A randomized, double-blind, placebo-controlled, multicentre trial, assessing the impact of ferric carboxymaltose on exercise capacity and functional status in pulmonary hypertension (IRON-PH)

The primary objective is to determine whether treatment with ferric carboxymaltose compared to placebo results in significant improvement in exercise capacity in patients with pulmonary hypertension and iron deficiency. Exercise capacity is assessed by measuring the change in 6-minute walking distance from baseline to 24 weeks of follow-up. This objective addresses the clinical relevance of correcting iron deficiency in pulmonary hypertension patients, as impaired exercise tolerance is a key functional limitation and prognostic indicator in this population.

The secondary objective is to measure the change in disease-specific health status and health-related quality of life.

The sponsor does not provide information regarding the total number of participants enrolled in this clinical trial. The study population includes both **male** and **female** subjects aged 18 years and older, encompassing adult and elderly age groups. Participants are individuals diagnosed with **pulmonary hypertension** across specific World Health Organization functional classes II through IV, who also present with **iron deficiency** defined as transferrin saturation below 21%. The trial encompasses patients from three distinct pulmonary hypertension categories: Group 1 includes those with **idiopathic**, **hereditary**, **drug-induced**, or **associated pulmonary arterial hypertension** related to **connective tissue disease** or **congenital heart disease** who are receiving stable, optimized pulmonary arterial hypertension-targeted therapies; Group 2 comprises patients with pulmonary hypertension and **heart failure with preserved ejection fraction** (baseline left ventricular ejection fraction greater than 50%) on stable doses of loop diuretics and heart failure therapies; Group 4 includes individuals with inoperable or persistent/recurrent **chronic thromboembolic pulmonary hypertension** ineligible for further interventional procedures. Selection criteria require documented echocardiographic or **right heart catheterization** evidence of pulmonary hypertension according to established guidelines, with specific hemodynamic parameters defined for each group. The trial does not include vulnerable populations.

This is a **randomized**, **double-blind**, **placebo-controlled**, **multicentre** clinical trial evaluating the impact of **ferric carboxymaltose** on exercise capacity and functional status in patients with **pulmonary hypertension** and **iron deficiency**. The study is classified as a **phase IV** **low interventional clinical trial**. The trial investigates whether treatment with ferric carboxymaltose, administered according to the summary of product characteristics, leads to a significant improvement in exercise capacity compared to matching placebo. The investigational medicinal product is ferric carboxymaltose 50 mg iron/ml solution for injection/infusion, administered via the **intravenous** route, with a maximum daily dose of 1000 mg and a maximum total dose of 2000 mg over a treatment period of 4 weeks. The placebo consists of **sodium chloride** solution for infusion, also administered intravenously, with a maximum daily dose of 100 ml and a maximum total dose of 200 ml over 4 weeks.

The primary objective is to determine whether treatment with ferric carboxymaltose in patients with pulmonary hypertension suffering from iron deficiency results in a significant improvement in exercise capacity, measured as the change in **6-minute walking distance** from baseline to 24 weeks of follow-up. Secondary objectives include evaluating changes in quality of life measures assessed by the **EQ5D**, **Minnesota Living with Heart Failure Questionnaire**, and **Fatigue Severity Scale** from baseline to 24 weeks, as well as determining the hazard ratio between treatment arms for developing a composite clinical worsening event throughout the entire trial period.

The trial will enroll adult patients aged 18 years or older with **WHO functional class II to IV** pulmonary hypertension and iron deficiency defined as **transferrin saturation** less than 21%. Eligible participants include patients with WHO Group 1 pulmonary hypertension (idiopathic, hereditary, drug-induced, or associated with connective tissue disease or congenital heart disease), Group 2 pulmonary hypertension with preserved left ventricular ejection fraction greater than 50%, or Group 4 pulmonary hypertension (inoperable or persistent/recurrent **chronic thromboembolic pulmonary hypertension**). Diagnosis of pulmonary hypertension must be confirmed by **echocardiography** and/or **right heart catheterization** according to established guidelines, with specific hemodynamic and echocardiographic criteria defined for each WHO group.

The estimated trial duration spans from January 2026 to April 2029, with recruitment starting in January 2026 and completion anticipated by April 2029. Individual participant involvement extends for 24 weeks following randomization, during which subjects will attend scheduled study visits for assessment of efficacy endpoints, safety monitoring, and administration of study medication. The screening visit establishes eligibility through evaluation of inclusion and exclusion criteria, including confirmation of iron deficiency status and pulmonary hypertension diagnosis. Follow-up visits are conducted at predetermined intervals to assess changes in exercise capacity through the 6-minute walking distance test, administer quality of life questionnaires, monitor safety parameters, and evaluate for clinical worsening events. The end-of-study visit at 24 weeks includes final assessments of all primary and secondary endpoints. Conditions that may lead to early termination from the study include withdrawal of consent, development of unacceptable adverse events, protocol violations, investigator decision based on safety concerns, or loss to follow-up.

The experimental treatment consists of **ferric carboxymaltose** administered as a solution for injection/infusion at a concentration of 50 mg iron/ml. The medicinal product is supplied by ROWEX LTD and contains ferric carboxymaltose as the **active substance**, which is classified as a polymer. The **pharmaceutical form** is a solution for injection/infusion, and the product is administered via the **intravenous route**. The **maximum daily dose** is 1000 mg, with a **maximum total dose** of 2000 mg over the treatment period. The **maximum treatment period** is 4 weeks. Dosing is defined according to the Summary of Product Characteristics (SmPC). The product is classified under **ATC code** B03AC (iron trivalent, parenteral preparations) and is authorized under marketing authorization number PA0711/315/001 in Ireland.

The **placebo** comparator consists of **sodium chloride** solution for infusion. This product contains sodium chloride as the active substance, which is of chemical origin. The placebo is administered via the **intravenous route** and is formulated to match the experimental treatment. The maximum daily dose is 100 ml, with a maximum total dose of 200 ml over the treatment period. The maximum treatment period for placebo administration is 4 weeks, corresponding to the experimental treatment duration.

The trial follows a **randomized, double-blind, placebo-controlled** design to assess the impact of ferric carboxymaltose on **exercise capacity** and functional status in patients with **pulmonary hypertension** suffering from **iron deficiency**. Treatment allocation and administration schedules are designed to maintain blinding throughout the study period. The primary efficacy endpoint is evaluated through the change in **6-minute walking distance** from baseline to 24 weeks of follow-up.

Efficacy will be assessed using the change in **6-minute walking distance** (6MWD) from baseline to 24 weeks of follow-up as the primary endpoint. Secondary efficacy endpoints include the change in **EQ5D** from baseline to 24 weeks of follow-up, the change in **MLHFQ** from baseline to 24 weeks of follow-up, and the change in **FSS** from baseline to 24 weeks of follow-up. Additionally, the hazard ratio between treatment arms in developing a composite clinical worsening event in the overall trial population from first patient visit to last patient visit will be evaluated. These parameters will be measured to determine if treatment with **ferric carboxymaltose** in patients with **pulmonary hypertension** suffering from **iron deficiency** leads to a significant improvement in **exercise capacity** and functional status compared to placebo.