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

NCT03036462 | Completed Phase 4 DMC

• 2 other identifiers: FAIR-HF2FAIR-HF2-DZHK5
• Study Type: interventional
• Target: 1,105
• Locations: 7 countries
• Sites: 51

Brief Summary

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.

Conditions

Systolic Heart Failure; Iron Deficiency

Keywords

intravenous iron; systolic heart failure; iron deficiency; morbidity; mortality

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (10)

• Changes in 6-minute walk-test (nomogram)

  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)

  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)

  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)

  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)

  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.

Study Arms (2)

Verum group (FCM)

EXPERIMENTAL

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

Placebo group (NaCL)

PLACEBO COMPARATOR

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

Interventions

Iron DRUG

i.v. iron administration

Verum group (FCM)

Saline DRUG

i.v. NaCl administration

Also known as: salin

Placebo group (NaCL)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Universitätsklinikum Hamburg-Eppendorf: lead
• Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK): collaborator
• Charite University, Berlin, Germany: collaborator

Study Sites (51)

Cardiologicum Hamburg

Hamburg, Hamburg, 22041, Germany

Location

SLK-Kliniken Heilbronn GmbH Klinikum am Plattenwald

Bad Friedrichshall, 74177, Germany

Location

Kerckhoff Klinik Bad Nauheim

Bad Nauheim, 61231, Germany

Location

Universitätsmedizin Berlin Campus Benjamin Franklin

Berlin, 12203, Germany

Location

Charité Berlin (Campus Virchow-Klinikum)

Berlin, 13353, Germany

Location

Stiftung Bremer Herzen Bremer Institut für Herz- und Kreislauf- Forschung

Bremen, 28277, Germany

Location

Herzzentrum Dresden, Universitätsklinik

Dresden, 01307, Germany

Location

Universitätsmedizin Göttingen

Göttingen, 37075, Germany

Location

Uniklinik Greifswald, Klinik und Poliklinik für Innere Medizin B

Greifswald, 17475, Germany

Location

Universitätsklinikum Halle (Saale)

Halle, 06120, Germany

Location

Universitärsklinikum Hamburg-Eppendorf

Hamburg, 20251, Germany

Location

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

Location

Universitätsklinikum des Saarlandes

Homburg, 66421, Germany

Location

Universitätsklinikum Jena, Kardiologie

Jena, 07747, Germany

Location

Universitätsklinikum Schleswig-Holstein Campus Kiel

Kiel, 24105, Germany

Location

Universitätsklinikum Schleswig-Holstein Campus Lübeck

Lübeck, 23538, Germany

Location

Universitätsklinikum Magdeburg

Magdeburg, 39120, Germany

Location

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, 55131, Germany

Location

Universitätsmedizin Mannheim

Mannheim, 68167, Germany

Location

Kliniken Maria Hilf GmbH, Innere Medizin II, Klinik für Kardiologie

Mönchengladbach, 41063, Germany

Location

Praxis Dr. Schön Mühldorf

Mühldorf, 84453, Germany

Location

LMU München Medizinische Klinik und Poliklinik 1

München, 81377, Germany

Location

Klinikum rechts der Isar I. Medizinische Klinik und Poliklinik

München, 81675, Germany

Location

Gemeinschaftspraxis Hagenmiller/ Jeserich

Nuremberg, 90402, Germany

Location

Universitätsklinik Medizinische Klinik 8 - Kardiologie Paracelsus Medizinische Privatuniversität Klinikum Nürnberg, Campus Süd

Nuremberg, 90471, Germany

Location

KardioPrax Remscheid

Remscheid, 42853, Germany

Location

Kardiologische Praxis Dr. Jens Placke

Rostock, 18059, Germany

Location

Studienzentrum Herzklinik Ulm GbR

Ulm, 89077, Germany

Location

Universitätsklinikum Ulm

Ulm, 89081, Germany

Location

Szent Imre Kórház

Budapest, 1115, Hungary

Location

Semmelweis Egyetem

Budapest, 1122, Hungary

Location

Szent János kórház és Észak-budai Egyesített kórházak

Budapest, 1125, Hungary

Location

Honvéd Kórház

Budapest, 1134, Hungary

Location

Almási Balogh Pál Kórház

Ózd, 3600, Hungary

Location

Pécsi Orvostudományi

Pécs, 7624, Hungary

Location

IRCCS San Raffaele Pisana (06-01)

Rome, 00163, Italy

Location

Cermed Hernik (05-07)

Bialystok, 15-270, Poland

Location

Oddział Kardiologii Uniwersyteckiego (05-06)

Opole, 45-401, Poland

Location

Klinika Niewydolności Serca I Transplantologii (05-04)

Warsaw, 04-743, Poland

Location

Wroclaw Medical University (05-01)

Warsaw, 50-981, Poland

Location

KLIMED Marek Klimkiewicz Lomza (05-05)

Łomża, 18-404, Poland

Location

Hospital de la Luz

Lisbon, 1500-650, Portugal

Location

Santa Maria University Hospital

Lisbon, 1649-028, Portugal

Location

University Medical Centre Ljubljana (07-03)

Ljubljana, 1000, Slovenia

Location

General Hospital Murska Sobota Division of Cardiology (07-01)

Murska Sobota, 9000, Slovenia

Location

Hospital Topolšica (07-03)

Topolšica, SI-3326, Slovenia

Location

Hospital del Mar (04-01)

Barcelona, 08003, Spain

Location

Hospital Universitario Clinico San Carlos Madrid (04-04)

Madrid, 28040, Spain

Location

Hospital Universitarion Virgen de la Victoria (04-03)

Málaga, 29010, Spain

Location

Hospital Clinico Universitario Valencia (04-02)

Valencia, 46010, Spain

Location

Hospital la Fe de Valencia (04-05)

Valencia, 46026, Spain

Location

Related Publications (3)

• Karakas M, Friede T, Butler J, Talha KM, Placzek M, Asendorf T, Diek M, Nosko A, Stas A, Kluge S, Jarczak D, DeHeer G, Rybczynski M, Bayes-Genis A, Bohm M, Coats AJS, Edelmann F, Filippatos G, Hasenfuss G, Haverkamp W, Lainscak M, Landmesser U, Macdougall IC, Merkely B, Pieske BM, Pinto FJ, Rassaf T, Visser-Rogers JK, Rosano G, Volterrani M, von Haehling S, Anker MS, Doehner W, Ince H, Koehler F, Savarese G, Khan MS, Krohnert UR, Gori T, Trenkwalder T, Akin I, Paitazoglou C, Kobielusz-Gembala I, Kuthi L, Frey N, Licka M, Kaab S, Laugwitz KL, Ponikowski P, Anker SD. Intravenous ferric carboxymaltose in heart failure with iron deficiency (FAIR-HF2 DZHK05 trial): Sex-specific outcomes. Eur J Heart Fail. 2025 Nov;27(11):2328-2342. doi: 10.1002/ejhf.3742. Epub 2025 Jul 31.

  PMID: 40740027 DERIVED

• Anker SD, Friede T, Butler J, Talha KM, Placzek M, Diek M, Nosko A, Stas A, Kluge S, Jarczak D, Deheer G, Rybczynski M, Bayes-Genis A, Edelmann F, Filippatos G, Hasenfuss G, Haverkamp W, Lainscak M, Landmesser U, Macdougall IC, Merkely B, Pieske BM, Pinto FJ, Rassaf T, Volterrani M, von Haehling S, Anker MS, Doehner W, Ince H, Koehler F, Savarese G, Rauch-Krohnert U, Gori T, Trenkwalder T, Akin I, Paitazoglou C, Kobielusz-Gembala I, Zmuda W, Kuthi L, Frey N, Licka M, Kaab S, Laugwitz KL, Ponikowski P, Karakas M. Ferric carboxymaltose assessment of morbidity and mortality in patients with iron deficiency and chronic heart failure (FAIR-HF2-DZHK05) trial: Baseline characteristics and comparison to other relevant clinical trials. Eur J Heart Fail. 2025 Aug;27(8):1436-1443. doi: 10.1002/ejhf.3658. Epub 2025 Apr 29.

  PMID: 40300786 DERIVED

• Anker SD, Friede T, Butler J, Talha KM, Placzek M, Diek M, Nosko A, Stas A, Kluge S, Jarczak D, deHeer G, Rybczynski M, Bayes-Genis A, Bohm M, Coats AJS, Edelmann F, Filippatos G, Hasenfuss G, Haverkamp W, Lainscak M, Landmesser U, Macdougall IC, Merkely B, Pieske BM, Pinto FJ, Rassaf T, Visser-Rogers JK, Rosano G, Volterrani M, von Haehling S, Anker MS, Doehner W, Ince H, Koehler F, Savarese G, Khan MS, Rauch-Krohnert U, Gori T, Trenkwalder T, Akin I, Paitazoglou C, Kobielusz-Gembala I, Kuthi L, Frey N, Licka M, Kaab S, Laugwitz KL, Ponikowski P, Karakas M. Intravenous Ferric Carboxymaltose in Heart Failure With Iron Deficiency: The FAIR-HF2 DZHK05 Randomized Clinical Trial. JAMA. 2025 Jun 10;333(22):1965-1976. doi: 10.1001/jama.2025.3833.

  PMID: 40159390 DERIVED

MeSH Terms

Conditions

Heart Failure, Systolic; Iron Deficiencies

Interventions

Iron; Sodium Chloride

Condition Hierarchy (Ancestors)

Heart Failure; Heart Diseases; Cardiovascular Diseases; Iron Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Metals, Heavy; Elements; Inorganic Chemicals; Transition Elements; Metals; Chlorides; Hydrochloric Acid; Chlorine Compounds; Sodium Compounds

Study Officials

• Mahir Karaks, MD

  Universitätsklinikum Hamburg-Eppendorf

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 15, 2016
• First Posted: January 30, 2017
• Study Start: March 7, 2017
• Primary Completion: May 2, 2024
• Study Completion: May 2, 2024
• Last Updated: January 28, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

DE (29); HU (6); PL (5); IT (1); PT (2); ES (5); SL (3)