Clinical trial NCT03398681: Changes in Myocardial Iron After Iron Administration
Official title: Changes in Myocardial Iron Content Following Administration of Intravenous Iron (Myocardial-IRON)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Heart Failure
Iron-deficiency
Keywords: Heart failure
Iron deficiency
Cardiac magnetic resonance
Ferric carboxymaltose
Myocardial iron
Lead sponsor: Fundación para la Investigación del Hospital Clínico de Valencia
Sponsor class: OTHER
First posted: 2018-01-12
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: After providing informed consent, patients will be randomly assigned, with a remote, web-based computer-generated block randomization procedure in an allocation 1:1 ratio, to either receive intravenous ferric carboxymaltose (FCM) or placebo. Intramyocardial iron will be evaluated at 3 time points: before administration of CMF/placebo, and at 7 and 30 days. At 30 days, patients assigned to placebo will receive intravenous CMF if iron deficiency persists.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Changes in myocardial iron content assessed by CMR T2*
timeFrame: 7 and 30 days
measure: Changes in myocardial iron content assessed by CMR T1-mapping
timeFrame: 7 and 30 days
Secondary outcomes:
measure: Changes in left ventricular systolic function evaluated with cardiac magnetic resonance
timeFrame: 7 and 30 days
measure: 6-minute walking test
timeFrame: 7 and 30 days
measure: New York Heart Association (NYHA) class.
timeFrame: 7 and 30 days
measure: The Kansas City quality of life questionnaire (KCCQ)
timeFrame: 7 and 30 days
measure: Antigen carbohydrate 125 (CA125)
timeFrame: 30 days
measure: Amino-terminal pro-brain natriuretic peptide (NT-proBNP)
timeFrame: 30 days
measure: Galectin-3
timeFrame: 30 days
measure: ST-2
timeFrame: 30 days
measure: High-sensitivity troponin (hsTnT)
timeFrame: 30 days
measure: Cystatin C
timeFrame: 30 days
measure: Neutrophil gelatinase-associated lipocalin (NGAL)
timeFrame: 30 days
measure: Serum creatinine
timeFrame: 30 days
measure: Urea
timeFrame: 30 days
measure: Estimated glomerular filtration rate (eGFR)
timeFrame: 30 days
measure: Hemoglobin
timeFrame: 30 days
measure: Ferritin
timeFrame: 30 days
measure: Transferrin saturation (TSAT)
timeFrame: 30 days
measure: soluble transferrin receptor (sTfR)
timeFrame: 30 days
measure: Hepcidin
timeFrame: 30 days
measure: Clinical events: all-cause hospitalizations
timeFrame: 30 days
measure: Clinical events: cardiovascular hospitalizations.
timeFrame: 30 days
measure: Clinical events: heart failure hospitalizations.
timeFrame: 30 days
measure: Clinical events: time to first hospitalization for any reason.
timeFrame: 30 days
measure: Clinical events: time to first hospitalization for any cardiovascular reason.
timeFrame: 30 days
measure: Clinical events: time to first hospitalization due to worsening heart failure.
timeFrame: 30 days
Other outcomes:
Locations:
city: Castellón De La Plana
country: Spain
facility: Hospital General de Castellón
state: Castellón
city: Manises
country: Spain
facility: Hospital de Manises
state: Valencia
city: Valencia
country: Spain
facility: ERESA
city: Valencia
country: Spain
facility: Fundación Investigación Hospital Clínico Universitario de Valencia. Instituto de Investigación Sanitaria INCLIVA.
city: Valencia
country: Spain
facility: Hospital General de Valencia
city: Valencia
country: Spain
facility: Hospital la Fe
Study officials:
affiliation: Fundación Investigación Hospital Clínico Universitario de Valencia. Instituto de Investigación Sanitaria INCLIVA.
name: Julio Nuñez, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.