Clinical trial NCT04171635: Quantitative Susceptibility Mapping (QSM) to Guide Iron Chelating Therapy
Official title: Quantitative Susceptibility Mapping (QSM) to Guide Iron Chelating Therapy in Transfusional Iron Overload
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: MRI Scans
Keywords: Quantitative Susceptibility Mapping
Iron chelating therapy
Iron overload
Liver iron concentration
erythrocyte transfusion
liver transplantation
magnetic resonance imaging
thalassemia major
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
Collaborators: name: Columbia University
name: National Institutes of Health (NIH)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2019-11-21
Enrollment: 42
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
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.

Brief summary: The overall goal of this research is to help develop a new magnetic resonance (MR) method, Quantitative Susceptibility Mapping (QSM), to improve the measurement of liver iron concentrations without the need for a liver biopsy. Measurement of liver iron is important to diagnose and treat patients who have too much iron in their bodies (iron overload). Liver iron measurements by current MRI methods (R2 and R2\*) can be inaccurate because of the effects of fat, fibrosis and other abnormalities. QSM should not be affected by these factors and should be free of these errors. In this study, MRI measurements (QSM, R2 and R2\*) of iron in patients before liver transplant will be compared with chemical analysis of iron in liver explants (livers removed from patients undergoing liver transplant). The liver explants would otherwise be discarded. Investigators expect that this study will show that the new MRI method, QSM, is superior to the current MRI methods, R2 and R2\*.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Demonstration of efficacy of quantitative susceptibility mapping (QSM) MRI in quantifying liver iron concentration (LIC)
timeFrame: Five years
Secondary outcomes:
measure: Fibrosis as determined by in vivo R2*, an MRI method that provides quantitative information on iron levels
timeFrame: Five years
measure: Fibrosis as determined by in vitro R2*, an MRI method that provides quantitative information on iron levels
timeFrame: Five years
measure: Fibrosis as determined by in vivo hQSM, an MRI post-processing technique that provides quantitative information on iron levels
timeFrame: Five years
measure: Fibrosis as determined by in vitro hQSM, an MRI post processing technique that provides quantitative information on iron levels
timeFrame: Five years
measure: Steatosis as determined by in vivo R2*, an MRI method that provides quantitative information on iron levels
timeFrame: Five years
measure: Steatosis as determined by in vitro R2*, an MRI method that provides quantitative information on iron levels
timeFrame: Five years
measure: Steatosis as determined by in vivo hQSM, an MRI post-processing technique that provides quantitative information on iron levels
timeFrame: Five years
measure: Steatosis as determined by in vitro hQSM, an MRI post-processing technique that provides quantitative information on iron levels
timeFrame: Five years
measure: Necroinflammation as determined by in vivo R2*, an MRI method that provides quantitative information on iron levels
timeFrame: Five years
measure: Necroinflammation as determined by in vitro R2*, an MRI method that provides quantitative information on iron levels
timeFrame: Five years
measure: Necroinflammation as determined by in vivo hQSM, an MRI post-processing technique that provides quantitative information on iron levels
timeFrame: Five years
measure: Necroinflammation as determined by in vitro hQSM, an MRI post-processing technique that provides quantitative information on iron levels
timeFrame: Five years
Other outcomes:
Locations:
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
Study officials:
affiliation: Columbia University
name: Gary M Brittenham, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Weill Medical College of Cornell University
name: Yi Wang, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Weill Medical College of Cornell University
name: Sujit S Sheth, MD
role: PRINCIPAL_INVESTIGATOR
References: