Please select the eligibility criteria that correspond to the clinical trial below.
Title: Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex
Brief Summary: Tuberous sclerosis complex (TSC) is a genetic disease that leads to mental retardation in over 50% of patients, and to learning problems, behavioral problems, autism and epilepsy in up to 90% of patients. The underlying deficit of TSC, loss of inhibition of the mammalian target of rapamycin (mTOR) protein due to dysfunction of the tuberin/hamartin protein complex, can be rescued by everolimus. Everolimus has been registered as treatment for renal cell carcinoma and giant cell astrocytoma (SEGA). Evidence in human and animal studies suggests that mTOR inhibitors improve learning and development in patients with TSC.


Options:
A: Inclusion Criteria:

* Children with a definite diagnosis of TSC between 4 and 15 years.
* With an IQ estimated \<80 and/or special schooling and/or autism spectrum disorder and/or learning disability requiring remedial teaching.
* Written informed consent by parents/care-takers, and the patient if he or she is 12 years or older and cognitively able to consent.
* In girls after menarche, appropriate contraception must be used or abstinence practiced.

Exclusion Criteria:

* Hepatic dysfunction
* Surgery \<6wk
* Current infection at time of inclusion
* Developmental age estimated below 3.5 years
* Intractable epilepsy with more than 1 seizure/week
* Inability to comply with the treatment protocol
* Additional diseases or disorders that may influence the endpoints, including:

  * SEGA requiring treatment
  * Uncontrolled diabetes mellitus
  * Known impaired lung function
* Allergy for any of the components of the study medication
* Prior treatment with mTOR inhibitors
* HIV seropositivity
* Bleeding diathesis or oral anti-vitamin K medication
* Serum creatinine \> 1.5 x ULN
* Uncontrolled hyperlipidemia (fasting serum cholesterol \> 7.75 mmol/L, fasting serum triglycerides \> 2.5 x ULN)
* Use of investigational drug within 30 days prior to inclusion
* History of myocardial infarction, angina or stroke related to atherosclerosis, organ transplantation, malignancy in the past 2 years
* Pregnancy or breastfeeding
* Children at risk for Hepatitis B (HB), unless hepatitis B serology is normal. Risk groups are children who have lived in Asia, Africa, Central and South America, Eastern Europe, Spain, Portugal, and Greece, children with known or suspected past or current hepatitis B infection, current or prior IV illicit drug use, current or prior dialysis, household contact with hepatitis B infected patient(s), current or prior high-risk sexual activity, body piercing or tattoos, mother known to have hepatitis B history. If vaccinated, presence of HBs Ab is normal.
* Known or suspected hepatitis C infection, unless hepatitis C serology is normal.
B: 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 :

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  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
C: Inclusion Criteria:

* Subject is willing and able to comply with all trial requirements
* Subject is male or female and over 13 years of age
* Subject has a diagnosis of either TSC or NF1 and has visible fibromatous lesions (angiofibromas or neurofibromas)
* Female subjects of child-bearing potential must not be pregnant and must agree to use appropriate contraceptive methods for the duration of the trial

Exclusion Criteria:

* Subject is currently receiving therapy with rapamycin or sirolimus
* Subject is receiving any form of immunosuppression or has previously experienced immune dysfunction
* Subject is currently participating in or has participated within the last 30 days in any clinical trial involving an investigational drug
* Subject has a known hypersensitivity to either the PVDF coating (Skincerity®) or rapamycin
* Subject is a pregnant or nursing female
D: Inclusion Criteria:

* If female, documentation of negative pregnancy test prior to enrolment.
* Participants, including males, must use an effective form of contraception, whilst taking sirolimus and for twelve weeks after stopping the drug
* One or more renal angiomyolipomata of at least two centimetres or greater in largest diameter
* Adequate renal function :glomerular filtration rate \> 40 ml/min
* Clinically definite diagnosis of tuberous sclerosis (modified Gomez criteria) or sporadic LAM (biopsy-proven or compatible high resolution chest CT scan and respiratory function tests.)
* Signed and dated informed consent

Exclusion Criteria:

* History of non-compliance or inability to give informed consent
* Significant haematological or hepatic abnormality (i.e. transaminase levels \> 150 i.u./L serum albumin \< 30 g/L, haematocrit\< 30%, platelets \< 100,000/ mm3, adjusted absolute neutrophil count \< 1,500/mm3, total WBC \< 3,000/ mm3)
* Greater than 1 g proteinuria daily
* Multiple bilateral AMLs, where individual lesions cannot be distinguished
* Renal haemorrhage within preceding year
* In those who have had a renal haemorrhage, known conservatively managed renal aneurysm(s) greater than 10mm
* Patients who have had embolisation for AML(s) within the preceding 6 months
* Patients who are unable to walk 100 metres on the flat
* Continuous requirement for supplemental oxygen
* Patients who have had or are being considered for organ transplant
* Uncontrolled hyperlipidaemia
* Intercurrent infection at initiation of Sirolimus
* Surgery within last 2 months
* Pregnant or lactating women
* Use of an investigational drug within the last 30 days
* Change in anti epileptic drug medication within the last 3 months
* Likely to need vaccination e.g. for travel during the course of the trial (except for influenza vaccine in patients with LAM)
* Current usage of strong inhibitors of CYP3AE ( such as ketoconazole, voriconazole, itraconazole, tilithromycin or clarithromycin) or strong inducers (such as rifampicin or rifabutin)

Answer: A