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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 366
- 试验地点
- 23
- 主要终点
- Core Phase: European Medicine Agency (EMA): Seizure Frequency Response Rate
研究概览
简要总结
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].
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 2 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female between the ages of 2 and 65 years (except in Europe where minimum age will be 1).
- •Clinically definite diagnosis of TSC per modified Gomez criteria
- •Diagnosis of partial-onset epilepsy according to the classification of the International League Against Epilepsy (1989) and revised in
- •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.
- •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).
- •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
- •Sexually active males must use a condom during intercourse while taking study drug, and for 8 weeks after stopping study treatment
- •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
- •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.
- •Patient or caregiver must be able to reliably record seizures and keep a daily diary and recall adverse events.
排除标准
- •Patients with seizures secondary to metabolic, toxic, infectious or psychogenic disorder or drug abuse or current seizures related to an acute medical illness.
- •Presence of only non-motor partial seizures (NOT APPLICABLE per Amendment 2)
- •Patients with TSC who have SEGA in need of immediate surgical intervention.
- •Patients under 2 years of age with untreated infantile spasms.
- •Within 52 weeks prior to study entry, an episode of status epilepticus as defined in the protocol.
- •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.
- •Patients who require rescue medication during the baseline phase for more than 6 days
- •Patients with non-TSC related progressive encephalopathy.
- •Patients who weigh less than 12 kg.
- •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.
- •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 >
- •Active (acute or chronic) or uncontrolled severe infections.
- •A known history of HIV seropositivity or other active viral infections.
- •Patients with an active, bleeding diathesis.
- •Patient with uncontrolled hyperlipidemia: fasting serum cholesterol > 300 mg/dL OR >7.75 mmol/L AND fasting triglycerides > 2.5 x ULN.
- •Patients who have had a major surgery or significant traumatic injury within 4 weeks of study entry.
- •Patients with a prior history of organ transplant.
- •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.
- •Patients being treated with felbamate, unless treatment has been continuous for ≥ 1 year.
- •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.).
- •Prior treatment with any investigational drug within the preceding 4 weeks prior to study entry.
- •Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent at study entry. Topical or inhaled corticosteroids are allowed.
- •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.
- •Patients with a known hypersensitivity to everolimus or other rapamycin-analogues (sirolimus, temsirolimus) or to its excipients.
- •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
- •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.
- •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.
- •Maintenance of a diet consisting of <40 g of carbohydrate per day within 3 months of screening
研究组 & 干预措施
Everolimus LT target of 3 - 7 ng/mL
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.
干预措施: RAD001 (Drug)
Everolimus LT target of 3 - 7 ng/mL
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.
干预措施: Antiepileptic drug (1 to 3 only) (Drug)
Everolimus LT target of 3 - 7 ng/mL
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.
干预措施: open label RAD001 (only used for post-extension phase) (Drug)
Everolimus HT target of 9 -15 ng/mL
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.
干预措施: RAD001 (Drug)
Everolimus HT target of 9 -15 ng/mL
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.
干预措施: Antiepileptic drug (1 to 3 only) (Drug)
Everolimus HT target of 9 -15 ng/mL
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.
干预措施: open label RAD001 (only used for post-extension phase) (Drug)
Placebo
Participants received placebo plus 1 to 3 antiepileptic drugs.
干预措施: Placebo (Drug)
Placebo
Participants received placebo plus 1 to 3 antiepileptic drugs.
干预措施: Antiepileptic drug (1 to 3 only) (Drug)
Placebo
Participants received placebo plus 1 to 3 antiepileptic drugs.
干预措施: open label RAD001 (only used for post-extension phase) (Drug)
结局指标
主要结局
Core Phase: European Medicine Agency (EMA): Seizure Frequency Response Rate
时间窗: Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase)
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.
Core Phase: Food & Drug Administration (FDA): Percentage Change From Baseline in Partial Onset-seizure Frequency
时间窗: Baseline (8-week period before randomization), Week 7 to 18 (12-week 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.
次要结局
- Core Phase: Distribution of Reduction From Baseline in Seizure Frequency(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(Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase))
- Percentage of Seizure-free Patients 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: Change From Baseline in the QOLCE Overall Quality-of-life Score for Patients <11 Years(Baseline, Week 18)
- Long Term Evaluation: Effect of Everolimus Over Time in the Overall Wechsler Nonverbal Composite Score(Baseline, Weeks 18, 42, 66 and 90)
- Core Phase: Probability That a Patient Remains On-treatment up to a Specified Time Point(Week 6, Week 12, Week 18)
- Core Phase: Change From Baseline in the QOLIE-AD-48 Overall Quality-of-life Score for Patients >=11 to 18 Years(Baseline, Week 18)
- Core Phase: Change From Baseline in the QOLIE-31-P Overall Quality-of-life Score for Patients Aged >=18 Years(Baseline, Week 18)
- Long Term Evaluation: Relationship Between Seizure Frequency and Time-normalized Everolimus Concentration at Trough (Cmin,TN) - Repeated Measures Analysis(During everolimus treatment from start of everolimus up to the end of the extension phase, an average of 1.7 year)
- Core Phase: Percentage of Patients With at Least a 25% Reduction in Seizure Frequency(Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase))
- Core Phase: Impact of Everolimus on Anti-epileptic Drugs (AEDs) Concentrations(Baseline, Weeks 1 & 3)
- Long Term Evaluation: Percentage Change From Start of Everolimus in Seizure Frequency by Time Window(Baseline (8-week period before start of everolimus), Week 7 to 18, Week 19 to 30, and 12 weeks thereafter up to Week 102)
- Core Phase: Changes From Baseline in Number of Seizure-free Days(Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase))
- Core Phase: Change From Baseline in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score(Baseline, 18 weeks)
- Long Term Evaluation: Effect of Everolimus Over Time in the Overall Vineland-II Adaptive Behavior Composite (ABC) Score(Baseline, Weeks 18, 42, 66 and 90)
- Core Phase: Response Rate in Seizure Frequency by Time Normalized Minimum Concentration(Baseline (8-week period before randomization), Week 7 to 18 (12-week maintenance period of the core phase))
- Seizure Free Rates by Time Window(Weeks 18, 30, 42, 54, 66, 78, 90 & 102)
- Core Phase: Change From Baseline in Wechsler Nonverbal Composite Score(Baseline, Week 18)
- Core Phase: Incidence of Suicide Attempt, Suicidal Ideation or Behavior During Core Phase Per Columbia Suicide Severity Rating Scale (C-SSRS) Outcomes(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(During everolimus treatment from start of everolimus up to permanent discontinuation of everolimus, an average of 2.3 years)