Neoplasms

Nervous System Diseases

All Conditions

Symptoms and General Pathology

Respiratory Tract (Lung and Bronchial) Diseases

Blood and Lymph Conditions

Immune System Diseases

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Rare Diseases

Brain Neoplasms

Astrocytoma

Sclerosis

Lung Diseases

Seizures

Lymphangioleiomyomatosis

Tuberous Sclerosis

Angiomyolipoma

Hamartoma

Neoplasms, Multiple Primary

Syndrome

Neoplastic Syndromes, Hereditary

Congenital Abnormalities

Malformations of Cortical Development

Nervous System Malformations

Neurocutaneous Syndromes

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Genetic Diseases, Inborn

Lymphangiomyoma

Neoplasms by Histologic Type

Perivascular Epithelioid Cell Neoplasms

Neoplasms, Connective and Soft Tissue

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Neoplasms, Adipose Tissue

Tuberous Sclerosis Complex

Subependymal Giant Cell Astrocytoma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Everolimus

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Study drug was given by continuous oral daily dosing of two 5 mg tablets.

Placebo was given by continuous oral daily dosing of two 5 mg tablets.

Everolimus is used in 5 mg strength tablets, blister-packed under aluminum foil in units of ten tablets and dosed on a daily basis. 10mg daily dosing throughout the trial.

Everolimus (RAD001)

Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.

Everolimus Placebo

Novartis Pharmaceuticals

This study will evaluate the safety and efficacy of RAD001 in treating patients with Angiomyolipoma associated with Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis.

Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)

A Randomized, Double-blind, Placebo-controlled Study of RAD0001 in the Treatment of Angiomyolipoma in Patients With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)

Angiomyolipoma response defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; there were no kidney increases in volume \> 20% from nadir. The patient did not have any angiomyolipoma-related bleeding of ≥ grade 2.

For the everolimus (core/extension periods) treatment group, the baseline means the latest value on or before starting everolimus.

Time to angiomyolipoma progression (TTAP) is defined as time from date of randomization to date of first documented angiomyolipoma progression. Angiomyolipoma progression was defined as one or more of the following: Increase from nadir of ≥ 25% in angiomyolipoma volume to value greater than baseline; the appearance of a new angiomyolipoma ≥ 1.0 cm in longest diameter; an increase from nadir of 20% or more in the volume of either kidney to a value greater than baseline; angiomyolipoma-related bleeding grade ≥ 2.

For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma progression is defined starting from the start of everolimus. The baseline means the latest value on or before starting everolimus.

Skin lesion response rate in the double-blind period was determined only among patients with at least one skin lesion at baseline, and is the percentage of this group of patients with a best overall skin lesion response on the Physician's Global Assessment of Clinical Condition (PGA) of either complete clinical response (CCR) or partial response (PR). A complete clinical response (CCR) requires a grading of 0 indicating the absence of disease (histological confirmation is not required). Grades 1, 2, and 3 constitute partial response, indicating improvement of at least 50 percent, but less than 100 percent improvement. For the everolimus (core/extension periods) treatment group, the baseline means the latest value on or before starting everolimus.

Renal Impairment was measured by glomerular filtration rate which was calculated using the Modification of Diet in Renal Disease formula. Percentage of participants with renal impairment was reported. Severe renal impairment was defined as a GFR of \<30ml/min/1.73m2.

Blood samples for biomarker assessment were collected immediately prior to study administration. On-treatment samples was compared to baseline samples with the change from baseline.

Cmin values collected prior to dose administration on the same study day and at 20-28 hours after previous dose, at steady state, and patient did not vomit within 4 hours of previous dose. Samples collected during the first 4 days of dosing were excluded from all analyses.

C2h values collected 1-3 hours after dose administration on the same study day, at steady state, and patient did not vomit between taking previous dose and blood collection. Samples collected during the first 4 days of dosing will be excluded from all analyses.

Time to angiomyolipoma response was defined as the time from the date of randomization until the date of the first documented angiomyolipoma response. Angiomyolipoma response defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; no kidney increases in volume \> 20% from nadir; no angiomyolipoma-related bleeding of ≥ grade 2.

For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma response is from the start of everolimus. The baseline in the response definition means the latest value on or before starting everolimus.

Duration of angiomyolipoma response was defined as the time from the date of the first documented angiomyolipoma response until the date of the first documented angiomyolipoma progression . Angiomyolipoma response was defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; there were no kidney increases in volume \> 20% from nadir. The patient did not have any angiomyolipoma-related bleeding of ≥ grade 2.

Duration of skin lesion response is defined as the time from the date of the first skin lesion response until the date of the first skin lesion progression, according to the PGA (physician's global assessment of clinical condition). A progression is when the disease is worse than at baseline evaluation by \>=25% or more.

Patients who were randomized and treated with Everolimus during the Core and Extension phase

Everolimus Randomized (Core & Ext)

Patients who were randomized to placebo in the Core phase and who crossed-over to Everolimus in the Extension phase

Placebo Randomized/Crossed Over to Everolimus

Patients randomized to placebo who never crossed-over to Everolimus

Placebo Randomized/Never Crossed-over

Placebo

Total

Age, Continuous

<30 years

≥ 30 years

Age, Customized

Gender

Everolimus Randomized (Core Period)

Placebo Randomized (Core Period)

Patients initially randomized in everolimus and patients initially randomized in placebo but who crossed-over to everolimus during extension.

Everolimus (Core and/or Extension Period)

The Full Analysis Set (FAS) is defined according to the Intention-to-Treat principle and consists of all randomized patients.

Angiomyolipoma Response Rate as Per Central Radiology Review

Time to Angiomyolipoma Progression as Per Central Radiology Review

The Full Analysis Set (FAS) is defined according to the Intention-to-Treat principle and consists of all randomized patients. Only patients with at least one skin lesion at baseline are included in the analysis.

Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)

Glomerular filtration rate <30 ml/min/1.73m^2

Glomerular filtration rate≥ 30 ml/min/1.73m^2

Safety set consists of all patients who received at least 1 dose of the double-blind study drug with a valid post-baseline assessment. For the everolimus (core/extension) treatment arm, patients received at least 1 dose of everolimus with a valid post-baseline assessment, where baseline was defined as the assessment just before start of everolimus.

Percentage of Participants With Renal Impairment

Week 4 (n:56, 28)

Week 12 (n:56, 29)

Week 24 (n:53, 29)

Week 36 (n:26, 18)

Week 48 (n:16, 8)

Week 60 (n:0, 1)

Week 72 (n:0, 1)

The Full Analysis Set (FAS) is defined according to the Intention-to-Treat principle and consists of all randomized patients. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.

Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker

Prior to dosing at Week 2 (n:43)

Prior to dosing Week 4 (n:44)

Prior to dosing Week 12 (n:49)

Prior to dosing Week 24 (n:46)

Prior to dosing Week 48 (n:15)

The analysis was performed in the Safety Set population for patients treated only with Everolimus and with a confirmed PK sample.

Everolimus Trough Concentrations (Cmin)

2 hours post dose administration at Week 2 (n:55)

2 hours post dose administration at Week 4 (n:49)

2 hours post dose administration at Week 12 (n:56)

2 hours post dose administration at Week 24 (n:50)

2 hours post dose administration at Week 48 (n:14)

Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose

The analysis was performed on the Full analysis Set for patients in Everolimus arm and who experienced an angiomyolipoma response.

Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response

Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response

The analysis was performed on the Full analysis Set for patients in Everolimus arm and who experienced a best overall skin lesion response CCR or PR.

Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR)

Double-blind Period (Core Phase)

Everolimus Period (Core or Extension)

Hematinics

Liver Extracts

Participants with confirmed diagnosis of TSC-AML and who fulfil the local (Taiwan) reimbursement criteria of everolimus for TSC-AML treatment

Everolimus tablets for oral use. The recommended everolimus starting dose will be 10 mg orally taken once daily for all patients, except for those with impaired liver function, for whom the everolimus dose will be:

* Child-Pugh grade A: 7.5 mg once daily (for patients with mild hepatic impairment)
* Child-Pugh grade B: 5.0 mg once daily (for patients with moderate hepatic impairment)

The purpose of this prospective study is to assess the safety and efficacy of everolimus in Taiwanese patients with renal angiomyolipoma (AML) associated with tuberous sclerosis complex (TSC) . Only patients who fulfil the local reimbursement criteria of everolimus for TSC-AML will be included in this study.

This open-label, prospective, single-arm, multicenter Phase IV post approval commitment (PAC) study is planned to be conducted in approximately 10 patients with confirmed diagnosis of TSC-AML and who fulfil the local reimbursement criteria of everolimus for TSC-AML treatment.

The study will have a 30-day screening phase, and each patient will be on treatment up to 52 weeks. Enrollment will end at the latest within 52 weeks from Day 1 of the study, regardless of the number of patients actually recruited. After completion of the treatment phase/end of treatment (EOT), eligible patients will enter a 4-week safety follow up (FU) phase. Patients who continue to be on treatment beyond 52 weeks, based on the investigator's judgment will not be included in the 4-week safety FU phase.

A Phase IV Study of Safety and Efficacy of Everolimus in Taiwanese Patients With Tuberous Sclerosis Complex Who Have Renal Angiomyolipoma (TSC-AML)

Phase IV, Prospective Single Arm Study of Safety and Efficacy of Votubia (Everolimus) in Taiwanese Adults With Tuberous Sclerosis Complex Who Have Renal Angiomyolipoma

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Percentage of participants with AEs, SAEs and AESIs.

AML response rate is defined as the percentage of patients with an AML response. AML response will be defined as: A reduction in AML volume of at least 50% relative to screening, where AML volume is the sum of the volumes of all target AML identified at screening. In addition, AML response have to satisfy: no new AML ≥ 1 cm in longest diameter are identified, neither kidney increases in volume by more than 20% from nadir (where nadir is the lowest kidney volume at the screening), the participant does not have any angiomyolipoma-related bleeding of grade equal or over 2 (as defined by NCI CTCAE, version 5).

AML progression rate is defined as the percentage of patients with an AML progression. AML progression status is defined as one or more of the following: an increase from nadir of 25% or more in AML volume to a value greater than screening AML (where nadir is the lowest AML volume obtained for the participant previously in the trial), the appearance of a new AML ≥ 1.0 cm in longest diameter, an increase from nadir of 20% or more in the volume of either kidney to a value greater than screening (where nadir is the lowest kidney volume obtained for the participant previously in the trial), angiomyolipoma-related bleeding grade ≥2 (as defined by NCI CTCAE, version 5)

The laboratory assessment (including hematology, coagulation, biochemistry, and urinalysis) will be recorded at baseline and during the study based on changes in grade of laboratory abnormality.

Heart and Blood Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Thrombosis

Venous Thrombosis

Hemorrhage

Varicocele

Endoleak

Embolism

Embolism and Thrombosis

Vascular Diseases

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Male Urogenital Diseases

Aneurysm

Postoperative Hemorrhage

Postoperative Complications

Patients requiring embolization of varicocele, portal vein before ablation, type 2 endoleak, angiomyolipoma or active bleeding will be treated with the liquid embolic agent Easyx during index procedure.

Embolization will be done with Easyx liquid agent.

Easyx

Marc SAPOVAL, MD, PhD

Romaric LOFFROY, MD, PhD

Vincent VIDAL, MD, PhD

The EASYX™ Liquid Embolic is a new injectable, precipitating polymeric agent for the obliteration of vascular spaces through direct puncture or catheter access performed under X-ray guidance. The embolic liquid is an iodinized Polyvinyl Alcohol (PVA) Polymer ether. Iodine groups are covalently grafted to the PVA polymer backbone, whereby a stable nondegradable polymer with the desired features is created. The resulting polymer is dissolved in Dimethyl Sulfoxide (DMSO). EASYX™ is CE-marked since December 2016 and has been used in humans a few time for type II endoleaks, portal vein and varicocele (\<10 cases at the date of submission). The purpose of this study is to evaluate the safety and efficacy of EASYX™ embolization liquid for the percutaneous treatment of vascular lesions, i.e. embolization of varicocele, type II endoleaks, portal vein before surgery, active peripheral bleeding or angiomyolipoma (AML).

French multicenter, phase 2b (device), prospective study

EASYX-1 : A Multicenter Study on Safety and Efficacy of Easyx Liquid Embolization Agent Used in Five Separate Indications

Expected and unexpected per-procedure (SAE) related to the EASYX™ use (imputability "certain" or "probable")

Percentage of clinical success. The clinical success of type II endoleaks embolization is defined as the stability or reduction of aneurysm's both anterioposterior and transverse diameters assessed on CT-scan at 6 months compared to baseline (4mm threshold).

Percentage of clinical success before ablation for portal vein embolization. The clinical success of portal vein embolization is defined as the growth ≥15 % of the remnant liver assessed on presurgical CT-scan compared to baseline

Percentage of clinical success for varicocele embolization The clinical success of varicocele embolization is defined as the absence of reflux on ultrasound Doppler at one month follow-up.

Percentage of clinical success for angiomyolipoma embolization. The clinical success of angiomyolipoma embolization is defined as the reduction \>10% of at least one diameter on MRI or CT-scan at 3 months follow-up compared to baseline

Percentage of clinical success for active bleeding embolization The clinical success of active bleeding embolization is defined as the complete occlusion of the target vessel assessed by angiography during the index procedure

Total number of unanticipated ischemia of the target organ

Total number of secondary post-embolization orchi-epididymitis (varicocele embolization)

Total number of neural root lesion (type II endoleaks)

Total number of aneurysm rupture (type II endoleaks)

Total number of tumor rupture (angiomyolipoma)

Use of Visual Analog Scale (VAS) to evaluate the pain at device injection (between 0: no pain to 10: intolerable pain)

Use of Visual Analog Scale (VAS) to evaluate the painful varicocele (between 0: no pain to 10: intolerable pain)

Total number of unanticipated use of another liquid agent for embolization

Total number of procedures with immediate technical success

Mean volume of EASYX™ used during the index procedure

Mean degree of occlusion of the target vessel(s)

Total number of re-intervention for study procedure

Immediate technical satisfaction questionnaire (as perceived by the Interventional Radiologist)

Total number of embolization clinical efficacy

Total number of procedures with a need to complete with another liquid embolic to achieve optimal result

Technical success at follow-up assessed on CT-scan for type II endoleaks defined as the ability for the physician to give a diagnosis (absence or minor artifacts) on imaging

Antia Therapeutics AG

Assistance Publique - Hôpitaux de Paris

All patients with TSC, LAM or AML followed at Hospital das Clínicas, University of São Paulo Medical School will be included in the proposed study. Patients of all ages will participate in the study.

Carlos Roberto Ribeiro Carvalho, MD, PhD

Tuberous Sclerosis Complex (TSC) is a multisystemic autosomal dominant disease that is characterized by the development of benign neoplasms in brain, kidney, lung, skin and heart. TSC is caused by mutations in TSC1 and/or TSC2 genes, which encode, respectively, hamartin and tuberin, that are involved in the regulation of cell proliferation, cell cycle and protein synthesis. Most patients exhibit dermatological, renal, neurological and pulmonary (lymphangioleiomyomatosis, LAM) manifestations. Neurological involvement include subependymal nodules, subependymal giant cell astrocytomas and cortical tubers. LAM is characterized by the proliferation of LAM cells around the airways, blood vessels and lymphatics, which result in vascular and airway obstruction and cyst formation. The most frequent TSC manifestation in the kidney is the development of angiomyolipomas (AML). Dermatologic lesions represent the most common manifestations of TSC, mainly hypomelanotic macules and facial angiofibromas. The most significant functional implication of the tuberin-hamartin complex is its regulatory role upon the mammalian target of rapamycin (mTOR) pathway. Mutations in TSC1 or TSC2 lead to increased mTOR activity and favor tumor development and growth. All lesions associated with TSC, sporadic LAM and sporadic AML share a common molecular pathogenesis, based on TSC1/TSC2 mutations and mTOR hyperactivity. Up to date, TSC patients have been followed in separated medical services in our institution, according to their predominant phenotype. The current knowledge, however, suggest that the ideal follow up of such patients should be conducted in an integrated fashion among the specialties associated with the main disease manifestations. Experts in TSC from each of these areas have recently created a TSC/LAM/AML integrated program in the University of São Paulo Medical Center, and his project will be initiated with the generation of an integrated TSC/LAM/AML registry, which intends not only to clinically characterize this patient population but also to document the employed treatment modalities. Once this first goal is achieved, clinical trials are planned to be performed. The central aim of this observational study is to clinically characterize the TSC/LAM/AML subject population followed and referred to the University of São Paulo Medical Center. Specific aims: To characterize the pulmonary, the neurological, the renal and the dermatologic phenotypes of this patient population.

1. Introduction Tuberous Sclerosis Complex (TSC) is a multisystemic autosomal dominant disease , that is characterized by the development of histologically benign neoplasms in brain, kidney, lung, skin, heart and eyes, as well as by central nervous system (CNS) disorganization. TSC is caused by mutations in TSC1 (Tuberous Sclerosis Complex 1) and/or TSC2 genes, which encode, respectively, hamartin and tuberin, proteins that form a complex involved in the regulation of cell proliferation, cell cycle and protein synthesis. Although the majority of organs are susceptible, most patients exhibit dermatological, renal, neurological and pulmonary manifestations.

   Involvement of the CNS responds for most of TSC morbidity and include subependymal nodules, subependymal giant cell astrocytomas (SEGA) and cortical tubers, alterations prone to lead to ventricular obstruction, hydrocephalus, epilepsy, intellectual disability and psychiatric problems.

   Lymphangioleiomyomatosis (LAM) is a rare disease that is characterized by the proliferation of LAM cells around the airways, blood vessels and lymphatics, which can result in vascular and airway obstruction and cyst formation. LAM occurs sporadically or in association with tuberous sclerosis complex. The main clinical features are dyspnea, pneumothorax and chylothorax.

   The most frequent TSC manifestation in the kidney is the development of angiomyolipomas (AML), a tumor derived from perivascular epithelioid cells that comprises abnormally organized blood vessels, smooth muscle cells and adipose tissue. AML affects 60-80% of TSC patients, but it also occurs sporadically. The main AML-related complication is renal hemorrhage, the most common cause of mortality in adults with TSC.

   Dermatologic lesions represent the most common manifestations of TSC, mainly hypomelanotic macules and facial angiofibromas.

   The most significant functional implication of the tuberin-hamartin complex is its regulatory role upon the mammalian target of rapamycin (mTOR) pathway. Mutations in TSC1 or TSC2 lead to increased mTOR activity and favor tumor development and growth. Interestingly, all lesions associated with TSC, sporadic LAM and sporadic AML share a common molecular pathogenesis, based on TSC1/TSC2 mutations and mTOR hyperactivity.

   A number of studies have shown potentially beneficial effects of mTOR inhibitors on LAM and TSC patients with SEGA and AML, including sirolimus and everolimus. Such positive effects, however, are heterogeneous among these manifestations and critical pieces of information are lacking to define the true roles of mTOR inhibitors on each of TSC manifestations, as well as the sporadic forms of LAM and AML.
2. Study rational The University of São Paulo Medical School is the main and largest medical complex in Latin America. Up to date, TSC patients have been followed in separated medical services in our institution, according to their predominant phenotype. The current knowledge and therapeutic perspectives, however, suggest that from this moment on the ideal follow up of such patients should be conducted in an integrated fashion among the specialties associated with the main disease manifestations, ie, neurology, pulmonary, nephrology, urology and dermatology. Experts in TSC from each of these areas have recently come together to create a TSC/LAM/AML integrated program in the University of São Paulo Medical School, with the aim of building a Brazilian TSC Reference Center. This center is expected to provide integrated clinical follow up of TSC patients. We also expect to bring this center to a reference status for the entire country.

   This project will be initiated with the generation of an integrated TSC/LAM/AML registry, including all TSC and LAM cases and selected AML patients according to potential severity. This database is planned to be fed and accessed by all physicians included in the current proposal. Such this registry intends not only to clinically characterize this patient population but also to document the employed treatment modalities. Once this first goal is achieved, strategic and well-designed clinical studies are planned to be performed, including clinical trials with mTOR inhibitors.
3. Objectives 3.1. Primary objective The central aim of this observational study is to clinically characterize all patients with TSC, LAM and AML followed and referred to the University of São Paulo Medical School.

   3.2. Secondary objectives

   - To characterize the pulmonary phenotype of this patient sample, by integrating conventional clinical findings with radiological and pulmonary functional test features.
   * To characterize the neurological phenotype of the analyzed patient population, by composing the clinical observations with radiological findings and surgical and post-surgery follow-ups.
   * To characterize the renal phenotype of the evaluated patient population by integrating the clinical findings with radiologic alterations and surgical and post-surgery follow-ups.
   * To characterize the dermatologic phenotype of this patient population.
   * To establish data about loss of productivity and hospitalizations during the study in the analyzed patient population.
4. Study design This is an observational study that aims to describe mainly respiratory, neurological, renal and dermatological features of the all patients with TSC, LAM or AML followed at the University of São Paulo Medical Center. The study also aims to establish the impact of these diseases on loss of productivity and also to establish data about hospitalizations during the study in the patient population. This proposal intends to expand the comprehension of TSC pathogenesis and manifestations and to create a robust platform to perform interventional clinical trials.

The flow of the current study comprises the following steps:

1. Creation of an integrated database 2. Patient selection according to the inclusion criteria 3. Data collection 4. Data analysis and assessment 5. Interpretation of results and generation of reports

5. Population The population of this study is composed of patients with TSC, LAM or AML. The estimated sample size for this study is 200 patients.

5.1. Inclusion criteria

• All patients with TSC, LAM or AML followed at Hospital das Clínicas, University of São Paulo Medical School will be included in the proposed study. Patients of all ages will participate in the study.

5.2. Exclusion criteria • There is no exclusion criteria. 6. Assessments

This study includes the following evaluations:

A) Clinical evaluation

- Demographic and anthropometric data

- Criteria for tuberous sclerosis complex (if present)

- Family history for the diseases evaluated in the study

- Previous and current treatments

- Data about loss of productivity and hospitalizations during the study

* Quality of life evaluation with the questionnaire Short-Form Health Survey - 36
* Characterization of skin lesions
* Urinary and abdominal complaints
* Previous or current smoking
* Respiratory symptoms
* Assessment of the degree of dyspnea using baseline dyspnea index B) Skin biopsy (if necessary) C) Abdominal ultrasonography D) Abdominal computed tomography or nuclear magnetic resonance (if there is a suspected or a definitive lesion identified in abdominal ultrasonography) E) Chest high resolution computed tomography F) Computed tomography or nuclear magnetic resonance of the brain G) Electroencephalogram H) Spirometry I) Pulmonary volumes and diffusion capacity for carbon monoxide (if there is any change in spirometry and/or in chest high resolution computed tomography) J) Transthoracic echocardiography K) Six-minute walking test (if there is any change in spirometry and/or in chest high resolution computed tomography) 7. Data collection and management Data will be collected and stored in a database developed specifically for this study.

  8. Statistical methods and data analysis 8.1. Sample size The estimated sample size for this study is 200 patients. All patients followed in the Neurology, Respiratory, Nephrology, Urology and Dermatology services at University of Sao Paulo Medical School will be included in the study.

9.2. Population for analysis We will analyze data about all patients included in the database. 9.3. Statistical methods Data will be presented as mean and standard deviation (or standard error) for parametric variables, defined by the normal curve on the histogram, and as median and interquartile range (IQ) for nonparametric variables. Categorical variables will be expressed as percentages.

9. Ethical aspects 9.1. Ethics and Good Pharmacoepidemiology Practices By signing the protocol, the investigator agrees to comply with the instructions described and the Good Pharmacoepidemiology Practices (GPP), the Declaration of Helsinki and other applicable regulatory requirements. The study will also be performed so that local legal requirements are met.

9.2. Institutional Review Board / Independent Ethics Committee IN PROGRESS 9.3. Informed Consent Form Eligible patients may only be enrolled in the study after providing the written informed consent (witnessed, whenever required by law or regulation), approved by the EC or, if unable to do it, after this consent is provided by an accepted legal representative of the patient. In cases in which the patient's representative provides the consent, the patient must be informed about the study as far as possible, considering his/her understanding. If the patient is able to understand, he/she must indicate his/her consent by personally signing and dating the written informed consent form or a separate consent form. Informed consent form must be obtained before the conduction of any procedure specific to the study (i.e., all the procedures described in the protocol).

9.4. Declaration of Helsinki The participant investigator should conduct the study according to the principles of the Declaration of Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon request or may be accessed through the website of the World Medical Association at http://www.wma.net/e/policy/17-c_e.html.

10. Recording of data and retention of documents Study duration: 24 months Study start : March 2015 Recruitment end: March 2016 Study end: March 2017 Follow-up: From March 2016 to March 2017 11. Study sponsorship and funding This study was fully prepared by the investigator-sponsor. The investigator-sponsor and local institution are responsible for the costs arising from this study. Novartis Biociências S.A. does not have any participation in preparation, logistics, data collection and storage, statistical evaluation, result interpretation and manuscript wording for publication. There is no type of restriction or external control by Novartis Biociências S.A. The contribution of Novartis Biociências S.A. is only intended to make viable part of the Study aspects that, otherwise, would not be feasible. The Investigator-Sponsor and the investigator institution will be in charge of insurance matters.

Characterization of Patients With Tuberous Sclerosis Complex, Lymphangioleiomyomatosis and Angiomyolipoma

Clinical Profile Characterization of Patients With Tuberous Sclerosis Complex, Lymphangioleiomyomatosis and Angiomyolipoma Followed at Hospital Das Clínicas, University of Sao Paulo Medical School

Decline of forced expiratory volume in the first second

Renal angiomyolipoma, lymphangioleiomyoma

Describe skin lesions in the study population

Describe all respiratory symptoms in the study population

Describe urinary and abdominal complaints in the study population

Assessment of the degree of dyspnea using baseline dyspnea index

To describe previous and current treatments performed

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)	NCT00790400	Tuberous Sclero... Lymphangioleiom...	Everolimus (RAD... Everolimus Plac...	18 Years -	Novartis
A Phase IV Study of Safety and Efficacy of Everolimus in Taiwanese Patients With Tuberous Sclerosis Complex Who Have Renal Angiomyolipoma (TSC-AML)	NCT05252585	Renal Angiomyol...	Everolimus	20 Years - 65 Years	Novartis
EASYX-1 : A Multicenter Study on Safety and Efficacy of Easyx Liquid Embolization Agent Used in Five Separate Indications	NCT03477149	Varicocele Endoleak Portal Vein Thr... Bleeding Angiomyolipoma	Easyx	18 Years -	Assistance Publique - Hôpitaux de Paris
Characterization of Patients With Tuberous Sclerosis Complex, Lymphangioleiomyomatosis and Angiomyolipoma	NCT02325505	Tuberous Sclero... Lymphangioleiom... Angiomyolipoma		-	InCor Heart Institute
EASYX-1 : A Multicenter Study on Safety and Efficacy of Easyx Liquid Embolization Agent Used in Five Separate Indications	NCT03477149	Varicocele Endoleak Portal Vein Thr... Bleeding Angiomyolipoma	Easyx	18 Years -	Assistance Publique - Hôpitaux de Paris
RAPAMYCIN FOR KIDNEY ANGIOMYOLIPOMAS	NCT00126672	Nonmalignant Ne... Tuberous Sclero... Lymphangioleimy... Kidney Angiomyo...	Rapamycin	3 Years - 65 Years	Dana-Farber Cancer Institute
MRI Functional Imaging Characteristics and Fat Quantification of CT-fat-free Renal Neoplasms: Relationships With Histological Classifications and Molecular Markers	NCT06126159	Kidney Neoplasm...	multiparametric...	20 Years -	Chang Gung Memorial Hospital
A Phase IV Study of Safety and Efficacy of Everolimus in Taiwanese Patients With Tuberous Sclerosis Complex Who Have Renal Angiomyolipoma (TSC-AML)	NCT05252585	Renal Angiomyol...	Everolimus	20 Years - 65 Years	Novartis
RAPAMYCIN FOR KIDNEY ANGIOMYOLIPOMAS	NCT00126672	Nonmalignant Ne... Tuberous Sclero... Lymphangioleimy... Kidney Angiomyo...	Rapamycin	3 Years - 65 Years	Dana-Farber Cancer Institute
Rapamycin In Angiomyolipomas In Patients With Tuberous Sclerosis	NCT01217125	Angiomyolipoma	Sirolimus	10 Years -	Fundacio Puigvert
Rapamycin In Angiomyolipomas In Patients With Tuberous Sclerosis	NCT01217125	Angiomyolipoma	Sirolimus	10 Years -	Fundacio Puigvert

Spots Global Cancer Trial Database for angiomyolipoma