Quebec | H3T 1C5 | Canada |
| Novartis Investigative Site | Cali | Valle del Cauca Department | Colombia |
| Novartis Investigative Site | Bogotá | Colombia |
| Novartis Investigative Site | MedellÃn | Colombia |
| Novartis Investigative Site | Aarhus | 8000 C | Denmark |
| Novartis Investigative Site | Amiens | 80054 | France |
| Novartis Investigative Site | Angers | 49933 | France |
| Novartis Investigative Site | Bron | 69677 | France |
| Novartis Investigative Site | Lille | 59037 | France |
| Novartis Investigative Site | Marseille | 13385 | France |
| Novartis Investigative Site | Strasbourg | F-67098 | France |
| Novartis Investigative Site | Berlin | 12351 | Germany |
| Novartis Investigative Site | Bielefeld | 33617 | Germany |
| Novartis Investigative Site | Kehl-Kork | 77694 | Germany |
| Novartis Investigative Site | Kiel | 24105 | Germany |
| Novartis Investigative Site | Ioannina | GR | 455 00 | Greece |
| Novartis Investigative Site | Athens | 15236 | Greece |
| Novartis Investigative Site | Budapest | 1145 | Hungary |
| Novartis Investigative Site | Kaposvár | 7400 | Hungary |
| Novartis Investigative Site | NyÃregyháza | 4400 | Hungary |
| Novartis Investigative Site | Dublin | 12 | Ireland |
| Novartis Investigative Site | Bari | BA | 70124 | Italy |
| Novartis Investigative Site | Bologna | BO | 40133 | Italy |
| Novartis Investigative Site | Catania | CT | 95100 | Italy |
| Novartis Investigative Site | Genova | GE | 16147 | Italy |
| Novartis Investigative Site | Milan | MI | 20142 | Italy |
| Novartis Investigative Site | Pavia | PV | 27100 | Italy |
| Novartis Investigative Site | Roma | RM | 00161 | Italy |
| Novartis Investigative Site | Siena | SI | 53100 | Italy |
| Novartis Investigative Site | Okayama | Okayama-ken | 700-8558 | Japan |
| Novartis Investigative Site | Izumi | Osaka | 594-1101 | Japan |
| Novartis Investigative Site | Suita | Osaka | 565 0871 | Japan |
| Novartis Investigative Site | Shizuoka | Shizuoka | 420-8688 | Japan |
| Novartis Investigative Site | Setagaya-ku | Tokyo | 157-8535 | Japan |
| Novartis Investigative Site | Osaka | 534-0021 | Japan |
| Novartis Investigative Site | Guadalajara | Jalisco | 44280 | Mexico |
| Novartis Investigative Site | Heeze | 5591 VE | Netherlands |
| Novartis Investigative Site | Rotterdam | 3015 CN | Netherlands |
| Novartis Investigative Site | Utrecht | 3584CX | Netherlands |
| Novartis Investigative Site | Oslo | 0424 | Norway |
| Novartis Investigative Site | Warsaw | 04 730 | Poland |
| Novartis Investigative Site | Samara | Samara Oblast | 443095 | Russia |
| Novartis Investigative Site | Voronezh | Voronezh Oblast | 394024 | Russia |
| Novartis Investigative Site | Moscow | 119991 | Russia |
| Novartis Investigative Site | Moscow | 127412 | Russia |
| Novartis Investigative Site | Seoul | Korea | 03080 | South Korea |
| Novartis Investigative Site | Seoul | Korea | 05505 | South Korea |
| Novartis Investigative Site | Seoul | Korea | 06351 | South Korea |
| Novartis Investigative Site | Seoul | 03722 | South Korea |
| Novartis Investigative Site | Seville | Andalusia | 41013 | Spain |
| Novartis Investigative Site | Donostia / San Sebastian | Basque Country | 20080 | Spain |
| Novartis Investigative Site | Barcelona | Catalonia | 08035 | Spain |
| Novartis Investigative Site | Valencia | Valencia | 46026 | Spain |
| Novartis Investigative Site | Madrid | 28009 | Spain |
| Novartis Investigative Site | Tainan | Taiwan ROC | 70421 | Taiwan |
| Novartis Investigative Site | Kaohsiung City | 83301 | Taiwan |
| Novartis Investigative Site | Taipei | 10002 | Taiwan |
| Novartis Investigative Site | Bangkok | 10330 | Thailand |
| Novartis Investigative Site | Bangkok | 10400 | Thailand |
| Novartis Investigative Site | Bangkok | 10700 | Thailand |
| Novartis Investigative Site | Ankara | 06100 | Turkey (Türkiye) |
| Novartis Investigative Site | Ankara | 06500 | Turkey (Türkiye) |
| Novartis Investigative Site | Istanbul | 34093 | Turkey (Türkiye) |
| Novartis Investigative Site | Birmingham | B15 2WB | United Kingdom |
| Novartis Investigative Site | Buckinghamshire | SL9 0RJ | United Kingdom |
| Novartis Investigative Site | Cambridge | CB2 2QQ | United Kingdom |
| Novartis Investigative Site | Liverpool | L12 2AP | United Kingdom |
| Novartis Investigative Site | London | SW17 0QT | United Kingdom |
| Novartis Investigative Site | London | WC1N 3JH | United Kingdom |
| Novartis Investigative Site | Sheffield | S10 2TH | United Kingdom |
| Novartis Investigative Site | York | YO31 7EX | United Kingdom |
| Derived |
| French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, Curatolo P, de Vries PJ, Dlugos DJ, Berkowitz N, Voi M, Peyrard S, Pelov D, Franz DN. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Oct 29;388(10056):2153-2163. doi: 10.1016/S0140-6736(16)31419-2. Epub 2016 Sep 6. |
| 25682485 | Derived | Goyer I, Dahdah N, Major P. Use of mTOR inhibitor everolimus in three neonates for treatment of tumors associated with tuberous sclerosis complex. Pediatr Neurol. 2015 Apr;52(4):450-3. doi: 10.1016/j.pediatrneurol.2015.01.004. Epub 2015 Jan 14. |
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
| FG002 | Placebo | Participants who received placebo dispersible tablets for oral suspension at study start and switched to everolimus in Extension. |
| Completed Core Phase |
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| Continued in Ext. Phase |
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| Completed Ext. Phase |
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| Continued in Post-Ext. Phase |
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| Completed Post-Ext Phase |
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| Did Not Continue in Ext Phase |
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| Did Not Cont. in Post-Ext Phase |
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| COMPLETED |
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| NOT COMPLETED |
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Full Analysis Set: The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Everolimus LT Target of 3 to 7 ng/mL | 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 |
| BG001 | Everolimus HT Target of 9 to 15 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 |
| BG002 | Placebo | Participants were randomized to receive placebo dispersible tablets for oral suspension. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization. | Median | Full Range | years |
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| Age, Customized | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization. | Count of Participants | Participants |
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| Sex: Female, Male | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization. | Count of Participants | Participants |
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| Race/Ethnicity, Customized | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization. | Count of Participants | Participants |
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| Weight | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization. | Mean | Standard Deviation | kg |
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| Height | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization. | Mean | Standard Deviation | cm |
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| Body surface area | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization. | Mean | Standard Deviation | m^2 |
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| Body mass index | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization. | Mean | Standard Deviation | kg/m^2 |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Core Phase: European Medicine Agency (EMA): Seizure Frequency Response Rate | 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. | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization | Posted | Number | 95% Confidence Interval | Percentage of responders | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
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| Primary | Core Phase: Food & Drug Administration (FDA): Percentage Change From Baseline in Partial Onset-seizure Frequency | 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. | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization | Posted | Median | 95% Confidence Interval | Percentage change from baseline | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
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| Secondary | Percentage of Seizure-free Patients During the Maintenance Period of the Core Phase | 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. | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization | Posted | Number | 95% Confidence Interval | Percentage of seizure-free participants | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
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| Secondary | Core Phase: Percentage of Patients With at Least a 25% Reduction in Seizure Frequency | 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. | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization | Posted | Number | 95% Confidence Interval | Percentage of participants | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
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| Secondary | Core Phase: Distribution of Reduction From Baseline in Seizure Frequency | 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 | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization | Posted | Number | Percentage of participants | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
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| Secondary | Core Phase: Changes From Baseline in Number of Seizure-free Days | 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 | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization | Posted | Median | Full Range | Number of seizure-free days -per 28 days | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
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| Secondary | Core Phase: Probability That a Patient Remains On-treatment up to a Specified Time Point | 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) | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization | Posted | Number | 95% Confidence Interval | Percentage event-free prob. estimates | Week 6, Week 12, Week 18 |
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| Secondary | Core Phase: Change From Baseline in the QOLCE Overall Quality-of-life Score for Patients <11 Years | 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. | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization | Posted | Median | Full Range | scores on a scale | Baseline, Week 18 |
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| Secondary | Core Phase: Change From Baseline in the QOLIE-AD-48 Overall Quality-of-life Score for Patients >=11 to 18 Years | 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. | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization | Posted | Median | Full Range | scores on a scale | Baseline, Week 18 |
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| Secondary | Core Phase: Change From Baseline in the QOLIE-31-P Overall Quality-of-life Score for Patients Aged >=18 Years | 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. | The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization | Posted | Median | Full Range | scores on a scale | Baseline, Week 18 |
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| Secondary | Core Phase: Change From Baseline in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score | 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. | 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). | Posted | Median | Full Range | scores on a scale | Baseline, 18 weeks |
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| Secondary | Long Term Evaluation: Effect of Everolimus Over Time in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score | 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. | 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. | Posted | Median | Full Range | scores on a scale | Baseline, Weeks 18, 42, 66 and 90 |
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| Secondary | Core Phase: Change From Baseline in Wechsler Nonverbal Composite Score | 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. | 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. | Posted | Median | Full Range | scores on a scale | Baseline, Week 18 |
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| Secondary | Long Term Evaluation: Effect of Everolimus Over Time in the Overall Wechsler Nonverbal Composite Score | 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 | 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. | Posted | Median | Full Range | scores on a scale | Baseline, Weeks 18, 42, 66 and 90 |
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| Secondary | Core Phase: Response Rate in Seizure Frequency by Time Normalized Minimum Concentration | 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. | 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. | Posted | Median | 95% Confidence Interval | Percentage of responders | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
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| Secondary | Core Phase: Median Percentage Change From Baseline in Seizure Frequency by Time Normalized Minimum Concentration | 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. | 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. | Posted | Median | 95% Confidence Interval | Percentage change | Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase) |
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| Secondary | Long Term Evaluation: Relationship Between Seizure Frequency and Time-normalized Everolimus Concentration at Trough (Cmin,TN) - Repeated Measures Analysis | 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. | 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 | Posted | Mean | 95% Confidence Interval | % change over 2-wk in seizures freq. | During everolimus treatment from start of everolimus up to the end of the extension phase, an average of 1.7 year |
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| Secondary | Core Phase: Impact of Everolimus on Anti-epileptic Drugs (AEDs) Concentrations | 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). | 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. | Posted | Geometric Mean | 90% Confidence Interval | ng/mL | Baseline, Weeks 1 & 3 |
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| Secondary | Long Term Evaluation: Percentage Change From Start of Everolimus in Seizure Frequency by Time Window | 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. | 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. | Posted | Median | 95% Confidence Interval | Percent change | Baseline (8-week period before start of everolimus), Week 7 to 18, Week 19 to 30, and 12 weeks thereafter up to Week 102 |
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| Secondary | Seizure Free Rates by Time Window | Percentage of seizure-free participants for each 12-week time window. | 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. | Posted | Number | 95% Confidence Interval | Percentage of seizure-free participants | Weeks 18, 30, 42, 54, 66, 78, 90 & 102 |
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| Secondary | Core Phase: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes | 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. | 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). | Posted | Number | Participants | Baseline, Week 18 |
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| Secondary | Long Term Evaluation: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes | 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. | 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. | Posted | Number | Participants | During everolimus treatment from start of everolimus up to permanent discontinuation of everolimus, an average of 2.3 years |
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Adverse Events were collected during everolimus treatment from start of everolimus up to permanent discontinuation of everolimus, an average of 2.3 years
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.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Everolimus LT Target of 3 to 7 ng/mL | 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 | 1 | 117 | 50 | 117 | 110 | 117 |
| EG001 | Everolimus HT Target of 9 to 15 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 | 2 | 130 | 49 | 130 | 126 | 130 |
| EG002 | Everolimus Start Ext | Participants who received placebo dispersible tablets for oral suspension at study start and switched to everolimus in Extension. | 1 | 114 | 38 | 114 | 109 | 114 |
| EG003 | Everolimus All | 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. | 4 | 361 | 137 | 361 | 345 | 361 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (20.1) | Systematic Assessment |
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| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA (20.1) | Systematic Assessment |
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| Leukocytosis | Blood and lymphatic system disorders | MedDRA (20.1) | Systematic Assessment |
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| Leukopenia | Blood and lymphatic system disorders | MedDRA (20.1) | Systematic Assessment |
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| Pancytopenia | Blood and lymphatic system disorders | MedDRA (20.1) | Systematic Assessment |
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| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (20.1) | Systematic Assessment |
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| Cardiac arrest | Cardiac disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Ear pain | Ear and labyrinth disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Blepharitis | Eye disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Meibomianitis | Eye disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Retinal detachment | Eye disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Retinopathy proliferative | Eye disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Abdominal distension | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Food poisoning | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Gastric ileus | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Intestinal ischaemia | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Mouth ulceration | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Stomatitis | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Swollen tongue | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Asthenia | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Sudden unexplained death in epilepsy | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hepatitis | Hepatobiliary disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Anaphylactic reaction | Immune system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Abscess | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Abscess limb | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Appendicitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Bacteraemia | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Bronchitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Campylobacter colitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Cellulitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Corona virus infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Croup infectious | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Dacryocanaliculitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Ear infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Febrile infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Gastroenteritis viral | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Gastrointestinal infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| H1N1 influenza | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Herpangina | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Lower respiratory tract infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Lung infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Mastoiditis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Meningitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Oral herpes | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Osteomyelitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Otitis media | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Periorbital cellulitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Perirectal abscess | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Pharyngitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Pharyngitis streptococcal | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Pneumonia bacterial | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Pneumonia influenzal | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Pneumonia mycoplasmal | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Pneumonia viral | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Pseudocroup | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Pyelonephritis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Pyelonephritis acute | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Respiratory tract infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Rotavirus infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Sepsis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Septic shock | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Sinusitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Skin infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Tonsillitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Tooth abscess | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Tooth infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Urosepsis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Varicella | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Viraemia | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Viral infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Craniocerebral injury | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Fall | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Femur fracture | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Head injury | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Humerus fracture | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Tibia fracture | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Tongue injury | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Toxicity to various agents | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Hepatic enzyme increased | Investigations | MedDRA (20.1) | Systematic Assessment |
| |
| Oxygen saturation decreased | Investigations | MedDRA (20.1) | Systematic Assessment |
| |
| Urine output decreased | Investigations | MedDRA (20.1) | Systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Dehydration | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Feeding intolerance | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypocalcaemia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypophagia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypophosphataemia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Ataxia | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Dyskinesia | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Encephalopathy | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Epilepsy | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Febrile convulsion | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Generalised tonic-clonic seizure | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Ischaemic stroke | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Lethargy | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Loss of consciousness | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Moyamoya disease | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Seizure | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Seizure cluster | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Status epilepticus | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Stupor | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Tremor | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Affect lability | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Aggression | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Confusional state | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Mental status changes | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Mood altered | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Psychotic disorder | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Acute kidney injury | Renal and urinary disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Post streptococcal glomerulonephritis | Renal and urinary disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Menorrhagia | Reproductive system and breast disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Aspiration | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Interstitial lung disease | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Lung disorder | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Pneumonia aspiration | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Pulmonary haemorrhage | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Erythema nodosum | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Rash generalised | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Skin lesion | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Sexual abuse | Social circumstances | MedDRA (20.1) | Systematic Assessment |
| |
| Hypertension | Vascular disorders | MedDRA (20.1) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Neutropenia | Blood and lymphatic system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Abdominal pain upper | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Aphthous ulcer | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Dental caries | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Mouth ulceration | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Stomatitis | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Bronchitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Conjunctivitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Ear infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Gingivitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Hordeolum | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Lower respiratory tract infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Pharyngitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Respiratory tract infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Rhinitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Sinusitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Tonsillitis | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Viral infection | Infections and infestations | MedDRA (20.1) | Systematic Assessment |
| |
| Arthropod bite | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Contusion | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Fall | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Laceration | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Skin abrasion | Injury, poisoning and procedural complications | MedDRA (20.1) | Systematic Assessment |
| |
| Blood cholesterol increased | Investigations | MedDRA (20.1) | Systematic Assessment |
| |
| Blood triglycerides increased | Investigations | MedDRA (20.1) | Systematic Assessment |
| |
| Low density lipoprotein increased | Investigations | MedDRA (20.1) | Systematic Assessment |
| |
| Weight decreased | Investigations | MedDRA (20.1) | Systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hyperlipidaemia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypertriglyceridaemia | Metabolism and nutrition disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Somnolence | Nervous system disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Aggression | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Agitation | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Irritability | Psychiatric disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Menstruation irregular | Reproductive system and breast disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Acne | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Dermatitis | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA (20.1) | Systematic Assessment |
| |
| Hypertension | Vascular disorders | MedDRA (20.1) | Systematic Assessment |
|
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Disclosure Office | Novartis Pharmaceuticals | 862-778-8300 | novartis.email@novartis.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 11, 2017 | Oct 4, 2018 | SAP_001.pdf |
| ID | Term |
|---|---|
| D000068338 | Everolimus |
| D000927 | Anticonvulsants |
| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D002491 | Central Nervous System Agents |
| D045506 | Therapeutic Uses |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
Not provided
Not provided
| 6 to <12 years |
|
| 12 to <18 years |
|
| 18 to <65 years |
|
| Male |
|
| Asian |
|
| Black |
|
| Native American |
|
| Pacific Islander |
|
| Other |
|
| Odds Ratio (OR) |
| 3.93 |
| 2-Sided |
| 95 |
| 2.10 |
| 7.32 |
| Superiority |
| OG002 | Placebo | Participants were randomized to receive placebo dispersible tablets for oral suspension. |
|
|
|
|
|
|
|
|
|
|
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
Participants were randomized to receive placebo dispersible tablets for oral suspension.
|
|
|
| OG002 |
| Placebo |
Participants were randomized to receive placebo dispersible tablets for oral suspension. |
|
|
|
| OG002 | Placebo | Participants were randomized to receive placebo dispersible tablets for oral suspension. |
|
|
|
| OG002 | Placebo | Participants were randomized to receive placebo dispersible tablets for oral suspension. |
|
|
|
| Everolimus HT Target of 9 to 15 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 |
| OG002 | Placebo | Participants were randomized to receive placebo dispersible tablets for oral suspension. |
|
|
| Everolimus HT Target of 9 to 15 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 |
| OG002 | Placebo | Participants were randomized to receive placebo dispersible tablets for oral suspension. |
| OG003 | Everolimus Long Term Evaluation (LTE) | 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. |
|
|
| OG002 | Placebo | Participants were randomized to receive placebo dispersible tablets for oral suspension. |
| OG003 | Everolimus Long Term Evaluation (LTE) | 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. |
|
|
| OG002 | Placebo | Participants were randomized to receive placebo dispersible tablets for oral suspension. |
| OG003 | Everolimus Long Term Evaluation (LTE) | 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. |
|
|
| OG003 | 9-15 ng/mL | Observed TN-Cmin concentration during the maintenance of the core phase: 9 - 15 ng/mL |
| OG004 | >15 ng/mL | Observed TN-Cmin concentration during the maintenance of the core phase: >15 ng/mL |
|
|
| >7-<9 ng/mL |
Observed TN-Cmin concentration during the maintenance of the core phase: >7 - <9 ng/mL |
| OG003 | 9-15 ng/mL | Observed TN-Cmin concentration during the maintenance of the core phase: 9 - 15 ng/mL |
| OG004 | >15 ng/mL | Observed TN-Cmin concentration during the maintenance of the core phase: >15 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
| OG002 | Placebo | Participants were randomized to receive placebo dispersible tablets for oral suspension. |
| OG003 | Everolimus Long Term Evaluation (LTE) | 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. |
|
|
antiepileptic drug |
| OG004 | Topiramate | antiepileptic drug |
| OG005 | TRI477 | antiepileptic drug |
| OG006 | TRI476 | antiepileptic drug |
| OG007 | Clonazepam | antiepileptic drug |
| OG008 | Zonisamide | antiepileptic drug |
| OG009 | Phenobarbital | antiepileptic drug |
| OG010 | Phenytoin | antiepileptic drug |
|
|
| OG002 |
| Placebo |
Participants were randomized to receive placebo dispersible tablets for oral suspension. |
| OG003 | Everolimus Long Term Evaluation (LTE) | 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. |
|
|
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.
|
|
| OG002 | Placebo | Participants were randomized to receive placebo dispersible tablets for oral suspension. |
|
|
Participants were randomized to receive placebo dispersible tablets for oral suspension. |
| OG003 | Everolimus Long Term Evaluation (LTE) | 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. |
|
|
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