Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency: IRONMAN

Study Overview
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Brief Summary
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This study will address whether the additional use of Intravenous (IV) iron on top of standard care will improve the outlook for patients with heart failure and iron deficiency. One group of participants will receive treatment with iron injections and the other group will not receive any iron injections.

Detailed Description
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Chronic heart failure (CHF) is a very common medical problem. Despite improvements in treatment, many patients suffer limiting symptoms of shortness of breath and fatigue. Hospitalisation for CHF is common and life expectancy reduced. Many patients with CHF have a deficiency of iron (low iron levels or cannot use iron properly), and this is associated with poorer outcomes. Some small research studies have suggested that giving patients intravenous iron improves symptoms in the short term. It is unknown, however, whether correcting iron deficiency is beneficial to patients with CHF in the long term and whether it improves life expectancy and keeps them out of hospital. This study will help us answer these key questions. This study will address whether the additional use of Intravenous (IV) iron on top of standard care will improve the outlook for patients with heart failure and iron deficiency. One group of participants will receive treatment with iron injections and the other group will not receive any iron injections. The study will take place in about 70 secondary care sites (hospitals) across the UK. Participants will be recruited over a period of about five years and will be followed up for a minimum of three months (average duration of about four years per participant). After the initial visits, participants will be seen every four months.

Official Title
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Effectiveness of Intravenous Iron Treatment vs Standard Care in Patients With Heart Failure and Iron Deficiency: a Randomised, Open-label Multicentre Trial (IRONMAN)

Conditions
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Iron Deficiency, Chronic Heart Failure, Left Ventricular Systolic Dysfunction

Intervention / Treatment
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* Drug: Ferric Derisomaltose


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Age ≥18 years LVEF ≤45% within the prior two years using any conventional imaging modality (this should be the most recent assessment of LVEF) New York Heart Association (NYHA) class II - IV Iron deficient - defined as TSAT <20% and/or ferritin <100 ug/L Evidence of being in a higher risk HF group: (a) Current (with the expectation that patient will survive to discharge) or recent (within 6 months) hospitalisation for HF, OR (b) Out-patients with NT-proBNP >250 ng/L in sinus rhythm or >1,000 ng/L in atrial fibrillation (or BNP of > 75 pg/mL or 300 pg/mL, respectively) Able and willing to provide informed consent Exclusion criteria Haematological criteria: ferritin >400ug/L; haemoglobin <9.0, or >13 g/dL in women or >14g/dL in men; (B12 or folate deficiency should be corrected but do not exclude the patient) MDRD/CKD-EPI estimated glomerular filtration rate (eGFR) <15ml/min/1.73m2 Already planned to receive IV iron Likely to need or already receiving erythropoiesis stimulating agents (ESA) Any of the following apply: (a) planned cardiac surgery or revascularisation; (b) within 3 months of any of the following: a primary diagnosis of type 1 myocardial infarction (excluding small troponin elevations in the context of heart failure admissions), cerebrovascular accident (CVA), major CV surgery or percutaneous coronary intervention (PCI), or blood transfusion; (c) on active cardiac transplant list; (d) left ventricular assist device implanted. Any of the following comorbidities: active infection (if the patient is suffering from a significant ongoing infection as judged by the investigator recruitment should be postponed until the infection has passed or is controlled by antibiotics), other disease with life expectancy of <2 years, active clinically relevant bleeding in the investigator's opinion, known or suspected gastro-intestinal malignancy Pregnancy, women of childbearing potential (i.e. continuing menstrual cycle) not using effective contraception (see Appendix 3) or breast-feeding women Contra-indication to IV iron in the investigator's opinion according to current approved Summary of Product Characteristics: hypersensitivity to the active substance, to Monofer® or any of its excipients (water for injections, sodium hydroxide (for pH adjustment), hydrochloric acid (for pH adjustment)); known serious hypersensitivity to other parenteral iron products; non-iron deficiency anaemia (e.g. haemolytic anaemia); iron overload or disturbances in utilisation of iron (e.g. haemochromatosis, haemosiderosis); decompensated liver disease. Participation in another intervention study involving a drug or device within the past 90 days (co-enrolment in observational studies is permitted)

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard care<br>Participants in this arm will receive their usual care | |
| Experimental: Standard care plus IV iron infusion<br>Iron to be administered as iron (III) isomaltoside 1000 / ferric derisomaltose. Infused over a minimum of 15 mins for doses up to and including 1000mg, and a minimum of 30 mins for doses >1000mg Where Hb ≥10 g/dL, dosage according to body weight is as follows: Body weight <50 kg: 20 mg/kg; Body weight 50 to <70 kg: 1000 mg; Body weight ≥70 kg: 20 mg/kg up to a maximum of 1500 mg. Where Hb <10 g/dL, dosage according to body weight is as follows: Body weight <50 kg: 20 mg/kg; Body weight 50 to <70 kg: 20 mg/kg; Body weight ≥70 kg: 20 mg/kg up to a maximum of 2000 mg. | Drug: Ferric Derisomaltose<br> <br> * Other names: Monofer;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CV mortality or hospitalisation for worsening heart failure (analysis will include first and recurrent hospitalisations) |  | Minimum of 3 months follow-up from last patient recruited | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospitalisation for worsening heart failure (recurrent events) |  | Minimum of 3 months follow-up from last patient recruited | 
| CV hospitalisation (first event) |  | Minimum of 3 months follow-up from last patient recruited | 
| CV death or hospitalisation for heart failure analysed as time to first event |  | Minimum of 3 months follow-up from last patient recruited | 
| Overall Score from Minnesota Living with Heart Failure |  | At 4 months | 
| Cardiovascular mortality |  | Minimum of 3 months follow-up from last patient recruited | 
| Overall EQ-5D VAS |  | At 4 months | 
| Overall EQ-5D index |  | At 4 months | 
| CV mortality or hospitalisation for major CV event (stroke, MI, heart failure) (first event) |  | Minimum of 3 months follow-up from last patient recruited | 
| All-cause mortality |  | Minimum of 3 months follow-up from last patient recruited | 
| All-cause hospitalisation (first event) |  | Minimum of 3 months follow-up from last patient recruited | 
| Combined all-cause mortality or first all-cause unplanned hospitalisation |  | Minimum of 3 months follow-up from last patient recruited | 
| Physical domain of QoL (Minnesota Living With Heart Failure) |  | At 4 months | 
| Physical domain of QoL (Minnesota Living With Heart Failure) |  | At 20 months | 
| Overall EQ-5D VAS |  | At 20 months | 
| Overall EQ-5D index |  | At 20 months | 
| Overall Score from Minnesota Living With Heart Failure |  | At 20 months | 
| Days dead or hospitalised |  | At 36 months | 
| Quality-adjusted days alive and out of hospital |  | At 12 months | 
| 6 minute walk test |  | At 4 months | 
| 6 minute walk test |  | At 20 months | 
| Death due to infection |  | Minimum of 3 months follow-up from last patient recruited | 
| Hospitalisation primarily for infection (first event) |  | Minimum of 3 months follow-up from last patient recruited | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intravenous iron, PROBE design