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

A Double-blind,Randomized, Placebo-controlled Study to Assess Exercise Tolerance After Iron Repletion With Ferric Derisomaltose (Monoferric®) IV Compared to Placebo in Heart Failure With Preserved Ejection Fraction and With Iron Deficiency.

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.

Study Overview

• Status: Recruiting
• Conditions: Iron-deficiency; Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Placebo; Drug: Ferric Derisomaltose 1000 Mg in 100 mL INTRAVENOUS SOLUTION [Monoferric]

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)

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Greg Lewis, MD; Phone Number: 617-724-9254; Email: glewis@partners.org
• Study Contact Backup: Name: Rajeev Malhotra, MD; Email: rmalhotra@mgh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Greg Lewis, MD; Phone Number: 617-724-9254; Email: glewis@partners.org
      • Contact: Diane Cocca-Spofford, BSN; Phone Number: 617 726 8228; Email: dcoccaspofford@mgh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1; Ferric derisomaltose (Monoferric®) 1000 mg X 1 (for subject <50 kg, 20 mg/kg X1)	Drug: Ferric Derisomaltose 1000 Mg in 100 mL INTRAVENOUS SOLUTION [Monoferric]; Ferric derisomaltose (Monoferric) 1000 mg X1 (for subject <50 kg, 20 mg/kg; Other Names: Monoferric
Placebo Comparator: Arm 2; Normal Saline	Drug: Placebo; Normal saline; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in peak oxygen uptake (peak VO2) from baseline to week 12 in HFpEF subjects with functional iron deficiency following a single dose of ferric derisomaltose or placebo.	Peak VO2 measured by a maximal effort Cardiopulmonary Exercise Test (CPET)	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in resting pulmonary capillary wedge pressure (PCWP)	Measured by right heart catheterization with CPET	Baseline to week 12
Change in resting pulmonary artery pressure (PAP)	Measured by right heart catheterization with CPET	Baseline to week 12
Change in exercise pulmonary capillary wedge pressure/ cardiac output slope (PCWP/CO slope)	Measured by right heart catheterization with CPET	Baseline to week 12
Change in exercise pulmonary arterial pressure/ cardiac output slope (PAP/CO slope)	Measured by right heart catheterization with CPET	Baseline to week 12
Change in exercise peripheral oxygen extraction C(a-v)O2	Measured by right heart catheterization with CPET	Baseline to week 12
Change in resting and exercise pulmonary vascular resistance (PVR)	Measured by right heart catheterization with CPET	Baseline to week 12
Change in hepcidin	Measured in blood samples	Baseline and week 12
Change in transferrin saturation to hepcidin ratio	Measured in blood samples	Baseline and week 12
Change in hemojuvelin	Measured in blood samples	Baseline and week 12
Change in soluble transferrin receptor level	Measured in blood samples	Baseline and week 12
Change in NTpBNP	Measured in blood samples	Baseline and week 12
Change in C-reactive Protein	Measured in blood samples	Baseline and week 12
Change in physical activity level as measured by accelerometer motion-sensing data collection	Measured by Actigraphy	Baseline to week 12
Change in Quality of Life	Measured by Kansas City Cardiomyopathy Questionnaire	Baseline to week 12

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH); Pharmacosmos A/S
• Investigators: Principal Investigator: Greg Lewis, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• 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. Erratum In: JAMA. 2017 Jun 20;317(23 ):2453.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 26, 2021
• Primary Completion (Estimated): February 28, 2025
• Study Completion (Estimated): May 31, 2025

Study Registration Dates

• First Submitted: June 15, 2021
• First Submitted That Met QC Criteria: June 22, 2021
• First Posted (Actual): June 30, 2021

Study Record Updates

• Last Update Posted (Actual): September 26, 2023
• Last Update Submitted That Met QC Criteria: September 25, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Iron Deficiency; Heart Failure with Preserved Ejection Fraction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Hematologic Diseases; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Heart Failure; Anemia, Iron-Deficiency; Iron Deficiencies
• Other Study ID Numbers: 2021P001501; R01HL151841 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No