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Heart failure (HF) is associated with substantial morbidity and mortality, highlighting a critical need for novel therapies. AB-1002, an engineered AAV vector gene therapy candidate, delivers a constitutively active form of protein phosphatase inhibitor (I-1c) to restore cardiomyocyte intracellular calcium homeostasis. Preliminary results from an ongoing Phase (Ph) 1 trial (NCT04179643) of AB-1002 showed favourable safety and tolerability. Here we describe the design of AB-1002 Ph 2 trial (GenePHIT; NCT05598333) to evaluate efficacy, safety, and tolerability. This phase 2 adaptive, double-blind, placebo-controlled, randomized, multi-centre trial (currently US; European sites planned) includes a 52-week observation and 4-year follow-up period. Eligible patients are ≥18 years of age with non-ischaemic cardiomyopathy and New York Health Association (NYHA) Class III HF symptoms (Figure). Patients will be randomized 1:1:1 (n=30-50/treatment arm), including a single dose of AB-1002 administered via antegrade intracoronary infusion at 1 of 2 different doses, or placebo, all in addition to standard of care. The primary endpoint will evaluate efficacy at 52 weeks based on the composite endpoint by modified win ratio, which includes cardiovascular-related death, change in NYHA classification, and for the responders, improvements in LVEF (≥5%), pVO2 ≥1.5 mL/kg/min, and 6MWT >30 metres. Key secondary efficacy endpoints include functional status and hospitalisations at 24 and 52 weeks, by assessing changes over time in NYHA classification, LVEF, pVO2, 6MWT, biomarkers (NT-proBNP, troponin), quality of life questionnaires (MLHFQ, KCCQ), and physiological assessments. Key safety endpoints will be assessed through 52 weeks and include TEAEs and SAEs. Exploratory endpoints will evaluate AAV2i8 antibody titres, T-cell response to AAV2i8 capsid and I-1c, and optional right ventricular biopsy testing. Long-term follow-up will assess TEAEs, SAEs, and number of HF hospitalisations. Data safety monitoring board assessment will occur every 3 months. Primary efficacy endpoint will compare both active dose groups combined versus placebo using the joint rank test. Key secondary endpoints will be analyzed using Analysis of Covariance with baseline as a continuous covariate. Multiple imputations will be used to address missing data. Interim efficacy analysis will be performed using a Bayesian adaptive sample size algorithm. GenePHIT is currently recruiting and will evaluate the efficacy, safety, and tolerability of intracoronary infusion of AB-1002, a gene therapy targeting ventricular dysfunction in HF. [ABSTRACT FROM AUTHOR]