Background: Transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) is a fatal condition caused by misfolding and aggregation of transthyretin (TTR). Despite the treatment with a TTR stabilizer, tafamidis, disease progression still occurs. Eplontersen is an antisense oligonucleotide that inhibits TTR production by the liver. It has the same sequence as inotersen but is conjugated to a triantennary N-acetyl galactosamine (GalNAc) moiety, which allows the use of a lower dose to achieve identical pharmacodynamic results. Study Design and Methods: CARDIO-TTRansform (ClinicalTrials.gov NCT04136171) is a Phase 3 global, double-blind, randomized, placebo-controlled study assessing the efficacy and safety of Eplontersen in hereditary and wild-type ATTR-CM patients. Approximately 750 patients will be randomized 1:1 to receive either Eplontersen 45 mg or placebo administered by monthly SC injection. Key inclusion criteria include ATTR-CM diagnosis by biopsy or positive PYP/DPD/HMDP scan, interventricular septum thickness >12mm, NT-proBNP >600 pg/mL, NYHA class I-III and 6-minute walk distance (6MWD) ≥150m. Concomitant treatment with tafamidis is allowed. Primary efficacy endpoint is the composite of cardiovascular (CV) mortality and recurrent CV clinical events at Week 120 study visit using the Andersen-Gill method. Conclusions: The CARDIO-TTRansform trial is a Phase 3 trial designed to evaluate the clinical efficacy and safety of Eplontersen for the treatment of ATTR-CM.