Impact of Intravenous Iron Repletion On Mechanisms of Exercise InTolerance in HFpEF (IRONMET-HFpEF)

NCT ID: NCT04945707

Last Updated: 2025-10-02

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 66 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-26
• Study Completion Date: 2026-05-31

Brief Summary

The primary objective of this study is to determine if the correction of functional iron deficiency by administering a single dose of intravenous iron (ferric derimaltose or Monoferric®) in participants with heart failure with preserved ejection fraction (HFpEF) will improve exercise capacity as measured by the change in peak oxygen uptake (peak VO2) from baseline to 12 weeks.

Detailed Description

A double-blind, prospective, randomized, placebo-controlled study to assess change in exercise capacity after iron repletion with a single dose of ferric derisomaltose (Monoferric®) IV compared to placebo in heart failure with preserved ejection fraction and with functional iron deficiency.

Sixty-six HFpEF participants who have functional iron deficiency will be recruited from the Cardiopulmonary Exercise Testing (CPET) Laboratory and will have a recent or scheduled clinical care CPET with exercise hemodynamic assessment. These measurements will serve as baseline measures. After undergoing other baseline measurements such as echocardiogram, actigraphy, research biomarkers, and the Kansas City Cardiomyopathy Questionnaire (KCCQ) participants will be randomized (2:1) to either a single dose of ferric derisomaltose (Monoferric®)1000 mg/100 ml (n=44) or placebo (n=22).

Given that the iron drug formulation is of brown color and the placebo is clear, unblinded staff members will be assigned to order, pick up and administer drug to the subject. The subject is blinded; therefore, the drug will be infused using a tented covering over the arm in which the IV has been placed. The tented covering will allow adequate viewing of the IV site, but outside of the view of the subject. All blinded staff will not be present during study drug infusion. Prior to infusion the subject will undergo vital signs; blood pressure, heart rate, and temperature. A peripheral intravenous catheter will be placed followed by an infusion of Monoferric 1000 mg (for subjects less than 50 kg, 20 mg/kg) as per current FDA-approved dosing or placebo over 20 minutes. Vital signs will be performed immediately after dosing and after 30 minutes. Subjects will remain in the clinic for observation for 30 minutes following infusion.

Randomization will be stratified by sex and will be performed in permutated blocks of 4 to assure balanced group sizes. In order to allocate without bias, and in a manner blinded to both participants and investigators, we will use random number generation at the time of randomization.

Participants will return for a CPET, echocardiogram, actigraphy, KCCQ, ECG, complete metabolic panel, and blood draw for research biomarkers, cardiovascular exam, and assessment of adverse experiences. A subset of subjects (n=33) will undergo a CPET with exercise hemodynamic assessment. The remaining subjects will undergo an noninvasive CPET (N=33)

Conditions

Iron-deficiency; Heart Failure With Preserved Ejection Fraction

Study Design

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

Study Groups

Arm 1

Ferric derisomaltose (Monoferric®) 1000 mg X 1 (for subject \<50 kg, 20 mg/kg X1)

Group Type: ACTIVE_COMPARATOR

Ferric Derisomaltose 1000 Mg in 100 mL INTRAVENOUS SOLUTION [Monoferric]

Intervention Type: DRUG

Ferric derisomaltose (Monoferric) 1000 mg X1 (for subject \<50 kg, 20 mg/kg

Arm 2

Normal Saline

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Normal saline

Interventions

Ferric Derisomaltose 1000 Mg in 100 mL INTRAVENOUS SOLUTION [Monoferric]

Ferric derisomaltose (Monoferric) 1000 mg X1 (for subject \<50 kg, 20 mg/kg

Intervention Type: DRUG

Placebo

Normal saline

Intervention Type: DRUG

Other Intervention Names

Monoferric; Normal Saline

Eligibility Criteria

Inclusion Criteria

1. Adult (≥18 years of age) able to provide informed consent.

2. Stable heart failure (NYHA II-IV) for at least 4 weeks

3. Heart Failure with Preserved left ventricular ejection fraction.(Left ventricular ejection fraction ≥ 50 % obtained within 6 months of informed consent.

4. NT-proBNP ≥ 125 pg/mL without ongoing atrial fibrillation/flutter. If ongoing atrial fibrillation/flutter at the time of sample collection, NT-proBNP must be ≥ 250 pg/mL OR patients must have a history of pulmonary capillary wedge pressure ≥ 15 mm Hg during rest or the slope of pulmonary capillary wedge pressure to cardiac output (PCWP/CO) ≥ 2.0 mmHg/L/min during upright exercise (Eisman et al., Circ Heart Fail. 2018 May;11(5):e004750.).OR subjects must have a heart failure hospitalization within the last 12 months prior to screening OR Chronic diastolic dysfunction on echocardiography as evidenced by: Left Atrial Enlargement (LAE): LA diameter ≥ 3.8cm in women, ≥ 4.0 cm in men or LA length ≥ 5.0 cm or LA area ≥ 20 cm2 OR LA volume ≥ 55mL or LA volume index ≥ 29ml/m2 or Left Ventricular Hypertrophy (LVH): septal thickness or posterior wall thickness ≥ 1.1 cm OR For patients in sinus rhythm: E/e' ratio ≥15 at septal annulus, or E/e' ratio ³13 at lateral annulus, or average E/e' ratio ³14. For patients in atrial fibrillation: E/e' ≥ 11 at the septal annulus.

5. Hemoglobin >9.0 g/dL AND <15.0 g/dL .

6. Serum ferritin <100 ng/mL OR 100 to 300 ng/mL with TSAT <20%, but NOT ferritin < 15 ng/mL.

7. Demonstrate diminished exercise capacity: ≤ 75 % predicted peak VO2 as determined by a Cardiopulmonary Exercise Test (CPET) at the time of screening

8. Perform a maximal effort CPET by achieving a Respiratory Exchange Ratio (RER) of ≥ 1.05

Exclusion Criteria

1. Current or planned intravenous iron supplementation. Iron-containing multivitamins (<30 mgs /day) are permitted.

2. Known hypersensitivity reaction to any component of ferric derisomaltose (Monofer®)

3. History of acquired iron overload (e.g. hemochromatosis), or the recent receipt (within 3 months) of erythropoietin stimulating agent, IV iron therapy, or blood transfusion.

4. Documented active gastrointestinal bleeding

5. Anemia with known cause other than iron deficiency or chronic disease

6. Acute myocardial infarction, acute coronary syndrome, transient ischemic attack, or stroke within 3 months of enrollment.

7 Presence of any condition that precludes exercise testing such as:

a. Claudication that limits exertion b. Uncontrolled bradyarrhythmia or tachyarrhythmia (according to Investigator judgment, pacemaker treatment is allowed as long as the same pacing mode/activity can be used at baseline and follow-up CPET) c. Clinically significant musculoskeletal disease or orthopedic conditions that limit the ability to perform the CPET (e.g., arthritis or injury in the foot, leg, knee or hip) d. Severe obesity (BMI > 50.0 kg/m2) e. Any other non-heart failure condition that, in the opinion of the Investigator, that is the primary limitation to exercise. 8. Severe renal dysfunction (eGFR< 20 ml/min/1.73m2) 9. Severe liver disease (ALT or AST > 3x upper limit of normal, alkaline phosphatase or bilirubin >2x upper limit of normal) 10. Active malignancy other than non-melanoma skin cancers 11. Female participant of child-bearing potential who is pregnant, lactating, or not willing to use adequate contraceptive precautions during the study and for up to 5 days after the last scheduled dose of study medication.

12. Planned surgical procedure during the trial period 13. Inability to return for follow up visits

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

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Pharmacosmos A/S

INDUSTRY

Sponsor Role: collaborator

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Gregory D. Lewis, M.D.

Assistant Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Greg Lewis, MD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Locations

Massachusetts General Hospital

Boston, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Greg Lewis, MD

Role: CONTACT

glewis@partners.org

617-724-9254

Rajeev Malhotra, MD

Role: CONTACT

rmalhotra@mgh.harvard.edu

Facility Contacts

Greg Lewis, MD

Role: primary

glewis@partners.org

6177249254

Diane Cocca-Spofford, BSN

Role: backup

dcoccaspofford@mgh.harvard.edu

617 726 8228

References

Lewis GD, Malhotra R, Hernandez AF, McNulty SE, Smith A, Felker GM, Tang WHW, LaRue SJ, Redfield MM, Semigran MJ, Givertz MM, Van Buren P, Whellan D, Anstrom KJ, Shah MR, Desvigne-Nickens P, Butler J, Braunwald E; NHLBI Heart Failure Clinical Research Network. Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial. JAMA. 2017 May 16;317(19):1958-1966. doi: 10.1001/jama.2017.5427.

Reference Type: BACKGROUND

PMID: 28510680 (View on PubMed)

Houstis NE, Eisman AS, Pappagianopoulos PP, Wooster L, Bailey CS, Wagner PD, Lewis GD. Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Diagnosing and Ranking Its Causes Using Personalized O2 Pathway Analysis. Circulation. 2018 Jan 9;137(2):148-161. doi: 10.1161/CIRCULATIONAHA.117.029058. Epub 2017 Oct 9.

Reference Type: BACKGROUND

PMID: 28993402 (View on PubMed)

Other Identifiers

R01HL151841

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2021P001501

Identifier Type: -

Identifier Source: org_study_id