Effect of IV Iron in Patients With Heart Failure With Preserved Ejection Fraction

Phase 4

Completed

• Conditions: Iron-deficiency; Heart Failure
• Interventions: Drug: Ferric Carboxymaltose 50Mg/Ml Inj 15Ml; Drug: Saline Solution for Injection

• Registration Number: NCT03074591
• Lead Sponsor: Charite University, Berlin, Germany

Brief Summary

This study addresses, whether treatment with IV iron for patients with heart failure with preserved ejection fraction (HFpEF) and iron deficiency (ID), both with or without anaemia, can improve exercise capacity as measured by 6-minute walking test (6-MWT) and symptoms while being safe

Detailed Description

All previous trials have excluded patients with HFpEF. This study addresses, whether treatment with IV iron for patients with heart failure with preserved ejection fraction (HFpEF) and iron deficiency (ID), both with or without anaemia, can improve exercise capacity as measured by 6-minute walking test (6-MWT) and symptoms while being safe. The FAIR-HFpEF study was designed to evaluate the efficacy of Ferinject® in improving symptoms of HFpEF in patients with ID. Analyses will focus both on subjective and objective measures as well as on patients with and without anaemia. Furthermore, the tolerability and safety of Ferinject® treatment will be evaluated.

Study Timeline

• Study First Submitted: 2017-03-01
• Study First Submitted QC: 2017-03-03
• Study First Posted: 2017-03-09
• Study Start: 2017-08-01
• Primary Completion: 2022-12-13
• Study Completion: 2024-04-10
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-30
• Last Update Posted: 2024-05-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

1. Patient is willing to participate and provides written informed consent;

2. Age ≥18 years;

3. Clinical diagnosis of heart failure with preserved ejection fraction (HFpEF) with LVEF ≥45% at screening or within 6 months prior to planned randomisation (assessed by echocardiography or MRI);

4. Ambulatory for at least 7 days with NYHA class II or III at time of randomisation (the screening visit can take place at the end of a hospitalisation);

5. Treated with a diuretic;

6. Presence of atrial fibrillation (AF) at screening or randomisation is allowed in 2 out of 4 patients (calculated per centre);

7. At screening or randomisation, presence of one of the following criteria:

   1. hospitalisation with a diagnosis of HF within 12 months prior to planned randomisation; OR
   2. raised plasma levels of natriuretic peptides in a patient with sinus rhythm (i.e. in patients without AF: NT-proBNP >300 pg/mL or BNP >100 pg/mL or MR-proANP >120 pmol/L; in patients with AF: NT-proBNP >600 pg/mL or BNP >200 pg/mL or MR-proANP >250 pmol/l)

8. Evidence of diastolic dysfunction at screening or randomisation, defined as:

   1. E/E' >13; OR
   2. LA width ≥38 mm; OR
   3. LA length ≥50 mm; OR
   4. LA area ≥20 cm2; OR
   5. LA volume ≥55 ml; OR
   6. left atrial volume index >28 mL/m2;

9. Haemoglobin >9.0 g/dL and ≤14.0 g/dL (at screening);

10. ID with ferritin <100 ng/mL or ferritin 100-299 plus TSAT <20% (at screening);

11. 6-minute-walking distance at baseline <450 m (average of the last 2 documented tests within 8 weeks prior to planned randomisation that also need to be within 20% of each other).

Exclusion Criteria

1. Unable to sign informed consent

2. Any prior echocardiography measurement of LVEF <40%;

3. Clinical signs and symptoms of infection including fever >38°C;

4. Use of IV iron, erythropoietin or blood transfusions within the previous 60 days;

5. Use of concurrent immunosuppressive therapy;

6. History of acquired iron overload or haemochromatosis (or a first relative with haemochromatosis);

7. Known hypersensitivity to FCM or any other IV iron product;

8. Known bleeding or haemolytic anemia;

9. Presence of any condition that precludes exercise testing, such as decompensated HF, significant musculoskeletal disease, unstable angina pectoris, obstructive cardiomyopathy, severe uncorrected valvular disease, or uncontrolled brady-arrhythmias or tachy-arrhythmias;

10. Probable alternative diagnoses that in the opiniton of the investigator could account for the patient's HF symptoms such as severe obesity, primary pulmonary hypertension, or chronic obstructive pulmonary disease (COPD); hence, patients with the following are excluded:

    1. Severe COPD, i.e. with known FEV1 <50%, requiring home oxygen therapy, or on chronic oral steroid therapy;
    2. body mass index ≥40.0 kg/m2;

11. Presence of uncontrolled atrial fibrillation with resting heart rate >110/min;

12. Presence of uncontrolled hypertension with blood pressure >160/100 mm Hg;

13. Renal replacement therapy;

14. Concurrent therapy with an erythropoiesis stimulating agent;

15. Known active malignancy;

16. Known HIV or active hepatitis infection;

17. Pregnancy;

18. Patients, who may be dependent on the sponsor, the investigator or the trial sites, have to be excluded from the trial

19. Lack of willingness to storage and disclosure of pseudonymous disease data in the context of the clinical trial.

20. Participation in another clinical trial within previous 30 days and/ or anticipated participation in another trial during this study.

21. Inability to fully comprehend and/or perform study procedures in the investigator's opinion;

22. Persons staying at an institution due to order by a national body or a court of law.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment	Ferric Carboxymaltose 50Mg/Ml Inj 15Ml	Active treatment: Ferric Carboxymaltose solution (Ferinject®) for parenteral application, 50 mg/mL iron. Medication will be given as a short time infusion over 15 minutes in 100mL NaCl.
Placebo	Saline Solution for Injection	Placebo: Normal saline (0.9% weight/volume (w/v) NaCl) administered in analogy to active treatment procedures.

Primary Outcome Measures

Name	Time	Method
exercise capacity	24 weeks	The difference of 6-minute walking distance in meters from baseline to week 24 in symptomatic patients with HFpEF with documented ID compared to the control group.

Secondary Outcome Measures

Name	Time	Method
NYHA functional class	52 weeks	Difference in NYHA class from baseline to end of study in symptomatic patients with HFpEF
Change in quality of life assessments	52 weeks	Difference in quality of life assessments (EQ-5D (= European Quality of Life 5 Dimensions 3 Level Version; = tool for Patient-Reported Outcomes (PRO) measurement); KCCQ (= Kansas City Cardiomyopathy Questionnaire)) from baseline to end of study in symptomatic patients with HFpEF.; KCCQ: (0-100) -\> 100=best; EQ-5D (5-point Likert scale, 5 dimensions (mobility, self-care, usual activities, pain, anxiety) 5 levels (1 = no problems level 5 = extreme problems))
Rate of recurrent heart failure hospitalisations and death	52 weeks	Difference in the rate of recurrent heart failure hospitalisations and deaths in symptomatic patients with HFpEF and ID.
6min-walking distance	52 weeks	Difference in 6-minute walking distance in meters from baseline to end of study in symptomatic patients with HFpEF with documented ID compared to the control group
Patient Global Assessment (PGA)	52 weeks	Difference in Patient Global Assessment (PGA) in symptomatic patients with HFpEF with documented ID from baseline to end of study.; (7-point Likert scale \[non-parametric\])

Trial Locations

Locations (7)

Innere Medizin/Kardiologie; 🇩🇪 Nurnberg, Bavaria, Germany

University Medical Center Göttingen; 🇩🇪 Gottingen, Lower Saxony, Germany

Saarland University Medical Center; 🇩🇪 Homburg, Saarland, Germany

Charité University Medicine Berlin; 🇩🇪 Berlin, Germany

Universitäres Herzzentrum Hamburg; 🇩🇪 Hamburg, Germany

Herzklinik Ulm; 🇩🇪 Ulm, Germany

Herzzentrum Dresden GmbH; 🇩🇪 Dresden, Saxonia, Germany