Evaluation of Calcifediol Supplementation on Vitamin D Deficiency in Patients with Pulmonary Arterial Hypertension: A Randomized Controlled Trial

The primary objective of the study is to evaluate whether a **vitamin D** supplement, specifically 0.266 mg of calcifediol administered once every ten days for the first 12 weeks and once every two weeks for the subsequent 12 weeks, induces clinical improvement without clinical worsening at week 24 in patients with Pulmonary Arterial Hypertension (PAH) compared to placebo. Clinical improvement is defined by changes in at least two of the following parameters: an increase in 6-minute walking distance (6MWD) by ≥10% or more than 30 meters, a change in risk score according to the 2022 ERS/ESC guidelines, a reduction in BNP or NT-proBNP by ≥30%, or an increase in the TAPSE/SPAP ratio by ≥25%. Clinical worsening is characterized by events such as hospitalization related to PAH, therapeutic escalation, progression of symptoms, lung or cardiopulmonary transplantation, atrial septostomy, and mortality related to PAH. This objective is clinically relevant as it aims to determine the efficacy of calcifediol in improving clinical outcomes in PAH patients, potentially offering a new therapeutic approach.

The secondary objectives include assessing changes in: - 6-minute walking distance (6MWD) - NT-proBNP levels - Functional class (WHO/NYAS) - Estimated pulmonary systolic pressure (PASP) - TAPSE/PASP ratio - Serum noggin levels - Non-invasive risk score (NIRS) - Quality of life (emPHasis-10) - Adverse effects, with additional analysis of plasma intact parathormone (i-PTH), calcium, and phosphate at baseline, 12 weeks, and at the end of the treatment period. These objectives aim to provide a comprehensive evaluation of the treatment's impact on various clinical and biochemical parameters, further elucidating its potential benefits and safety profile in the management of PAH.

The clinical trial involves **patients** diagnosed with **Pulmonary Arterial Hypertension** (PAH) of specific types, including idiopathic, hereditary, drug- and toxin-induced PAH, or PAH associated with connective tissue disease, as per the 2022 ERS/ESC guidelines. The study population comprises both male and female participants aged between 18 and 75 years. Participants are required to be stable and on standard PAH medications, either as monotherapy or in combination, including calcium channel blockers, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, prostacyclin analogues, or selexipag, with a stable dose of diuretics and no treatment modifications for at least six weeks prior to randomization. Additionally, participants must have an intermediate-low or intermediate-high risk score and a severe deficiency of vitamin D, defined as plasma or serum 25(OH)vitD levels equal to or lower than 12 ng/ml. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants must be capable of understanding and following instructions and willing to participate for the entire duration of the study, having given written informed consent. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **calcifediol** supplementation in patients diagnosed with **pulmonary arterial hypertension** (PAH) according to the 2022 ERS/ESC guidelines. This is a randomized, double-blind, placebo-controlled trial with a total duration of 24 weeks. The trial aims to determine whether a vitamin D supplement, specifically 0.266 mg of calcifediol administered orally once every ten days for the first 12 weeks and once every two weeks for the subsequent 12 weeks, can induce clinical improvement without clinical worsening at the end of the study period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, PAH diagnosis, stability on standard PAH medications, and severe vitamin D deficiency. Following successful screening, participants will be randomized to receive either the active treatment or placebo. The study includes regular follow-up visits to monitor efficacy and safety outcomes, including changes in six-minute walk distance, risk scores, and serum biomarkers. The end-of-study visit will evaluate the primary endpoint of clinical improvement and the absence of clinical worsening, alongside secondary endpoints such as safety and quality of life measures.

Participant involvement is expected to last for the entire 24-week treatment period unless early termination is warranted. Conditions that may lead to early withdrawal include significant adverse effects, non-compliance with study procedures, or any event that compromises participant safety. The trial is categorized as a Phase IV, low-intervention clinical trial, with an estimated recruitment start date in June 2025 and an anticipated completion by November 2027.

The clinical trial involves the administration of **TRIGLYCERIDES MEDIUM CHAIN**, which is provided in the form of an emulsion for infusion. The active substance, triglycerides medium chain, is of chemical origin. The maximum daily dose is 1.5 mg, with a total maximum dose of 25 mg over a treatment period of 24 weeks. The route of administration is oral, and the formulation is not specifically designed for pediatric use. Participant compliance will be monitored throughout the study to ensure adherence to the dosing schedule.

Another experimental medication used in the trial is **ALPHA-TOCOPHEROL**, which is administered as an oral suspension. The active substance, alpha-tocopherol, is also of chemical origin. The maximum daily dose is 1.5 mg, with a total maximum dose of 21 mg over the 24-week treatment period. The oral route of administration is employed, and the formulation is not pediatric-specific. Compliance with the dosing regimen will be closely monitored to maintain the integrity of the study data.

The primary experimental treatment in this trial is **CALCIFEDIOL**, administered orally. Calcifediol is a chemical compound used to address vitamin D deficiency. The dosing regimen involves administering 0.266 mg of calcifediol once every ten days for the first 12 weeks, followed by administration once every two weeks for the subsequent 12 weeks. The maximum daily dose is 0.27 mg, with a total maximum dose of 3.72 mg over the 24-week period. The formulation is not intended for pediatric use. Participant adherence to the dosing schedule will be monitored to ensure accurate assessment of the treatment's efficacy.

In addition to the experimental treatments, a placebo is used as a comparator in the study. The placebo is administered in a manner consistent with the experimental treatments to maintain blinding and ensure the validity of the trial results. Compliance with the placebo administration schedule will be monitored similarly to the experimental treatments.

Efficacy in the clinical trial will be assessed by evaluating clinical improvement and the absence of clinical worsening in patients with pulmonary arterial hypertension (PAH). Clinical improvement is defined by a change in at least two of the following parameters: an increase in the 6-minute walking distance (6MWD) by at least 10% or more than 30 meters, a change in risk score according to the 2022 ERS/ESC guidelines, a reduction in **BNP** or **NT-proBNP** levels by at least 30%, and an increase in the TAPSE/SPAP ratio by at least 25%. Clinical worsening is identified by events such as hospitalization related to PAH, therapeutic escalation, progression of symptoms, lung or cardiopulmonary transplantation, atrial septostomy, and mortality related to PAH.

The primary endpoint for efficacy is the combination of clinical improvement and no clinical worsening. Secondary endpoints include safety assessments such as serum 25(OH) vitamin D concentration, 6MWD, plasmatic levels of NT-proBNP, functional class (WHO/NYAS), estimated pulmonary systolic pressure (PASP), the TAPSE/PASP ratio, serum noggin protein level, non-invasive risk score (NIRS), quality of life measured by emPHasis-10, and adverse effects. These parameters will be measured and collected at specified intervals throughout the trial, with the primary assessment occurring at week 24.