- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04171635
Quantitative Susceptibility Mapping (QSM) to Guide Iron Chelating Therapy
Quantitative Susceptibility Mapping (QSM) to Guide Iron Chelating Therapy in Transfusional Iron Overload
Study Overview
Status
Conditions
Detailed Description
The overall objective of this research is to improve the safety of iron-chelating therapy (ICT) in patients with transfusional iron overload by developing an accurate non-invasive measurement of the liver iron concentration (LIC), the best measure of the body iron burden in all forms of systemic iron overload. The scientific premise is that quantitative susceptibility mapping (QSM) provides a quantitative biophysical connection to LIC. Safe ICT requires careful adjustment of the iron chelator dose to the body iron burden to optimize iron excretion while avoiding chelator toxicity, including gastrointestinal disorders, audiovisual impairment, neutropenia, arthropathy, growth retardation, and hepatic and renal failure. QSM enables accurate measurement of LIC by overcoming the inherent cellular interference in current R2 (=1/T2) and R2* (=R2+R2') estimates that lack a well-defined biophysical connection to the LIC. A fundamental biophysical limitation of the R2 and R2* approaches is that intravoxel contents other than iron, including fibrosis, steatosis and necroinflammation, also alter relaxation. In the liver, paramagnetic iron stored in ferritin and hemosiderin is the dominant susceptibility source for QSM. Consequently, magnetic susceptibility measured by QSM has a simple linear relationship with the concentration of iron in the liver and is little affected by fibrosis, steatosis and necroinflammation. The investigator's research plan has 3 specific aims:
Aim 1. Develop hQSM for accurate measurement of LIC without interfering errors. Investigators will optimize data acquisition and processing for free-breathing navigator acquisition with robust fat-water separation.
Aim 2. Validate hQSM using histology and chemical measurement of LIC in liver explants. Investigators will assess the accuracies of LICs measured by hQSM and R2* in patients before liver transplant with histologic examination using the reference standard of chemical measurement of LIC in liver explants.
Aim 3. Evaluate hQSM in patients with transfusional iron overload under ICT. In patients regularly transfused for thalassemia major, investigators will conduct a double-blind clinical study comparing the accuracy of hQSM and R2* in measuring annual changes in LIC, using regression against the year-long amount of iron administered in red blood cell transfusions and the year-long cumulative dose of iron chelator.
Study Type
Enrollment (Estimated)
Contacts and Locations
Study Contact
- Name: Gary M Brittenham, MD
- Phone Number: 212-305-7005
- Email: gmb31@cumc.columbia.edu
Study Locations
-
-
New York
-
New York, New York, United States, 10032
- Recruiting
- Columbia University Medical Center
-
Principal Investigator:
- Gary M Brittenham, MD
-
Sub-Investigator:
- Anne Koehne de Gonzalez, MD
-
New York, New York, United States, 10021
- Recruiting
- Weill Cornell Medical College
-
Contact:
- Yi Wang, PhD
- Phone Number: 212-962-2631
- Email: yiwang@med.cornell.edu
-
Principal Investigator:
- Sujit Sheth, MD
-
Sub-Investigator:
- Kelly Gillen, PhD
-
Sub-Investigator:
- Yi Wang, PhD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Sampling Method
Study Population
Healthy subjects will be selected from the community through personal contact and written description of the research, and online advertising.
Subjects will be selected at Columbia from those awaiting liver transplant to be enrolled in the study.
Description
Inclusion Criteria:
- Established diagnosis of thalassemia major
- Treatment with deferasirox formulated as Jadenu® as the sole iron chelating therapy (ICT)
- Regular transfusion with records maintained in the Cornell Thalassemia Program
- 2 years of age or older
- Females who are not pregnant
Inclusion Criteria (for healthy subjects):
- Men and women aged 21 years or older
- Able and willing to give consent
- No known hematological and liver disease
- No contraindications for MRI
Exclusion Criteria:
- A history of auditory or ocular toxicity related to ICT
- A history of poor adherence to prescribed therapy
- An inability to tolerate MRI examinations
- Treatment for mental illness
- Institutionalization or imprisonment
Study Plan
How is the study designed?
Design Details
- Observational Models: Cohort
- Time Perspectives: Prospective
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
Patients with transfusional iron overload
The subject population of patients with transfusional iron overload awaiting liver transplant has been chosen because of the clinical indication for MRI examination every three months and the availability of liver explants for analysis after transplant.
Explants will receive QSM or R2* MRI to provide a quantitative biophysical connection to liver iron concentration (LIC).
|
Investigators will validate hepatic QSM (hQSM) using histological examination and chemical measurement of liver iron concentration (LIC).
Patients will undergo clinical MRI in Aim 1.
In patients with increased LIC their liver explants will undergo MRI, pathological examination, and chemical determination of the LIC.
Investigators will be able to validate hQSM in measuring liver iron concentration (LIC) by comparing it to this traditional MRI technique
|
Healthy subjects
Healthy control subjects over the age of 21 with no known hematological or liver disease and no contraindications for MRI
|
Investigators will validate hepatic QSM (hQSM) using histological examination and chemical measurement of liver iron concentration (LIC).
Patients will undergo clinical MRI in Aim 1.
In patients with increased LIC their liver explants will undergo MRI, pathological examination, and chemical determination of the LIC.
Investigators will be able to validate hQSM in measuring liver iron concentration (LIC) by comparing it to this traditional MRI technique
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Demonstration of efficacy of quantitative susceptibility mapping (QSM) MRI in quantifying liver iron concentration (LIC)
Time Frame: Five years
|
Investigators will assess the accuracy of liver iron concentrations measured by QSM in patients before liver transplant with histologic examination using the gold standard chemical measurement of LIC in liver explants.
|
Five years
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Fibrosis as determined by in vivo R2*, an MRI method that provides quantitative information on iron levels
Time Frame: Five years
|
R2* is an imaging method used in MRI.
R2* = (1/T2*) where R2* is a relaxation rate measured in units of Hz ([1/sec]).
R2* is commonly used to look at iron levels by measuring the relaxation times of hydrogen nuclei affected by iron.
The presence of the iron results in the shortening of proton relaxation times (T2*), thus increasing R2*.
|
Five years
|
Fibrosis as determined by in vitro R2*, an MRI method that provides quantitative information on iron levels
Time Frame: Five years
|
R2* is an imaging method used in MRI.
R2* = (1/T2*) where R2* is a relaxation rate measured in units of Hz ([1/sec]).
R2* is commonly used to look at iron levels by measuring the relaxation times of hydrogen nuclei affected by iron.
The presence of the iron results in the shortening of proton relaxation times (T2*), thus increasing R2*.
|
Five years
|
Fibrosis as determined by in vivo hQSM, an MRI post-processing technique that provides quantitative information on iron levels
Time Frame: Five years
|
Quantitative susceptibility mapping (QSM) is widely used by the imaging research community in applications to detect iron.
Tissue can become magnetized in response to a magnetic field, and the extent of magnetization is known as susceptibility, which arises from unpaired electrons in iron or external sources such as contrast agents.
QSM permits visualization of the sizes and shapes of iron sources, delivers precise estimates of iron concentrations (units: parts per billion [ppb] or parts per million [ppm]).
|
Five years
|
Fibrosis as determined by in vitro hQSM, an MRI post processing technique that provides quantitative information on iron levels
Time Frame: Five years
|
Quantitative susceptibility mapping (QSM) is widely used by the imaging research community in applications to detect iron.
Tissue can become magnetized in response to a magnetic field, and the extent of magnetization is known as susceptibility, which arises from unpaired electrons in iron or external sources such as contrast agents.
QSM permits visualization of the sizes and shapes of iron sources, delivers precise estimates of iron concentrations (units: parts per billion [ppb] or parts per million [ppm]).
|
Five years
|
Steatosis as determined by in vivo R2*, an MRI method that provides quantitative information on iron levels
Time Frame: Five years
|
R2* is an imaging method used in MRI.
R2* = (1/T2*) where R2* is a relaxation rate measured in units of Hz ([1/sec]).
R2* is commonly used to look at iron levels by measuring the relaxation times of hydrogen nuclei affected by iron.
The presence of the iron results in the shortening of proton relaxation times (T2*), thus increasing R2*.
|
Five years
|
Steatosis as determined by in vitro R2*, an MRI method that provides quantitative information on iron levels
Time Frame: Five years
|
R2* is an imaging method used in MRI.
R2* = (1/T2*) where R2* is a relaxation rate measured in units of Hz ([1/sec]).
R2* is commonly used to look at iron levels by measuring the relaxation times of hydrogen nuclei affected by iron.
The presence of the iron results in the shortening of proton relaxation times (T2*), thus increasing R2*.
|
Five years
|
Steatosis as determined by in vivo hQSM, an MRI post-processing technique that provides quantitative information on iron levels
Time Frame: Five years
|
Quantitative susceptibility mapping (QSM) is widely used by the imaging research community in applications to detect iron.
Tissue can become magnetized in response to a magnetic field, and the extent of magnetization is known as susceptibility, which arises from unpaired electrons in iron or external sources such as contrast agents.
QSM permits visualization of the sizes and shapes of iron sources, delivers precise estimates of iron concentrations (units: parts per billion [ppb] or parts per million [ppm]).
|
Five years
|
Steatosis as determined by in vitro hQSM, an MRI post-processing technique that provides quantitative information on iron levels
Time Frame: Five years
|
Quantitative susceptibility mapping (QSM) is widely used by the imaging research community in applications to detect iron.
Tissue can become magnetized in response to a magnetic field, and the extent of magnetization is known as susceptibility, which arises from unpaired electrons in iron or external sources such as contrast agents.
QSM permits visualization of the sizes and shapes of iron sources, delivers precise estimates of iron concentrations (units: parts per billion [ppb] or parts per million [ppm]).
|
Five years
|
Necroinflammation as determined by in vivo R2*, an MRI method that provides quantitative information on iron levels
Time Frame: Five years
|
R2* is an imaging method used in MRI.
R2* = (1/T2*) where R2* is a relaxation rate measured in units of Hz ([1/sec]).
R2* is commonly used to look at iron levels by measuring the relaxation times of hydrogen nuclei affected by iron.
The presence of the iron results in the shortening of proton relaxation times (T2*), thus increasing R2*.
|
Five years
|
Necroinflammation as determined by in vitro R2*, an MRI method that provides quantitative information on iron levels
Time Frame: Five years
|
R2* is an imaging method used in MRI.
R2* = (1/T2*) where R2* is a relaxation rate measured in units of Hz ([1/sec]).
R2* is commonly used to look at iron levels by measuring the relaxation times of hydrogen nuclei affected by iron.
The presence of the iron results in the shortening of proton relaxation times (T2*), thus increasing R2*.
|
Five years
|
Necroinflammation as determined by in vivo hQSM, an MRI post-processing technique that provides quantitative information on iron levels
Time Frame: Five years
|
Quantitative susceptibility mapping (QSM) is widely used by the imaging research community in applications to detect iron.
Tissue can become magnetized in response to a magnetic field, and the extent of magnetization is known as susceptibility, which arises from unpaired electrons in iron or external sources such as contrast agents.
QSM permits visualization of the sizes and shapes of iron sources, delivers precise estimates of iron concentrations (units: parts per billion [ppb] or parts per million [ppm]).
|
Five years
|
Necroinflammation as determined by in vitro hQSM, an MRI post-processing technique that provides quantitative information on iron levels
Time Frame: Five years
|
Quantitative susceptibility mapping (QSM) is widely used by the imaging research community in applications to detect iron.
Tissue can become magnetized in response to a magnetic field, and the extent of magnetization is known as susceptibility, which arises from unpaired electrons in iron or external sources such as contrast agents.
QSM permits visualization of the sizes and shapes of iron sources, delivers precise estimates of iron concentrations (units: parts per billion [ppb] or parts per million [ppm]).
|
Five years
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Gary M Brittenham, MD, Columbia University
- Principal Investigator: Yi Wang, PhD, Weill Medical College of Cornell University
- Principal Investigator: Sujit S Sheth, MD, Weill Medical College of Cornell University
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 1706018263
- R01DK116126-01A1 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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