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.
- - 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.
