Clinical Trial: Multi-Center Study of Iron Overload: Pilot Study

Study Status: Terminated
Recruit Status: Unknown status
Study Type: Observational

Official Title: Pilot Study Examining Mechanisms of Iron Trafficking and Extra-hepatic Iron Distribution in Sickle Cell Disease, Thalassemia, and Other Iron Loading Anemias

Brief Summary: The purpose of this study is to initiate pilot studies to demonstrate that a sufficient number of iron-overloaded thalassemia, SCD and DBA populations with similar duration of chronic transfusion, and age at start of transfusions would be available for a confirmatory study and to validate that proposed multicenter MRI and biochemical studies can be completed. The study will examine the hypothesis that a chronic inflammatory state in Sickle Cell Disease (SCD) leads to hepcidin- and cytokine-mediated iron withholding within the RES (reticuloendothelial system), lower plasma NTBI (non transferrin bound iron) levels, less distribution of iron to the heart in SCD.

Detailed Summary:

A detailed iron burden, transfusion and chelation history will be obtained from chart review or from participant recall.

Iron burden data will include: 1) documentation of liver iron, and 2) average annual ferritin values.

Transfusion data will include: (1) age at onset of regular transfusions, (2) years of chronic transfusion therapy, and (3) pre-transfusion Hb calculated as average of all assessments for each year.

MRI will be performed measuring pituitary, cardiac, and liver iron.

Laboratory samples should be obtained pre-transfusion and mid-cycle.

All interviews, exams, laboratory tests, study procedures and MRI assessments should be completed within a 0 to 12 weeks time span.

In addition, a healthy control group will also be recruited with similar age, gender, and ethnicity as the disease groups.


Sponsor: Children's Hospital & Research Center Oakland

Current Primary Outcome: Pilot study of biochemical mechanisms of iron deposition in patients with Sickle Cell Disease, Thalassemia and Diamond-Blackfan Anemia. [ Time Frame: March 2010 - August 2012 ]

To examine the hypothesis that a chronic inflammatory state in Sickle Cell Disease (SCD) leads to hepcidin- and cytokine-mediated iron withholding within the RES (reticuloendothelial system), lower plasma NTBI (non transferrin bound iron) levels, less distribution of iron to the heart in SCD, and finally lower uptake and enhanced export of NTBI by cardiomyocytes conditioned by SCD serum, when compared with similarly iron overloaded patients with beta thalassemia and diamond blackfan anemia.


Original Primary Outcome: Identification of iron overloaded patients with Sickle Cell Disease and Thalassemia eligible for future study of iron deposition and biochemical mechanisms [ Time Frame: March 2010 - Feb 2011 ]

Patients with similar duration of chronic transfusion and age at onset of chronic transfusion therapy will be identified from 10 participating centers. Detailed information on iron burden and transfusion, medical, and chelation histories will be obtained in order to establish a cohort of patients that could be available for a future powered study of extra-hepatic iron deposition and underlying biochemical mechanisms.


Current Secondary Outcome:

  • Comparison of cardiac and pituitary iron content by MRI [ Time Frame: March 2010 - August 2012 ]
    We will measure cardiac and pituitary iron deposition by MRI in SCD with 10-20 years of transfusion exposure (0.2-0.6 mg Fe/kg/day) and compare this to measurements in a similarly transfused group of TM (or DBA). Patients with similar duration of chronic transfusion and age at onset of chronic transfusion therapy will be compared.
  • Characterization of levels and speciation of NTBI in heavily transfused SCD vs. TM (or DBA) [ Time Frame: March 2010 - August 2012 ]
    Levels of total and speciated NTBI (directly chelatable, labile plasma (LPI) and bleomycin-reactive) will be correlated with inflammatory biomarkers, hepcidin levels and organ iron deposition in patients with SCD, TM (or DBA). Results from the 3 patient populations will be compared to determine the possible effect of ineffective erythropoiesis in TM on the amount or species of NTBI present in the circulation.
  • To examine mediators of iron trafficking including inflammatory and regulatory cytokines (TNF-α, IL-1, IL-6, IL-10, TGF β), hepcidin, and nutritional factors (Vitamin C and D) in heavily transfused patients with SCD and TM (or DBA) [ Time Frame: March 2010 - August 2012 ]
    To examine the hypothesis that disease-related differences in inflammatory markers, hepcidin, and nutritional factors affect NTBI deposition, we will define the relationships between plasma and monocyte cytokines known to have cellular effects on iron cell trafficking (IL-1, IL-6, IL-10, TNFalpha, and TGFbeta), hepcidin concentration, and nutrient factors on NTBI levels and characteristics.
  • To examine the cellular mechanisms of iron sequestration in the RES and uptake of iron into other iron storage sites in SCD relative to TM (or DBA) [ Time Frame: March 2010 - August 2012 ]
    We will examine iron homeostasis in primary monocytes obtained from the 4 study groups to ascertain whether there is increased iron accumulation in monocytes in SCD patients. We will determine total cellular iron and ferritin-bound iron in monocytes isolated from the blood of SCD, TM and DBA patients.


Original Secondary Outcome:

  • Comparison of cardiac and pituitary iron content by MRI [ Time Frame: March 2010 - December 2010 ]
    We will measure cardiac and pituitary iron deposition by MRI in SCD with 10-20 years of transfusion exposure (0.2-0.6 mg Fe/kg/day) and compare this to measurements in a similarly transfused group of TM (or DBA). Patients with similar duration of chronic transfusion and age at onset of chronic transfusion therapy will be compared.
  • Characterization of levels and speciation of NTBI in heavily transfused SCD vs. TM (or DBA) [ Time Frame: March 2010 - December 2010 ]
    Levels of total and speciated NTBI (directly chelatable, labile plasma (LPI) and bleomycin-reactive) will be correlated with inflammatory biomarkers, hepcidin levels and organ iron deposition in patients with SCD, TM (or DBA). Results from the 3 patient populations will be compared to determine the possible effect of ineffective erythropoiesis in TM on the amount or species of NTBI present in the circulation.
  • To examine mediators of iron trafficking including inflammatory and regulatory cytokines (TNF-α, IL-1, IL-6, IL-10, TGF β), hepcidin, and nutritional factors (Vitamin C and D) in heavily transfused patients with SCD and TM (or DBA) [ Time Frame: March 2010 - December 2010 ]
    To examine the hypothesis that disease-related differences in inflammatory markers, hepcidin, and nutritional factors affect NTBI deposition, we will define the relationships between plasma and monocyte cytokines known to have cellular effects on iron cell trafficking (IL-1, IL-6, IL-10, TNFalpha, and TGFbeta), hepcidin concentration, and nutrient factors on NTBI levels and characteristics.
  • To examine the cellular mechanisms of iron sequestration in the RES and uptake of iron into other iron storage sites in SCD relative to TM (or DBA) [ Time Frame: March 2010 - December 2010 ]
    We will examine iron homeostasis in primary monocytes obtained from the 4 study groups to ascertain whether there is increased iron accumulation in monocytes in SCD patients. We will determine total cellular iron and ferritin-bound iron in monocytes isolated from the blood of SCD, TM and DBA patients.


Information By: Children's Hospital & Research Center Oakland

Dates:
Date Received: April 30, 2010
Date Started: November 2009
Date Completion: September 2013
Last Updated: July 29, 2013
Last Verified: July 2013