Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Double-blind, Randomized, Placebo-controlled Phase III Trial to Investigate the Efficacy and Safety of NPC-12G Gel (Topical Formulation of Sirolimus) to Angiofibroma and Other Skin Lesions in Patients With Tuberous Sclerosis Complex
Brief Summary: The purpose of this trial is to evaluate the efficacy and safety of NPC-12G gel (topical formulation of sirolimus) versus placebo gel to facial angiofibroma and other skin lesions in patients with tuberous sclerosis complex (TSC)


Options:
A: Inclusion Criteria:

* Age 3-65 years old (females of reproductive age must not be pregnant or breastfeeding)
* Kidney ANGIOMYOLIPOMA 2 cm or greater on baseline MRI (a CT scan may be used for patients who cannot undergo MRI imaging)
* No evidence of severe LAM (not on continuous oxygen)
* Informed consent, including consent for submission of blood, urine and tissue samples as described in the appendix.
* Adequate renal and liver function (eGFR of 30 or higher, SGOT, SGPT, TBili, Alk Phos all\<2x normal)
* HCT\>27%
* ANC \> 1500 and platelet count \>100,000
* Diagnosis of TSC or LAM (diagnosis of TSC using revised diagnostic criteria \[45\], diagnosis of LAM made by chest CT scan and reviewed by a pulmonologist).
* Fertility/Reproductive issues: The effects of rapamycin on the developing fetus at the doses used in this study are unknown. For this reason, rapamycin should not be taken during pregnancy. Participants who are fertile must maintain adequate contraception while they are taking rapamycin and for twelve weeks after stopping the drug. Acceptable contraceptive measures include prior hysterectomy, oophorectomy or tubal ligation, complete abstinence, barrier methods which include both a cervical diaphragm and spermicidal jelly, and progestin based contraceptives. Pregnancy tests will be obtained at enrollment and during study visits at 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 52 weeks.

  * Note: Eligibility requirement of ECOG PS of 0 or 1 has been removed to allow participation of those subjects with TSC who are classified as ECOG PS of 2,3, or 4 because of cognitive impairment rather than progressive disease. This change allows site Pl's to individualize decision making on whether or not to enroll such subjects after discussing details of the study with prospective participant and legal guardian. The decision to enroll individuals with ECOG PS of 2,3, or 4 will be at the discretion of the Principal Investigator.

Exclusion criteria:

* Unstable seizures (defined as changes in anti-epileptics OR increase in frequency and/or severity or seizures in the 60 days prior to study entry)
* Significant bleed associated with kidney angiomyolipoma(s) (defined as bleed associated with shock OR requiring a blood transfusion in the 30 days prior to study entry)
* Severe LAM (defined as dependent on continuous supplemental oxygen)
* Evidence for accelerating renal dysfunction or acute renal failure
* Diagnosis of Renal Cell Cancer that has not been treated (additional clarification: individuals with a prior history of renal cancer who have had appropriate surgery and have no evidence of metastatic disease can be enrolled)
* Active infection
* Patients will be excluded if they have been treated with any investigational agent in the 30 days prior to study entry
* Patients may not be treated with other investigational agents while on study
* Prior history of coronary artery disease
* Vascular embolization for treatment of kidney angiomyolipoma(s) within 6 months
* Patients who must take diltiazem, ketoconazole or rifampin chronically will be excluded because of known drug interactions. Both diltiazem and ketoconazole are strong inhibitors of CYP3A4 and are known to increase rapamycin levels. Rifampin is a known CYP3A4 and P-glycoprotein inducer and is known to significantly reduce rapamycin levels.
B: Inclusion Criteria:

1. Male or female patients 3 years old or greater at the time of informed consent
2. Patients who are diagnosed as definite diagnosis according to diagnostic criteria for tuberous sclerosis complex (International Tuberous Sclerosis Complex Consensus Conference 2012)
3. Patients with three or more papules of angiofibroma ( \>= 2 mm in diameter with redness in each) on the face at screening tests
4. Patients who are not suitable for therapy with laser or surgery, or who do not want therapy with laser or surgery
5. Patients or his/her guardian who give a written informed consent in understanding and willingness after having received enough explanation of the test drug and the current trial plan

Exclusion Criteria:

1. Patients who are hard to apply the test drug topically with keeping compliance
2. Patients with clinical findings such as erosion, ulcer and eruption on or around the lesion of angiofibroma, which may affect assessment of safety or efficacy
3. Patients who are hard to be taken pictures of their lesions adequately in such cases that they may not follow instruction of stillness
4. Patients with a history of hypersensitivity to alcohol or allergy to sirolimus
5. Patients who have complications such as malignant tumor, infection, serious heart disease, hepatic function disorder, renal function disorder or blood disorders which severity are considered by investigator as grade 2 or more severe with reference to ''Concerning classification criteria for seriousness of adverse drug reactions of medical agents''
6. Patients who have complications such as diseases unsuitable for the trial participation, for examples, uncontrolled diabetes (fasting blood glucose level \>140 mg/dL or postprandial blood glucose level \> 200 mg/dL), dyslipidemia (cholesterol level \> 300 mg/dL or \> 7.75 mmol/L, triglycerides level \> 300 mg/dL or \> 3.42 mmol/L), etc.
7. Patients who have taken drugs with mTOR inhibitory action including sirolimus, everolimus or temsirolimus within 12 months before the initial registration
8. Patients who have applied topical tacrolimus on the lesion of angiofibroma within 3 months before the initial registration
9. Patients who have received therapy with laser or surgery to the lesion of angiofibroma within 6 months before the initial registration
10. Female patients who may be pregnancy or are lactating
11. Patients who cannot agree to take appropriate measures of contraception until completion of post-treatment phase or follow-up period after discontinuation from informed consent
12. Patients who have participated in other clinical trial and have taken a trial drug within 6 months before the initial registration
13. Others, patients who are considered by the investigator as unsuitable for participation in the trial
C: 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.
D: 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

Answer: B