Intravenous Iron Supplement for Iron Deficiency in Cardiac Transplant Recipients

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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Intravenous Iron Supplement for Iron Deficiency in Cardiac Transplant Recipients

Conditions
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Heart Transplant Recipients

Intervention / Treatment
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* Drug: Iron Isomaltoside 1000
* Other: Placebo: NaCl 0,9%


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, placebo controlled, parallel group, double blind design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Iron isomaltoside 1000<br>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<br>* Intravenous infusion<br>* Other names: Monofer B03AC-;|
| Placebo Comparator: Placebo<br>Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9% | Other: Placebo: NaCl 0,9%<br>* Intravenous infusion<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart transplant, Iron deficiency, Intravenous iron supplement, Peak oxygen consumption, Cardiopulmonary exercise test, Cognitive function, Muscle strength