The D-FISH Trial: A Randomized, Double-Blind, Non-Inferiority Trial Comparing Fish Processing By-Product-Derived Versus Synthetic Vitamin D<sub>3</sub> Supplementation in Adults with Suboptimal 25-Hydroxyvitamin D.

Abstract

Vitamin D insufficiency remains common in adults, and supplementation with cholecalciferol (vitamin D₃) is widely used to improve circulating 25-hydroxyvitamin D [25(OH)D]. At the same time, circular-economy strategies are increasingly applied to nutraceutical production, including the valorization of fish processing by-products as sources of lipid-soluble bioactives. However, clinical evidence directly comparing fish processing by-product-derived vitamin D₃ with conventional synthetic vitamin D₃ at commonly used nutritional doses remains limited. D-FISH is a single-center, randomized, double-blind, parallel-group, non-inferiority trial enrolling adults aged 18-60 years with a baseline plasma of 25(OH)D 20-40 ng/mL. Participants will be randomized (1:1) to receive either fish processing by-product-derived or synthetic vitamin D₃ at the same nutritional dose (600 IU once daily with the evening meal) for 12 weeks. The primary endpoint is the between-group difference in the change in plasma 25(OH)D from day 0 to day 84, assessed against a pre-specified non-inferiority margin of 5 ng/mL, with analyses conducted in full analysis and per-protocol populations. Secondary endpoints include markers of mineral metabolism (calcium, phosphorus, PTH), fasting lipid profile, anthropometrics, and tolerability/safety outcomes; early 25(OH)D kinetics will be explored at 72 h, day 7, and day 28. The study will inform biochemical non-inferiority and short-term tolerability but is not powered to evaluate clinical outcomes (NCT07127796).