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
Condition: Tuberous Sclerosis Complex-associated Refractory Seizures
MeSH terms: Tuberous Sclerosis; Seizures; Sclerosis
Intervention: RAD001; Placebo; Antiepileptic drug (1 to 3 only); open label RAD001 (only used for post-extension phase)
Intervention description: 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.; 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.; 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; 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.
Intervention MeSH terms: Everolimus; Anticonvulsants
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 366.0
Sex: All
Minimum age: 2 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: TSC seizures; TSC epilepsy; mTOR inhibitor; RAD001; Everolimus

Summary:

      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].
    

Eligibility criteria:

        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