Multi-Center Study of Iron Overload: Pilot Study (MCSIO)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
University College London (UCL) Cancer Institute
Universitätsklinikum Hamburg-Eppendorf
Medical University Innsbruck
Information provided by (Responsible Party):
Elliott Vichinsky, Children's Hospital & Research Center Oakland
ClinicalTrials.gov Identifier:
NCT01114776
First received: April 30, 2010
Last updated: July 29, 2013
Last verified: July 2013
  Purpose

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.


Condition
Sickle Cell Disease
Thalassemia
Diamond-Blackfan Anemia

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: Pilot Study Examining Mechanisms of Iron Trafficking and Extra-hepatic Iron Distribution in Sickle Cell Disease, Thalassemia, and Other Iron Loading Anemias

Resource links provided by NLM:


Further study details as provided by Children's Hospital & Research Center Oakland:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Comparison of cardiac and pituitary iron content by MRI [ Time Frame: March 2010 - August 2012 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Biospecimen Retention:   Samples With DNA

whole blood, serum, plasma, and urine


Enrollment: 20
Study Start Date: November 2009
Estimated Study Completion Date: September 2013
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Groups/Cohorts
Sickle Cell Disease (SCD)
Patients with sickle cell diseases, 16 years or older with 10-20 years of transfusion (defined as 0.2-0.6mg Fe/kg/day exposure with annual ferritin levels greater than 2500 in at least 60% of years of chronic transfusion); 0 to 9 years old at the initiation of chronic transfusions; no exchange transfusions in the previous 6 months; and iron overload documented by either liver biopsy, MRI or SQUID with estimated LIC of greater than 7 mg/g dry wt in the previous 6 months or ferritin level greater than 1500mg/dl.
Thalassemia Major (TM)
Patients with β-thalassemia major and transfusion-dependent E-beta THAL. 16 years or older with 10-20 years of chronic transfusion (defined above), 0 to 9 years old at the initiation of chronic transfusions, iron overload documented by either liver biopsy, MRI or SQUID with estimated LIC of greater than 7 mg/g dry wt in the previous 6 months.
Diamond Blackfan Anemia (DBA)
Patients with DBA, 16 years or older with 10-20 years of transfusion, 0 to 9 years old at the initiation of chronic transfusions, iron overload documented by either liver biopsy, MRI or SQUID with estimated LIC of greater than 7 mg/g dry wt in the previous 6 months.
Controls

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

There is no gender predisposition for sickle cell disease, thalassemia major, or Diamond-Blackfan anemia. Sickle cell anemia most frequently affects people of African descent, thalassemia affects people of Mediterranian, northern African, Southeast Asia and Indian descent. Diamond-Blackfan anemia occurs across all racial and ethnic groups.

Criteria

Inclusion Criteria:

  • 10-20 years of transfusion (defined as 0.2-0.6mg Fe/kg/day exposure with annual ferritin levels greater than 2500 in at least 60% of years of chronic transfusion);
  • 0 to 9 years old at the initiation of chronic transfusions; no exchange transfusions in the previous 6 months
  • iron overload documented by either liver biopsy, MRI or SQUID with estimated LIC of greater than 7 mg/g dry wt in the previous 6 months or ferritin level greater than 1500mg/dl.

Exclusion Criteria:

  • Patients with HbSC, HbS/β thalassemia
  • Pacemaker (active or inactive) or other implanted magnetic devices, severe claustrophobia, or other contraindications to MRI; Unable to remove ferro-magnetic objects from the body in regions to be imaged (e.g., jewelry or piercing)
  • Presence of any other condition which, in the opinion of the investigator, would make the patient unsuitable for enrollment;
  • Any chronic inflammatory illness other than the SCD, TM or DBA;
  • Any acute illness within a 14 day period prior to blood sampling;
  • Patients receiving intensive chelation in the 6 months prior to enrollment including deferoxamine 24 hours per day, 7 days per week or combination treatment with 2 chelators
  • Pregnancy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01114776

Locations
United States, California
Children's Hospital & Research Center Oakland
Oakland, California, United States, 94609
Germany
Universitätsklinikum Hamburg-Eppendorf
Hamburg-Eppendorf, Germany
United Kingdom
UCL Cancer Institute
London, United Kingdom, WC1E 6BT
Sponsors and Collaborators
Children's Hospital & Research Center Oakland
University College London (UCL) Cancer Institute
Universitätsklinikum Hamburg-Eppendorf
Medical University Innsbruck
Investigators
Principal Investigator: Elliott Vichinsky, MD Children's Hospital & Research Center Oakland
Principal Investigator: John B Porter, MD University College London (UCL) Cancer Institute
  More Information

No publications provided

Responsible Party: Elliott Vichinsky, Elliott Vichinsky, MD, Children's Hospital & Research Center Oakland., Children's Hospital & Research Center Oakland
ClinicalTrials.gov Identifier: NCT01114776     History of Changes
Other Study ID Numbers: 2009-068, R01DK057778-06A1
Study First Received: April 30, 2010
Last Updated: July 29, 2013
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Anemia
Anemia, Diamond-Blackfan
Anemia, Sickle Cell
Thalassemia
Anemia, Aplastic
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Anemia, Hypoplastic, Congenital
Bone Marrow Diseases
Genetic Diseases, Inborn
Hematologic Diseases
Hemoglobinopathies
Red-Cell Aplasia, Pure

ClinicalTrials.gov processed this record on October 23, 2014