Changes in Myocardial Iron After Iron Administration

Changes in Myocardial Iron Content Following Administration of Intravenous Iron (Myocardial-IRON)

Recent studies have shown that treatment with intravenous iron in patients with iron deficiency (ID) and heart failure with reduced ejection fraction (HFrEF) improves symptomatology, functional capacity, quality of life, and decreases hospitalizations regardless of anemia. In addition, a decrease in myocardial iron content has been observed in patients with chronic HFrEF. This preliminary evidence has led to postulate that myocardial iron deficiency could play a direct role in the pathogenesis and progression of the disease.

The investigators hypothesize that the repletion of myocardial iron would explain part of the benefit of this treatment. Thus, the investigators postulate that cardiac magnetic resonance (CMR) (T2* and T1-mapping sequences) will be sensible enough to detect changes in myocardial iron content as a result of intravenous iron administration, and that such changes will correlate with simultaneous changes in parameters of heart failure severity.

In this double-blind 1:1 randomized study controlled by placebo the investigators aim to determine the changes in myocardial iron content after treatment with intravenous ferric carboxymaltose (FCM) by CMR at 7 and 30 days in patients with stable HFrEF and ID.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Iron-deficiency
• Intervention / Treatment: Drug: Ferric carboymaltose; Diagnostic test: Cardiac magnetic resonance; Drug: Placebo (Normal saline)

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Valencia, Spain
    • Hospital General de Valencia
  • Valencia, Spain
    • Hospital La Fe
  • Valencia, Spain, 46010
    • ERESA
  • Valencia, Spain, 46010
    • Fundación Investigación Hospital Clínico Universitario de Valencia. Instituto de Investigación Sanitaria INCLIVA.
  • Castellón
    • Castellón De La Plana, Castellón, Spain
      • Hospital General de Castellón
  • Valencia
    • Manises, Valencia, Spain
      • Hospital de Manises

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with ambulatory chronic heart failure
• Older than 18 years
• Patients in NYHA class II-III on optimal background therapy (as determined by the investigator) for at least 4 weeks with no dose changes of HF drugs during the last 2 weeks (with the exception of diuretics)
• Elevated natriuretic peptides levels (NT-proBNP >400 pg/ml) at the screening visit
• Left ventricle ejection fraction <50% documented in the last 12 months
• Iron deficiency defined as: serum ferritin level <100 μg/L or ferritin level 100-299 μg/L when TSAT is less than 20%, and hemoglobin <15 g/dL (all at screening)
• Participant is willing and able to give informed consent for participation in the study

Exclusion Criteria:

• Known sensitivity to any of the products to be administered per protocol.
• History of acquired iron overload.
• Severe valve disease, or being scheduled for cardiac surgery within the next 30 days.
• Acute myocardial infarction or acute coronary syndrome, transient ischemic attack, or stroke within the last 3 months prior to randomization.
• Coronary artery bypass graft, percutaneous intervention (e.g. cardiac, cerebrovascular, and aortic; diagnostic catheters are allowed), or major surgery, including thoracic and cardiac surgery, within the last 3 months prior to randomization.
• Ischemic heart disease scheduled for revascularization procedures within the next 30 days.
• HF scheduled for cardiac resynchronization therapy within the next 30 days.
• Patients with active bleeding in the last 30 days.
• Known active infection or active malignancy.
• Subject at an immediate need of transfusion or hemoglobin ≥15 g/dL.
• Anemia due to reasons other than iron deficiency
• Immunosuppressive therapy or renal dialysis
• History of erythropoietin, intravenous iron therapy, and blood transfusion in the previous 12 weeks.
• Oral iron therapy at doses >100 mg/day in previous 1 week prior to randomization.
• Subjects with an immediate need for transfusion.
• Pregnant or breastfeeding women.
• Subject of childbearing potential who is not willing to use adequate contraceptive precautions during the study and for up to 5 days after the last scheduled dose of study medication.
• Subject currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study, or subject is receiving other investigational agent(s).
• Any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Intravenous ferric carboxymaltose; Ferric Carboxymaltose solution [Ferinject® (FCM), Vifor Pharma (Glattbrugg, Switzerland)] will be given as a perfusion of 20 mL (which is the amount of FCM that is equivalent to 1000 mg of iron) diluted in a sterile saline solution (0.9% weight/volume (w/v) NaCl) administered over at least 15 min.	Drug: Ferric carboymaltose; Ferric Carboxymaltose solution [Ferinject® (FCM), Vifor Pharma (Glattbrugg, Switzerland)]; Other Names: Ferinject, intravenous iron; Diagnostic test: Cardiac magnetic resonance; Cardiac magnetic resonance including T2* and T1-mapping sequences
PLACEBO_COMPARATOR: Normal saline; Normal saline (0.9% weight/volume (w/v) NaCl) administered as per the instructions for active therapy.	Diagnostic test: Cardiac magnetic resonance; Cardiac magnetic resonance including T2* and T1-mapping sequences; Drug: Placebo (Normal saline); Normal saline (0.9% weight/volume (w/v) NaCl)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Changes in myocardial iron content assessed by CMR T2*	7 and 30 days
Changes in myocardial iron content assessed by CMR T1-mapping	7 and 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in left ventricular systolic function evaluated with cardiac magnetic resonance	Changes in left ventricular systolic function evaluated with cardiac magnetic resonance	7 and 30 days
6-minute walking test	Changes in functional capacity assessed by distance walked in 6 minutes (6-minute walking test)	7 and 30 days
New York Heart Association (NYHA) class.	Changes in functional capacity assessed by New York Heart Association (NYHA) class.	7 and 30 days
The Kansas City quality of life questionnaire (KCCQ)	Quality of life assessed by The Kansas City quality of life questionnaire (KCCQ). KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.	7 and 30 days
Antigen carbohydrate 125 (CA125)	Laboratory tests, biomarkers: antigen carbohydrate 125 (CA125)	30 days
Amino-terminal pro-brain natriuretic peptide (NT-proBNP)	Laboratory tests, biomarkers: amino-terminal pro-brain natriuretic peptide (NT-proBNP)	30 days
Galectin-3	Laboratory tests, biomarkers: galectin-3	30 days
ST-2	Laboratory tests, biomarkers: ST-2	30 days
High-sensitivity troponin (hsTnT)	Laboratory tests, biomarkers: high-sensitivity troponin (hsTnT)	30 days
Cystatin C	Laboratory tests, biomarkers: cystatin C	30 days
Neutrophil gelatinase-associated lipocalin (NGAL)	Laboratory tests, biomarkers: neutrophil gelatinase-associated lipocalin (NGAL)	30 days
Serum creatinine	Laboratory tests: serum creatinine	30 days
Urea	Laboratory tests: urea	30 days
Estimated glomerular filtration rate (eGFR)	Laboratory tests: estimated glomerular filtration rate (eGFR)	30 days
Hemoglobin	Laboratory tests: hemoglobin	30 days
Ferritin	Laboratory tests: ferritin	30 days
Transferrin saturation (TSAT)	Laboratory tests: transferrin saturation (TSAT)	30 days
soluble transferrin receptor (sTfR)	Laboratory tests: soluble transferrin receptor (sTfR)	30 days
Hepcidin	Laboratory tests: hepcidin.	30 days
Clinical events: all-cause hospitalizations	All-cause hospitalizations	30 days
Clinical events: cardiovascular hospitalizations.	Cardiovascular hospitalizations	30 days
Clinical events: heart failure hospitalizations.	Heart failure hospitalizations	30 days
Clinical events: time to first hospitalization for any reason.	Time to first hospitalization for any reason.	30 days
Clinical events: time to first hospitalization for any cardiovascular reason.	Time to first hospitalization for any cardiovascular reason.	30 days
Clinical events: time to first hospitalization due to worsening heart failure.	Time to first hospitalization due to worsening heart failure.	30 days

Collaborators and Investigators

• Sponsor: Fundación para la Investigación del Hospital Clínico de Valencia
• Investigators: Principal Investigator: Julio Nuñez, MD PhD, Fundación Investigación Hospital Clínico Universitario de Valencia. Instituto de Investigación Sanitaria INCLIVA.

Publications and helpful links

General Publications

• Del Canto I, Santas E, Cardells I, Minana G, Palau P, Llacer P, Facila L, Lopez-Vilella R, Almenar L, Bodi V, Lopez-Lereu MP, Monmeneu JV, Sanchis J, Moratal D, Maceira AM, de la Espriella R, Chorro FJ, Bayes-Genis A, Nunez J; Myocardial-IRON Investigators dagger. Short-Term Changes in Left and Right Ventricular Cardiac Magnetic Resonance Feature Tracking Strain Following Ferric Carboxymaltose in Patients With Heart Failure: A Substudy of the Myocardial-IRON Trial. J Am Heart Assoc. 2022 Apr 5;11(7):e022214. doi: 10.1161/JAHA.121.022214. Epub 2022 Mar 18.
• Meucci MC, Reinders MEJ, Groeneweg KE, Bezstarosti S, Ajmone Marsan N, Bax JJ, De Fijter JW, Delgado V. Cardiovascular Effects of Autologous Bone Marrow-Derived Mesenchymal Stromal Cell Therapy With Early Tacrolimus Withdrawal in Renal Transplant Recipients: An Analysis of the Randomized TRITON Study. J Am Heart Assoc. 2021 Dec 21;10(24):e023300. doi: 10.1161/JAHA.121.023300. Epub 2021 Dec 16.
• Nunez J, Minana G, Cardells I, Palau P, Llacer P, Facila L, Almenar L, Lopez-Lereu MP, Monmeneu JV, Amiguet M, Gonzalez J, Serrano A, Montagud V, Lopez-Vilella R, Valero E, Garcia-Blas S, Bodi V, de la Espriella-Juan R, Lupon J, Navarro J, Gorriz JL, Sanchis J, Chorro FJ, Comin-Colet J, Bayes-Genis A; Myocardial-IRON Investigators* dagger. Noninvasive Imaging Estimation of Myocardial Iron Repletion Following Administration of Intravenous Iron: The Myocardial-IRON Trial. J Am Heart Assoc. 2020 Feb 18;9(4):e014254. doi: 10.1161/JAHA.119.014254. Epub 2020 Feb 13.
• Minana G, Cardells I, Palau P, Llacer P, Facila L, Almenar L, Lopez-Lereu MP, Monmeneu JV, Amiguet M, Gonzalez J, Serrano A, Montagud V, Lopez-Vilella R, Valero E, Garcia-Blas S, Bodi V, de la Espriella-Juan R, Sanchis J, Chorro FJ, Bayes-Genis A, Nunez J; Myocardial-IRON Investigators. Changes in myocardial iron content following administration of intravenous iron (Myocardial-IRON): Study design. Clin Cardiol. 2018 Jun;41(6):729-735. doi: 10.1002/clc.22956. Epub 2018 Jun 5.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2017
• Primary Completion (ACTUAL): July 30, 2018
• Study Completion (ACTUAL): July 30, 2018

Study Registration Dates

• First Submitted: November 21, 2017
• First Submitted That Met QC Criteria: January 7, 2018
• First Posted (ACTUAL): January 12, 2018

Study Record Updates

• Last Update Posted (ACTUAL): July 30, 2019
• Last Update Submitted That Met QC Criteria: July 29, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Heart failure; Iron deficiency; Cardiac magnetic resonance; Ferric carboxymaltose; Myocardial iron
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Hematologic Diseases; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Heart Failure; Anemia, Iron-Deficiency
• Other Study ID Numbers: MYOCARDIAL-IRON; 2016-004194-40 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No