Nervous System Diseases

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Epilepsy

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Tuberous Sclerosis Complex

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Channel Blockers

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Everolimus

Sirolimus

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Zonisamide

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Clonazepam

Topiramate

Phenobarbital

Temsirolimus

MTOR Inhibitors

Clobazam

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

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.

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.

Participants received placebo plus 1 to 3 antiepileptic drugs.

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.

RAD001

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.

Placebo

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

Antiepileptic drug (1 to 3 only)

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.

open label RAD001 (only used for post-extension phase)

Novartis Pharmaceuticals

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 \[from end of Extension phase to end of study\].

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

A Three-arm, Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of Two Trough-ranges of Everolimus as Adjunctive Therapy in Patients With Tuberous Sclerosis Complex (TSC) Who Have Refractory Partial-onset Seizures

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

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.

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.

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.

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.

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

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

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)

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.

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.

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.

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 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 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

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.

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.

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.

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).

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.

Percentage of seizure-free participants for each 12-week time window.

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 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 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.

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

Everolimus LT Target 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

Everolimus HT Target of 9 to 15 ng/mL

Participants who received placebo dispersible tablets for oral suspension at study start and switched to everolimus in Extension.

Everolimus Start Ext

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.

Everolimus All

Participants were randomized to receive placebo dispersible tablets for oral suspension.

Total

The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization.

Age, Continuous

< 6 years

6 to <12 years

12 to <18 years

18 to <65 years

Age, Customized

Sex: Female, Male

Caucasian

Asian

Black

Native American

Pacific Islander

Other

Race/Ethnicity, Customized

Weight

Height

Body surface area

Body mass index

Full Analysis Set: The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization.

Clinical Disclosure Office

The Full Analysis Set (FAS) comprised all patients to whom study treatment was assigned by randomization

Core Phase: European Medicine Agency (EMA): Seizure Frequency Response Rate

Core Phase: Food & Drug Administration (FDA): Percentage Change From Baseline in Partial Onset-seizure Frequency

Percentage of Seizure-free Patients During the Maintenance Period of the Core Phase

Core Phase: Percentage of Patients With at Least a 25% Reduction in Seizure Frequency

100% (seizure free)

≥ 75 to <100 (75% responder)

≥ 50 to <75 (50% responder)

≥ 25 to <50 (25% responder)

>-25 to <25 (No change)

≤ -25 (Exacerbation)

Missing (missing)

Core Phase: Distribution of Reduction From Baseline in Seizure Frequency

Core Phase: Changes From Baseline in Number of Seizure-free Days

Week 6

Week 12

Week 18

Core Phase: Probability That a Patient Remains On-treatment up to a Specified Time Point

Baseline

End of Core Phase

Change from Baseline

Core Phase: Change From Baseline in the QOLCE Overall Quality-of-life Score for Patients <11 Years

Core Phase: Change From Baseline in the QOLIE-AD-48 Overall Quality-of-life Score for Patients >=11 to 18 Years

Core Phase: Change From Baseline in the QOLIE-31-P Overall Quality-of-life Score for Patients Aged >=18 Years

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).

Core Phase: Change From Baseline in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score

Week 42

Week 66

Week 90

Everolimus Long Term Evaluation (LTE)

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.

Long Term Evaluation: Effect of Everolimus Over Time in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score

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.

Core Phase: Change From Baseline in Wechsler Nonverbal Composite Score

Long Term Evaluation: Effect of Everolimus Over Time in the Overall Wechsler Nonverbal Composite Score

Observed TN-Cmin concentration during the maintenance of the core phase: \<3 ng/mL

<3 ng/mL

Observed TN-Cmin concentration during the maintenance of the core phase:3 - 7 ng/mL

3-7 ng/mL

Observed TN-Cmin concentration during the maintenance of the core phase: \>7 - \<9 ng/mL

>7-<9 ng/mL

Observed TN-Cmin concentration during the maintenance of the core phase: 9 - 15 ng/mL

9-15 ng/mL

Observed TN-Cmin concentration during the maintenance of the core phase: \>15 ng/mL

>15 ng/mL

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.

Core Phase: Response Rate in Seizure Frequency by Time Normalized Minimum Concentration

Core Phase: Median Percentage Change From Baseline in Seizure Frequency by Time Normalized Minimum Concentration

By doubling the time-normalized Cmin (log scale)

By reporting half the seizure freq. at baseline

By adding 12 weeks on treatmen

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

Long Term Evaluation: Relationship Between Seizure Frequency and Time-normalized Everolimus Concentration at Trough (Cmin,TN) - Repeated Measures Analysis

Valporic Acid

N-desmethylclobazam

TRI477

TRI476

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.

Core Phase: Impact of Everolimus on Anti-epileptic Drugs (AEDs) Concentrations

Week 30

Week 54

Week 78

Week 102

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.

Long Term Evaluation: Percentage Change From Start of Everolimus in Seizure Frequency by 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.

Seizure Free Rates by Time Window

Completed suicide

Suicide attempt

Prep actions toward imminent suicidal behavior

Suicidal ideation

Self-injurious behavior without suicide intent

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).

Core Phase: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes

Suicidal attempt

Prep. actions toward imminent suicidal behavior

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.

Long Term Evaluation: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	NCT01713946	Tuberous Sclero...	RAD001 Placebo Antiepileptic d... open label RAD0...	2 Years - 65 Years	Novartis
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	NCT01713946	Tuberous Sclero...	RAD001 Placebo Antiepileptic d... open label RAD0...	2 Years - 65 Years	Novartis
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	NCT01713946	Tuberous Sclero...	RAD001 Placebo Antiepileptic d... open label RAD0...	2 Years - 65 Years	Novartis

Spots Global Cancer Trial Database for antiepileptic drug (1 to 3 only)