Characterization of Patients With Tuberous Sclerosis Complex, Lymphangioleiomyomatosis and Angiomyolipoma

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Brief Title

Characterization of Patients With Tuberous Sclerosis Complex, Lymphangioleiomyomatosis and Angiomyolipoma

Official Title

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

Brief Summary

      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.
    

Detailed Description

      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.
    


Study Type

Observational [Patient Registry]


Primary Outcome

Pulmonary function tests

Secondary Outcome

 Six-minute walking distance and dessaturation during six-minute walk test

Condition

Tuberous Sclerosis


Study Arms / Comparison Groups

 Tuberous sclerosis complex
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

200

Start Date

April 2016

Completion Date

August 2021

Primary Completion Date

April 2021

Eligibility Criteria

        Inclusion Criteria:

          -  All patients with TSC, LAM (sporadic or associated with TSC) or AML (sporadic or
             associated with TSC or with LAM) 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.

        Exclusion Criteria:

          -  There is no exclusion criteria.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Carlos Roberto Ribeiro Carvalho, MD, PhD, 551126615695, [email protected]

Location Countries

Brazil

Location Countries

Brazil

Administrative Informations


NCT ID

NCT02325505

Organization ID

4147/14/127


Responsible Party

Principal Investigator

Study Sponsor

InCor Heart Institute

Collaborators

 Novartis

Study Sponsor

Carlos Roberto Ribeiro Carvalho, MD, PhD, Principal Investigator, InCor Heart Institute


Verification Date

July 2020