Adipose tissue-derived mesenchymal stromal cell therapy in nonischemic heart failure with reduced ejection fraction - ARIISE study design.

Heart failure (HF) remains a major clinical and healthcare challenge with high morbidity, mortality, and impaired quality of life (QOL). Approximately 30-40% of HF cases in the western world are of nonischemic heart failure (NIHF) origin; yet, regenerative therapies are lacking. Evidence suggests that systemic inflammation contributes to disease progression in NIHF, highlighting immunomodulation as a potential therapeutic target. Mesenchymal stromal cells (MSCs) possess regenerative and immunomodulatory properties, with adipose tissue derived stromal cells (ASCs) emerging as particularly promising. ARIISE is a Danish, multicenter, randomized, double-blinded, placebo-controlled study evaluating the efficacy and safety of intravenous allogeneic ASC therapy (C2C_ASC110) in patients with NIHF and reduced left ventricular ejection fraction (LVEF ≤ 45%). Ninety patients will be randomized to receive either C2C_ASC110 or placebo dimethyl sulfoxide (DMSO) (Cryostor®) intravenously twice 1 month apart, in addition to optimal guideline-directed medical therapy. The primary endpoint is a change in LVEF at 6-month follow-up after second ASC/placebo infusion. Secondary endpoints include other echocardiographic measurements, functional capacity, biomarkers, quality of life (QOL), and safety outcomes. If successful, ARIISE may establish clinical evidence for intravenous ASC therapy as a safe, feasible, and effective regenerative treatment for patients with NIHF.Clinical trial registration: EU CT number: 2025-520837-22-00, UTN number: U1111-1315-7011, Clinicaltrials.gov number: NCT06840275.