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

Novartis Pharmaceuticals366 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

366

Conditions

Tuberous Sclerosis Complex-associated Refractory Seizures

Interventions

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

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.

Eligibility

Sex: ALLMin age: 2 YearsMax age: 65 Years

Medical Language ↔ Plain English

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: 1. 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. 2. 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. 3. 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. 4. 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 :  1. AST and ALT levels \< 2.5 x ULN 2. serum bilirubin \<1.5 × ULN (this limit does not apply to patients with an elevated indirect bilirubin, if they have Gilbert's Syndrome), 3. serum creatinine \< 1.5 x ULN 4. hemoglobin ≥ 9 g/dL 5. platelets ≥ 80,000/mm3 6. 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: 1. 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. 2. Significant symptomatic deterioration of lung function 3. 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). 4. liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis 5. Uncontrolled diabetes as defined by fasting serum glucose \> 1.5 × ULN. 6. Active skin, mucosa, ocular or GI disorders of Grade \> 1. 7. Active (acute or chronic) or uncontrolled severe infections. 8. 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

Locations (104)

University of Alabama at Birmingham SC

Birmingham, Alabama, United States

TGen/APNNA

Phoenix, Arizona, United States

University of California at Los Angeles SC

Los Angeles, California, United States

Children's Hospital Oakland SC

Oakland, California, United States

Children's Hospital of Orange County SC

Orange, California, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, 18 weeks

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

Time frame: 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.

Time frame: Baseline, Week 18

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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: Baseline (8-week period before start of everolimus), Week 7 to 18, Week 19 to 30, and 12 weeks thereafter up to Week 102

Seizure Free Rates by Time Window

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

Time frame: 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.

Time frame: 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.

Time frame: During everolimus treatment from start of everolimus up to permanent discontinuation of everolimus, an average of 2.3 years