Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Trial of the Efficacy and Safety of Sirolimus(Rapamycin)Therapy for Renal Angiomyolipmoas in Patients With Tuberous Sclerosis Complex and Sporadic Lymphangioleiomyomatosis
Brief Summary: The purpose of this study is to determine the safety and efficacy of the mTOR inhibitor sirolimus as a treatment for renal angiomyolipomas in patients with tyberous sclerosis complex or sporadic lymphangioleiomyomatosis.


Options:
A: Inclusion Criteria:

* All Ages
* Definite diagnosis of Tuberous Sclerosis according to the modified Gomez criteria
* At least one Subependymal Giant Cell Astrocytoma of at least 1 cm in diameter
* Evidence of SEGA worsening as compared to prior MRI scans
* Females of child bearing potential must use birth control
* Written informed consent

Exclusion Criteria:

* SEGA related surgery is likely to be required in the opinion of the investigator
* Recent heart attack, cardiac related chest pain or stroke
* Severely impaired lung function
* Severe liver dysfunction
* Severe kidney dysfunction
* Pregnancy or breast feeding
* Current infection
* History of organ transplant
* Surgery within two months prior to study enrollment
* Prior therapy with a medication in the same class as Everolimus
* Uncontrolled high cholesterol
* Uncontrolled diabetes
* HIV
* Patients with metal implants thus prohibiting MRI evaluations

Other protocol-defined inclusion/exclusion criteria may apply
B: Inclusion Criteria:

1. Definite TSC by current clinical criteria (28);
2. Male or female aged 16 to 60 yrs;
3. IQ over 60 by Wechsler Abbreviated Scales of Intelligence (WASI) and able to participate in direct neuropsychological tests;
4. A score falling on, or below, the 5th percentile (approximately equivalent to -1.5 SD) in one or more of the primary outcome measures:
5. Calculated GFR \> 60ml/min/1.73m2 except in case of renal impairment associated with TSC complicating kidneys, where a calculated GFR should be ≥30ml/min/1.73m2;
6. INR 1.5 or less (anticoagulation permitted if target INR on stable dose of warfarin or LMW heparin for \> 2 weeks at time of randomisation) ;
7. Adequate liver function as shown by: serum bilirubin less than or equal to 1.5 x ULN, ALT and AST less than or equal to 2.5 x ULN;
8. If sexually active - negative pregnancy test in females at the time of informed consent, contraception for males and pre-menopausal females on study);
9. Seizure free or stable seizures as defined by no change in type of AEDs in 6 months prior to full recruitment and randomization at baseline. Doses of drugs may have been changed in the 6 months prior to recruitment;
10. Hepatitis B surface antigen negative, Hepatitis C antibody negative.
11. All patients must be able to communicate well with the investigator, to understand and comply with the requirements of the study, understand and sign the written informed consent;
12. Female patients of childbearing potential must be prepared to use two acceptable methods of contraception, (e.g., intra-uterine device plus condom, spermicidal gel plus condom, diaphragm plus condom, etc.), from the time of screening.

Exclusion Criteria:

1. Prior treatment with an mTOR inhibitor;
2. Investigational agent \<30 days prior to randomisation;
3. Surgery in last 2 months;
4. Previous brain neurosurgery;
5. Significant haematological abnormality i.e. haemoglobin \< 8g/dL, platelets \<80,000/mm3, absolute neutrophil count \< 1000/mm3);
6. Urine protein/creatinine \>0.02g/mmol except in case of renal impairment associated with TSC complication of kidneys, where urine protein/creatinine ratio should be \>0.1g/mmol for exclusion;
7. Serum creatinine \> 1.5 x ULN except in case of renal impairment associated with TSC complication of kidneys, where serum creatinine should be \>300µmol/L for exclusion;
8. Uncontrolled hyperlipidaemia (fasting cholesterol \> 300mg/dL or \>7.75 mmol/L and fasting triglycerides \>2.5 x ULN, or diabetes with fasting serum glucose \> 1.5 x ULN;
9. History of myocardial infarction, angina or stroke related to atherosclerosis, or any other significant cardiac disease, HIV seropositivity, organ transplant, malignancy other than squamous or basal cell skin cancer;
10. lymphangioleiomyomatosis with FEV1 \<70% of predicted, or any other restrictive pulmonary disease;
11. Bleeding diathesis or on oral anti-vitamin K medication other than low dose warfarin;
12. Pregnancy/lactation;
13. Live vaccine required during trial;
14. Use of strong inhibitor of CYP3AE;
15. Use of strong inducer of CYP3AE except for anti epileptic drugs;
16. Intercurrent infection at time of randomisation;
17. Inability to complete study materials (outcome measures) in English;
18. History of significant trauma-related cognitive deficit;
19. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of Everolimus (e.g. pancreatic insufficiency);
20. Known sensitivity to Everolimus or other Rapamycin analogues or to its excipients;
21. Inability to attend scheduled visits.
C: Inclusion Criteria:

* Subjects must be willing and able to comply with all trial requirements.
* Subject has a diagnosis of TSC and has visible facial angiofibromas.
* Female subjects of child bearing potential must not be pregnant and must agree to use appropriate contraceptive methods .

Exclusion Criteria:

* Subject is currently receiving therapy with Rapamycin.
* 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 a clinical trial involving an investigational drug.
* Subject has a known hypersensitivity to either the vehicle or Rapamycin.
* Subject is a pregnant or nursing female.
* Subject has other dermatologic conditions that would preclude or prevent adequate assessment of changes to their facial angiofibromas.
* Subject has had laser surgery, cryotherapy, or other dermatologic treatment to their facial angiofibromas within the previous 6 months.
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: D