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Objectives Randomized controlled trials (RCTs) in systemic lupus erythematosus (SLE) frequently fail in late development despite promising early efficacy signals. We aimed to identify trial-level design and conduct characteristics associated with success or failure across recent phase II and III SLE RCTs.Methods We performed a structured comparative analysis of 26 randomized, double-blind, placebo-controlled phase II and III trials of biologic or targeted synthetic therapies for non-renal SLE published between 2009 and 2023. Trials were classified as successful, indeterminate, or unsuccessful based on achievement of primary and key secondary endpoints. Trial-level characteristics—including sample size, duration, background therapy, endpoint definition, and geographical recruitment—were extracted and compared descriptively. Concordance between phase II and phase III treatment effects was explored for compounds with paired development programs.Results Twelve trials were classified as successful, seven as indeterminate, and seven as unsuccessful. Baseline demographic characteristics and aggregate disease activity measures were broadly comparable across outcome categories ( table 1). Successful trials were more often smaller and shorter, enrolled proportionally more patients from North America and Europe, and included higher baseline exposure to moderate-dose glucocorticoids. Concordance between phase II and phase III treatment effects was limited, with frequent attenuation of early efficacy signals in confirmatory trials (figure 1). Trial outcomes varied according to endpoint choice, with discordant results observed between SRI-4- and BICLA-based primary endpoints.Abstract LBA:01:36 Table 1Abstract LBA:01:36 Figure 1Conclusions Outcomes of SLE RCTs appear to be driven in part by trial design and conduct rather than therapeutic mechanism alone. ‘Scaling up’ from phase 2 to phase 3 appears particularly vulnerable to negative effects related to the need for including large numbers in multiple centers, and longer durations. Future lupus trials may benefit from designs that maintain limits on size and duration, protocol-mandated minimum levels of background therapy, improved composite endpoints, and enrichment strategies aligned with drug mechanism. Such approaches may improve the reliability of phase II–III translation and increase the likelihood of successful lupus drug development.