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

NCT ID: NCT03036462

Last Updated: 2025-01-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 1105 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-07
• Study Completion Date: 2024-05-02

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.

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.

Conditions

Systolic Heart Failure; Iron Deficiency

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Iron

Intervention Type: DRUG

i.v. iron administration

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.

Group Type: PLACEBO_COMPARATOR

Saline

Intervention Type: DRUG

i.v. NaCl administration

Interventions

Iron

i.v. iron administration

Intervention Type: DRUG

Saline

i.v. NaCl administration

Intervention Type: DRUG

Other Intervention Names

salin

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)

OTHER

Sponsor Role: collaborator

Charite University, Berlin, Germany

OTHER

Sponsor Role: collaborator

Universitätsklinikum Hamburg-Eppendorf

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mahir Karaks, MD

Role: PRINCIPAL_INVESTIGATOR

Universitätsklinikum Hamburg-Eppendorf

Locations

Cardiologicum Hamburg

Hamburg, City state of Hamburg, Germany

SLK-Kliniken Heilbronn GmbH Klinikum am Plattenwald

Bad Friedrichshall, , Germany

Kerckhoff Klinik Bad Nauheim

Bad Nauheim, , Germany

Universitätsmedizin Berlin Campus Benjamin Franklin

Berlin, , Germany

Charité Berlin (Campus Virchow-Klinikum)

Berlin, , Germany

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

Bremen, , Germany

Herzzentrum Dresden, Universitätsklinik

Dresden, , Germany

Universitätsmedizin Göttingen

Göttingen, , Germany

Uniklinik Greifswald, Klinik und Poliklinik für Innere Medizin B

Greifswald, , Germany

Universitätsklinikum Halle (Saale)

Halle, , Germany

Universitärsklinikum Hamburg-Eppendorf

Hamburg, , Germany

Universitätsklinikum Heidelberg

Heidelberg, , Germany

Universitätsklinikum des Saarlandes

Homburg, , Germany

Universitätsklinikum Jena, Kardiologie

Jena, , Germany

Universitätsklinikum Schleswig-Holstein Campus Kiel

Kiel, , Germany

Universitätsklinikum Schleswig-Holstein Campus Lübeck

Lübeck, , Germany

Universitätsklinikum Magdeburg

Magdeburg, , Germany

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, , Germany

Universitätsmedizin Mannheim

Mannheim, , Germany

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

Mönchengladbach, , Germany

Praxis Dr. Schön Mühldorf

Mühldorf, , Germany

LMU München Medizinische Klinik und Poliklinik 1

München, , Germany

Klinikum rechts der Isar I. Medizinische Klinik und Poliklinik

München, , Germany

Gemeinschaftspraxis Hagenmiller/ Jeserich

Nuremberg, , Germany

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

Nuremberg, , Germany

KardioPrax Remscheid

Remscheid, , Germany

Kardiologische Praxis Dr. Jens Placke

Rostock, , Germany

Studienzentrum Herzklinik Ulm GbR

Ulm, , Germany

Universitätsklinikum Ulm

Ulm, , Germany

Szent Imre Kórház

Budapest, , Hungary

Semmelweis Egyetem

Budapest, , Hungary

Szent János kórház és Észak-budai Egyesített kórházak

Budapest, , Hungary

Honvéd Kórház

Budapest, , Hungary

Almási Balogh Pál Kórház

Ózd, , Hungary

Pécsi Orvostudományi

Pécs, , Hungary

IRCCS San Raffaele Pisana (06-01)

Rome, , Italy

Cermed Hernik (05-07)

Bialystok, , Poland

Oddział Kardiologii Uniwersyteckiego (05-06)

Opole, , Poland

Klinika Niewydolności Serca I Transplantologii (05-04)

Warsaw, , Poland

Wroclaw Medical University (05-01)

Warsaw, , Poland

KLIMED Marek Klimkiewicz Lomza (05-05)

Łomża, , Poland

Hospital de la Luz

Lisbon, , Portugal

Santa Maria University Hospital

Lisbon, , Portugal

University Medical Centre Ljubljana (07-03)

Ljubljana, , Slovenia

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

Murska Sobota, , Slovenia

Hospital Topolšica (07-03)

Topolšica, , Slovenia

Hospital del Mar (04-01)

Barcelona, , Spain

Hospital Universitario Clinico San Carlos Madrid (04-04)

Madrid, , Spain

Hospital Universitarion Virgen de la Victoria (04-03)

Málaga, , Spain

Hospital Clinico Universitario Valencia (04-02)

Valencia, , Spain

Hospital la Fe de Valencia (04-05)

Valencia, , Spain

Countries

Germany; Hungary; Italy; Poland; Portugal; Slovenia; Spain

References

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 Jul 31. doi: 10.1002/ejhf.3742. Online ahead of print.

Reference Type: DERIVED

PMID: 40740027 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 40300786 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 40159390 (View on PubMed)

Other Identifiers

FAIR-HF2-DZHK5

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

FAIR-HF2

Identifier Type: -

Identifier Source: org_study_id