Thalassemia (Cooley's Anemia) Clinical Research Network (TCRN)
Condition: Anemia, Cooley's; Beta-Thalassemia; Hematologic Diseases; Thalassemia; Osteoporosis; Iron Overload; Hypertension, Pulmonary
MeSH terms: Osteoporosis; Hypertension, Pulmonary; Anemia; Thalassemia; Hematologic Diseases; beta-Thalassemia; Iron Overload
Study type: Observational

Summary: 
      The purpose of the TCRN is to accelerate research in the management of thalassemia,
      standardize existing treatments, and evaluate new ones in a network of clinical centers in
      North America. The emphasis will be on clinical trials that help identify optimal therapy.
      Therapeutic trials may involve investigational drugs, drugs already approved but not
      currently used, and drugs currently used.
    

Detailed description: 
      BACKGROUND:

      Cooley's anemia (beta-thalassemia major, hereafter referred to as thalassemia) is a severe,
      inherited blood disorder characterized by a quantitative defect in the synthesis of the beta
      chain of hemoglobin caused by any 1 of more than 100 known mutations in and around the beta
      globin gene cluster. The disease is characterized by severe anemia beginning in the first 6
      to 12 months of life. If untreated, the life expectancy is less than 5 years of age. Chronic
      red blood cell transfusions to maintain hemoglobin levels between 9 and 11 gm/dl
      ("hypertransfusion") alleviate the anemia and partially suppress erythropoiesis. The regular
      administration of red blood cells also improves growth, delays or prevents enlargement of the
      liver and spleen, and prevents the development of bone abnormalities that cause fractures as
      well as disfiguring changes known as Cooley's facies. Transfusions carry risks of
      alloimmunization, iron overload, and blood-transmitted infections. In the absence of
      effective iron chelation therapy, iron overload leads to numerous complications, including
      delayed or absent sexual development, diabetes mellitus, cirrhosis, cardiac arrhythmias, and
      congestive heart failure. Nonchelated or poorly chelated patients usually die of heart
      disease by 20 to 30 years of age.

      The addition of chelation therapy with deferoxamine (DFO) to the treatment of Cooley's anemia
      has dramatically improved the outcome for affected patients. With regular chelation therapy,
      the accumulation of excessive iron can be prevented. Studies have demonstrated that
      well-chelated patients have normal or only modest increases in liver iron, improved growth,
      sexual development, and most importantly, a markedly reduced chance of developing
      iron-induced heart disease.

      In the past few years, several new approaches to the treatment of thalassemia have included
      marrow or stem cell transplantation; the use of young red blood cells ("neocytes") for
      transfusion; maintenance of a higher pretransfusion hemoglobin level; new iron chelators; and
      the use of drugs such as hydroxyurea, erythropoietin, and butyrate compounds.

      It is recognized that even with a clinical network, the number of patients with Cooley's
      anemia who can be enrolled in a research protocol is likely to be small. Therefore, although
      a randomized clinical trial may be the preferred way of assessing the clinical benefits of a
      new therapy, it may not be feasible in some instances, even using biomarkers or other
      surrogate outcome measures. Depending upon the specific questions being addressed, other
      study designs might be appropriate. These might include pre- and post-treatment assessment or
      historical control studies. In all cases, the proposed design, including sample size, would
      be evaluated by the Protocol Review Committee.

      There is an urgent need to evaluate new and existing therapeutic approaches for persons with
      thalassemia and to disseminate the findings to health care professionals, patients, and the
      public. There are several reasons why a thalassemia clinical research network will accelerate
      clinical research and meet this need. The highly variable and sometimes complicated clinical
      manifestations of thalassemia often make it difficult to accumulate a large number of
      comparable patients in one center. Furthermore, uniformity in treatment protocols may reduce
      the number of patients needed at each clinical center. Also, the TCRN mechanism will help
      pool the necessary clinical expertise and administrative resources to facilitate the conduct
      of multiple and novel therapeutic trials in a timely, efficient manner. This, in turn, would
      promote rapid dissemination of research findings to health care professionals.

      DESIGN NARRATIVE:

      The network was originally funded in 2000 and has been extended through June 2010 to perform
      interventional clinical trials in key areas of thalassemia care. Two major trials are
      proposed: First, a randomized, controlled trial to examine the effect of DFO alone versus DFO
      plus deferiprone on cardiac disease due to transfusional iron overload; second, a randomized
      trial of arginine versus sildenafil for pulmonary hypertension, an important problem in
      thalassemia intermedia and other hemolytic states. Goals are to provide an infrastructure for
      development, launch, and prompt completion of small, innovative trials in thalassemia and to
      improve assessment of phenotype and clinical outcomes in thalassemia to facilitate current
      and future clinical trials. This will be accomplished by two studies: The Thalassemia
      Longitudinal Cohort (TLC) study and the Iron Burden Study, which is 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 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.
      Please refer to individual Clinicaltrials.gov study listings for TCRN study specifics and
      current information about trials, eligibility, and site participation. Thank you.
    

Intervention name(s): Deferoxamine; Deferiprone; Arginine; Sildenafil; Decitabine
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention MeSH terms: Decitabine; Sildenafil Citrate; Deferiprone; Deferoxamine
Time perspective: Prospective
Keywords: chelator; iron; transfusion; anemia; thalassemia