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

Primary Purpose

Iron-deficiency, Heart Failure With Preserved Ejection Fraction

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Ferric Derisomaltose 1000 Mg in 100 mL INTRAVENOUS SOLUTION [Monoferric]
Placebo
Sponsored by
Massachusetts General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Iron-deficiency focused on measuring Heart Failure with Preserved Ejection Fraction, Iron Deficiency

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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
  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

Sites / Locations

  • Massachusetts General HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Arm 1

Arm 2

Arm Description

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

Normal Saline

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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

Full Information

First Posted
June 15, 2021
Last Updated
September 25, 2023
Sponsor
Massachusetts General Hospital
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), Pharmacosmos A/S, National Institutes of Health (NIH)
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1. Study Identification

Unique Protocol Identification Number
NCT04945707
Brief Title
Impact of Intravenous Iron Repletion On Mechanisms of Exercise InTolerance in HFpEF (IRONMET-HFpEF)
Acronym
IRONMETHFpEF
Official Title
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.
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 26, 2021 (Actual)
Primary Completion Date
February 28, 2025 (Anticipated)
Study Completion Date
May 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts General Hospital
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), Pharmacosmos A/S, National Institutes of Health (NIH)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Iron-deficiency, Heart Failure With Preserved Ejection Fraction
Keywords
Heart Failure with Preserved Ejection Fraction, Iron Deficiency

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
This is a double-blind, prospective, randomized, placebo-controlled study to assess exercise tolerance after iron repletion with a single dose of ferric derisomaltose (Monoferric®) IV compared to placebo in heart failure with preserved ejection fraction and with iron deficiency. Randomization will be stratified by sex and will be performed in permutated blocks of 4 to assure balanced group sizes
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Unblinded staff (clinical research nurse and unblinded investigator) prepare and administer study drug to subject and document and follow safety events. The subject is blinded. A 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.
Allocation
Randomized
Enrollment
66 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm 1
Arm Type
Active Comparator
Arm Description
Ferric derisomaltose (Monoferric®) 1000 mg X 1 (for subject <50 kg, 20 mg/kg X1)
Arm Title
Arm 2
Arm Type
Placebo Comparator
Arm Description
Normal Saline
Intervention Type
Drug
Intervention Name(s)
Ferric Derisomaltose 1000 Mg in 100 mL INTRAVENOUS SOLUTION [Monoferric]
Other Intervention Name(s)
Monoferric
Intervention Description
Ferric derisomaltose (Monoferric) 1000 mg X1 (for subject <50 kg, 20 mg/kg
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Normal Saline
Intervention Description
Normal saline
Primary Outcome Measure Information:
Title
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.
Description
Peak VO2 measured by a maximal effort Cardiopulmonary Exercise Test (CPET)
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Change in resting pulmonary capillary wedge pressure (PCWP)
Description
Measured by right heart catheterization with CPET
Time Frame
Baseline to week 12
Title
Change in resting pulmonary artery pressure (PAP)
Description
Measured by right heart catheterization with CPET
Time Frame
Baseline to week 12
Title
Change in exercise pulmonary capillary wedge pressure/ cardiac output slope (PCWP/CO slope)
Description
Measured by right heart catheterization with CPET
Time Frame
Baseline to week 12
Title
Change in exercise pulmonary arterial pressure/ cardiac output slope (PAP/CO slope)
Description
Measured by right heart catheterization with CPET
Time Frame
Baseline to week 12
Title
Change in exercise peripheral oxygen extraction C(a-v)O2
Description
Measured by right heart catheterization with CPET
Time Frame
Baseline to week 12
Title
Change in resting and exercise pulmonary vascular resistance (PVR)
Description
Measured by right heart catheterization with CPET
Time Frame
Baseline to week 12
Title
Change in hepcidin
Description
Measured in blood samples
Time Frame
Baseline and week 12
Title
Change in transferrin saturation to hepcidin ratio
Description
Measured in blood samples
Time Frame
Baseline and week 12
Title
Change in hemojuvelin
Description
Measured in blood samples
Time Frame
Baseline and week 12
Title
Change in soluble transferrin receptor level
Description
Measured in blood samples
Time Frame
Baseline and week 12
Title
Change in NTpBNP
Description
Measured in blood samples
Time Frame
Baseline and week 12
Title
Change in C-reactive Protein
Description
Measured in blood samples
Time Frame
Baseline and week 12
Title
Change in physical activity level as measured by accelerometer motion-sensing data collection
Description
Measured by Actigraphy
Time Frame
Baseline to week 12
Title
Change in Quality of Life
Description
Measured by Kansas City Cardiomyopathy Questionnaire
Time Frame
Baseline to week 12

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult (≥18 years of age) able to provide informed consent. Stable heart failure (NYHA II-IV) for at least 4 weeks Heart Failure with Preserved left ventricular ejection fraction.(Left ventricular ejection fraction ≥ 50 % obtained within 6 months of informed consent. 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. Hemoglobin >9.0 g/dL AND <15.0 g/dL . Serum ferritin <100 ng/mL OR 100 to 300 ng/mL with TSAT <20%, but NOT ferritin < 15 ng/mL. Demonstrate diminished exercise capacity: ≤ 75 % predicted peak VO2 as determined by a Cardiopulmonary Exercise Test (CPET) at the time of screening Perform a maximal effort CPET by achieving a Respiratory Exchange Ratio (RER) of ≥ 1.05 Exclusion Criteria: Current or planned intravenous iron supplementation. Iron-containing multivitamins (<30 mgs /day) are permitted. Known hypersensitivity reaction to any component of ferric derisomaltose (Monofer®) 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. Documented active gastrointestinal bleeding Anemia with known cause other than iron deficiency or chronic disease 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Greg Lewis, MD
Phone
617-724-9254
Email
glewis@partners.org
First Name & Middle Initial & Last Name or Official Title & Degree
Rajeev Malhotra, MD
Email
rmalhotra@mgh.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Greg Lewis, MD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Greg Lewis, MD
Phone
617-724-9254
Email
glewis@partners.org
First Name & Middle Initial & Last Name & Degree
Diane Cocca-Spofford, BSN
Phone
617 726 8228
Email
dcoccaspofford@mgh.harvard.edu

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28510680
Citation
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.
Results Reference
background
PubMed Identifier
28993402
Citation
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.
Results Reference
background

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

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