Intravenous Iron in Patients with Systolic Heart Failure and Iron Deficiency to Improve Morbidity & Mortality (FAIR-HF2)

Ferric Carboxymaltose Assessment of Morbidity and Mortality in Patients with IRon Deficiency and Chronic Heart Failure

The purpose of this study is to determine whether intravenous iron supplementation using ferric carboxymaltosis (FCM) extends the time-to-first-event of heart failure hospitalisations and cardiovascular (CV) death and reduces hospitalisation and mortality in patients with iron deficiency and heart failure.

Study Overview

• Status: Completed
• Conditions: Iron Deficiency; Systolic Heart Failure
• Intervention / Treatment: Drug: Iron; Drug: Saline

Detailed Description

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 extend the time-to-first-event of heart failure hospitalisations and cardiovascular (CV) death (in the full population and in the population of patients with TSAT<20%) and reduce the rate of recurrent events of heart failure hospitalisations.

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.

• Study Type: Interventional
• Enrollment (Actual): 1105
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Bad Friedrichshall, Germany, 74177
    • SLK-Kliniken Heilbronn GmbH Klinikum am Plattenwald
  • Bad Nauheim, Germany, 61231
    • Kerckhoff Klinik Bad Nauheim
  • Berlin, Germany, 12203
    • Universitätsmedizin Berlin Campus Benjamin Franklin
  • Berlin, Germany, 13353
    • Charite Berlin (Campus Virchow-Klinikum)
  • Bremen, Germany, 28277
    • Stiftung Bremer Herzen Bremer Institut für Herz- und Kreislauf- Forschung
  • Dresden, Germany, 01307
    • Herzzentrum Dresden, Universitätsklinik
  • Greifswald, Germany, 17475
    • Uniklinik Greifswald, Klinik und Poliklinik für Innere Medizin B
  • Göttingen, Germany, 37075
    • Universitatsmedizin Gottingen
  • Halle, Germany, 06120
    • Universitatsklinikum Halle (Saale)
  • Hamburg, Germany, 22041
    • Cardiologicum Hamburg
  • Hamburg, Germany, 20251
    • Universitärsklinikum Hamburg-Eppendorf
  • Heidelberg, Germany, 69120
    • Universitätsklinikum Heidelberg
  • Homburg, Germany, 66421
    • Universitätsklinikum des Saarlandes
  • Jena, Germany, 07747
    • Universitätsklinikum Jena, Kardiologie
  • Kiel, Germany, 24105
    • Universitätsklinikum Schleswig-Holstein Campus Kiel
  • Lübeck, Germany, 23538
    • Universitätsklinikum Schleswig-Holstein Campus Lübeck
  • Magdeburg, Germany, 39120
    • Universitätsklinikum Magdeburg
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
  • Mannheim, Germany, 68167
    • Universitätsmedizin Mannheim
  • Mönchengladbach, Germany, 41063
    • Kliniken Maria Hilf GmbH, Innere Medizin II, Klinik für Kardiologie
  • Mühldorf, Germany, 84453
    • Praxis Dr. Schön Mühldorf
  • München, Germany, 81377
    • LMU München Medizinische Klinik und Poliklinik 1
  • München, Germany, 81675
    • Klinikum rechts der Isar I. Medizinische Klinik und Poliklinik
  • Nürnberg, Germany, 90402
    • Gemeinschaftspraxis Hagenmiller/ Jeserich
  • Nürnberg, Germany, 90471
    • Universitätsklinik Medizinische Klinik 8 - Kardiologie Paracelsus Medizinische Privatuniversität Klinikum Nürnberg, Campus Süd
  • Remscheid, Germany, 42853
    • KardioPrax Remscheid
  • Rostock, Germany, 18059
    • Kardiologische Praxis Dr. Jens Placke
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm
  • Ulm, Germany, 89077
    • Studienzentrum Herzklinik Ulm GbR
• Hungary
  • Budapest, Hungary, 1125
    • Szent Janos Korhaz es Eszak-Budai Egyesitett Korhazak
  • Budapest, Hungary, 1122
    • Semmelweis Egyetem
  • Budapest, Hungary, 1134
    • Honvéd Kórház
  • Budapest, Hungary, 1115
    • Szent Imre Korhaz
  • Pecs, Hungary, 7624
    • Pécsi Orvostudományi
  • Ózd, Hungary, 3600
    • Almási Balogh Pál Kórház
• Italy
  • Rome, Italy, 00163
    • IRCCS San Raffaele Pisana (06-01)
• Poland
  • Białystok, Poland, 15-270
    • Cermed Hernik (05-07)
  • Opole, Poland, 45-401
    • Oddział Kardiologii Uniwersyteckiego (05-06)
  • Warsaw, Poland, 04-743
    • Klinika Niewydolności Serca I Transplantologii (05-04)
  • Warschau, Poland, 50-981
    • Wroclaw Medical University (05-01)
  • Łomża, Poland, 18-404
    • KLIMED Marek Klimkiewicz Lomza (05-05)
• Portugal
  • Lisbon, Portugal, 1500-650
    • Hospital de la Luz
  • Lisbon, Portugal, 1649-028
    • Santa Maria University Hospital
• Slovenia
  • Ljubljana, Slovenia, 1000
    • University Medical Centre Ljubljana (07-03)
  • Murska Sobota, Slovenia, 9000
    • General Hospital Murska Sobota Division of Cardiology (07-01)
  • Topolšica, Slovenia, SI-3326
    • Hospital Topolšica (07-03)
• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar (04-01)
  • Madrid, Spain, 28040
    • Hospital Universitario Clinico San Carlos Madrid (04-04)
  • Málaga, Spain, 29010
    • Hospital Universitarion Virgen de la Victoria (04-03)
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario Valencia (04-02)
  • Valencia, Spain, 46026
    • Hospital la Fe de Valencia (04-05)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with chronic HFrEF (CHF) of at least 3 months duration and a history of documented LVEF<45%.
2. Confirmed presence of ID (ferritin < 100 ng/mL or ferritin 100 - 299 ng/mL with TSAT < 20 %)
3. Serum haemoglobin of 9.5 - 14.0 g/dL
4. 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)
5. Written informed consent

Exclusion Criteria:

1. Hypersensitivity to the active substance, to FCM or any of its excipients
2. Known serious hypersensitivity to other parenteral iron products
3. Anaemia not attributed to iron deficiency, e.g. other microcytic anaemia
4. Evidence of iron overload or disturbances in the utilisation of iron
5. History of severe asthma with known FEV1 <50%
6. Acute bacterial infection
7. Presence of a deficiency for vitamin B12 and/or serum folate (if present, this needs to be corrected first)
8. Use of renal replacement therapy
9. Treatment with an erythropoietin stimulating agent (ESA), any i.v. iron and/or a blood transfusion in the previous 6 weeks prior to randomisation.
10. More than 500 meters in the initial 6-minutes walking-test

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Verum group (FCM); 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; i.v. iron administration
Placebo Comparator: Placebo group (NaCL); 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; i.v. NaCl administration; Other Names: salin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-to-first event of CV death or HF hospitalisation	Show that treatment of patients with systolic heart failure (HF) and iron deficiency (ID) with i.v. iron (Ferric Carboxymaltose, FCM) versus placebo (i.v. NaCl) can extend the time-to-first-event of heart failure hospitalisations and cardiovascular (CV) death. Type I error rate control across the three primary endpoints will be ensured by using the Hochberg procedure.	The whole follow-up period. We aim for a minimum average follow-up of >2 years. We aim for a minimum follow-up of 6 months for all patients, but not less than 3 months.
Rate of total (first and recurrent) events of hospitalisations for heart failure (HF)	Show that treatment of patients with systolic heart failure (HF) and iron deficiency (ID) with i.v. iron (Ferric Carboxymaltose, FCM) versus placebo (i.v. NaCl) reduces the rate of recurrent events of heart failure hospitalisations.	The wohle follow-up period. We aim for a minimum average follow-up of >2 years. We aim for a minimum follow-up of 6 months for all patients, but not less than 3 months.
Time-to-first event of CV death or HF hospitalisation in patients with TSAT <20%	Show that treatment of patients with systolic heart failure (HF) and iron deficiency (ID) with i.v. iron (Ferric Carboxymaltose, FCM) versus placebo (i.v. NaCl) can extend the time-to-first-event of heart failure hospitalisations and cardiovascular (CV) death in the population of patients with TSAT<20%.	During the wohle follow-up period. We aim for a minimum average follow-up of >2 years. We aim for a minimum follow-up of 6 months for all patients, but not less than 3 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in 6-minute walk-test (nomogram)	Changes in 6-minute walk-test during follow-up	The wohle follow-up period. We aim for a minimum average follow-up of >2 years. We aim for a minimum follow-up of 6 months for all patients, but not less than 3 months.
Changes in NYHA (New York Heart Association) functional class (scale)	Changes in NYHA functional class during follow-up	The wohle follow-up period. We aim for a minimum average follow-up of >2 years. We aim for a minimum follow-up of 6 months for all patients, but not less than 3 months.
Changes in EQ-5D (questionnaire)	Changes EQ-5D during follow-up	The wohle follow-up period. We aim for a minimum average follow-up of >2 years. We aim for a minimum follow-up of 6 months for all patients, but not less than 3 months.
Changes in Patient Global Assessment (PGA) of wellbeing (questionnaire)	Changes in PGA of wellbeing during follow-up	The wohle follow-up period. We aim for a minimum average follow-up of >2 years. We aim for a minimum follow-up of 6 months for all patients, but not less than 3 months.
Changes in renal parameters (laboratory parameters)	Changes in renal parameters from baseline to end of follow-up, assessing creatinine levels	The wohle follow-up period. We aim for a minimum average follow-up of >2 years. We aim for a minimum follow-up of 6 months for all patients, but not less than 3 months.
Changes in cardiovascular parameters (laboratory parameters)	Changes in cardiovascular parameters from baseline to end of follow-up, assessing natriuretic peptide levels	The wohle follow-up period. We aim for a minimum average follow-up of >2 years. We aim for a minimum follow-up of 6 months for all patients, but not less than 3 months.
Changes in inflammatory parameters (laboratory parameters)	Changes in inflammatory parameters from baseline to end of follow-up, assessing C-reactive protein levels	The wohle follow-up period. We aim for a minimum average follow-up of >2 years. We aim for a minimum follow-up of 6 months for all patients, but not less than 3 months.
Changes in metabolic parameters (laboratory parameters)	Changes in metabolic parameters from baseline to end of follow-up, assessing aspartate or alanine transaminase levels	The wohle follow-up period. We aim for a minimum average follow-up of >2 years. We aim for a minimum follow-up of 6 months for all patients, but not less than 3 months.
Key Safety Endpoint: cardiovascular mortality	cardiovascular mortality during 36 months of follow-up	36 months of follow-up
Key Safety Endpoint: All-cause mortality	All-cause mortality during 36 months of follow-up	36 months of follow-up

Collaborators and Investigators

• Sponsor: Universitätsklinikum Hamburg-Eppendorf
• Collaborators: Charite University, Berlin, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
• Investigators: Principal Investigator: Mahir Karaks, MD, Universitätsklinikum Hamburg-Eppendorf

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2017
• Primary Completion (Actual): May 2, 2024
• Study Completion (Actual): May 2, 2024

Study Registration Dates

• First Submitted: September 15, 2016
• First Submitted That Met QC Criteria: January 26, 2017
• First Posted (Estimated): January 30, 2017

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 23, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: mortality; morbidity; iron deficiency; intravenous iron; systolic heart failure
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Metabolic Diseases; Hematologic Diseases; Anemia; Heart Murmurs; Iron Metabolism Disorders; Anemia, Hypochromic; Iron Deficiencies; Heart Failure; Systolic Murmurs; Anemia, Iron-Deficiency; Heart Failure, Systolic
• Other Study ID Numbers: FAIR-HF2; FAIR-HF2-DZHK5 (Other Grant/Funding Number: Deutsches Zentrum für Herzkreislaufforschung)

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