Intravenous Iron in Patients With Systolic Heart Failure and Iron Deficiency to Improve Morbidity & Mortality

Study Overview
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Brief Summary
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The purpose of this study is to determine whether intravenous iron supplementation using ferric carboxymaltosis (FCM) reduces hospitalisation and mortality in patients with iron deficiency and heart failure.

Detailed Description
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The clinical trial is designed as an international, prospective, multi-centre, double-blind, parallel group, randomised, controlled, interventional trial to investigate whether a long-term therapy with i.v. iron (ferric carboxymaltosis) compared to placebo can reduce the rate of recurrent heart failure hospitalisations and cardiovascular (CV) death in patients with heart failure with reduced ejection fraction (HFrEF). I.v. iron administration in the form of ferric carboxymaltosis (FCM) will be carried out according to the Summary of Product Characteristics (SmPC). Bolus administration (1000 mg) will be followed by an optional administration of 500-1000 mg within the first 4 weeks (up to a total of 2000 mg which is in-label) according to approved dosing rules, followed by administration of 500 mg FCM at every 4 months, except when haemoglobin is > 16.0 g/dL or ferritin is > 800 µg/L. In the verum group, all patients will receive a saline administration, when no iron is indicated at the time of the visit and according to the values listed above. Patients originally assigned to the placebo group will receive a saline administration at all visits. In the control group i.v. NaCl at a volume according to the dosing rules for FCM at all visits will be administered in a double-blind manner.

Official Title
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Intravenous Iron in Patients With Systolic Heart Failure and Iron Deficiency to Improve Morbidity & Mortality - FAIR-HF2

Conditions
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Systolic Heart Failure, Iron Deficiency

Intervention / Treatment
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* Drug: Iron
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with chronic HFrEF (CHF) of at least 3 months duration and a history of documented LVEF<45%. Confirmed presence of ID (ferritin < 100 ng/mL or ferritin 100 - 299 ng/mL with TSAT < 20 %) Serum haemoglobin of 9.5 - 14.0 g/dL At time of screening considered re-stabilised and planned for discharge within next 24 h (NYHA 2 or 3), or stable ambulatory with a HF hospitalisation in the past 12 months (NYHA 2-4), or stable ambulatory with BNP > 100 pg/mL or NT-proBNP > 300 pg/mL or MR-proANP > 120 pmol/L (NYHA 2-4) Written informed consent Exclusion Criteria: Hypersensitivity to the active substance, to FCM or any of its excipients Known serious hypersensitivity to other parenteral iron products Anaemia not attributed to iron deficiency, e.g. other microcytic anaemia Evidence of iron overload or disturbances in the utilisation of iron History of severe asthma with known FEV1 <50% Acute bacterial infection Presence of a deficiency for vitamin B12 and/or serum folate (if present, this needs to be corrected first) Use of renal replacement therapy Treatment with an erythropoietin stimulating agent (ESA), any i.v. iron and/or a blood transfusion in the previous 6 weeks prior to randomisation. More than 500 meters in the initial 6-minutes walking-test

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Verum group (FCM)<br>I.v. iron administration in the form of FCM will be carried out according to SmPC. I.v. iron bolus administration (1000 mg) will be followed by an optional administration of 500-1000 mg within the first 4 weeks, (up to a total of 2000 mg which is in-label), according to the approved dosing rules, followed by administration of 500 mg FCM at every 4 months, except when haemoglobin is > 16.0 g/dL or ferritin is > 800 µg/L .In the verum group, all patients will receive a saline administration, when no iron is indicated at the time of the visit and according to the values listed above. | Drug: Iron<br>* i.v. iron administration<br>|
| Placebo Comparator: Placebo group (NaCL)<br>Administration of i.v. NaCl at a volume according to the dosing rules for FCM, i.e. as described for the verum group. | Drug: Saline<br>* i.v. NaCl administration<br>* Other names: salin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined rate of recurrent hospitalisations for heart failure (HF) and of cardiovascular death (number of events) | Combined rate of recurrent hospitalisations for heart failure and of cardiovascular death during follow-up. | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined rate of recurrent cardiovascular hospitalisations and of cardiovascular death (number of events) | Combined rate of recurrent cardiovascular hospitalisations and of cardiovascular death during follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| Combined rate of recurrent hospitalisations for any reason and of cardiovascular death (number of events) | Combined rate of recurrent hospitalisations for any reason and of cardiovascular death during follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| Rate of recurrent cardiovascular hospitalisations (number of events) | Rate of recurrent cardiovascular hospitalisations during follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| Rate of recurrent HF hospitalisations (number of events) | Rate of recurrent HF hospitalisations during follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| Rate of recurrent hospitalisations of any kind (number of events) | Rate of recurrent hospitalisations of any kind during follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| All-cause mortality (number of events) | All-cause mortality during follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| cardiovascular mortality (number of events) | cardiovascular mortality during follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| Changes in NYHA (New York Heart Association) functional class (scale) | Changes in NYHA functional class during follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| Changes in 6-minute walk-test (nomogram) | Changes in 6-minute walk-test during follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| Changes in EQ-5D (questionnaire) | Changes EQ-5D during follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| Changes in Patient Global Assessment (PGA) of wellbeing (questionnaire) | Changes in PGA of wellbeing during follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| Changes in renal parameters (laboratory parameters) | Changes in renal from baseline to end of follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| Changes in cardiovascular parameters (laboratory parameters) | Changes in cardiovascular parameters from baseline to end of follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| Changes in inflammatory parameters (laboratory parameters) | Changes in inflammatory parameters from baseline to end of follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 
| Changes in metabolic parameters (laboratory parameters) | Changes in metabolic parameters from baseline to end of follow-up | for a minimum average follow-up of >2 years (We aim for a minimum follow-up of 6 months for all patients) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intravenous iron, systolic heart failure, iron deficiency, morbidity, mortality