Comparative Phase III Trial of Ferric Derisomaltose Versus No Intravenous Iron in Iron-Deficient Patients with Symptomatic Chronic Heart Failure

Trial ID: 2024-519059-28-00
Protocol: P-Monofer-CHF-02
Sponsor: Pharmacosmos A/S

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Diseases & Conditions

Cardiac failure chronic Iron deficiency

Objectives

The primary objective of this phase III, randomized, open-label, blinded endpoint trial is to compare the **efficacy** of ferric derisomaltose versus no intravenous iron on cardiovascular mortality and hospitalizations for worsening heart failure in iron-deficient subjects with symptomatic chronic heart failure (CHF). This is clinically relevant as it addresses the potential impact of iron supplementation on critical outcomes in patients with CHF, a condition characterized by high morbidity and mortality.

Secondary objectives include:

Comparing the efficacy of ferric derisomaltose to no IV iron on cardiovascular mortality, all-cause mortality, hospitalizations for worsening heart failure, and all-cause hospitalizations in iron-deficient subjects with symptomatic CHF.
Evaluating the efficacy of ferric derisomaltose on hospitalizations for cardiovascular, respiratory, or renal disease and other cardiovascular endpoints in the same patient population.
Assessing the pharmacodynamic effects of ferric derisomaltose on hemoglobin (Hb), serum ferritin, transferrin saturation (TSAT), serum iron, and total iron binding capacity (TIBC).
Evaluating the safety of ferric derisomaltose compared to no IV iron.

Participants

The clinical trial involves a total of **1224 participants** diagnosed with **Chronic Heart Failure**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including a left ventricular ejection fraction of 45% or less, a history of heart failure classified as New York Heart Association class II, III, or IV, and specific hemoglobin and transferrin saturation levels. All subjects are on maximally tolerated guideline-directed medical therapy for heart failure. The trial also considers individuals with a higher risk of heart failure, such as those currently hospitalized for worsening heart failure or those identified in outpatient settings with elevated natriuretic peptides. The study population includes individuals with a medical history of ischemic heart failure etiology, prior acute myocardial infarction, or prior coronary revascularization. Participants are required to have an estimated glomerular filtration rate of 45 mL/min/1.73 m² or less and meet specific anemia criteria. The trial does not exclude vulnerable populations, and all participants have provided informed consent to participate in the study.

Plans and Procedures

The clinical trial is a **phase III**, randomized, open-label, blinded endpoint, comparative study designed to evaluate the efficacy of **ferric derisomaltose** versus no intravenous iron in subjects with iron deficiency and symptomatic **chronic heart failure**. The primary objective is to assess the impact on cardiovascular mortality and hospitalizations due to worsening heart failure. The trial is expected to commence recruitment on June 27, 2025, and conclude by April 26, 2027. Participants will be randomly assigned to receive either ferric derisomaltose or no intravenous iron, with endpoints assessed in a blinded manner to ensure unbiased results.

The trial will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, left ventricular ejection fraction, and hemoglobin levels, followed by regular follow-up visits to monitor health status and treatment effects. The end-of-study visit will evaluate the primary and secondary endpoints, including cardiovascular deaths and hospitalizations. Participants will be involved in the study for a maximum treatment period of two years, with the possibility of early termination if they experience serious adverse events or fail to adhere to the study protocol.

Inclusion criteria require participants to be at least 18 years old, with a history of heart failure and specific laboratory values indicating iron deficiency. Exclusion criteria are not explicitly detailed in the provided data. The study will measure primary efficacy endpoints such as the number of cardiovascular deaths and hospitalizations for worsening heart failure. Secondary endpoints include time to first hospitalization for worsening heart failure or cardiovascular death, and changes in New York Heart Association classification. Safety assessments will include monitoring of serious adverse events and vital signs.

Treatment

The clinical trial involves the administration of **ferric derisomaltose**, marketed under the name Monofer, as the experimental medication. This pharmaceutical product is presented in the form of a **solution for injection/infusion**. The active substance, ferric derisomaltose, is of polymer origin and is classified under the ATC code B03AC, which pertains to iron trivalent, parenteral preparations. The medication is administered via the **intravenous route**. The dosing regimen allows for a maximum daily dose of 2000 mg, with a total maximum dose of 4000 mg over the course of the treatment period, which spans up to 2 weeks. The product has undergone modifications limited to secondary packaging and labeling, ensuring that these changes do not impact the product's quality. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

In this study, the comparator treatment is the absence of intravenous iron administration, serving as the control group. This design allows for the evaluation of the efficacy of ferric derisomaltose in comparison to no treatment in iron-deficient subjects with symptomatic chronic heart failure. The trial aims to assess the impact of the experimental medication on cardiovascular mortality and hospitalizations due to worsening heart failure. No additional non-experimental treatments, such as standard-of-care therapy or placebo, are utilized in this trial. The study's objective is to provide a clear comparison between the effects of ferric derisomaltose and the absence of intravenous iron therapy.

Efficacy

The efficacy of ferric derisomaltose in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the number of cardiovascular deaths and hospitalizations for worsening heart failure, including urgent and unscheduled outpatient intravenous diuretic treatment. Key secondary efficacy endpoints include the time to first hospitalization for worsening heart failure or cardiovascular death, the number of hospitalizations for worsening heart failure, the number of all-cause hospitalizations, time to cardiovascular death, and time to all-cause death.

Additional secondary endpoints will evaluate the number of hospitalizations for cardiovascular, respiratory, or renal disease, time to cardiovascular, respiratory, or renal death, and the number of hospitalizations for cardiovascular events such as stroke, acute myocardial infarction (AMI), and heart failure. The trial will also measure the time to cardiovascular death or first hospitalization for cardiovascular events, time to all-cause death or first hospitalization, and days hospitalized or dead for cardiovascular reasons at week 52. Changes in the New York Heart Association (NYHA) classification from baseline to weeks 12, 26, and 52, as well as all-cause rehospitalizations at 30 and 60 days, and rehospitalizations for worsening heart failure at 30 and 60 days, will be assessed.

Pharmacodynamic endpoints include changes in hemoglobin (Hb), serum ferritin, transferrin saturation (TSAT), serum iron, and total iron-binding capacity (TIBC) from baseline to weeks 26 and 52. Safety endpoints will focus on the type and incidence of serious adverse events (SAEs), with vital signs and safety laboratory parameters measured as part of standard safety assessments. The trial is designed to provide comprehensive data on the efficacy and safety of ferric derisomaltose in subjects with symptomatic chronic heart failure and iron deficiency.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subjects aged ≥18 years at the time of signing the ICF
LVEF of ≤45 %
History of heart failure and NYHA class II, III or IV
Hb ≥9 g/dL and ≤13 g/dL for women; ≥9 g/dL and ≤14 g/dL for men
TSAT <20 %
On maximally tolerated guideline-directed medical therapy for heart failure as determined by Investigator
Evidence of being in a higher risk heart failure group: • Currently hospitalized for worsening heart failure (hemodynamically stabilized and expected to survive to discharge). Hospital admission with, or complicated by signs of, worsening heart failure that has resulted in the use of IV diuretics or initiation of or a substantial increase in medication used to treat heart failure (e.g., increase in oral diuretics by 40 mg or more for furosemide or 1 mg or more for bumetanide and/or the addition of a thiazide like diuretic or the addition of a mineralocorticoid receptor antagonist and/or the addition of a sodium-glucose co-transporter 2 inhibitor and/or the addition of sacubitril/valsartan) • Hemodynamically stable CHF subjects identified in outpatient ambulatory services/practice or emergency departments with elevated natriuretic peptides: NT-proBNP >500 pg/mL in sinus rhythm or >1,000 pg/mL in atrial fibrillation (or BNP of >150 pg/mL or 300 pg/mL, respectively)
At least 1 of the following prognostic enrichment criteria: • Medical history of ischemic heart failure etiology, and/or prior AMI, and/or prior coronary revascularization o eGFR ≤45 mL/min/1.73 m² o TSAT ≤15 % • Anemia as defined by a Hb of ≥9 and <12 g/dL for women and ≥9 and <13 g/dL for men
Willingness to participate and signing the ICF

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Exclusion Criteria

eGFR <15mL/min/1.73m² or on renal replacement therapy
Chronic defined need for IV iron therapy
Likely to need or already receiving ESA
Any of the following cardiovascular comorbidities: • Planned cardiac surgery or revascularization or cardiac device implantation • Within 3 months of screening any of the following: a primary diagnosis of type 1 myocardial infarction (excluding small troponin elevations in the context of heart failure admissions), cerebrovascular accident, major cardiovascular surgery or percutaneous coronary intervention, or blood/plasma transfusion • On active cardiac transplant list • Left ventricular assist device implanted
Any of the following other comorbidities: • Other disease with life expectancy of <2 years • Active clinically relevant bleeding in the Investigator’s opinion • Known or suspected gastrointestinal malignancy
Pregnant or nursing women. To avoid pregnancy, women of childbearing potential must agree to use contraception as described in Section 16 during the whole trial period and at least 7 days after the last dosing if the subject decides to withdraw
Previous serious hypersensitivity reactions to any IV iron compounds including ferric derisomaltose
Iron overload or disturbances in utilization of iron (e.g., haemochromatosis, hemosiderosis)
ALAT and/or ASAT >3 times upper limit of normal
Received an investigational drug and/or invasive device within 30 days or 5 half-lives, whichever is longer, prior to screening
Treatment with IV or IM iron within 6 months prior to screening
Treatment with radiotherapy, chemotherapy or other drugs that suppress the bone marrow, and drugs which have anemia as side effect within 90 days prior to screening
Any non-viral infection (non-viral infection that has been fully treated before the baseline visit is accepted)
Any other laboratory abnormality (known B12 or folate deficiency should be corrected but do not exclude the subject), medical condition, or psychiatric disorders which, in the opinion of the Investigator, will put the subject’s disease management at risk or may result in the subject being unable to comply with the trial requirements.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Recruiting	27 Jun 2025	117
Croatia	Recruiting	27 Jun 2025	81
Czechia	Recruiting	27 Jun 2025	63
Denmark	Recruiting	27 Jun 2025	51
Hungary	Recruiting	27 Jun 2025	46
Latvia	Recruiting	27 Jun 2025	63
Lithuania	Recruiting	27 Jun 2025	62
Norway	Recruiting	27 Jun 2025	47
Poland	Recruiting	27 Jun 2025	180
Portugal	Recruiting	27 Jun 2025	63