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

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ClinicalTrials.gov Identifier: NCT01114776
Recruitment Status : Completed
First Posted : May 3, 2010
Last Update Posted : September 24, 2020
Sponsor:
Collaborators:
University College London (UCL) Cancer Institute
Universitätsklinikum Hamburg-Eppendorf
Medical University Innsbruck
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
UCSF Benioff Children's Hospital Oakland

Tracking Information
First Submitted Date April 30, 2010
First Posted Date May 3, 2010
Last Update Posted Date September 24, 2020
Study Start Date November 1, 2009
Actual Primary Completion Date July 31, 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: June 19, 2012)
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 Measures
 (submitted: April 30, 2010)
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.
Change History
Current Secondary Outcome Measures
 (submitted: June 19, 2012)
  • 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 Measures
 (submitted: April 30, 2010)
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Multi-Center Study of Iron Overload: Pilot Study
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 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.

Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
whole blood, serum, plasma, and urine
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.
Condition
  • Sickle Cell Disease
  • Thalassemia
  • Diamond-Blackfan Anemia
Intervention Not Provided
Study 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
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: April 30, 2010)
20
Original Estimated Enrollment Same as current
Actual Study Completion Date September 30, 2013
Actual Primary Completion Date July 31, 2013   (Final data collection date for primary outcome measure)
Eligibility 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
Sex/Gender
Sexes Eligible for Study: All
Ages 16 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers Yes
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Germany,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT01114776
Other Study ID Numbers 2009-068
R01DK057778-06A1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party UCSF Benioff Children's Hospital Oakland
Study Sponsor UCSF Benioff Children's Hospital Oakland
Collaborators
  • University College London (UCL) Cancer Institute
  • Universitätsklinikum Hamburg-Eppendorf
  • Medical University Innsbruck
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
Principal Investigator: Elliott Vichinsky, MD UCSF Benioff Children's Hospital Oakland
Principal Investigator: John B Porter, MD University College London (UCL) Cancer Institute
PRS Account UCSF Benioff Children's Hospital Oakland
Verification Date September 2020