Intravenous Iron Supplement for Iron Deficiency in Cardiac Transplant Recipients (IronIC)

Iron deficiency is prevalent in heart transplant recipients, and may be associated with reduced functional capacity. The IronIC trial is designed to assess the effect of intravenous iron isomaltoside on exercise capacity, muscle strength, cognition and quality of life in iron-deficient heart transplant recipients

Study Overview

• Status: Completed
• Conditions: Heart Transplant Recipients
• Intervention / Treatment: Drug: Iron Isomaltoside 1000; Other: Placebo: NaCl 0,9%

Detailed Description

Iron deficiency is prevalent in patients with heart failure. Iron deficiency is associated with a worse prognosis, and randomised controlled trials have shown that correction of iron deficiency with intravenous iron therapy improves functional capacity, quality of life, and 6-minute walk distance. Current guidelines therefore recommend intravenous iron substitution in patients with heart failure with reduced ejection fraction and iron deficiency. Intravenous iron is more effective, better tolerated, and improves quality of life to a greater extent than oral iron supplements. In the IRONOUT HF trial, in which 225 patients with systolic heart failure were randomised to oral iron supplement or placebo, there was no effect on oxygen uptake, 6-minute walk distance, or quality of life. The authors attributed the negative results to the minimal effect on iron stores, suggesting that oral iron does not adequately replenish iron stores in patients with heart failure.

Cardiac allograft recipients resemble patients with heart failure in many respects. Prior to transplantation, and in some instances after heart transplantation, they have had overt heart failure. Moreover, due to the immunologic challenge posed by the allograft, and their susceptibility to infection due to immunosuppressive treatment, cardiac allograft recipients have low-grade inflammation. This low-grade inflammation makes it difficult to interpret iron stores, and results in dysregulated iron metabolism.

There have been no studies to assess the effect of intravenous iron therapy in heart transplant recipients who have iron deficiency. There is reason to believe that a liberal definition of iron deficiency should be used in cardiac allograft recipients, and the investigators have elected to use the well-established definition used in patients with heart failure: serum ferritin < 100 µg/l or ferritin between 100 and 300 µg/l in combination with a transferrin saturation < 20 %. Because oral iron supplement is less effective then intravenous iron in general, and in patients with heart failure in particular, the investigators assume that oral iron supplement is inadequate in heart transplant recipients. the investigators have designed the IronIC trial to assess the effect of intravenous iron isomaltoside on exercise capacity, muscle strength, cognition and quality of life in iron-deficient heart transplant recipients.

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0372
    • Oslo University Hospital, Rikshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Cardiac allograft.
• Presentation at least one year after heart transplantation.
• Iron deficiency defined as serum ferritin < 100 µg/l or ferritin between 100 and 300 µg/l in combination with a transferrin saturation < 20 %.
• Age between 18 and 80 years.
• Informed consent obtained and documented according to Good Clinical Practice (GCP), and national/regional regulations.

Exclusion Criteria:

• Anaemia (Haemoglobin < 100 mg/l)
• Haemochromatosis
• Haemosiderosis
• Porphyria cutanea tarda
• Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells
• Decompensated liver disease (Child-Pugh score 7 or higher)
• End-stage renal failure, i.e. estimated glomerular filtration rate < 15 ml/min or on renal replacement therapy
• Planned cardiac surgery or angioplasty within 6 months
• Planned major surgery within 6 months
• Medical history of unresolved cancer (except for basal cell carcinoma)
• Treatment with systemic steroids more than the equivalent of 10 mg Prednisone/day at the time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent
• Any uncontrolled endocrine disorder except type 2 diabetes
• Pregnancy
• On erythropoietin analogues
• Known sensitivity or intolerance to iron isomaltoside or other parenteral iron preparations
• Intravenous iron supplement within 6 months prior to inclusion
• On oral iron substitution (unless the subject agrees to stop treatment prior to randomisation)
• Ongoing rejections or infections
• Alcohol or drug abuse within 3 months of informed consent that would interfere with trial participation or any ongoing condition leading to decreased compliance with study procedures or study drug intake
• Intake of an investigational drug in another trial within 30 days prior to intake of study medication in this trial or participating in another trial involving an investigational drug and/or follow-up

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Iron isomaltoside 1000; The active drug, iron isomaltoside 1000 will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment).	Drug: Iron Isomaltoside 1000; Intravenous infusion; Other Names: Monofer B03AC-
Placebo Comparator: Placebo; Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9%	Other: Placebo: NaCl 0,9%; Intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Oxygen Consumption	The primary endpoint will be the baseline-adjusted between-group difference in peak oxygen consumption as measured on a treadmill exercise test	6 months after intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Iron Deficiency	The number of patients with absolute or functional iron deficiency	6 months after intervention
Muscle Strength	Baseline-adjusted muscle strength as measured by a hand-grip dynamometer	6 months after intervention
Health Related Quality of Life: SF-36, Physical Component Summary (PCS)	Baseline-adjusted quality of life as assessed with the 36-item short form survey (SF-36), which measures each of the following 8 health domains: 1= general health, 2= physical function, 3= role physical, 4= bodily pain, 5= vitality, 6= social function, 7= role emotional, 8= mental health. Total score for each domain are scaled 0 (minimum) to 100 (maximum), where higher scores represented higher level of functioning. Two norm-based sum scores, the physical and the mental component summaries with a mean of 50±10, were generated from the eight scale scores using a T-score transformation. Higher scores represented higher level of functioning.	6 months after intervention
N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP)	The between-group difference in baseline-adjusted NT-proBNP	6 months after intervention
Cardiac Troponin T (TnT)	The between-group difference in baseline-adjusted TnT	6 months after intervention
Health Related Quality of Life: SF-36, Mental Component Summary (MCS)	Baseline-adjusted quality of life as assessed with the 36-item short form survey (SF-36), which measures each of the following 8 health domains: 1= general health, 2= physical function, 3= role physical, 4= bodily pain, 5= vitality, 6= social function, 7= role emotional, 8= mental health. Total score for each domain are scaled 0 (minimum) to 100 (maximum), where higher scores represented higher level of functioning. Two norm-based sum scores, the physical and the mental component summaries with a mean of 50±10, were generated from the eight scale scores using a T-score transformation. Higher scores represented higher level of functioning.	6 months after intervention

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: Pharmacosmos A/S

Publications and helpful links

General Publications

• Brautaset Englund KV, Ostby CM, Rolid K, Gude E, Andreassen AK, Gullestad L, Broch K. Intravenous iron supplement for iron deficiency in cardiac transplant recipients (IronIC): A randomized clinical trial. J Heart Lung Transplant. 2021 May;40(5):359-367. doi: 10.1016/j.healun.2021.01.1390. Epub 2021 Jan 23.

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2018
• Primary Completion (Actual): February 27, 2020
• Study Completion (Actual): February 27, 2020

Study Registration Dates

• First Submitted: April 17, 2018
• First Submitted That Met QC Criteria: September 6, 2018
• First Posted (Actual): September 7, 2018

Study Record Updates

• Last Update Posted (Actual): May 25, 2021
• Last Update Submitted That Met QC Criteria: April 30, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Heart transplant; Cognitive function; Muscle strength; Iron deficiency; Cardiopulmonary exercise test; Peak oxygen consumption; Intravenous iron supplement
• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Anemia, Iron-Deficiency; Hematinics; Iron isomaltoside 1000
• Other Study ID Numbers: IronIC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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