This is a five-year renewal application for the Thalassemia Clinical Research Network (TCRN). TCRN's mission is to accelerate research in the management of thalassemia. Syndromes encompassed by this mission include the ? thalassemia: homozygous or compound heterozygous plus Hemoglobin E/? thalassemia;and the alpha thalassemia: homozygous, hemoglobin H disease, and HbH/Constant Spring. The network is composed of four core U.S. sites, a data coordinating center, several large affiliated clinical sites in the U.S., Canada, and England, and several smaller regional """"""""satellite"""""""" sites to the core centers, in a cooperative agreement with NHLBI. Key strengths of the TCRN include a demonstrated ability of the investigators and sites cooperatively to standardize patient assessment and care;to design, implement and conduct clinical trials with observational, interventional, and ancillary designs. The multicenter network has been crucial due to sample size considerations. A pivotal accomplishment of the initial grant period is the establishment and analysis of the TCRN Registry, from which subjects for trials are identified. The registry now includes over 800 patients from 22 sites, including ?-thalassemia major (n=422), ? -thal intermedia (n=121), Hb E/ ? thal (n=103), transfusion-dependent a-thal major (n=9), HbH disease (n=l 05), and HbH/Constant Spring (n=44).
The Specific Aims of the renewal grant are: (I) To perform interventional clinical trials in key areas of thalassemia care. Two trials are proposed. First, a randomized, controlled trial to examine the effect of deferoxamine alone v. deferoxamine plus deferiprone, on cardiac disease due to transfusional iron overload. Second, a randomized trial of arginine v. placebo for pulmonary hypertension, an important problem in thalassemia intermedia and other hemolytic states. (II) To provide an infrastructure for development, launch, and prompt completion of small, innovative trials in thalassemia. (Ill) To improve assessment of phenotype and clinical outcomes in thalassemia, in order to facilitate current and future clinical trials. This will be accomplished by two studies. The Thalassemia Longitudinal Cohort study, as well as a detailed study of iron-related organ damage, comparing measures of iron burden in the heart, liver and pancreas, to outcomes of iron-related organ dysfunction. Combined with the proposed clinical trials and the ability to perform detailed genotype/phenotype correlations, these improved phenotype and outcome measures are powerful tools to enhance knowledge about thalassemia clinical care, as envisioned by the NIH's 2003 Director's Roadmap.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL065232-10
Application #
7665074
Study Section
Special Emphasis Panel (ZHL1-CSR-C (M2))
Program Officer
Luksenburg, Harvey
Project Start
2000-07-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
10
Fiscal Year
2009
Total Cost
$144,540
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Morris, Claudia R; Kim, Hae-Young; Klings, Elizabeth S et al. (2015) Dysregulated arginine metabolism and cardiopulmonary dysfunction in patients with thalassaemia. Br J Haematol 169:887-98
Tubman, Venée N; Fung, Ellen B; Vogiatzi, Maria et al. (2015) Guidelines for the Standard Monitoring of Patients With Thalassemia: Report of the Thalassemia Longitudinal Cohort. J Pediatr Hematol Oncol 37:e162-9
Trachtenberg, Felicia L; Gerstenberger, Eric; Xu, Yan et al. (2014) Relationship among chelator adherence, change in chelators, and quality of life in thalassemia. Qual Life Res 23:2277-88
Green, Sage T; Martin, Marie B; Haines, Dru et al. (2014) Variance of pain prevalence and associated severity during the transfusion cycle of adult thalassaemia patients. Br J Haematol 166:797-800
Porter, John B; Wood, John; Olivieri, Nancy et al. (2013) Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone. J Cardiovasc Magn Reson 15:38
Oliveros, Olivia; Trachtenberg, Felicia; Haines, Dru et al. (2013) Pain over time and its effects on life in thalassemia. Am J Hematol 88:939-43
Haines, Dru; Martin, Marie; Carson, Susan et al. (2013) Pain in thalassaemia: the effects of age on pain frequency and severity. Br J Haematol 160:680-7
Morris, Claudia R; Kim, Hae-Young; Wood, John et al. (2013) Sildenafil therapy in thalassemia patients with Doppler-defined risk of pulmonary hypertension. Haematologica 98:1359-67
Walter, Patrick B; Porter, John; Evans, Patricia et al. (2013) Increased leucocyte apoptosis in transfused ?-thalassaemia patients. Br J Haematol 160:399-403
Thompson, Alexis A; Kim, Hae-Young; Singer, Sylvia T et al. (2013) Pregnancy outcomes in women with thalassemia in North America and the United Kingdom. Am J Hematol 88:771-3

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