Characterization of Patients With Tuberous Sclerosis Complex, Lymphangioleiomyomatosis and Angiomyolipoma

NCT02325505 | Completed DMC

• 1 other identifier: 4147/14/127
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 3

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.

Conditions

Tuberous Sclerosis; Lymphangioleiomyomatosis; Angiomyolipoma

Outcome Measures

Primary Outcomes (11)

• Pulmonary function tests

  Decline of forced expiratory volume in the first second

  Baseline and change after one year

• Chest high resolution computed tomography findings

  Extent of pulmonary cysts

  Baseline and change after one year

• Findings on computed tomography of the brain

  TSC lesions

  Baseline and change after one year

• Abdominal computed tomography findings

  Renal angiomyolipoma, lymphangioleiomyoma

  Baseline and change after one year

• Skin lesions

  Describe skin lesions in the study population

  Baseline and change after one year

• Respiratory symptoms Describe all respiratory symptoms in the study population)

  Describe all respiratory symptoms in the study population

  Baseline and change after one year

• Quality of life evaluation with the questionnaire Short-Form Health Survey - 36 (SF-36)

  Absolute variation

  Baseline and change after one year

• Urinary and abdominal complaints

  Describe urinary and abdominal complaints in the study population

  Baseline and change after one year

• Baseline dyspna index

  Assessment of the degree of dyspnea using baseline dyspnea index

  Baseline and change after one year

• Treatments performed (previous and current treatments performed)

  To describe previous and current treatments performed

  Baseline

• Neurological complaints

  Describe neurological complaints in the study population

  Baseline and after one year

Secondary Outcomes (3)

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

  Baseline and change after one year

• Systolic pulmonary arterial pressure

  Baseline and after one year

• Histopathological characteristics of samples obtained from skin biopsy

  Baseline

Study Arms (1)

Tuberous sclerosis complex

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.

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The population of this study is composed of patients with TSC, LAM (sporadic or associated with TSC) or AML (sporadic or associated with TSC or with LAM). The estimated sample size for this study is about 200 patients, all of them followed at University of Sao Paulo Medical School.

You may qualify if:

• 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.

Sponsors & Collaborators

• InCor Heart Institute: lead
• Novartis: collaborator

Study Sites (3)

InCor Heart Institute

São Paulo, 05303900, Brazil

Location

InCor Heart Institute, Research Center

São Paulo, 05403900, Brazil

Location

InCor Heart Institute

São Paulo, 05403900, Brazil

Location

Related Publications (25)

• Franz DN, Bissler JJ, McCormack FX. Tuberous sclerosis complex: neurological, renal and pulmonary manifestations. Neuropediatrics. 2010 Oct;41(5):199-208. doi: 10.1055/s-0030-1269906. Epub 2011 Jan 5.

  PMID: 21210335 BACKGROUND

• Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008 Aug 23;372(9639):657-68. doi: 10.1016/S0140-6736(08)61279-9.

  PMID: 18722871 BACKGROUND

• Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006 Sep 28;355(13):1345-56. doi: 10.1056/NEJMra055323. No abstract available.

  PMID: 17005952 BACKGROUND

• Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Whittemore VH, Thiele EA, Ford JP, Shah G, Cauwel H, Lebwohl D, Sahmoud T, Jozwiak S. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013 Jan 12;381(9861):125-32. doi: 10.1016/S0140-6736(12)61134-9. Epub 2012 Nov 14.

  PMID: 23158522 BACKGROUND

• Datta AN, Hahn CD, Sahin M. Clinical presentation and diagnosis of tuberous sclerosis complex in infancy. J Child Neurol. 2008 Mar;23(3):268-73. doi: 10.1177/0883073807309250. Epub 2008 Jan 29.

  PMID: 18230839 BACKGROUND

• Johnson SR, Cordier JF, Lazor R, Cottin V, Costabel U, Harari S, Reynaud-Gaubert M, Boehler A, Brauner M, Popper H, Bonetti F, Kingswood C; Review Panel of the ERS LAM Task Force. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J. 2010 Jan;35(1):14-26. doi: 10.1183/09031936.00076209. No abstract available.

  PMID: 20044458 BACKGROUND

• Ryu JH, Moss J, Beck GJ, Lee JC, Brown KK, Chapman JT, Finlay GA, Olson EJ, Ruoss SJ, Maurer JR, Raffin TA, Peavy HH, McCarthy K, Taveira-Dasilva A, McCormack FX, Avila NA, Decastro RM, Jacobs SS, Stylianou M, Fanburg BL; NHLBI LAM Registry Group. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med. 2006 Jan 1;173(1):105-11. doi: 10.1164/rccm.200409-1298OC. Epub 2005 Oct 6.

  PMID: 16210669 BACKGROUND

• Baldi BG, Albuquerque AL, Pimenta SP, Salge JM, Kairalla RA, Carvalho CR. Exercise performance and dynamic hyperinflation in lymphangioleiomyomatosis. Am J Respir Crit Care Med. 2012 Aug 15;186(4):341-8. doi: 10.1164/rccm.201203-0372OC. Epub 2012 Jun 14.

  PMID: 22700863 BACKGROUND

• Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Whittemore VH, Chen D, Sahmoud T, Shah G, Lincy J, Lebwohl D, Budde K. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2013 Mar 9;381(9869):817-24. doi: 10.1016/S0140-6736(12)61767-X.

  PMID: 23312829 BACKGROUND

• Schwartz RA, Fernandez G, Kotulska K, Jozwiak S. Tuberous sclerosis complex: advances in diagnosis, genetics, and management. J Am Acad Dermatol. 2007 Aug;57(2):189-202. doi: 10.1016/j.jaad.2007.05.004.

  PMID: 17637444 BACKGROUND

• Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol. 1998 Dec;13(12):624-8. doi: 10.1177/088307389801301206.

  PMID: 9881533 BACKGROUND

• McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011 Apr 28;364(17):1595-606. doi: 10.1056/NEJMoa1100391. Epub 2011 Mar 16.

  PMID: 21410393 BACKGROUND

• Ware JE Jr. SF-36 health survey update. Spine (Phila Pa 1976). 2000 Dec 15;25(24):3130-9. doi: 10.1097/00007632-200012150-00008. No abstract available.

  PMID: 11124729 BACKGROUND

• Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea. Contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest. 1984 Jun;85(6):751-8. doi: 10.1378/chest.85.6.751.

  PMID: 6723384 BACKGROUND

• Mahler DA, Harver A, Rosiello R, Daubenspeck JA. Measurement of respiratory sensation in interstitial lung disease. Evaluation of clinical dyspnea ratings and magnitude scaling. Chest. 1989 Oct;96(4):767-71. doi: 10.1378/chest.96.4.767.

  PMID: 2791670 BACKGROUND

• Assumpcao Junior FB, Kuczynski E, Gabriel MR, Rocca CC. [Evaluation scale of autistic behavior. Validity and reliability of a scale for autistic behavior detection]. Arq Neuropsiquiatr. 1999 Mar;57(1):23-9. doi: 10.1590/s0004-282x1999000100005. Portuguese.

  PMID: 10347719 BACKGROUND

• Santos RS, Araujo AP, Porto MA. Early diagnosis of abnormal development of preterm newborns: assessment instruments. J Pediatr (Rio J). 2008 Jul-Aug;84(4):289-99. doi: 10.2223/JPED.1815.

  PMID: 18688553 BACKGROUND

• Miotto EC, Sato J, Lucia MC, Camargo CH, Scaff M. Development of an adapted version of the Boston Naming Test for Portuguese speakers. Braz J Psychiatry. 2010 Sep;32(3):279-82. doi: 10.1590/s1516-44462010005000006. Epub 2010 Apr 30.

  PMID: 20428731 BACKGROUND

• Gerstadt CL, Hong YJ, Diamond A. The relationship between cognition and action: performance of children 3 1/2-7 years old on a Stroop-like day-night test. Cognition. 1994 Nov;53(2):129-53. doi: 10.1016/0010-0277(94)90068-x.

  PMID: 7805351 BACKGROUND

• Pereira CA, Sato T, Rodrigues SC. New reference values for forced spirometry in white adults in Brazil. J Bras Pneumol. 2007 Jul-Aug;33(4):397-406. doi: 10.1590/s1806-37132007000400008. English, Portuguese.

  PMID: 17982531 BACKGROUND

• Duarte AA, Pereira CA, Rodrigues SC. Validation of new brazilian predicted values for forced spirometry in caucasians and comparison with predicted values obtained using other reference equations. J Bras Pneumol. 2007 Sep-Oct;33(5):527-35. doi: 10.1590/s1806-37132007000500007. English, Portuguese.

  PMID: 18026650 BACKGROUND

• Neder JA, Andreoni S, Castelo-Filho A, Nery LE. Reference values for lung function tests. I. Static volumes. Braz J Med Biol Res. 1999 Jun;32(6):703-17. doi: 10.1590/s0100-879x1999000600006.

  PMID: 10412549 BACKGROUND

• Neder JA, Andreoni S, Peres C, Nery LE. Reference values for lung function tests. III. Carbon monoxide diffusing capacity (transfer factor). Braz J Med Biol Res. 1999 Jun;32(6):729-37. doi: 10.1590/s0100-879x1999000600008.

  PMID: 10412551 BACKGROUND

• Soaresa MR, Pereira CA. Six-minute walk test: reference values for healthy adults in Brazil. J Bras Pneumol. 2011 Sep-Oct;37(5):576-83. doi: 10.1590/s1806-37132011000500003. English, Portuguese.

  PMID: 22042388 BACKGROUND

• ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102. No abstract available.

  PMID: 12091180 BACKGROUND

MeSH Terms

Conditions

Tuberous Sclerosis; Lymphangioleiomyomatosis; Angiomyolipoma

Condition Hierarchy (Ancestors)

Hamartoma; Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Nervous System Diseases; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Lymphangiomyoma; Neoplasm, Lymphatic Tissue; Neoplasms by Histologic Type; Perivascular Epithelioid Cell Neoplasms; Neoplasms, Connective and Soft Tissue; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms, Adipose Tissue

Study Officials

• Carlos Roberto Ribeiro Carvalho, MD, PhD

  InCor Heart Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 2 Years
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Assistant

Study Record Dates

• First Submitted: December 14, 2014
• First Posted: December 25, 2014
• Study Start: April 1, 2016
• Primary Completion: April 1, 2021
• Study Completion: August 1, 2022
• Last Updated: August 4, 2022

Record last verified: 2022-08

Locations

BR (3)