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
- 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
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
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
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
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 both screening and randomization:
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.
- 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 3. Patients with TSC who have SEGA in
need of immediate surgical intervention. 4. Patients who suffer from active 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
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
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. 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.