Heart Failure With Normal Ejection FractionPhase 4IRON-HFpEFNCT05477498
Iron Substitution With Ferric Carboxymaltose as Treatment Strategy for Heart Failure Patients With Preserved Ejection Fraction
A Phase 4 study testing Ferric carboxymaltose in people with Heart Failure With Normal Ejection Fraction and Iron-deficiency, run by Cantonal Hospital, Baselland.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure With Normal Ejection Fraction, Iron-deficiency
- What is being tested?
- Ferric carboxymaltose
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- 1 Dec 2021to 31 Dec 2022
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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%
Who cannot join
- 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
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- 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
About this study
Official title: Iron Substitution With Ferric Carboxymaltose as Treatment Strategy for Heart Failure Patients With Preserved Ejection Fraction: A Prospective, Double-blind, Randomized, Placebo-controlled Trial
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.
Read the 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.
- Being tested
- Ferric carboxymaltose, Placebo
- Keywords
- Exercise tolerance, iron substitution
- Medical subject headings
- Anemia, Iron-Deficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ferric carboxymaltoseDrug
Also called Ferinject®
Application of FCM solution (Ferinject®, Vifor Pharma AG, Villars-sur-Glâne, Switzerland) by intravenous injection.
PlaceboDrug
Also called NaCl 0.9%
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.
| Study group | Role | What they receive |
|---|---|---|
| Iron substitution | Experimental | 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). Receives: Drug: Ferric carboxymaltose |
| Placebo | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in peak oxygen uptake (VO2peak)
Change of VO2peak will be measured by spiroergometry at the baseline and post-intervention visit.
Measured: 12 weeks
Secondary outcomes (11)
Change in ventriculo-arterial coupling (VAC)
VAC is defined as the ratio of arterial elastance (Ea) and end-systolic elastance (Ees) and will be approximated echocardiographically based on the method described by Antonini-Canterin et al.
Measured: 12 weeks
Change in arteriovenous oxygen difference (Da-vO2)
Da-vO2 will be calculated using the Fick Principle
Measured: 12 weeks
Change in pulse wave velocity (PWV)
PWV will be measured at the same time as the echocardiographic parameters with the VaSera VS-2000 Vascular Screening System (Fukuda Denshi Co. Ltd, Tokyo, Japan) and evaluated by experienced blinded members of the study team.
Measured: 12 weeks
Change in New York Heart Association (NYHA) functional class
NYHA functional class will be determined according to the New York Heart Association classification.
Measured: 12 weeks
Change in habitual physical activity
Habitual physical activity will be measured by an accelerometer over a period of 14 consecutive days for 24 hours per day following baseline and post-intervention visits. Patients will wear a waterproof micro-electromechanical triaxial activity bracelet on the non-dominant wrist (GeneActiv, Activinsights Ltd, Kimbolton, Cambridgeshire, UK) to assess physical activity intensity (light, moderate, vigorous) and periods of inactivity, sleep and wake.
Measured: 12 weeks
Change in body composition measured by body mass index (BMI)
BMI will be calculated from measured height in meters and weight in kilograms. Weight and height will be combined to report BMI in kg/m^2.
Measured: 12 weeks
Change in baseline body composition measured by waist to hip ratio (WHR)
WHR will be calculated from measured waist circumference (WC) and hip circumference (HC) in centimetres. WC will be divided by HC to report WHR.
Measured: 12 weeks
Change in total hemoglobin mass (tHb-mass)
tHB-mass will be measured with the carbon monoxide (CO)-rebreathing method
Measured: 12 weeks
Change in quality of life (QoL) by the 36-Item Short Form Health Survey (SF-36)
The SF-36 consists of 36 items, which are formatted as binary questions or as semantic 6-point differential scales. It refers to the past 4 weeks and includes 9 content areas concerning vitality, general health perception, physical functioning, social functioning, role limitations (emotional/physical problems), pain, mental health and health change.
Measured: 12 weeks
Change in baseline quality of life (QoL) by the Kansas City Cardiomyopathy Questionnaire (KCCQ) at 12 weeks.
The KCCQ consists of 15 items concerning overall symptoms, emotional, social and mental status within the past 2 weeks.
Measured: 12 weeks
Change in quality of life (QoL) by the Minnesota Living with Heart Failure Questionnaire (MLWHFQ) at 12 weeks.
The MLWHFQ refers to the past 4 weeks and includes 21 questions on a 6-point scale with a maximum of 105 points (<24 good QoL, >45 poor QoL).
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jul 2022
- Study start1 Dec 2021 (estimated)
- Primary completion31 Aug 2022 (estimated)
- Study completion31 Dec 2022 (estimated)
Why it stopped: Principal Investigator left institution
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Heart Failure With Normal Ejection FractionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Intervention group: Active treatment with ferric carboxymaltose, given as diluted solution by intravenous injection Control group: Placebo, administered as normal saline 0.9%
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Cantonal Hospital, Baselland
- Sponsor type
- University, hospital or other
- Collaborators
- Clinical Trial Unit, University Hospital Basel, Switzerland
- Responsible party
- Principal investigator, Maria Bösing, Cantonal Hospital, Baselland
- Investigators
- Thomas Dieterle, MD, Principal investigator, University Department of Internal Medicine, Cantonal Hospital Baselland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05477498
- Sponsor's protocol ID
- 2018-02280
- Other IDs
- 2018
- Acronym
- IRON-HFpEF
- Status last verified
- Jul 2022
- First submitted
- 5 Jul 2019
- Last updated
- 28 Jul 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Patient-level anonymised datasets can be requested after completion of all planned analyses and publications from the study centre (anticipated by mid 2022). Public access to the study protocol will be granted by publishing it in a scientific journal.
Study at a glance
From the registry record, last updated by the sponsor on 28 Jul 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Iron Substitution With Ferric Carboxymaltose as Treatment Strategy for Heart Failure Patients With Preserved Ejection Fraction: A Prospective, Double-blind, Randomized, Placebo-controlled Trial
- ClinicalTrials.gov ID
- NCT05477498
- Acronym / sponsor ID
- IRON-HFpEF / 2018-02280
- Keywords
- Exercise tolerance, iron substitution
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Principal Investigator left institution
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Cantonal Hospital, BasellandUniversity, hospital or other
- Collaborators
- Clinical Trial Unit, University Hospital Basel, Switzerland
- Study start
- 1 Dec 2021 (estimated)
- Primary completion
- 31 Aug 2022 (estimated)
- Study completion
- 31 Dec 2022 (estimated)
- First posted
- 28 Jul 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Intervention group: Active treatment with ferric carboxymaltose, given as diluted solution by intravenous injection Control group: Placebo, administered as normal saline 0.9%
| Arm | Type | Receives |
|---|---|---|
| Iron substitution | Experimental | Drug: Ferric carboxymaltoseIron 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). |
| Placebo | Placebo comparator | Drug: PlaceboPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (19 listed)
- Informed consent as documented by signature
- NYHA functional classes II-III
- Signs and symptoms of chronic HF, such as:
- Dyspnea
- Paroxysmal nocturnal dyspnea
Key exclusion criteria (22 listed)
- Age <18 years
- Pregnancy or lactation
- Life-expectancy <6 months
- Planned cardiac interventions in the following 6 months
- Unstable angina pectoris
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ferric carboxymaltoseAlso: Ferinject®Application of FCM solution (Ferinject®, Vifor Pharma AG, Villars-sur-Glâne, Switzerland) by intravenous injection. | Drug | Iron substitution |
| PlaceboAlso: NaCl 0.9%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. | Drug | Placebo |
Primary outcome
Change in peak oxygen uptake (VO2peak)
Time frame: 12 weeks
Change of VO2peak will be measured by spiroergometry at the baseline and post-intervention visit.
11 secondary outcomes
Change in ventriculo-arterial coupling (VAC)
Time frame: 12 weeks
Change in arteriovenous oxygen difference (Da-vO2)
Time frame: 12 weeks
Change in pulse wave velocity (PWV)
Time frame: 12 weeks
Change in New York Heart Association (NYHA) functional class
Time frame: 12 weeks
Change in habitual physical activity
Time frame: 12 weeks
Change in body composition measured by body mass index (BMI)
Time frame: 12 weeks
Change in baseline body composition measured by waist to hip ratio (WHR)
Time frame: 12 weeks
Change in total hemoglobin mass (tHb-mass)
Time frame: 12 weeks
Change in quality of life (QoL) by the 36-Item Short Form Health Survey (SF-36)
Time frame: 12 weeks
Change in baseline quality of life (QoL) by the Kansas City Cardiomyopathy Questionnaire (KCCQ) at 12 weeks.
Time frame: 12 weeks
Change in quality of life (QoL) by the Minnesota Living with Heart Failure Questionnaire (MLWHFQ) at 12 weeks.
Time frame: 12 weeks
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Jul 2022.
- Individual participant dataSharing planned: Yes. Patient-level anonymised datasets can be requested after completion of all planned analyses and publications from the study centre (anticipated by mid 2022). Public access to the study protocol will be granted by publishing it in a scientific journal.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Thomas Dieterle, MD principal investigator
University Department of Internal Medicine, Cantonal Hospital Baselland
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ferric carboxymaltose in people with Heart Failure With Normal Ejection Fraction and Iron-deficiency, run by Cantonal Hospital, Baselland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 28 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in peak oxygen uptake (VO2peak) (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jul 2022.