Calcifediol Monohydrate Supplementation to Reduce Myocardial Fibrosis in Patients with Acute Myocarditis and Low 25‑OHD: A Multicenter Randomized Controlled Trial

Myocardial fibrosis at 6 months, assessed by LGE CMR, is the primary efficacy endpoint, evaluating whether oral calcifediol reduces fibrotic burden in patients with uncomplicated acute myocarditis and low 25‑OHD levels. Secondary objectives include: • assessment of major adverse cardiac events and premature ventricular complex burden; • evaluation of additional cardiac remodeling parameters by CMR; • measurement of cardiac biomarkers and inflammatory markers; • determination of safety and tolerability of oral calcifediol in this population.

The trial enrolled adult patients (≥18 years) of both sexes diagnosed with uncomplicated acute myocarditis and low serum 25‑hydroxyvitamin D (<25 ng/mL). Eligibility required a left ventricular ejection fraction of at least 40 % and the presence of late‑gadolinium enhancement on cardiac magnetic resonance imaging, indicating myocardial fibrosis. The sponsor did not provide the total number of participants. Selection was based on these clinical and imaging criteria, and all subjects met the specified inclusion parameters.

The EDIT‑AM trial is a multicenter, open‑label, randomized controlled study evaluating the effect of oral calcifediol monohydrate (266 µg daily) on myocardial fibrosis in patients with acute myocarditis, left ventricular ejection fraction ≥ 40 %, LGE on CMR, and 25‑OHD < 25 ng/mL. Eligible participants undergo a screening visit that includes CMR confirmation, laboratory assessment of 25‑OHD, and baseline safety labs. At the randomization visit, subjects are allocated 1:1 to calcifediol supplementation or standard care and receive study medication. Follow‑up visits are scheduled at week 6 for safety monitoring (serum calcium, 25‑OHD, troponin, NT‑ProBNP, CRP) and at month 6, which serves as the end‑of‑study visit and includes repeat CMR with LGE quantification, 24‑h Holter ECG, and the full laboratory panel. Participant involvement therefore spans approximately six months from randomization to the final assessment. Early termination may occur if a participant develops symptomatic hypervitaminosis D, hypercalcemia, experiences a serious adverse event related to the study drug, withdraws consent, or fails to adhere to protocol‑defined assessments. The overall recruitment period is projected from July 2026 to June 2028, with each subject contributing data for the six‑month follow‑up period.

The investigational product is calcifediol monohydrate, administered orally at a dose of 266 µg once daily. The formulation is provided as a single‑dose oral preparation; the specific pharmaceutical form is not detailed in the protocol. Participants assigned to the experimental arm receive the study medication each morning throughout the 6‑month treatment period.

Control participants receive no vitamin D supplementation and continue with standard clinical management for acute myocarditis as per local practice guidelines. No placebo is employed, reflecting the open‑label design of the trial.

Dosing is scheduled for daily intake at consistent times to promote adherence. Compliance is assessed by pill count at each study visit and reinforced through patient counseling regarding the importance of uninterrupted administration.

Efficacy will be primarily evaluated by quantifying the extent of late gadolinium enhancement (LGE) as a percentage of left‑ventricular mass on cardiac magnetic resonance (CMR) performed at month 6. All CMR images will be analysed by a central core laboratory blinded to treatment allocation, ensuring consistent measurement across study sites.

Secondary efficacy assessments include: the proportion of participants experiencing cardiovascular mortality, heart‑failure hospitalization, or sustained ventricular arrhythmias from baseline to month 6; ventricular premature‑contraction burden on a 24‑hour Holter‑ECG recorded at month 6; the percentage of participants without LGE or with LGE < 5 % of left‑ventricular mass at month 6; extracellular volume (ECV) and T2‑mapping values on CMR at month 6; left‑ventricular ejection fraction, diastolic and systolic volumes, and regional wall‑motion abnormalities on CMR at month 6; serum concentrations of 25‑OHD, high‑sensitivity troponin, NT‑ProBNP, CRP, and calcium measured at weeks 6 and month 6; the proportion of participants achieving 25‑OHD > 100 ng/mL, developing symptomatic hypervitaminosis D, calcium > 10.5 mg/dL, or symptomatic hypercalcemia at the same time points. All laboratory analyses will be performed using validated assays, and imaging parameters will follow standardized CMR protocols. Event data will be adjudicated by an independent committee, and statistical analyses will compare the treatment and control groups using appropriate parametric or non‑parametric methods based on data distribution.