Iron Substitution With Ferric Carboxymaltose as Treatment Strategy for Heart Failure Patients With Preserved Ejection Fraction

NCT ID: NCT05477498

Last Updated: 2022-07-28

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-12-01
• Study Completion Date: 2022-12-31

Brief Summary

This study aims to investigate the effects of treatment with intravenous ferric carboxymaltose on exercise tolerance measured as VO2peak in patients with HFpEF and iron deficiency, compared to placebo.

Detailed Description

Iron deficiency is a common comorbidity associated with chronic heart failure (HF) in both, patients with preserved (HFpEF) and reduced ejection fraction (HFrEF), which has unfavorable clinical and prognostic effects. Previous studies have confirmed that HF patients with iron deficiency have a lower exercise tolerance than those without iron deficiency. In iron deficient patients with HFrEF, treatment with intravenous ferric carboxymaltose (FCM) improved symptoms, exercise tolerance and quality of life (QoL). Since the latest guidelines published by the European Society of Cardiology (ESC) in 2016, iron substitution is an official class IIa recommendation in HFrEF, while it has not yet been endorsed in the treatment guidelines for HFpEF. To date, no evidence is available on iron supplementation in HFpEF. Therefore, a clear rationale exists for examining the effects of correcting iron deficiency in this high-risk and steadily growing patient group.

The proposed study will be a single-centre, prospective, double-blind, randomized, placebo-controlled trial in a primary care setting including 86 patients with stable HFpEF and iron deficiency. Participants will undergo three study visits: a baseline visit, a status control visit, and a post-intervention visit. At the baseline visit, measurements of exercise tolerance (using spiroergometry), laboratory parameters and disease-specific biomarkers (using blood samples), tHb-mass (using the carbon monoxide rebreathing method), cardiac and arterial vessel structure and function (using electrocardiogram, echocardiography and PVW), QoL (using 3 validated questionnaires), body composition (using BMI and WHR), and habitual physical activity (using a wrist-worn accelerometer) will be performed. Then, patients randomized to the treatment group will receive FCM (Vifor Pharma AG, Villars-sur-Glâne, Switzerland), whereas those in the control group will receive placebo. At week 6, iron deficiency status will be re-evaluated in all patients and, if necessary, another application of FCM or placebo will be administered, respectively. After the 12-week treatment period, the study measurements will be repeated in all patients (post-intervention visit) to investigate the effects of the intervention.

Conditions

Heart Failure With Normal Ejection Fraction; Iron-deficiency

Study Design

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

Study Groups

Iron substitution

Iron deficiency status will be assessed at the baseline visit (Day 0) as well as after 6 weeks of iron substitution (Week 6). The study drug will be given as FCM solution (Ferinject®, Vifor Pharma AG, Villars-sur-Glâne, Switzerland) by intravenous injection. Infusions of 10 or 20 mL (which is the amount of FCM that is equivalent to 500 or 1000 mg of iron, respectively) will be administered in ≥6 minutes diluted in ≈100 mL of sterile 0.9% sodium chloride solution (NaCl) for 10 mL, or in ≥15 minutes diluted in ≈200 mL for 20 mL. Dosing will be based on screening Hb level and weight, rather than on ferritin and TSAT results. On Day 0 (baseline visit), patients with Hb ≤14 g/dL, both \<70 kg and \>70 kg will receive 1000 mg FCM (20 mL), whereas patients with Hb \>14g/dL will receive 500 mg FCM (10 mL).

Group Type: EXPERIMENTAL

Ferric carboxymaltose

Intervention Type: DRUG

Application of FCM solution (Ferinject®, Vifor Pharma AG, Villars-sur-Glâne, Switzerland) by intravenous injection.

Placebo

Patients in the control group will receive a placebo solution administered as normal saline (0.9% weight/volume (w/v) NaCl) by intravenous injection as per the instructions for active treatment.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Application of placebo solution administered as normal saline (0.9% weight/volume (w/v) NaCl) by intravenous injection as per the instructions for active treatment.

Interventions

Ferric carboxymaltose

Application of FCM solution (Ferinject®, Vifor Pharma AG, Villars-sur-Glâne, Switzerland) by intravenous injection.

Intervention Type: DRUG

Placebo

Application of placebo solution administered as normal saline (0.9% weight/volume (w/v) NaCl) by intravenous injection as per the instructions for active treatment.

Intervention Type: DRUG

Other Intervention Names

Ferinject®; NaCl 0.9%

Eligibility Criteria

Inclusion Criteria

• Informed consent as documented by signature
• NYHA functional classes II-III
• Signs and symptoms of chronic HF, such as:
• Dyspnea
• Paroxysmal nocturnal dyspnea
• Reduced exercise tolerance
• Fatigue
• Extended recovery after exercising
• Peripheral edema (lower leg, ankle)
• EF (ejection fraction) >50%
• Structural or functional changes in echocardiography:
• Left atrial volume index (LAVI) >34 ml/m2 OR
• Left ventricular mass index (LVMI) >115 g/m2 (men), >95 g/m2 (women) OR
• E/E' (ratio between mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E')) >13 AND mean E' septal and lateral wall <9 cm/s
• NT-proBNP >125 pg/ml
• At least 4 weeks on stable medical treatment or without signs and symptoms of cardiac decompensation
• Iron deficiency defined as:
• Ferritin <100 ng/ml OR
• Ferritin <300 ng/ml with a transferrin saturation (TSAT) <20%

Exclusion Criteria

• Age <18 years
• Pregnancy or lactation
• Life-expectancy <6 months
• Planned cardiac interventions in the following 6 months
• Unstable angina pectoris
• Uncontrolled brady- or tachyarrhythmia
• Severe uncorrected valvular heart disease
• Paroxysmal atrial fibrillation
• Clinically significant concomitant disease states (e.g. hypertension grades 2-3 (>160/100 mmHg), severe renal failure (GFR <30 ml/min/1.73m2), hepatic dysfunction (ALT or AST >3x upper limit of normal, chronic obstructive pulmonary disease (COPD) grades III-IV)
• On-going cancer treatment
• Significant musculoskeletal disease limiting exercise tolerance
• Active infection
• Immunosuppressive medical therapy
• Earlier hypersensitivity to parenteral iron preparation
• Anemia and iron deficiency due to active and/or chronic bleeding
• Blood transfusion within the previous 30 days
• Red cell, folate and vitamin B12 deficiency
• Known or suspected non-compliance, drug or alcohol abuse
• Inability to follow the procedures of the study, e.g. due to insufficient language skills, psychological disorders, dementia, etc.
• Participation in another intervention study
• Enrolment of the investigators, their family members, and other persons involved in the study procedures
• Hemoglobin < 120 ng/ml in male patients or < 110 ng/ml in female patients

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

Sponsors

Clinical Trial Unit, University Hospital Basel, Switzerland

OTHER

Sponsor Role: collaborator

Cantonal Hosptal, Baselland

OTHER

Sponsor Role: lead

Responsible Party

Maria Bösing

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Thomas Dieterle, MD

Role: PRINCIPAL_INVESTIGATOR

University Department of Internal Medicine, Cantonal Hospital Baselland

Other Identifiers

2018-02280

Identifier Type: -

Identifier Source: org_study_id